Benzazepine derivative, process for producing the same, and use
Granted 28 Aug 2007 · 2 office actions
Assignee: Takeda Pharmaceutical Company Limited
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Inventors: Mitsuru Shiraishi, Masanori Baba, Naoki Miyamoto, Masaki Seto +3 · Examiner: Brenda Coleman · AU 1624 · TC 1600
Life of the application
11 dated eventsAbstract
The present invention provides a novel benzazepine derivative represented by formula: [structure] wherein, R 1 is a 5- or 6-membered aromatic ring, R 2 is lower alkyl group, etc., Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, W is formula —W 1 —X 2 —W 2 — (W 1 and W 2 are independently S(O) m1 (m1 is 0, 1, or 2), etc., and X 2 is an optionally substituted alkylene group etc.), a preparation method and use thereof.
Description
245 parts›This application is the National Phase filing of…
This application is the National Phase filing of International Patent Application No. PCT/JP02/08045, filed 07 Aug. 2002.
›TECHNICAL FIELD
The present invention relates to a novel benzazepine derivative, a process for producing the same and use thereof.
›BACKGROUND ART
In recent years, HIV (human immunodeficiency virus) protease inhibitors have been developed for the treatment of AIDS (acquired immunodeficiency syndrome), and by combining with conventional two HIV reverse transcriptase inhibitors, the treatment of AIDS have made a remarkable progress. However, these drugs are not sufficient for the eradication of AIDS, and development of new anti-AIDS drugs having different action mechanism have been desired.
As a receptor from which HIV invades target cell, CD4 has been so far known, and CCR5 as a second receptor of macrophage-tropic HIV and 7-transmembrane G protein-coupled chemokine receptor called CXCR4 as a second receptor of T cell-tropic HIV, have recently been found. These chemokine receptors are thought to play an essential role in the infection and transmission of HIV. In fact, it has been reported that humans who are resistant to HIV infection in spite of repeated exposures retains a homo deletion mutation of the CCR5 gene. Therefore, a CCR5 antagonist is expected to be a new anti-HIV drug. However, to date, there has not been a report of a CCR5 antagonist developed as a therapeutic agent against AIDS. Further, JP-A 2001-058992 and JP-A 2001-026586 disclose that a compound having CCR5 antagonism is useful as an agent for preventing or treating AIDS, but the compound has a different structure from that of compound of the present invention.
›DISCLOSURE OF INVENTION
In order to investigate anti-AIDS drug based on CCR5 antagonism, it is necessary to clone the CCR5 gene from a human tissue derived cDNA library, to ligate said gene into an expression vector for animal cells, to introduce said gene into animal cells and to obtain cell strains expressing CCR5. In addition, using this transformant, it is necessary to screen a compound which strongly inhibits binding of CC chemokine RANTES, a natural ligand, to CCR5. However, there have been few reports on low-molecular weight compounds having the antagonism which are suitable for oral administration. The present invention is to provide a novel anilide derivative having CCR5 antagonism, which is useful for the treatment or prevention of infectious diseases of HIV, in particular, AIDS and is also suitable for oral administration, and a process for production and use thereof.
›SUMMARY OF THE INVENTION · 1 of 2
The present inventors have conducted extensive studies on compounds having CCR5 antagonism and as a result, found that a benzazepine derivative represented by the following formula (I) or a salt thereof [hereinafter, referred to as Compound (I) in some cases] possesses CC chemokine receptor (CCR) antagonism, in particular, potent CCR5 antagonism and a clinically desirable pharmaceutical effect such as remarkable inhibition of infection of human peripheral mononuclear cells, etc. with HIV and also that Compound (I) has superior absorbability when orally administered. Based on these findings, the present invention has been accomplished.
That is, the present invention provides:
(1) A compound represented by the formula (I):
wherein, R 1 is a 5- or 6-membered aromatic ring which has a substituent represented by formula R—Z 1 —X 1 —Z 2 — (wherein, R is a hydrogen atom or an optionally substituted hydrocarbon group, X 1 is an optionally substituted alkylene chain, Z 1 and Z 2 are independently a heteroatom) and may have a further substituent, the group represented by R may bind to said 5- or 6-membered aromatic ring to form a ring, R 2 is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group or a halogen atom, Y is an optionally substituted imino group, ring A and ring B are independently an optionally substituted aromatic ring, and W is a group represented by formula —W 1 —X 2 —W 2 — (wherein, W 1 and W 2 are independently O, S(O) m1 (m1 is 0, 1 or 2), an optionally substituted imino group or a bond, and X 2 is an optionally substituted alkylene group, an optionally substituted alkenylene group or a bond)] or a salt thereof.
(2) A prodrug of the compound according to the above-mentioned (1);
(3) The compound according to the above-mentioned (1), wherein the 5- or 6-membered aromatic ring of R 1 is benzene;
(4). The compound according to the above-mentioned (1), wherein R is an optionally halogenated lower alkyl group;
(5) The compound according to the above-mentioned (1), wherein X 1 is —(CH 2 ) n — (wherein n is an integer of 1 to 4);
(6) The compound according to the above-mentioned (1), wherein Z 1 is —O—;
(7) The compound according to the above-mentioned (1), wherein Z 2 is —O—;
(8) The compound according to the above-mentioned (1), wherein Y is —N(R 5′ )— (wherein R 5′ is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group or an optionally substituted acyl group);
(9) The compound according to the above-mentioned (8), wherein R 5′ is an optionally substituted C 1-4 alkyl, an optionally substituted benzyl or an optionally substituted 5- or 6-membered aromatic heterocyclic group;
(10) The compound according to the above-mentioned (1), wherein ring A is an optionally substituted benzene ring, an optionally substituted pyridine ring, an optionally substituted pyridazine ring or an optionally substituted benzimidazole ring;
(11) The compound according to the above-mentioned (1), wherein ring B is an imidazole ring substituted by an optionally substituted lower alkyl group, or a triazole ring substituted by an optionally substituted lower alkyl group;
(12) The compound according to the above-mentioned (1), wherein one of W 1 and W 2 is O, S(O) m1 (wherein m1 is 0, 1 or 2) or —N(R 3 )— (wherein R 3 is a hydrogen atom or an optionally substituted lower alkyl group) and the other is a bond and X 2 is —(CH 2 ) p — (wherein p is an integer of 1 to 3), or W is —CH(OH)—;
(13) The compound according to the above-mentioned (1), wherein ring A is a benzene ring, ring B is an optionally substituted imidazole ring or an optionally substituted triazole ring, one of W 1 and W 2 is S(O) m1 (wherein m1 is 0, 1 or 2) and the other is a bond, and X 2 is —(CH 2 ) p — (wherein p is an integer of 1 to 3), or W is —CH(OH)—;
(14) The compound according to the above-mentioned (1), wherein;
(15) The compound according to the above-mentioned (14), wherein the steric configuration of SO is (S) configuration;
(16) The compound according to the above-mentioned (1), wherein the compound is (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide, (−)-1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[([[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide, or a salt thereof;
(17) A process for producing a compound represented by the formula:
wherein, each symbol has the same meaning as defined in (1) or a salt thereof, which comprises subjecting to a condensation reaction of a compound represented by the formula:
wherein, each symbol has the same meaning as defined in (1), a salt or a reactive derivative thereof, with a compound represented by the formula:
wherein, each symbol has the same meaning as defined in (1), or a salt thereof;
(18) A pharmaceutical composition comprising the compound according to the above-mentioned (1) or a prodrug thereof;
(19) The composition according to the above-mentioned (18), which is a CC chemokine receptor antagonist;
(20) The composition according to the above-mentioned (18), which is a CCR5 antagonist and/or CCR2 antagonist;
(21) The composition according to the above-mentioned (18), which is a preventive or therapeutic agent for HIV infection, chronic rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic brain cell disorders, myocardial infarction, nephritis, nephropathy or arteriosclerosis;
(22) The composition according to the above-mentioned (18), which is a blood for blood transfusion or a blood product;
›SUMMARY OF THE INVENTION · 2 of 2
(23) The composition according to the above-mentioned (18), which is an agent for the prevention or treatment of graft versus host disease and/or rejection in the transplant of organ or bone marrow.
›BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the inhibitory effects against HIV infection of the compound according to the present invention.
›BRIEF DESCRIPTION OF THE DRAWINGS · 1 of 19
In the formula (I) above, examples of the “5- or 6-membered aromatic ring” in the “5- or 6-membered aromatic ring, which has a substituent represented by the formula R—Z 1 —X 1 —Z 2 — (wherein, R is a hydrogen atom or an optionally substituted hydrocarbon, X 1 is an optionally substituted alkylene chain, and Z 1 and Z 2 are independently a heteroatom) and may have a further substituent”, represented by R 1 include a 6-membered aromatic hydrocarbon such as benzene, etc., and a 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc., and among others, benzene, furan, thiophene, pyridine, etc., are preferable, and benzene, furan or thiophene is more preferable, and in particular, benzene is preferable.
Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R include
(1) alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 ) alkyl, and more preferably, lower (C 1-4 )alkyl, etc.);
(2) cycloalkyl (e.g., C 3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) alkenyl (e.g., C 2-10 alkenyl, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(4) cycloalkenyl (e.g., C 3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) alkynyl (e.g., C 2-10 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C 2-6 )alkynyl, etc.);
(6) aralkyl (e.g., phenyl-C 1-4 alkyl (e.g., benzyl, phenethyl, etc.) and the like);
(7) aryl (e.g., phenyl, naphthyl, etc.); and
(8) cycloalkyl-alkyl (e.g., C 3-7 cycloalkyl-C 1-4 alkyl, etc. such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, etc.). Examples of the substituent that the above-mentioned (1) alkyl, (2) cycloalkyl, (3) alkenyl, (4) cycloalkenyl, (5) alkynyl, (6) aralkyl, (7) aryl and (8) cycloalkyl-alkyl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C 1-4 alkylenedioxy (e.g., —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, etc.), an optionally substituted sulfonamide (for example, a group formed by bonding an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.) to —SO 2 —, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), an optionally substituted heterocyclic group, etc. The number of the substituents is preferably 1 to 3.
As used herein, examples of the “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent for the “optionally substituted hydrocarbon group” represented by R include a group formed by eliminating one hydrogen atom from aromatic or non-aromatic heterocyclic ring, etc. Examples of the aromatic heterocyclic ring include 5- or 6-membered aromatic heterocyclic rings containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, etc. Examples of the non-aromatic heterocyclic ring include 5- or 6-membered non-aromatic heterocyclic rings containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc. and non-aromatic heterocyclic ring wherein part or whole bond(s) of the above mentioned aromatic heterocyclic ring is (are) a saturated bond (preferably, aromatic heterocyclic ring such as pyrazole, thiazole, oxazole, tetrazole, etc.) and the like.
The “heterocyclic group” in the “optionally substituted heterocyclic group” as a substituent of the “optionally substituted hydrocarbon group” represented by R may have 1 to 3 substituents at any substitutable position. Examples of such substituent include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C 1-4 alkylenedioxy (e.g., —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, etc.), an optionally substituted sulfonamide (for example, a group formed by bonding an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.) to —SO 2 —, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), etc. (preferably, C 1-4 alkyl, etc.).
›BRIEF DESCRIPTION OF THE DRAWINGS · 2 of 19
In addition, when the group represented by the formula R—Z 1 —X 1 —Z 2 — (wherein, each symbol has the same meaning as defined in the above) is a mono-valent group (which does not bind to the 5- or 6-membered aromatic ring to form a ring), as the group R, an optionally substituted alkyl group is preferable, an optionally halogenated lower alkyl group is more preferable, and in particular, an optionally halogenated C 1-4 alkyl group is preferable.
Examples of the “optionally substituted alkylene chain” represented by X 1 include an optionally substituted, straight or branched C 1-6 alkylene, etc. The number of carbon atoms for the straight chain moiety of the alkylene chain is preferably 1 to 4, and inter alia, X 1 is preferably an optionally substituted straight C 1-4 alkylene (preferably ethylene or propylene).
The substituent that the “alkylene chain” in the “optionally substituted alkylene chain” represented by X 1 may have, is any one which may bind to a divalent chain constituting a straight chain moiety, and includes, for example, lower C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C 3-7 )cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C 2-7 )alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), an optionally esterified phosphono group, an optionally esterified carboxyl group, hydroxy group, oxo group, etc., and preferably, lower C 1-6 alkyl (preferably, C 1-3 alkyl), hydroxy group, oxo group, etc.
Examples of the optionally esterified phosphono group include a group represented by P(O)(OR 7a )(OR 8a ) [wherein, R 7a and R 8a are each hydrogen, C 1-6 alkyl group or C 3-7 cycloalkyl group, and R 7a and R 8a may bind together to form a 5- to 7-membered ring].
In the above formula, examples of C 1-6 alkyl group represented by R 7a and R 8a include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and examples of C 3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and preferably, straight lower C 1-6 alkyl, more preferably lower C 1-3 alkyl. R 7a and R 8a may be the same or different, and preferably the same. In addition, when R 7a and R 8a bind each other to form a 5-to 7-membered ring, R 7a and R 8a bind each other to form straight C 2-4 alkylene side chain represented by —(CH 2 ) 2 —, — (CH 2 ) 3 —, and —(CH 2 ) 4 —. The side chain may have a substituent, and examples of such substituents include hydroxy group, halogen, etc.
Examples of the ester of optionally esterified carboxyl group include a group wherein a carboxyl group binds to C 1-6 alkyl group or C 3-7 cycloalkyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.
As X 1 , an optionally substituted C 1-4 alkylene is preferable, and among them, C 1-4 alkylene optionally substituted with C 1-3 alkyl, hydroxy group or oxo, is preferable, and in particular, a group represented by the formula: —(CH 2 ) n — (n is an integer of 1 to 4) is preferable.
Examples of the heteroatom represented by Z 1 and Z 2 include —O—, —S(O) m2 — (m2 is an integer of 0 to 2), —N(R 4 )—(R 4 is a hydrogen atom or an optionally substituted lower alkyl group), etc., and Z 1 is preferably —O— or —S(O) m2 -(m 2 is an integer of 0 to 2) and more preferably, —O—. In addition, Z 2 is preferably —O— or —N(R 4 )— (R 4 is a hydrogen atom or an optionally substituted lower alkyl group) and more preferably —O—.
Examples of the optionally substituted lower alkyl group represented by R 4 include the same groups as those for the “optionally substituted lower alkyl group” exemplified with respect to the “optionally substituted hydrocarbon group” represented by R.
As the “substituent” that the “5- or 6-membered ring” of the “5- or 6-membered aromatic ring which has a substituent represented by the formula: R—Z 1 —X 1 Z 2 —(wherein, each symbol has the same meaning as defined in the above) and may have a further substituent” represented by R 1 may have in addition to the group represented by the formula: R—Z 1 —X 1 —Z 2 —, for example, halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group (the sulfur atom may be oxidized, or may form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, an optionally substituted aromatic group, etc. may be used.
Examples of the halogen as the substituent for R 1 include fluorine, chlorine, bromine, iodine, etc., and in particular, fluorine and chlorine are preferable.
Examples of the alkyl in the optionally substituted alkyl as the substituent for R 1 include straight or branched alkyl having a carbon number of 1 to 10, for example C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 ) alkyl. Examples of the substituent in the optionally substituted alkyl include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.)), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of the substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 3 of 19
Examples of the cycloalkyl in the optionally substituted cycloalkyl as the substituent for R 1 include C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Examples of the substituent in the optionally substituted cycloalkyl include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of the substituents is preferably 1 to 3.
Examples of the substituent in the optionally substituted hydroxy group as the substituent for R 1 include:
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.
(2) an optionally substituted cycloalkyl which may have a heteroatom (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; saturated 5- or 6-membered heterocyclic group containing 1 to 2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc. (preferably tetrahydropyranyl, etc.); etc.);
(3) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 ) alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e.g., phenyl-C 1-4 alkyl (e.g., benzyl, phenethyl, etc.) and the like.);
(6) formyl or an optionally substituted acyl (e.g., C 2-4 alkanoyl (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like.); and
(7) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like.
Examples of the substituent that the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl, and (7) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably an optionally halogenated C 1-4 alkoxy), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), an optionally substituted 5- or 6-membered aromatic heterocyclic ring [for example, 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; examples of the substituent that heterocyclic ring may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like, and the number of the substituents is preferably 1 to 3.]. The number of substituents is preferably 1 to 3.
Examples of the substituents in the optionally substituted thiol group as the substituent for R 1 include those similar to the above-exemplified “substituent in the optionally substituted hydroxy group as the substituent for R 1 ”, and among them,
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted aralkyl (e.g., phenyl-C 1-4 alkyl (e.g., benzyl, phenethyl, etc.) and the like.); and
(4) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like are preferable.
Examples of the substituents that the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) optionally substituted aryl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 4 of 19
Examples of the substituents in the optionally substituted amino group as the substituent of R 1 include the amino group that may have 1 to 2 substituents similar to the above-mentioned “substituent in the optionally substituted hydroxy group as the substituent of R 1 ” etc., and among them,
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) formyl or an optionally substituted acyl (e.g., C 2-4 alkanoyl (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like.); and
(6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like are preferable.
Examples of the substituents that the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl, and (6) optionally substituted aryl may have include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
In addition, the optionally substituted amino group as the substituent of R 1 may form a cyclic amino group (e.g., 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.) by binding the substituents of an amino group to each other. The cyclic amino group may have a substituent, and examples of such substituents include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the optionally substituted acyl group as a substituent of R 1 include a group formed by binding:
(1) hydrogen;
(2) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(6) an optionally substituted 5- or 6-membered monocyclic aromatic group (e.g., phenyl, 5- or 6-membered aromatic heterocyclic group (e.g., 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, etc.; preferably pyridyl, thienyl, etc.); and
(7) an optionally substituted 5- or 6-membered monocyclic non-aromatic heterocyclic group (e.g., a group formed by eliminating a hydrogen atom from 5- or 6-membered monocyclic non-aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as tetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc.; preferably, dioxolanyl, etc.), etc., to a carbonyl group or a sulfonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.), etc. Examples of the substituents that the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, (6) optionally substituted 5- or 6-membered monocyclic aromatic group and (7) optionally substituted 5- or 6-membered monocyclic non-aromatic heterocyclic group may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), C 1-4 alkylenedioxy (e.g., —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, etc.), an optionally substituted sulfonamide [for example, a group formed by bonding an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino (e.g., tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), etc.) to —SO 2 —, etc.], formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), etc. The number of substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 5 of 19
Examples of the optionally esterified carboxyl group as the substituent of R 1 include a group formed by binding:
(1) hydrogen;
(2) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); and (6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like,
to a carbonyloxy group, preferably carboxyl, lower (C 1-6 ) alkoxycarbonyl, aryloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), etc. Examples of the substituents that the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of the substituents is preferably 1 to 3.
In addition, examples of the optionally amidated carboxyl group as a substituent of R 1 include a group formed by binding “an optionally substituted amino group” to a carbonyl group, similar to the above mentioned “optionally substituted amino group as the substituent for R 1 ”, preferably carbamoyl, monoC 1-6 alkylcarbamoyl, diC 1-6 alkylcarbamoyl, etc.
Examples of the aromatic groups in the optionally substituted aromatic group as a substituent of R 1 include 5- or 6-membered homocyclic or heterocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, etc. and condensed heterocyclic aromatic group such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc. Examples of the substituents for these aromatic groups include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1 , 4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
The same or different 1 to 4 (preferably 1 or 2) of these substituents for R 1 may substitute at any possible position on the ring.
In addition, when the group represented by R binds to the 5- or 6-membered aromatic ring to form a ring, the group represented by the formula R—Z 1 —X 1 —Z 2 — (wherein, each symbol has the same meaning as defined in the above; R is preferably hydrogen) forms a divalent group such as lower (C 1-6 ) alkylenedioxy (e.g., —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —O—, etc.), oxy lower (C 1-6 )alkyleneamino (e.g., —O—CH 2 —NH—, —O—CH 2 —CH 2 —NH—, etc.), oxy lower (C 1-6 )alkylenethio (e.g., —O—CH 2 —S—, —O—CH 2 —CH 2 —S—, etc.), lower (C 1-6 )alkylenediamino (e.g., —NH—CH 2 —NH—, —NH—CH 2 —CH 2 —NH—, etc.), thia lower (C 1-6 )alkyleneamino (e.g., —S—CH 2 —NH—, —S—CH 2 —CH 2 —NH—, etc.), etc.
As the “substituent” that “5- or 6-membered ring” of the “5- or 6-membered aromatic ring which has a substituent represented by the formula R—Z 1 —X 1 —Z 2 — (wherein, each symbol has the same meaning as defined in the above) and may have a further substituent” represented by R 1 may have in addition to the group represented by the formula R—Z 1 —X 1 —Z 2 —, in particular, an optionally halogenated or lower (C 1-4 )alkoxylated lower (C 1-4 ) alkyl (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), an optionally halogenated or lower (C 1-4 )alkoxylated lower (C 1-4 )alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), halogen (e.g., fluorine, chlorine, etc.), nitro, cyano, an amino optionally substituted with 1 to 2 lower (C 1-4 )alkyls, formyl or lower (C 2-4 )alkanoyl (e.g., amino, methylamino, dimethylamino, formylamino, acetylamino, etc.), 5- or 6-membered cyclic amino (e.g., 1-pyrrolidinyl, 1-piperadinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.) and the like are exemplified.
›BRIEF DESCRIPTION OF THE DRAWINGS · 6 of 19
In addition, when R 1 is benzene, the substitution position of the group represented by the formula: R—Z 1 —X 1 —Z 2 — is preferably at the para position and the substitution position of the “substituent” which the “5- or 6-membered aromatic ring” may have in addition to the group represented by the formula: R—Z 1 —X 1 —Z 2 —, is preferably at the meta position.
In the above formula, examples of the “optionally substituted imino group” represented by Y include a divalent group represented by the formula —N(R 5 )— [wherein, R 5 is a hydrogen atom or a substituent], etc.
R 5 is, preferably, a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group (the sulfur atom may be optionally oxidized, or may form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally esterified or amidated carboxyl group, an optionally substituted acyl group, etc., and more preferably a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted acyl group, etc.
As a preferred form of R 5 , a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted 5- or 6-membered aromatic heterocyclic group, an optionally substituted acyl group, etc. are exemplified, and C 1-4 alkyl, C 1-4 alkylsulfonyl, formyl, C 2-5 alkanoyl, etc. are more preferred, C 1-4 alkyl, formyl, C 2-5 alkanoyl, etc. are further more preferred, and, in particular, propyl, cyclopropylmethyl or isobutyl is preferred. Other preferred examples of R 5 include a group represented by the formula: —(CH 2 ) k —R 6 [wherein, k is 0 or 1, R 6 is an optionally substituted 5- or 6-membered monocyclic aromatic group (e.g., the same groups as those of the “(6) optionally substituted 5- or 6-membered monocyclic aromatic group” exemplified with respect to the optionally substituted acyl group as the substituent for R 1 , etc.; preferably phenyl, pyrazolyl, thiazolyl, oxazolyl and tetrazolyl, each of which may be substituted with a halogen, an optionally halogenated C 1-4 alkyl or an optionally halogenated C 1-4 alkoxy, etc.)], etc.
In addition, specific examples of the “optionally substituted hydrocarbon group” as R 5 include those similar to the “optionally substituted hydrocarbon group” as R, and specific examples of the “optionally substituted heterocyclic group” as R 5 include those similar to the “optionally substituted heterocyclic group” as the substituent for the “optionally substituted hydrocarbon group” represented by R, and specific examples of the “optionally substituted hydroxy group”, “optionally substituted thiol group”, “optionally substituted amino group”, “optionally esterified or amidated carboxyl group” and “optionally substituted acyl group” as R 5 , include those similar to the “optionally substituted hydroxy group”, “optionally substituted thiol group”, “optionally substituted amino group”, “optionally esterified or amidated carboxyl group” and “optionally substituted acyl group” as the substituent for R 1 .
In the above formula (I), examples of the lower alkyl group of the “optionally substituted lower alkyl group” represented by R 2 include C 1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
In the above formula (I), examples of the lower alkoxy group of the “optionally substituted lower alkoxy group” represented by R 2 include C 1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, etc.
Examples of the substituents that the “optionally substituted lower alkyl group” and “optionally substituted lower alkoxy group” may have, include halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxy group, amino, mono(lower alkyl)amino, di(lower alkyl)amino, lower alkanoyl, etc.
Examples of the lower alkyl in the mono(lower alkyl)amino and di(lower alkyl)amino include those similar to the lower alkyl group of the “optionally substituted lower alkyl group” represented by the above R 2 .
Examples of the lower alkanoyl include C 2-6 alkanoyl such as acetyl, propionyl, butyryl, isobutyryl, etc.
In the above formula (I), examples of the “halogen atom” represented by R 2 include fluorine, chlorine, bromine, iodine, etc.
As R 2 , among them, an optionally substituted lower C 1-6 alkyl group and a halogen atom are preferred, and in particular, an optionally substituted methyl group and a halogen atom are preferred.
In the above formula (I), examples of the “aromatic ring” of “optionally further substituted aromatic ring” represented by ring A and ring B include 6-membered aromatic hydrocarbon such as benzene, etc., 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of heteo-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, etc., or condensed aromatic heterocycle such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc. As ring A, among these, benzene, furan, thiophene, pyridine, pyridazine, benzimidazole, etc. are preferred, and benzene, pyridine, pyridazine, benzimidazole, etc., are more preferred, and in particular, benzene is preferred. As ring B, a nitrogen-containing aromatic heterocyclic ring such as imidazole, triazole, tetrazole, pyridine, imidazopyridine, etc. are preferred, and imidazole, triazole, pyridine, imidazopyridine, etc. are more preferred, and in particular, imidazole and triazole are preferred.
Examples of the “substituent” that the “aromatic ring” of the “optionally further substituted aromatic ring” represented by ring A and ring B may have, include halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group (the sulfur atom may be oxidized, and may form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified carboxyl group, an optionally substituted aromatic group, etc.
›BRIEF DESCRIPTION OF THE DRAWINGS · 7 of 19
Examples of the halogen as the substituent include fluorine, chlorine, bromine, iodine, etc., and preferably, fluorine and chlorine.
Examples of the alkyl in the optionally substituted alkyl as the “substituent” of ring A and ring B include straight or branched alkyl having 1 to 10 carbons, for example, C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower (C 1-6 )alkyl. Examples of the substituents in the optionally substituted alkyl include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as pyrrolidine, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc., etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the cycloalkyl in the optionally substituted cycloalkyl as the substituent of ring A and ring B include. C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Examples of the substituents in the optionally substituted cycloalkyl include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the substituents in the optionally substituted hydroxy group as the substituent for ring A and ring B include:
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(2) an optionally substituted cycloalkyl which may have a heteroatom (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.; saturated 5- or 6-membered heterocyclic group containing 1 to 2 heteroatoms such as tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, etc. (preferably, tetrahydropyranyl, etc.); etc.);
(3) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e.g., phenyl-C 1-4 alkyl (e.g., benzyl, phenethyl, etc.) and the like.);
(6) formyl or an optionally substituted acyl (e.g., C 2-4 alkanoyl (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like.); and
(7) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like.
Examples of the substituents that the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl, and (7) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.; preferably an optionally halogenated C 1-4 alkoxy), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.), an optionally substituted 5- or 6-membered aromatic heterocyclic ring [for example, 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 or 2 kinds of hetero-atoms selected from nitrogen atom, sulfur atom and oxygen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; examples of the substituent that the heterocyclic ring may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like and the number of the substituents is preferably 1 to 3.], etc. The number of substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 8 of 19
Examples of the substituents in the optionally substituted thiol group as the substituent of ring A and ring B include those similar to the above-mentioned “substituent in the optionally substituted hydroxy group as the substituent of ring A and ring B”, and among them,
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted aralkyl (e.g., phenyl-C 1-4 alkyl (e.g., benzyl, phenethyl, etc.) and the like.); and
(4) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like are preferred.
Examples of the substituent that the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl, and (4) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the substituent for the optionally substituted amino group as the substituent of ring A and ring B include an amino group optionally having 1 to 2 substituents similar to those of the above-mentioned “substituent in optionally substituted hydroxy group as the substituent of ring A and ring B”, and among them,
(1) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) formyl or an optionally substituted acyl (e.g., C 2-4 alkanoyl (e.g., acetyl, propionyl, butyryl, isobutyryl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like; and
(6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like, are preferred.
Examples of the substituents that the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl, and (6) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
In addition, the optionally substituted amino group as the substituent of ring A and ring B may form a cyclic amino group by binding the substituents for amino group to each other (e.g., a cyclic amino group which has a bond on the nitrogen atom and is formed by eliminating one hydrogen atom from ring-constituting nitrogen of 5- or 6-membered ring such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). The cyclic amino group may have a substituent, and the examples of such substituents include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy(e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of the substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 9 of 19
Examples of the optionally substituted acyl group as the substituent for ring A and ring B include a group formed by binding:
(1) hydrogen;
(2) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); and
(6) an optionally substituted 5- or 6-membered monocyclic aromatic group (e.g., phenyl, pyridyl, etc.) and the like, to carbonyl group or sulfonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.). Examples of the substituents that the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted 5- or 6-membered monocyclic aromatic group may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the optionally esterified carboxyl group as the substituent for ring A and ring B include a group formed by bindig:
(1) hydrogen;
(2) an optionally substituted alkyl (e.g., C 1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C 1-6 )alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g., C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e.g., C 2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C 2-6 )alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g., C 3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.); and
(6) an optionally substituted aryl (e.g., phenyl, naphthyl, etc.) and the like, to carbonyloxy group, preferably carboxyl, lower (C 1-6 )alkoxycarbonyl, aryloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphtoxycarbonyl, etc.) and the like. Examples of the substituents that the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl, and (6) optionally substituted aryl may have, include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), an optionally halogenated C 1-4 alkoxy-C 1-4 alkoxy (e.g., methoxymethoxy, methoxyethoxy, ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
Examples of the aromatic group in the optionally substituted aromatic group as the substituent for ring A and ring B include 5- or 6-membered homocyclic or heterocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, etc., and condensed heterocyclic aromatic group such as benzofuran, indole, benzothiophene, benzoxazole, benzthiazole, indazole, benzimidazole, quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc. Examples of substituents of these aromatic groups include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, an optionally substituted thiol group (e.g., thiol, C 1-4 alkylthio, etc.), an optionally substituted amino group (e.g., amino, monoC 1-4 alkylamino, diC 1-4 alkylamino, 5- or 6-membered cyclic amino such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.), an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), an optionally halogenated C 1-4 alkyl (e.g., trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C 1-4 alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.), formyl, C 2-4 alkanoyl (e.g., acetyl, propionyl, etc.), C 1-4 alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl, etc.) and the like. The number of substituents is preferably 1 to 3.
›BRIEF DESCRIPTION OF THE DRAWINGS · 10 of 19
The same or different 1 to 4 (preferably 1 to 2) substituents for ring A and ring B may substitute at any possible position on the ring. In addition, when “aromatic ring” in the “further optionally substituted aromatic ring” represented by ring A or “aromatic ring” in the “further optionally substituted aromatic ring” represented by ring B have a further 2 or more substituents, two of the substituents may bind together to form a group such as lower (C 1-6 )alkylene (e.g., trimethylene, tetramethylene, etc.), lower (C 1-6 )alkyleneoxy (e.g., —CH 2 —O—CH 2 —, —O—CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —CH 2 —, —O—C(CH 3 ) (CH 3 )—CH 2 —CH 2 —, etc.), lower (C 1-6 )alkylenethio (e.g., —CH 2 —S—CH 2 —, —S—CH 2 —CH 2 —, —S—CH 2 —CH 2 —CH 2 —, —S—CH 2 —CH 2 —CH 2 —CH 2 —, —S—C(CH 3 )(CH 3 )—CH 2 —CH 2 —, etc.), lower (C 1-6 )alkylenedioxy (e.g., —O—CH 2 —O—, —O—CH 2 —CH 2 —O—, —O—CH 2 —CH 2 —CH 2 —O—, etc.), lower (C 1-6 )alkylenedithio (e.g., —S—CH 2 —S—, —S—CH 2 —CH 2 —S—, —S—CH 2 —CH 2 —CH 2 —S—, etc.), oxy lower (C 1-6 )alkyleneamino (e.g., —O—CH 2 —NH—, —O—CH 2 —CH 2 —NH—, etc.), oxy lower (C 1-6 )alkylenethio (e.g., —O—CH 2 —S—, —O—CH 2 —CH 2 —S—, etc.), lower (C 1-6 ) alkyleneamino (e.g., —NH—CH 2 —CH 2 —, —NH—CH 2 —CH 2 —CH 2 —, etc.), lower (C 1-6 )alkylenediamino (e.g., —NH—CH 2 —NH—, —NH—CH 2 —CH 2 —NH—, etc.), thia lower (C 1-6 )alkyleneamino (e.g., —S—CH 2 —NH—, —S—CH 2 —CH 2 —NH—, etc.), lower (C 2-6 )alkenylene (e.g., —CH 2 —CH═CH—, —CH 2 —CH 2 —CH═CH—, —CH 2 —CH═CH—CH 2 —, etc.), lower (C 4-6 )alkadienylene (e.g., —CH═CH—CH═CH—, etc.) and the like.
Furthermore, the divalent group formed by binding 2 substituents for ring A to each other and the divalent group formed by binding 2 substituents for ring B to each other may have 1 to 3 substituents similar to those of the “substituent” that “aromatic ring” in the “further optionally substituted aromatic ring” represented by ring A and ring B may have (a halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group (the sulfur atom may be optionally oxidized, and may form an optionally substituted sulfinyl group or an optionally substituted sulfonyl group), an optionally substituted amino group, an optionally substituted acyl group, an optionally esterified or amidated carboxyl group, an optionally substituted aromatic group, etc.).
The “substituent” that “aromatic ring” in the “further optionally substituted aromatic ring” represented by ring A and ring B may have, includes, in particular, halogen atom, cyano, hydroxy group, nitro, an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, etc.), an optionally halogenated or lower (C 1-4 ) alkoxylated lower (C 1-4 ) alkyl (e.g., methyl, ethyl, t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, etc.), lower (C 1-4 )alkyl optionally substituted with hydroxy group or cyano group (e.g., hydroxyC 1-4 alkyl, cyanoC 1-4 alkyl, etc.), lower (C 1-4 )alkyl optionally substituted with an optionally esterified or amidated carboxyl group (e.g., carboxylC 1-4 alkyl, C 1-4 alkoxycarbonylC 1-4 alkyl, carbamoylC 1-4 alkyl, monoC 1-4 alkylcarbamoylC 1-4 alkyl, diC 1-4 alkylcarbamoylC 1-4 alkyl, pyrrolidinocarbonylC 1-4 alkyl, piperidinocarbonylC 1-4 alkyl, morpholinocarbonylC 1-4 alkyl, thiomorpholinocarbonylC 1-4 alkyl, etc.), an optionally halogenated or lower (C 1-4 )alkoxylated lower (C 1-4 )alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, t-butoxy, trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy, methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.), halogen (e.g., fluorine, chlorine, etc.), nitro, cyano, amino optionally substituted with 1 to 2 lower (C 1-4 )alkyl, formyl or lower (C 2-4 )alkanoyl (e.g., amino, methylamino, dimethylamino, formylamino, acetylamino, etc.), 5- or 6-membered cyclic amino group (e.g., 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl, etc.) and the like. As the substituent for ring A, among them, an optionally halogenated lower (C 1-4 )alkyl is preferred, and as the substituent for ring B, among them, an optionally substituted lower (C 1-4 )alkyl is preferred.
In the above formula (I), examples of the divalent group represented by W include a group of the formula —W 1 —X 2 —W 2 (W 1 and W 2 are independently 0.0, S(O) m1 (m1 is 0, 1 or 2), an optionally substituted imino group (—N(R 3 )—) or a bond, and X 2 is an optionally substituted alkylene group, an optionally substituted alkenylene group or a binding site), and the bonding position of W 1 may be at any position, but preferably at para position, when ring A is, for example, a benzene ring. Examples of the substituents (R 3 ) for the optionally substituted imino group represented by W 1 and W 2 include a hydrogen atom, an optionally substituted lower (C 1-6 )alkyl [for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, hydroxyC 1-6 alkyl (e.g., hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.), halogenated C 1-6 alkyl (e.g., trifluoromethyl, trifluoroethyl, etc.), cyanated C 1-6 alkyl (e.g., cyanoethyl, cyanopropyl, etc.), an optionally esterified or amidated carboxylC 1-6 alkyl, etc.], formyl, lower (C 2-5 )alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), lower (C 1-5 )alkylsulfonyl(methylsulfonyl, ethylsulfonyl, etc.) and the like.
Examples of the alkylene group of the “optionally substituted alkylene group” represented by X 2 include an alkylene chain represented by —(CH 2 ) k1 — (k1 is an integer of 1 to 4), etc. Examples of the alkenylene group of the “optionally substituted alkenylene group” represented by X 2 include an alkenylene chain represented by —(CH 2 ) k2 —(CH═CH)—(CH 2 ) k3 — (k2 and k3 are the same or different, and 0, 1 or 2, provided that the sum of k2 and k3 is 2 or less), etc. The alkylene group and the alkenylene group represented by X 2 may have a substituent at any position (preferably on carbon atom), and examples of such substituents include any one that may bind to the alkylene chain or alkenylene chain constituting the straight chain moiety, and for example, lower (C 1-6 )alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C 3-7 )cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), formyl, lower (C 2-7 )alkanoyl (e.g., acetyl, propionyl, butyryl, etc.), an optionally esterified phosphono group, an optionally esterified or amidated carboxyl group (e.g., carboxyl, C 1-4 alkoxycarbonyl, carbamoyl, monoC 1-4 alkylcarbamoyl, diC 1-4 alkylcarbamoyl, etc.), hydroxy group, oxo, a hydroxyimino group, an optionally substituted lower (C 1-6 )alkoxyimino group, etc., and preferably, lower (C 1-6 )alkyl (preferably, C 1-3 alkyl), hydroxy group, oxo, hydroxyimino group, and lower (C 1-6 )alkoxyimino group (optionally substituted with polar group such as hydroxy group, cyano group, an optionally esterified or amidated carboxyl group, etc.) and the like.
›BRIEF DESCRIPTION OF THE DRAWINGS · 11 of 19
Examples of the optionally esterified phosphono group include a group represented by —P(O) (OR 7b ) (OR 8b ) [wherein, R 7b and R 8b are independently hydrogen, C 1-6 alkyl group or C 3-7 cycloalkyl group, or R 7b and R 8b may be bound together to form a 5- to 7-membered ring].
In the above formula, examples of the C 1-6 alkyl group represented by R 7b and R 8b include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl etc., and examples of the C 3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., and preferably, straight C 1-6 lower alkyl, and more preferably C 1-3 lower alkyl. R 7b and R 8b may be the same or different, but preferably the same. In addition, when R 7b and R 8b are bound together to form a 5- to 7-membered ring, R 7b and R 8b are bound to each other to form a straight C 2-4 alkylene side chain represented by —(CH 2 ) 2 —, —(CH 2 ) 3 —, and —(CH 2 ) 4 —. The side chain may have a substituent, and examples of such substituent include hydroxy group, halogen, etc.
Examples of the ester of the optionally esterified carboxyl group include a group formed by bondingcarboxyl group and C 1-6 alkyl group or C 3-7 cycloalkyl group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, etc.
Examples of the amide of the optionally aminated carboxyl group include a group formed by bonding carboxyl group and C 1-6 alkylamino group, C 3-7 cycloalkyl amino group or 5- to 8-membered cyclic amine (e.g., pyrrolidine, piperidine, morpholine, etc.), for example carbamoyl, monoC 1-6 alkylcarbamoyl, diC 1-6 alkylcarbamoyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, etc.
As W, preferably, one of W 1 and W 2 is O, S(O) m1 (m1 is 0, 1 or 2) or —N(R 3 )— (R 3 is a hydrogen atom or an optionally substituted lower. C 1-4 alkyl group), and the other is a bond and X 2 is —(CH 2 ) p — (p is an integer of 1 to 3) or, W is a divalent group of —CH(OH)—, and, more preferably, one of W 1 and W 2 is O, S(O) m1 (m1 is 0, 1 or 2), and the other is a bond and X 2 is —(CH 2 ) p — (p is an integer of 1 to 3) or, W is a divalent group of —CH(OH)—, in particular, when W 1 binds to ring A, —SOCH 2 — is preferred.
As the compound represented by the above formula (I), the compound according to claim 1 wherein ring A is benzene ring, ring B is an optionally substituted imidazole ring or an optionally substituted triazole ring, one of W 1 and W 2 is S(O) m1 (m1 is 0, 1 or 2), and the other is a bond and X 2 is —(CH 2 ) p — (p is an integer of 1 to 3), or W is —CH(OH)—, is preferred, and among them, the compound wherein
is preferable, and in that case, the steric configuration of SO is preferably (S) configuration.
As the compound represented by the above formula (I), the following compounds are specifically preferred;
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[3-(4H-1,2,4-triazol-4-yl)propyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(4-propyl-1H-1,2,4-triazol-5-3-yl)methylsulfinyl]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-5-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methoxy-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-ethyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
›BRIEF DESCRIPTION OF THE DRAWINGS · 12 of 19
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-(2-methoxyethyl)imidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-[[(1-propylimidazol-5-yl)methyl]sulfinyl]benzimidazol-5-yl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
N-[4-[[[1-allylimidazol-2-yl]methyl]sulfinyl]phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-cyclopropylimidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isopropylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
(−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
(−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
(−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide,
(−)-1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide,
(+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide, etc.
Examples of the salts of the compound represented by the formula (I) of the present invention include a pharmaceutically acceptable salt such as a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid, etc. Suitable examples of the salt with the inorganic base include a salt with alkali metal such as sodium salt, potassium salt, etc.; a salt with alkaline earth metal such as calcium salt, magnesium salt, etc.); and aluminum salt, ammonium salt, etc. Suitable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc. Suitable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Suitable examples of the salt with basic amino acid include a salt with arginine, lysine, ornithine, etc. Suitable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid, etc. The compound of the formula (I) of the present invention or a salt thereof may be hydrated or non-hydrated. When the compound of the formula (I) of the present invention or a salt thereof exists as configurational isomer, diastereomer, conformer, etc., it is possible to isolate individual isomers with a per se known separation and purification method, if desired. When the compound represented by the formula (I) or a salt thereof is racemate, it can be separated into an (S)-isomer and an (R)-isomer with usual optical resolution means, and individual optical isomers and racemates thereof are included in the scope of the present invention.
The prodrug of the compound represented by formula (I) of the present invention or a salt thereof [hereinafter, referred to as Compound (I) in some cases] refers to a compound which is converted to Compound (I) by in vivo reaction with an enzyme, a gastric acid, etc. under physiological conditions, that is, a compound which is converted to Compound (I) by an enzymatic oxidation, reduction, hydrolysis, etc.; a compound which is converted to Compound (I) by hydrolysis with a gastric acid, etc. Examples of the prodrug of Compound (I) include a compound wherein an amino group of Compound (I) is acylated, alkylated or phosphorylated (e.g. a compound wherein the amino group of Compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, etc,); a compound wherein the hydroxy group of Compound (I) is acylated, alkylated, phosphorylated, borylated (e.g. a compound wherein the hydroxy group of Compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); a compound wherein the carboxyl group of Compound (I) is esterified or amidated (e.g. a compound wherein the carboxyl group of Compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified, methyl amidated, etc.); etc. These prodrugs can be produced from Compound (I) by methods known per se.
In addition, the prodrug of Compound (I) may be a compound which is converted into Compound (I) under a physiological condition, such as those described in “Development of Medicaments”, Vol.7, Molecular. Design, pages 163 to 198, published by Hirokawashoten in 1990.
›BRIEF DESCRIPTION OF THE DRAWINGS · 13 of 19
In addition, compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I, etc.) and the like.
The present invention is further to provide a preparation method of the compound represented by formula (I) or a salt thereof.
The compound of formula (I) or a salt thereof can be produced in accordance with methods known per se (for example, the methods described in JP-A H08-73476) or the method analogous thereto. The compound of the formula (I) or a salt thereof can also be produced in accordance with the methods described below.
As a salt of the compounds represented by the following formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (I′) and (I″) (hereinafter, abbreviated as Compound (II), Compound (III), Compound (IV), Compound (V), Compound (VI), Compound (VII), Compound (VIII), Compound (I′) and Compound (I″), respectively, in some cases), the salt similar to that with Compound (I) can be used.
In the following reactions, when the starting compounds have amino group, carboxyl group and/or hydroxy group as substituents, to these groups may be introduced a protective group that is generally used in peptide chemistry, etc. After the reaction, if necessary, the protective groups may be removed to obtain the desired compound.
Examples of the protective group for amino group include an optionally substituted C 1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, phenylcarbonyl, C 1-6 alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), phenyloxycarbonyl (e.g., benzoxycarbonyl, etc.), C 7-10 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, etc.), trityl, phthaloyl, etc. As the substituent of these protective groups, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C 1-6 alkylcarbonyl (e.g., acetyl, propionyl, butyryl, etc.), nitro group, etc. are used, and the number of substituents is preferably 1 to 3.
Examples of the protective group for carboxyl group include an optionally substituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl, etc. As the substituent of these protective groups, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C 1-6 alkylcarbonyl (e.g., acetyl, propionyl, butyryl, etc.), formyl, nitro group, etc. are used, and the number of substituents is preferably 1 to 3.
Examples of the protective group for hydroxy group include an optionally substituted C 1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C 7-10 aralkyl (e.g., benzyl, etc.), C 1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), formyl, phenyloxycarbonyl, C 7-10 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. As the substituent of these protective groups, halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C 1-6 alkyl, phenyl, C 7-10 aralkyl, nitro group, etc. are used, and the number of substituents is preferably 1 to 4.
These protective groups may be introduced or removed by methods known per se (e.g. a method described in Protective Groups in Organic Chemistry (J. F. W. McOmie et al.; Plenum Press Inc.) or the methods analogous thereto. For example, as a method for removing the protective groups, method of treating with an acid, a base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc. can be used.
wherein, each symbol has the same meaning as defined in the above.
In this production method, anilide Compound (I) can be obtained by reacting Compound (II) with Compound (III).
The condensation reaction of Compounds (II) and (III) is carried out by usual methods for peptide synthesis. Said methods for peptide synthesis are employed according to any known methods, and for example, methods described in “Peptide Synthesis” written by M. Bodansky and M. A. Ondetti, Interscience, New York, 1966; “The Proteins”, volume 2, written by F. M. Finn and K. Hofmann, H. Nenrath and R. L. Hill edition, Academic Press Inc., New York, 1976; “peputido-gosei no kiso to jikken (Basis and Experiment of Peptide Synthesis)” written by Nobuo Izumiya et al., Maruzen K. K., 1985; etc., as well as azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, method using Woodward reagent K, carbonyldiimidazole method, oxidation-reduction method, DCC/HONB method, etc. and in addition WSC method, method using diethyl cyanophosphate (DEPC), etc. are exemplified. In other words, as a reactive derivative, for example, reactive derivatives such as acid halide (e.g., acid chloride, acid bromide, etc.), acid azide, acid anhydride, mixed acid anhydride (e.g., monoC 1-6 alkylcarbonic acid mixed acid anhydride (e.g., mixed acid anhydride of free acid with mono-methylcarbonic acid, mono-ethylcarbonic acid, mono-isopropylcarbonic acid, mono-isobutylcarbonic acid, mono-tert-butylcarbonic acid, mono-benzylcarbonic acid, mono-(p-nitrobenzyl)carbonic acid, mono-allylcarbonic acid, or the like), C 1-6 aliphatic carboxylic acid mixed acid anhydride (e.g., mixed acid anhydride of free acid with acetic acid, trichloroacetic acid, cyanoacetic acid, propionic acid, butanoic acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid, trichloroacetic acid, acetoacetic acid, or the like), C 7-12 aromatic carboxylic acid mixed acid anhydride (e.g., mixed acid anhydride of free acid with benzoic acid, p-toluic acid, p-chlorobenzoic acid, or the like), organic sulfonic acid mixed acid anhydride (e.g., mixed acid anhydride of free acid with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or the like) and the like, active amide, active ester (e.g., diethoxyphosphoric acid ester, diphenoxyphosphoric acid ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, etc.), active thio ester (e.g., 2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc.) and the like may be used. The present condensation reaction can be carried out in a solvent. Examples of the solvent include anhydrous or hydrous N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, chloroform, dichloromethane, tetrahydrofuran (THF), dioxane, acetonitrile and the suitable mixture thereof.
›BRIEF DESCRIPTION OF THE DRAWINGS · 14 of 19
In the present condensation reaction, about 1 to 2 moles of the Compound (III) are usually used relative to 1 mole of the Compound (II). The reaction temperature is generally about −20° C. to about 50° C., preferably about −10° C. to about 30° C. and the reaction time is generally about 1 to about 100 hours, preferably about 2 to about 40 hours. The thus obtained Compound (I) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, solvent conversion, chromatography, etc.
V in Compound (IV) is a halogen atom (chlorine, bromine, iodine, etc.), and a sulfonyloxy group (methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), and the other symbols have the same meanings as defined in the above.
R a in Compound (I′) is a hydrogen or a substituent that the optionally substituted imino group represented by W 1 and W 2 may have.
By reacting Compound (IV) with Compound (V) having ring B, for example, Compound (I) having oxy group, thio group or imino group as W 2a like compound (I′) can be prepared. Usually about 1 to 3 moles of Compound (V) is used relative to 1 mole of compound (IV). The reaction can be smoothly proceeded, if necessary, by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc., and further sodium iodide, potassium iodide, etc. The present substitution reaction can be carried out in an inert solvent, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a mixture of these solvents. The reaction is carried out at the temperature range of about −10° C. to about 180° C., for about 1 hours to about 40 hours. In addition, the present reaction is preferably carried out under an inert gas (e.g. nitrogen, argon, etc.) atmosphere.
V′ in Compound (VII) is a halogen atom (chlorine, bromine, iodine, etc.), a sulfonyloxy group (methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), R b in compound (I″) is a hydrogen or the substituent that the optionally substituted imino group represented by W 1 and W 2 may have, and other symbols have the same meanings as defined in the above.
By reacting compound (VI) with compound (VII) having ring B, for example, Compound (I″) having oxy group, sulfinyl group or imino group as W 1a , can be prepared. Usually about 1 to 3 moles of compound (VII) is used relative to 1 mole of compound (VI). The reaction can be smoothly proceeded, if necessary, by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and further sodium iodide, potassium iodide, etc. The present substitution reaction can be carried out in an inert solvent, for example, methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), pyridine, etc., or a mixture of these solvents. The reaction is carried out at the temperature range of about −10° C. to about 180° C., for about 1 hours to about 40 hours. In addition, the present reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
Compound (VIII) [wherein, V″ is a halogen atom (bromine, iodine, etc.), and a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc.), other symbols have the same meaning as defined in the above.] is subjected to, for example, Suzuki reaction [cross condensation reaction of aryl boric acid with, for example aryl halide or aryl oxytrifluoromethane sulfonate in the presence of paradium catalyst; A. Suzuki et al., Synth. Commun. 1981, 11, 513], to prepare Compound (I) wherein R 1 is 5- or 6-membered ring aromatic group. Aryl boric acid is used in an amount of about 1 to 1.5 moles relative to 1 mole of Compound (VIII), to obtain Compound (I).
[E Method]
When W of compound (I) is, for example, —CO— or —S—, by a method known per se, for example, by a method described in Ojima, I., ed., Catalytic Asymmetric Synthesis, 2000, Wiley-VCH (New York) or the methods analoguous thereto, Compound (I) having optically active —CH(OH)— or —SO— can be prepared.
The resulting Compound (I) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, solvent conversion, chromatography, etc.
The Compound (II) used as the starting material can be produced by a known method (for example, method described in JP-A H08-73476, etc.) or methods analogous thereto, and for example, Compound (II) can be produced by a method shown in the following Reaction scheme I or II and a method described in the following Reference Examples or the methods analogous thereto.
wherein, R 9 is C 1-4 alkyl group, R 5′ has the same meaning as the substituent represented by R 5 , and other symbols have the same meanings as defined in the above.
In the present method, first the compound represented by formula (IX) is heated together with polyphosphoric acid, or Compound (IX) is converted to acid chloride with thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorous pentachloride, etc., followed by subjecting the acid chloride to conventional Friedel Crafts reaction and cyclizing the same to prepare Compound (X). Then, Compound (X) is reacted with carbonic acid ester in the presence of a base to prepare ketoester (XI). Compound (XI) is subjected to reduction reaction with catalytic hydrogenation or sodium boro hydride, etc. to produce Compound (XII). Compound (XII) is subjected to conventional dehydration reaction to produce Compound (XIII). Compound (XIII) is subjected to ester hydrolysis, to produce unsaturated carboxylic acid (II).
›BRIEF DESCRIPTION OF THE DRAWINGS · 15 of 19
wherein, R 10 is C 1-4 alkyl group, and the other symbols have the same meaning as defined in the above.
Compound (XIV) is subjected to a Dieckmann (type) condensation reaction (J. P. Schaefer and J. J. Bloomfield, Org. Reactions, 1967, 15, 1), to prepare Compound (XI) to Compound (XIII). Compound (XI) to Compound (XIII) is reacted subsequently according to the method described in the Reaction formula I to prepare unsaturated carboxylic acid compound (II).
In addition, Compound (III) also can be prepared by a known method (e.g., the method described in JP-A H08-73476, etc.) or the methods analogous thereto, and for example, can be prepared by a method shown in Reaction scheme III and a method described in the following Reference Examples, or the methods analogous thereto.
The reduction reaction of Compound (XV) can be carried out by a method known per se. For example, reduction with metal, reduction with metal hydride, reduction with metal hydrido complex compound, reduction with diborane or substituted borane, catalytic hydrogenation, etc. are used. In other words, this reaction is carried out by treating Compound (XV) with reducing agent. Examples of the reducing agent include metal such as reduced iron, zinc powder, etc., alkali metal borohydride (e.g., sodium borohydride, lithium borohydride, etc.), metal hydrido complex compound such as lithium aluminum hydride, etc., metal hydride such as sodium hydride, etc., organotin compound (triphenyl tin hydride, etc.), metal and metal salt such as nickel compound, zinc compound at the like, catalytic reducing agent using transition metal catalyst such as palladium, platinum, rhodium, etc., and hydrogen, and diborane, etc., and catalytic reduction using transition metal catalyst such as palladium, platinum, rhodium, etc., and hydrogen, and reduction with metal such as reduced iron, etc., are advantageously carried out. This reaction is carried out in organic solvent which does not affect the reaction. Examples of the solvents include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethylether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N,N-dimethylformamide, acetic acid or the mixed solvent thereof, etc. The solvent is suitably selected and used depending on the kinds of reducing agent. Reaction temperature is about −20° C. to about 150° C., in particular, about 0° C. to about 100° C. is preferable, and reaction time is about 1 to about 24 hours.
The resulting. Compound (II) or (III) can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, solvent conversion, chromatography, etc.
The compound represented by formula (I) of the present invention or a salt thereof including the above Compound (I′) and Compound (I″) (hereinafter, when briefly referred to as the compound represented by formula (I), it includes the compound represented by formula (I) and a salt thereof) may be administrated orally or parenterally alone or as a pharmaceutical composition compounded with a pharmaceutically acceptable carrier such as solid formulations such as tablets, capsules, granules, powders, etc.; or liquid formulations such as syrups, injectables, etc.), Examples of parenteral formulations include injectables, drip infusions, suppositories, pessaries, etc. In particular, pessaries are useful for the prophylaxis of HIV infection.
As the pharmaceutically acceptable carriers, various organic or inorganic carriers which are generally used conventionally as preparation materials are used. For example, an excipient, a lubricant, a binder, a disintegrating agent, etc. in solid formulations; and a solvent, a solubilizer, a suspending agent, an isotonizing agent, a buffer, a soothing agent, etc. in liquid formulations are compounded. In addition, if desired, preparation additives such as a preservative, an antioxidant, a colorant, a sweetener, etc. may be used. Suitable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicic acid anhydride, etc. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, colloidal silica, etc. Suitable examples of binders include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl-pyrrolidone, etc. Suitable examples of disintegrating agents include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, etc. Suitable examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, etc. Suitable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, etc.; and hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc. Suitable examples of isotonizing agents include sodium chloride, glycerin, D-mannitol, etc. Suitable examples of buffers include a buffer solution of phosphate, acetate, carbonate, citrate, etc. Suitable examples of soothing agents include benzylacohol, etc. Suitable examples of preservatives include paraoxybenzoic esters, chlorobutanol, benzylalcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc. Suitable examples of antioxidants include sulfite, ascorbic acid, etc.
The compound represented by formula (I) of the present invention or a salt thereof has an excellent CC chemokine receptor antagonism, especially CCR5 and/or CCR2 antagonism, in particular, potent CCR5 antagonism, and therefore, can be used for the prophylaxis or treatment of HIV infection, for example, AIDS or other various diseases in human. In addition, the compound represented by formula (I) of the present invention or a salt thereof is low toxic and can be used safely.
›BRIEF DESCRIPTION OF THE DRAWINGS · 16 of 19
For example, the pharmaceutical composition comprising the compound represented by formula (I) of the present invention or a salt thereof may be used as CCR5 antagonist, for example, as an agent for prophylaxis or treatment of AIDS and as an inhibiting agent for the progression of AIDS. In addition, the pharmaceutical composition comprising the compound represented by formula (I) of the present invention or a salt thereof may be used as an agent for prophylaxis and/or treatment of various diseases such as an agent for prophylaxis or treatment of graft versus host disease and/or rejection and an agent for prophylaxis or treatment of chronic rheumatoid arthritis, autoimmune diseases, allergic diseases, ischemic brain cell disorders, myocardial infarction, chronic nephritis, arteriosclerosis, etc., and.
Examples of the subject diseases of preventive and therapeutic agent of the present invention include graft rejection (posttransplantational rejection, posttransplantational polycythaemia, hypertension, organ disorder, vascular hypertrophy, graft versus host disease, etc.,); arthritic osteopathy such as osteomeningitis, etc., (chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, osteoporosis, abnormal growth of cell, fracture, refracture, osteomalacia, osseous Behcet's disease, rigorous myelitis, articular tissue destruction by gonarthrosis and similar diseases thereto, etc.); autoimmune diseases (collagen disease, systemic lupus erythematosus, pachyderma, polyarteritis, myasthenia gravis, multiple sclerosis, etc.); allergic diseases (allergic nasal catarrh, conjunctivitis, gastrointestinal allergy, pollinosis, anaphylaxis, atopic dermatitis, bronchial asthma, etc.); inflammatory enteropathy diseases (ulcerative colitis, Crohn disease, gastritis, gastric ulcer, gastric cancer, postgastrotomy disorder, dyspepsia, esophageal ulcer, pancreatitis, colon polyp, cholelithiasis, hemorrhoids, peptic ulcer, situational ileitis, etc.); inflammatory diseases (retinopathy, postoperative and posttraumatic inflammation, remission of puffiness, pharyngitis, cystitis, meningitides, inflammatory ophthalmic diseases, etc.); respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thromboembolism, pulmonary sarcoidosis, pulmonary tuberculosis, interstitial pneumonia, silicosis, adult tachypnea syndrome, chronic obliterative pulmonary diseases, etc.); infectious diseases (virus infection by cytomegalovirus, influenzavirus, herpesvirus and the like, rickettsia infection, bacterial infection, sexually transmitted diseases, carinii pneumonia, helicobacter pylori infection, systemic fungal infection, tuberculosis, invasive staphylococcal infection, acute viral encephalitis, acute bacteria meningitides, AIDS encephalopathia, septicemia, sepsis, sepsis gravis, septic shock, endotoxin shock, toxin shock syndromes, et.); cancers and accompanying cachexia, cancer metastases (bladder cancer, breast cancer, cervical cancer, ovarian cancer, chronic lymphoblastic leukemia, chronic myeloid leukemia, colon cancer, rectal cancer, colic cancer, multiple myeloma, malignant myeloma, prostatic cancer, lung cancer, gastric cancer, Hodgkin disease, malignant melanoma, malignant lymphoma, etc.); non-Hodgkin's lymphoma; non-small cell lung cancer; malignant melanoma, neurodegenerative diseases (Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis (ALS), Huntington chorea, diabetic neural disorder, Creutzfeldt-Jakob disease, etc.); mental diseases (depression, epilepsia, alcoholism etc.); schizophrenia; venous dysfunction; central nerve disorders (disorder and aftereffect/complication from intracerebral breeding, brain infarction and the like, cephalic trauma, spine damage, brain edema, sensory function disorder, sensory function abnormality, autonomic nervous function disorder, autonomic nervous function abnormality, etc.); centralis damage (cephalic trauma, spiral damage, whiplash injury, etc.); vascular dementia (multiinfarct dementia, Binswanger's disease, etc.); cerebro-vascular accident (asymptomatic cerebro-vascular accident, transient cerebral ischemic attack, stroke, multiinfarct dementia, hypertensive encephalopathia, etc.); recurrence and aftereffect of cerebro-vascular accident (neural sympton, mental symptom, subjective sympton, operational disorder in daily life, etc.); multiinfarct dementia; post-cerebrovascular obliteration central hypofunction; disorder or abnormality of autoregulation of cerebral circulation and renal circulation; blood brain barrier damage; anxiety symptom; acute coronary artery syndromes including unstable angina, etc.; anxious mental state; amnesia; prosopalgia; otolaryngological disease (Menuel syndrome, buzzing, gustation disorder, dizziness, dysequilibrium, dysphagia, etc.); migraine; chronic pain; dermatoses (keloid, angioma, psoriasis, etc.); arteriosclerosis obliterans; thromboangiitis obliterans; obstruction of peripheral artery; postischemic reperfusion injury; Raynaud disease; Buerger disease; myocarditis; cardiac ischemia; cardiac infarction; progress of cardiac failure after cardiac infarction; cardiomyopathy; cardiac hypertrophy; acute cardiac failure and chronic (including estatic) cardiac failure; angina pectoris; arrhythmia; tachycardia; circadian rhythm disorder of blood pressure; abnormality in characteristic of blood haemocyte components (enhancement in platelet aggregation, abnormality of erythrocyte deformability, enhancement in leucocyte adhesiveness, increase in blood viscosity, polycythaemia, vascular peliosis, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelopathy, etc.); arteriosclerosis including atherosclerosis (aneurysm, coronary arteriosclerosis, cerebro arteriosclerosis, peripheral arteriosclerosis, etc.); vascular reocclusion and restenosis after bypass operation; vascular hyperplasy or occlusion and organ malfunction after intervention (transdermal coronary arterioplasty, stent detention, coronary autoscope, vascular ultrasound therapy, coronary injection thrombolytic therapy, etc.); production and enhancement of vasoactive materials and thrombi inducing materials (endothelin, thromboxan A2, etc.); arterialization (including abnormal vasculogenesis in abnormal capillary vasoganglion formation of pultaceous arteriosclerosis outer membrane); thrombosis; fat storage disease acceleration; ophthalmic diseases (glaucoma, hyper-ocular-tension disease, etc.); hypertension; hypertensive buzzing; dialysis hypotension; endothelial cell and organ disorders; endocrinopathy (Addison disease, Cushing syndrome, melanocytoma, primary aldosteronism, etc.); nephritis; renal diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, dialysis complications, organ disorders including nephropathia by radiation, diabetic nephropathia, etc.); diabetic diseases (insulin-dependent diabetes, diabetic complications, diabetic retinopathy, diabetic microangiopathy, diabetic neuropathy, etc.); glucose tolerance abnormality; hepatic diseases (hepatitis (including chronic hepatitis), cirrhosis, etc.); interstitial hepatic diseases; chronic pancreatitis; portal blood pressure enhancement; obesity; male sterility; gynecologic diseases (climacteric disorder, gestational toxicosis, endometriosis, hysteromyoma, ovarian disease, mammary disease, etc.); dropsy; chronic fatigue syndromes; prostatomegaly; Behcet's disease; Hodgkin's disease; lacunar infarction; consciousness disorder; psoriasis; diseases due to environmental or occupational factors (radiational disorder, disorders by ultraviolet ray/infrared ray/laser ray, altitude sickness, etc.); and intermittent claudication.
›BRIEF DESCRIPTION OF THE DRAWINGS · 17 of 19
A pharmaceutical composition containing the compound of the formula (I) of the present invention or a salt thereof, may be used in combination with other medicines depending on the diseases to be treated. Examples of the other medicines include, HDL increasing drugs [squalene synthase inhibitor, CETP inhibitor, LPL activator, etc.]; preventive and therapeutic drug for HIV infectious disease [nucleic acid reverse transcriptase inhibitors such as zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, etc., non-nucleic acid reverse transcriptase inhibitors such as nevirapine, delavirdine, efavirenz, loviride, immuncal, oltipraz, etc., protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, palinavir, lasinavir, lopinavir, etc.]; NMG-CoA reductase inhibitors [cerivastatin, atorvastatin, pravastatin, simvastatin, itavastatin, lovastatin, fluvastatin, (+)-3R, 5S-7-[4-[4fluorophenyl]-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl)-3,5-dihydroxy-6 (E)heptenoic acid, etc.]; atopic dermatitis drugs [sodium cromoglicate, etc.]; allergic nasal catarrh drugs [sodium cromoglicate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine, mequitazine, etc.]; imipenemcilastatin sodium; endotoxin antagonists or antibodies; oxidosqualene-lanosterol cyclase. [e.g., decalin derivatives, azadecalin derivatives and indan derivatives]; calcium antagonists (diltiazem, etc.); glycerol; cholinesterase inhibitors (e.g., Aricept (donepezil), etc.); compounds suppressing cholesterol uptake [e.g., sitosterol, neomycin, etc.]; compounds inhibiting cholesterol biosynthses [e.g., HMG-CoA reductase inhibitors such as lovastatin, simvastatin, pravastatin, etc.]; cyclooxygenase depressants [Cox-I,Cox-II depressants such as celecoxib, rofecoxib, salicylic acid derivatives such as aspirin and the like, diclofenac, indometacin, loxoprofen, etc.]; sigal transduction inhibitors, squalene epoxidase inhibitors [e.g., NB-598 and the analogous compounds, etc.]; steroidal drugs [dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol, etc.]; diacerin; nicotinic acid and derivatives and analogues thereof [e.g., acipimox and probucol]; nicergoline, nephrotic syndrome drugs: prednisolone (Predonine), prednisolone sodium succinate (Predonine), methylprednisolone sodium succinate (Solu medrol), betamethasone (Rinderon), dipyridamole (Persantine), dilazep hydrochloride (Comelian), ticlopidine, clopidogrel, antiplatelet drugs an d anticoagulants such as FXa inhibitors, etc.; barbital-based anticonulsants or anaesthetic drugs (phenobarbital, mephobarbital, metharbital, etc.); Parkinson disease drugs (e.g., L-DOPA, etc.); histamine receptor blockers (cimetidine, famotidine, etc.); hidantoin-based anticonvulsant drugs (phenyloin, mephenyloin, ethotoin, etc.); pyroxicam, fibrates. [e.g., clofibrate, benzafibrate, gemfibrozil, etc.]; prostaglandins; megestrol acetate; gastric and intraduodenal ulcer drugs: antacids [e.g., histamine H2 antagonists (cimetidine, etc.), proton pump inhibitors (lansoprazole etc.,), etc.]; inflammatory mediator depressants; coronary vasodilators: nifedipine, diltiazem, nicorandil, nitrite drugs, etc.; infectious disease drugs: [e.g., antibiotic formulations (cefotiam hydrochloride, cefozopran hydrochloride, ampicillin, etc.), chemotherapeutic agents (sulfa drugs, synthetic antibacterial agents, antiviral agents, etc.), biologic formulations (vaccines, blood products including immunoglobulins) etc.] etc.; hepatic disease drugs: glycyrrhizin formulations [e.g., Stronger Minophagen, etc.]; liver hydrolysate; SH compounds [e.g., glutathione, etc.]; special amino acid formulations [e.g., aminoleban, etc.]; phospholipids [e.g., polyene-phosphatidyl choline, etc.]; vitamins [e.g., vitamin B 1 , B 2 , B 6 , B 12 , C, etc.]; adrenocortical hormones. [e.g., dexamethasone, betamethasone, etc.]; interferons [e.g., interferon α, β etc.]; hepatic encephalopathy drugs [e.g., lactulose, etc.]; hemostats used in cases of rapture of esophageal or gastric venous cancer [e.g., vasopressin, somatostatin, etc] etc.; arthritis drugs; muscle relaxants [pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine, etc.]; vasodilators[oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz, etc.]; vasoconstrictors [dopamine, dobutamine denopamine, etc.]; antiplatelet drugs (ozagrel, etc.); thrombogenesis preventive and therapeutic drugs: anticoagulant drugs [e.g., heparin sodium, heparin calcium, warfarin calcium (Warfarin), Xa inhibitor]; thrombolytic drugs [e.g., tPA, urokinase]; antiplatelet drugs [e.g., aspirin, sulfinpyrazone (Anturan), dipyridamole (Persantine), ticlopidine (Panaldine), cilostazol (Pletaal), GPIIb/IIIa antagonist (ReoPro)]; antidepressants [imipramine, clomipramine, noxiptiline, fenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, aluvoxamine maleate, trazodone hydrochloride, etc.]; antiepileptic drugs [gavapentin, phenyloin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sultiame, sodium valproate, clonazepam, diazepam, nitrazepam, etc.]; anti-allergic drugs [diphenhydramine, chlorpheniramine, tripelennamine, metodiramine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastin, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, fexofenadine, ebastine, bucillamine, oxatomide, Stronger Neo-Minophagen C, tranexamic acid, ketotifen fumarate, etc.]; anticholinergic drugs (e.g., ipratropium bromide, flutropium bromide, oxitropium bromide, etc.); anti-Parkinson drugs (dopamine, levodopa, etc.); antirheumatic drugs; anti-inflammatory drugs (e.g., aspirin, acetaminophen, diclofenac sodium, ibuprofen, indometacin, loxoprofen sodium, dexamethasone, etc.); anticoagulant and antiplatelet drugs. [sodium citrate, activated protein C, tissue factor pathway inhibitors, antithrombin III, dalteparin sodium, argatroban, gabexate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, pentoxifylline, tisokinase, streptokinase, heparin, etc.]; anticoagulant therapeutic drugs [dipyridamole (Persantine), dilazep hydrochloride (Comelian), ticlopidine, clopidogrel, Xa inhibitors]; antibacterial drugs [(1) sulfa drugs [sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, sulfadiazine silver, etc.], (2) quinolone-based antibacterial drugs [nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin, etc.], (3) antituberculous drugs [isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicyclic acid (calcium p-aminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine, etc.], (4) anti-acid fast bacteria drugs [diaphenylsulfone, rifampicillin, etc.], (5) antiviral drugs [idoxuridine, aciclovir, vidarabine, ganciclovir, etc.], (6) anti-HIV drugs [zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir, etc.], (7) spirocheticide, (8) antibiotics [tetracycline hydrochloride, ampicillin, piperacillin, gentamcin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, cefalexin, cefroxadine, cefadroxil, cefamandole, cefotiam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or salts thereof, griseofulvin, lankacidins [J. Antibiotics, 38, 877 to 885 (1985)], etc., cefixime, levofloxacin]; antithrombotic drugs (argatroban, etc.); antiprotozoal drugs [metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.]; antitumor drugs [6-O-(N-chloroacetylcarbamoyl] fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocartinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathiopurine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone, testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuproline acetate, buserelin acetate, etc.; antifungal drugs [(1) polyethylene-based antibiotics (e.g., amphotericin B, nystatin, trichomycin), (2) griseofulvin, pyrrolnitrin, etc., (3) cytosine metabolism antagonists (e.g., flucytosine), (4) imidazole derivatives (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole), (5) triazole derivatives (e.g., fluconazole, itoraconazole, azole compounds [2-[(1R,2R)-2-[2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-lyl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl-3(2H,4H)-1,2,4-triazolone], (6) thiocarbamate derivatives [e.g., trinaphthol], (7) echinocandin-based derivatives (e.g., caspofungin, FK-463, V-echinocandin), etc.]; antipsychotic drugs [chlorpromazine hydrochloride, prochlorperazine, trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine, etc.]; antiulcer drugs [metoclopramide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastron, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandins etc.]; anti diabetic drugs [e.g., pioglitazone, nateglinide, voglibose, acarbose, etc.]; antiobese drugs [mazindol, etc.]; antirheumatic drugs; antianxiety drugs [diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine, etc.]; antiarrhythmic drugs. [disopyramide, lidocaine, quinidine sulfate, flecainide acetate, mexiletine hydrochloride, amiodarone hydrochloride, and p blockers, Ca antagonists, etc.; antiasthmatic drugs [isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate., fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, beclomethasone propionate, fluticasone propionate, beclomethasone propionate, procaterol, etc.]; anti-hypothyroidism drugs. [dried thyroid (Thyreoid), levothyroxine sodium (Tyradin S), liothyronine sodium (thyronine, tyronine)]; nephrotic syndrome drugs [prednisolone (Predonine), prednisolone sodium succinate (Predonine), methylprednisolone sodium succinate (Solu medrol), betamethasone (Rinderon).]; antihypertensive drugs [(1) sympathetic nerve depressants [α2 stimulating drugs (e.g., clonidine, guanabenz, guanfacine, methyldopa, etc.), ganglionic blockers (e.g., hexamethonium, trimethaphan, etc.), presynaptic blockers (e.g., Alusa-Oxylone, dimethylamino reserupinate, rescinnamine, reserpine, syrosingopine, etc.), neuronal blockers (e.g., betanidine, guanethidine, etc.), αl blockers (e.g., bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.), β blockers (e.g., propranolol, nadolol, timolol, nipladilol, bunitrolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amosulalol, arotinolol, etc.), etc], (2) vasodilators [calcium channel antagonists (e.g., manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amlodipine, aranidipine, etc.), phthalazine derivatives (e.g., budralazine, cadralazine, ecarazine, hydralazine, todralazine, etc.), etc.], (3) ACE inhibitors [alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, perindopril, etc.)], (4) AII antagonists [losartan, candesartan, valsartan, telmisartan, irbesartan, forasartan, etc.], (5) diuretic drugs [e.g., diuretic drugs described above, etc.]; antihypertensive drugs [diuretic drugs [e.g., furosemide (Lasix), bumetanide (Lunetoron), azosemide (DIART)], antihypertensive drugs [e.g., ACE inhibitors, (enalapril maleate (RENIVACE) etc.,) and Ca antagonists (manidipine, amlodipine etc.), α or β receptor blockers, etc.], antihyperlipemia drugs. [HMG-CoA reductase inhibitors (e.g., fluvastatin, cerivastatin, atorvastatin, etc.), fibrates [e.g., simfibrate, aluminum clofibrate, clinofibrate, fenofibrate, etc.], anion exchange resin [e.g., cholestyramine, etc.], nicotinic acid drugs [e.g., nicomol, niceritrol, tocopherol nicotinate etc.], polyvalent unsaturated fatty acid derivatives [e.g., ethyl icosapentaenoic acid, polyene phosphatidyl choline, melinamide, etc.], phytosterols [e.g., gamma-oryzanol, soysterol, etc.], elastase, sodium dextran sulfate, squalene synthase inhibitors, CETP inhibitors, 2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]ethyl propionate [Chem. & Pharm. Bull., 38, 2792 to 2796 (1990)], etc.]; osseous disease drugs. [calcium formulations [e.g., calcium carbonate, etc.], calcitonin formulations, activated vitamin D 3 formulations [e.g., alfacalcidol (Alfarol etc.), calcitriol (Rocaltrol), etc.], sex hormones [e.g., estrogen, estradiol, etc.], hormone formulations [e.g., conjugated estrogen (Premarin), etc.], ipriflavone formulations [osten, etc.], vitamin K 2 , vitamin K 2 formulations [e.g., menatetrenone (Glakay), etc.], bis-phosphonate-based formulations [etidronate, etc.], prostaglandin E2, fluorine compounds [e.g., sodium fluoride, etc.], bone morphogenetic protein (BMP), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), transforming growth factor (TGF-β), insulin-like growth factor-1 and -2 (IGF-1, -2), parathyroid adrenal hormones (PTH), and compounds described in EP-Al-376197, EP-A1-460488, and EP-A1-719782 [e.g., (2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-bemzothiepin-2-carboxamide, etc.], etc.), lipid-soluble vitamin drugs [(1) vitamin A family (vitamin A 1 , vitamin A 2 , and retinol palmitate), (2) vitamin D family (vitamin D 1 , D 2 , D 3 , D 4 , and D 5 ), (3) vitamin E family (α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate.), (4) vitamin K family (vitamin K 1 , K 2 , K 3 , and K 4 ,), (5) folic acids (vitamin M), etc.]; vitamin derivatives [various vitamin derivatives, e.g., vitamin D 3 derivatives such as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, vitamin D 2 derivatives such as 5,6-trans-ergocalciferol, and the like]; disease-modifying antirheumatic and immunosuppressive drugs. [e.g., methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, the oral gold salts]; hypertensors [dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin, etc.]; myocardial protective drugs: heart ATP-K opener (Na-H exchange inhibitors, endothelin antagonists, urotensin antagonist, etc.), cardiac failure drugs [cardiac stimulants (e.g., digitoxin, digoxin, methyldigoxin, lanatoside C, proscillaridin, etc.), α, β stimulating drugs (e.g., epinephrine, norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine, denopamine, etc.), phosphodiesterase inhibitors (e.g., amrinone, milrinone, olprinone hydrochloride, etc.), calcium channel sensibility improvers (e.g., pimobendan, etc.), nitrate drugs (e.g., nitroglycerin, isosorbide nitrate, etc.), ACE inhibitors (e.g., the ACE inhibitor described above, etc.), diuretic drugs (e.g., diuretic drugs described above, etc.), calperitide, ubidecarenone, vesnarinone, aminophylline, etc.]; neurotrophic factors; renal failure and nephropathia drugs; biologics [e.g., monoclonal antibodies (e.g., anti-TNF-α antibodies , anti-IL-12 antibodies, anti-IL-6 antibodies, anti-ICAM-1 antibodies, anti-CD4 antibodies, etc.), soluble receptors (e.g., soluble TNF-α receptors, etc.), protein ligands (IL-I receptor antagonist, etc.)]; bile acid binding resins [e.g., cholestyramine, cholestipol, etc.]; biliary tract disease drugs: cholereticcholepoietic drugs [e.g., dehydrocholic acid, etc.], cholekinetic drugs [e.g., magnesium sulfate, etc.], etc.; central nervous system agonists: antianxiety drugs, hypnotic and sedative drugs, anesthetic drugs, spasmolytic drugs, autonomic drugs, anti-Parkinson drugs and other psychoneuro drugs, etc.; antitiussive and expectorants. [ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapin hydrochloride, arocloramide, chlofedanol, picoperidamine, cloperastine, protoxlol, isoproterenol, salbutamol, terbutaline, oxymetebanol, morphine hydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride, dimemorfan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocisteine, etc.], sedative drug [chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium, etc.], analgesic and antiphlogistic drugs [e.g., central analgesic drugs (e.g., morphine, codeine, pentazocine etc.), steroid drugs (e.g., prednisolone, dexamethasone, betamethasone), etc., antiphlogistic enzymic drugs (e.g., bromerain, lysozymes, protease, etc.)], diabetic drugs [sulfonylurea drugs (e.g., tolbutamide, chlorpropamide, glyclopyramide, acetohexamide, tolazamide, glibenclamide, glybuzole, etc.), biguanide drugs (e.g., metformin hydrochloride, buformin hydrochloride, etc.), α-glucosidase inhibitors (e.g., voglibose, acarbose, etc.), insulin resistance improvers (e.g., pioglitazone, troglytazone, etc.), insulin, glucagon, diabetic complication drugs (e.g., epalrestat, thioctic acid, etc.), actos, rosigliatazone, kinedak, penfill, humulin, euglucon, glimicron, daonil, novolin, monotard, insulin family, glucobay, dimelin, rastinone, bacilcon, deamelin S, iszilin family, etc.]; brain function reviving agents (e.g., idebenone, vinpocetin, etc.); urinary and male genital disease drugs [e.g., prostatomegaly drugs (tamsulosin hydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.), prostate cancer drugs (leuprorelin acetate, goserelin acetate, chlormadinone acetate, etc.)], etc; nonsteroidal antiinflammatory drugs [acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, fulfenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofenn, ketoprofen, naproxen, oxaoprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesilate, urinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicyclic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone or the salts thereof, etc.]; frequent urination and anischuria drugs [flavoxate hydrochloride, etc.]; unstable plague stablizers [MMP inhibitors, chymase inhibitors, etc.]; arrhythmic drugs [sodium channel blockers (e.g., quinidine, procainamide, disopyramide, ajmaline, cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone, flecainide, pilsicainide, phenyloin, etc.), β blockers (e.g., propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol, etc.), potassium channel blockers (e.g., amiodarone, etc.), calcium channel blockers (e.g., verapamil, diltiazem, etc.), etc.]; gynecologic disease drugs [e.g., climacteric disorder drugs (conjugated estrogen, estradiol, testosterone enanthate, estradiol valerate, etc.), breast cancer drugs (tamoxifen citrate, etc.), endometriosis and hysteromyoma drugs (leuprorelin acetate, danazol, etc.)], etc.; anesthetic drugs. [a local anaesthetic drugs [cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazaine], etc.]; b. general anesthetic drugs [(I) inhalation anesthetic drugs (e.g., ether, halothane, nitrous oxide, influrane, enflurane), (2) intravenous anesthetic drugs (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital), etc.]]; anesthetic antagonists [levallorphan, nalorphine, naloxone, or the salts thereof, etc.]; chronic cardiac failure drugs: cardiac stimulants [e.g., cardiac glycoside (digoxin, etc.), β receptor stimulating drugs (catecholamine preparations such as denopamine, dobutamine.), PDE inhibitors, etc.]; diuretic drugs [e.g., furosemide (Lasix), spironolactone (Aldactone), bumetanide (Lunetoron), azosemide (Diart), etc.]; ACE inhibitors. [e.g., enalapril maleate (Renivace), etc.]; Ca antagonists [e.g., amlodipine, manidipine, etc.] and β receptor blockers, etc.; immunomodulators [cyclosporin, tacrolimus, gusperimus, azathioprine, antilymphocyte sera, dried sulfonated immunoglobulins, erythropoietins, colony stimulating factors, interleukins, interferons, etc.]; diuretic drugs. [thiazide-based diuretic drugs (benzylhydrochlorothiazide, cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide, methylclothiazide, penflutiazide, polythiazide, trichlormethiazide, etc.), loop diuretic drugs (chlortalidone, clofenamide, indapamide, mefruside, meticrane, sotrazone, tripamide, quinethazone, metolazone, furosemide, mefruside, etc.), potassium-sparing diuretic drugs (spironolactone, triamterene, etc.)]; and erectile dysfunction drugs (Viagra, apomorphine, etc.).
›BRIEF DESCRIPTION OF THE DRAWINGS · 18 of 19
These drugs, separately or simultaneously may be prepared by mixing with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, and can be administered either orally or parenterally. When the drug is prepared separately, the separately prepared drugs may be administered with mixing with a diluent or the like before use, and each of the preparations separately prepared may be administered, simultaneously or separately at an interval, to the same subject. Kit products for administering the separately prepared preparations with mixing with a diluent and the like before using (for example, an injectable kit including ampoules containing each powdery drug, and a diluent for mixing to dissolve 2 or more drugs before using, and the like), kit products for administering each of the separately-prepared preparations, simultaneously or separately at an interval, to the same subject (for example, a tablet kit for administering 2 or more tablets, simultaneously or separately at an interval, wherein the tablet containing each drugs was put into the same or separate bags and, if necessary, a column wherein the drug administration time is to be indicated was provided on the bags, and the like), or the like are also included in the pharmaceutical composition of the present invention.
A dosage of the pharmaceutical composition of the present invention can be appropriately selected by taking into consideration of the administration subject, age and body weight of the administration subject, disease conditions, administration time, administration route, dosage form, etc.
The dosage for a particular patient is determined depending on the subject's age, body weight, general health condition, sex, meal, administration time, administration route, excretion rate and the degree of disease being treated at that time and by taking into consideration of these and other factors.
When the pharmaceutical composition described above is used as a preventive and therapeutic agent for AIDS and a depressant for disease progression of AIDS, the dosage of composition varies depending on the patient's condition, body weight and administration route However, in the case of oral administration, a daily dosage is in a range of about 5 to 1000 mg, preferably about 10 to 600 mg, and more preferably about 10 to 300 mg, especially preferably about 15 to 150 mg of active ingredient (i.e. as the compound of the formula (I)) per adult (body weight: 50 kg), and the composition may be administered once a day or 2 to 3 times a day.
When the pharmaceutical composition described above is used as a preventive and therapeutic agent for graft versus host disease and/or rejection associated with transplantation of organs such as heart, kidney, liver, bone marrow, etc., administration of the composition starts 3 days before the transplantation, and continues after the transplantation. A daily dosage of the pharmaceutical composition varies depending on the patient's condition, body weight and route of administration, and in the case of oral administration, about 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, and especially preferably about 15 to 150 mg, as an active ingredient (i.e., as the compound of the formula (I)), per adult (body weight: 50 kg) and the composition may be administered, once a day, or separately 2 or 3 times a day. In this case, the composition may be used in combination with a depressant for graft versus host disease and/or rejection in other organ transplantation. Specific examples of the depressant of graft versus host disease and/or rejection in organ transplantation which are used in combination with the compound represented by the compound of the formula (I) or a salt thereof include cyclosporin, tacrolimus, rapamycin, steroids, azathioprine, mycophenolate mophetil, mizoribine, etc. When one drug affects metabolism of other drugs in the case where these drugs are used in combination, dosage of each drugs is properly adjusted, but generally dosage of each of the drugs used in combination is that of each drugs when used independently.
When the compound of formula (I) or a salt thereof described above is used for the subject disease except for suppression of the graft versus host disease and/or rejection in organ transplantation, the daily dosage varies depending on the kind of subject disease, the patient's condition and body weight, and route of administration, and is usually, in oral administration, about 5 to 1000 mg, preferably about 10 to 600 mg, more preferably about 10 to 300 mg, and especially preferably about 15 to 150 mg of active ingredient (i.e., as the compound of the formula (I)), per adult (body weight: 50 kg), and the composition may be administered, once a day, or separately 2 to 3 times a day. When the compound is used in combination with other drugs, dosage of the other drugs is properly selected in a range of about 1/200 to 1/2 or more to about 2 to 3 times or less of usual dosage. Further, when in the case where the composition is used in combination with 2 or more drugs, one of the drugs affects metabolism of the other drug, dosage of each of the drugs is properly adjusted, but generally, dosage of each of the drugs used in combination is that of each drug when used independently.
Further, the compound of formula (I) or a salt thereof can be included in or used in combination with blood for blood transfusion or blood products. The blood for blood transfusion or blood products are produced by mixing blood obtained from multiple persons and, in some cases, uninfected cells are contaminated with cells infected with HIV virus. In such a case, uninfected cells are likely to be infected with HIV virus. When the compound represented by the formula (I) of the present invention is compounded to blood for blood transfusion or blood products, infection with the virus and proliferation thereof can be prevented or controlled. Especially, when blood products are stored, infection and proliferation of the virus is effectively prevented or controlled by addition of the compound of formula (I) of the present invention. In addition, when blood for blood transfusion or blood products contaminated with HIV virus are administered, infection and proliferation of HIV in the person's body can be prevented by adding the compound of formula (I) to the blood or blood products. For example, when the compound is administered orally to an adult (body weight: 50 kg) for preventing. HIV infection upon blood transfusion or using blood products, the single dosage is usually in a range of about 0.02 to 50 mg/kg, preferably about 0.05 to 30 mg/kg, and more preferably about 0.1 to 10 mg/kg of CCR antagonist, and the dosage may be administered once to thrice a day. As a matter of course, although the dosage range can be controlled on the basis of unit dosages necessary for dividing the daily dosage, as described above, a dosage can be determined depending on the property and degree of the diseases, the patient's age, body weight, general health condition, sex, meal, administration time, administration route and excretion rate, and by taking into consideration of these and other factors. In this case, the administration route is also appropriately selected and, the agent for preventing HIV infection of the present invention may be added directly to blood or blood products for transfusion before transfusion or using blood products. In such a case, desirably, the agent is mixed immediately to 24 hours before, preferably immediately to 12 hours before, more preferably immediately to 6 hours before transfusion or using blood products.
›BRIEF DESCRIPTION OF THE DRAWINGS · 19 of 19
When the agent for preventing HIV infection of the present invention is administered separately from the blood for transfusion or blood products on blood transfusion or in use of blood products, the agent is administered preferably at the same time of, or 1 hour before transfusion or using the blood products. More preferably, the agent is administered once to 3 times per day and administration is continued for 4 weeks.
Furthermore, when the compound of formula (I) or a salt thereof is used in combination with a reverse transcriptase inhibitor and/or a protease inhibitor, the dosage of the reverse transcriptase or the protease is properly selected from a range of about 1/200 to 1/2 or more, to about 2 to 3 times or less of the usual dosage.
The usual dosages of the representative reverse transcriptase inhibitor and protease inhibitor are as follows:
A typical embodiment of combined use of the compound of the formula (I) or a salt thereof, and a reverse transcriptase inhibitor and/or a protease inhibitor are as follows.
(1) About 10 to 300 mg of the compound of formula (I) or the salt thereof and about 50 to 200 mg of zidovudine, per an adult (body weight, 50 kg), are administered in combination to the same subject. Each medicine may be administered simultaneously or separately in a time interval of less than 12 hours.
(2) About 10 to 300 mg of the compound of formula (I) or the salt thereof and about 300 to 1200 mg of saquinavir, per adult (body weight, 50 kg), are administered in combination to the same subject. Each medicine may be administered simultaneously or separately in a time interval of less than 12 hours.
›EXAMPLES
The present invention is hereinafter illustrated in more detailed by Examples, Reference Examples, and Experiment. Examples, but the present invention is not intended to be limited to these Examples.
›Examples218
›Example 1
(Preparation of Compound 1)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) was dissolved in ethanol (30 ml), and to the solution, sodium borohydride (0.08 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 1) (0.26 g) as yellow crystals.
mp 198-201° C. (dec.).
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.1 Hz), 1.34 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.28 (3H, s), 2.97 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.61 (1H, br), 6.03 to 6.04 (1H, m), 6.69 to 6.73 (3H, m), 6.95 to 7.17 (3H, m), 7.26 to 7.34 (2H, m), 7.43 to 7.48 (5H, m), 7.63 to 7.67 (3H, m), 8.14 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2926, 2843, 1651, 1601 cm −1 .
Anal calcd for C 36 H 39 N 3 O 5 .0.25H 2 O: C, 72.28; H, 6.66; N, 7.02. Found: C, 71.99; H, 6.57; N, 6.91.
›Example 2
(Preparation of Compound 2)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) and isobutylaldehyde (0.15 ml) were dissolved in 1,2-dichloroethane (80 ml), and to the solution, triacetoxy sodium borohydride (0.27 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (1 ml) and triacetoxy sodium borohydride (1.3 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was washed with sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 2) (0.2 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 0.99 (9H, m), 1.22 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.08 (1H, br), 2.28 (3H, s), 2.93 (2H, t-like), 3.19 (2H, d, J=7.4 Hz), 3.37 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.05 (1H, s), 6.65 (H, br), 6.72 to 6.73 (1H, m), 6.90 to 7.06 (5H, m), 7.38 to 7.68 (10H, m), 8.16 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2957, 2934, 2870, 1653, 1607, 1514, 1499 cm −1 .
Anal calcd for C 40 H 47 N 3 O 5 .0.5H 2 O: C, 72.92; H, 7.34; N, 6.38. Found: C, 72.81; H, 7.43; N, 6.38.
›Example 3
(Preparation of Compound 3)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.4 g) was dissolved in ethanol (300 ml), and to the solution, sodium borohydride (0.11 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 3) (0.35 g) as yellow crystals.
mp 116 to 118° C.
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.1 Hz), 1.26 to 1.57 (4H, m), 2.96 (2H, t-like), 3.48 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.73 to 3.90 (5H, m), 4.16 (2H, t, J=5.0 Hz), 4.61 (1H, br), 6.33 (1H, d, J=4.8 Hz), 6.67 to 6.73 (2H, m), 6.87 to 7.00 (4H, m), 7.21 to 7.48 (7H, m), 7.63 to 7.75 (3H, m), 8.22 to 8.26 (1H, m).
IR (KBr) ν: 2934, 2872, 1651, 1609, 1499 cm −1 .
Anal calcd for C 36 H 39 N 3 O 6 .0.75H 2 O: C, 69.38; H, 6.55; N, 6.74. Found :C, 69.55; H, 6.66; N, 6.38.
›Example 4
(Preparation of Compound 4)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (15 ml), and to the solution, triacetoxy sodium borohydride (0.31 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was poured into water, neutralized with solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 4) (0.3 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.90 to 1.00 (9H, m), 1.26 to 1.65 (4H, m), 2.00 to 2.15 (1H, m), 2.93 (2H, t-like), 3.20 (2H, d, J=7.2 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.5 Hz), 3.74 to 3.83 (5H, m), 4.16 (2H, t, J=4.8 Hz), 6.33 (1H, d, J=4.8 Hz), 6.69 (1H, d, J=4.8 Hz), 6.88 to 7.00 (5H, m), 7.21 to 7.26 (1H, m), 7.40 to 7.52 (6H, m), 7.63 to 7.68 (2H, m), 7.77 (1H, s), 8.22 to 8.24 (1H, m).
IR (KBr) ν: 2959, 1653, 1605, 1499 cm −1 .
Anal calcd for C 40 H 47 N 3 O 6 .0.25H 2 O: C, 71.67; H, 7.14; N, 6.27. Found: C, 71.51; H, 7.24; N, 6.17.
›Example 5
(Preparation of Compound 5)
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.24 g) was dissolved in ethanol (30 ml), and to the solution, sodium borohydride (0.065 g) was added under ice-cooling and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 5) (0.3 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.3 Hz), 1.29 to 1.48 (2H, m), 1.54 to 1.72 (2H, m), 2.92 (2H, br), 3.43 (2H, br), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.12 (2H, t, J=4.8 Hz), 4.60 (1H, br), 6.39 (1H, s), 6.69 (1H, d, J=8.4 Hz), 6.85 to 6.98 (3H, m), 7.23 to 7.55 (9H, m), 7.60 to 8.00 (3H, m), 8.26 (1H, br).
IR (KBr) ν: 2934, 2872, 1692 cm −1 .
›Example 6
(Preparation of Compound 6)
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (30 ml), and to the solution, triacetoxy sodium borohydride (0.31 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (0.22 ml) and triacetoxy sodium borohydride (0.31 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give crude crystals, which were recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 6) (0.2 g) as yellow crystals.
mp 105 to 107° C.
1 H-NMR (δ, CDCl 3 ) 0.85 to 0.99 (9H, m), 1.22 to 1.68 (4H, m), 2.00 to 2.11 (1H, m), 2.92 (2H, t, J=4.6 Hz), 3.19 (2H, d, J=7.6 Hz), 3.37 (2H, t, J=4.6 Hz), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.39 (1H, d, J=3.7 Hz), 6.68 (1H, d, J=3.7 Hz), 6.82 to 7.00 (4H, m), 7.20 to 7.30 (1H, m), 7.38 to 7.51 (6H, m), 7.72 (1H, s), 7.78 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=2.2 Hz), 8.26 to 8.30 (1H, m).
IR (KBr) ν: 2957, 2934, 2870, 1651, 1659, 1607, 1588, 1499 cm −1 .
Anal calcd for C 39 H 44 ClN 3 O 5 .0.25H 2 O: C, 69.42; H, 6.65; N, 6.23. Found: C, 69.45; H, 6.52; N, 6.23.
›Example 7
(Preparation of Compound 7)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.13 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 7) (0.64 g) as yellow crystals.
mp 179 to 182° C. (dec.).
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.3 Hz), 1.22 to 1.64 (4H, m), 2.21 (3H, s), 2.96 (2H, t, J=4.4 Hz), 3.46 (2H, t, J=4.4 Hz), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.63 (1H, br), 6.27 (2H, s), 6.68 to 6.76 (2H, m), 6.97 (2H, d, J=8.8 Hz), 7.16 to 7.33 (3H, m), 7.43 to 7.47 (4H, m), 7.56 to 7.60 (2H, m), 7.70 (1H, s), 8.30 (1H, dd, J=1.0, 5.8 Hz).
IR (KBr) ν: 2955, 2928, 2872, 1645, 1609, 1501 cm −1 .
Anal calcd for C 36 H 39 N 3 O 5 0.5H 2 O: C, 71.74; H, 6.69; N, 6.97. Found: C, 71.75; H, 6.65; N, 6.81.
›Example 8
(Preparation of Compound 8)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) and isobutylaldehyde (0.46 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (0.64 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. To the mixture, isobutylaldehyde (0.46 ml) and triacetoxy sodium borohydride (0.64 g) were further added, and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 8) (0.6 g) as pale yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 0.99 (9H, m), 1.26 to 1.68 (4H, m), 2.04 to 2.14 (1H, m), 2.21 (3H, s), 2.93 (2H, t-like), 3.19 (2H, d, J=7.0 Hz), 3.36 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 6.27 (2H, br), 6.73 (1H, dd, J=2.4, 7.8 Hz), 6.90 to 6.99 (3H, m), 7.16 to 7.30 (2H, m), 7.37 to 7.60 (7H, m), 7.72 (1H, s), 8.30 (1H, d, J=4.8 Hz).
IR (KBr) ν: 2957, 2932, 2870, 1645, 1607, 1520, 1499 cm −1 .
Anal calcd for C 40 H 47 N 3 O 5 .0.5H 2 O: C, 72.92; H, 7.34; N, 6.38. Found: C, 72.74; H, 7.47; N, 6.18.
›Example 9
(Preparation of Compound 9)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.77 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.12 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 9) (0.56 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.3 Hz), 1.22 to 1.57 (4H, m), 2.27 (3H, s), 2.96 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.89 (5H, m), 4.16 (2H, t, J=4.8 Hz), 4.61 (1H, br), 6.32 (1H, s), 6.68 to 6.76 (2H, m), 6.85 to 7.02 (5H, m), 7.30 to 7.47 (5H, m), 7.62 (1H, d, J=8.6 Hz), 7.73 (1H, s), 7.80 (1H, br), 8.12 (1H, d, J=6.2 Hz).
IR (KBr) ν: 2936, 2868, 1647, 1607, 1507 cm −1 .
Anal calcd for C 37 H 41 N 3 O 6 .1.5H 2 O: C, 68.29; H, 6.81; N, 6.46. Found: C, 68.46; H, 6.52; N, 6.39.
›Example 10
(Preparation of Compound 10)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and isobutylaldehyde (0.23 ml) were dissolved in 1,2-dichloroethane (30 ml), and to the solution, triacetoxy sodium borohydride (0.85 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 10) (0.38 g) as yellow crystals.
mp 174 to 176° C.
1 H-NMR (δ, CDCl 3 ) 0.89 to 1.00 (9H, m), 1.23 to 1.65 (4H, m), 2.00 to 2.20 (1H, m), 2.27 (3H, s), 2.93 (2H, t-like), 3.20 (2H, d, J=6.8 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.5 Hz), 3.75 to 3.83 (5H, m), 4.16 (2H, t, J=5.0 Hz), 6.32 (1H, d, J=4.4 Hz), 6.74 (1H, s), 6.88 to 7.03 (6H, m), 7.39 to 7.52 (5H, m), 7.62 to 7.70 (2H, m), 7.77 (1H, d, J=1.8 Hz), 8.12 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2957, 2911, 1605, 1499 cm −1 .
Anal calcd for C 41 H 49 N 3 O 6 .0.5H 2 O: C, 71.49; H, 7.32; N, 6.10. Found: C, 71.46; H, 7.18; N, 6.12.
›Example 11
(Preparation of Compound 11)
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.85 g) was dissolved in ethanol (200 ml), and to the solution, sodium borohydride (0.13 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 11) (0.66 g) as yellow crystals.
mp 110 to 115° C.
1 H-NMR (δ, CDCl 3 ) 0.85 to 0.97 (6H, m), 1.23 to 1.65 (4H, m), 2.28 (3H, s), 2.96 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.02 to 4.18 (4H, m), 4.61 (1H, br), 6.27 to 6.28 (1H, m), 6.70 (1H, d, J=8.0 Hz), 6.85 to 7.03 (6H, m), 7.30 to 7.35 (2H, m), 7.43 to 7.47 (3H, m), 7.64 to 7.72 (3H, m), 8.10 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2936, 2870, 1651, 1609, 1499 cm −1 .
Anal calcd for C 38 H 43 N 3 O 6 .0.5H 2 O: C, 70.57; H, 6.86; N, 6.50. Found: C, 70.27; H, 7.00; N, 6.48.
›Example 12
(Preparation of Compound 12)
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.6 g) and isobutylaldehyde (0.27 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (1 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 12) (0.53 g) as yellow crystals.
mp 108 to 110° C.
1 H-NMR (δ, CDCl 3 ) 0.85 to 0.99 (12H, m), 1.23 to 1.65 (4H, m), 2.00 to 2.15 (1H, m), 2.28 (3H, s), 2.92 (2H, t-like), 3.19 (2H, d, J=7.4 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.5 Hz), 3.80 (2H, t, J=5.0 Hz), 4.02 to 4.18 (4H, m), 6.29 (1H, d, J=5.6 Hz), 6.84 to 7.06 (7H, m), 7.38 to 7.53 (5H, m), 7.65 to 7.69 (2H, m), 7.75 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2959, 2870, 1651, 1605, 1499 cm −1 . Anal calcd for C 42 H 51 N 3 O 6 H 2 O: C, 70.86; H, 7.50; N, 5.90. Found: C, 71.25; H, 7.57; N, 6.00.
›Example 13
(Preparation of Compound 13)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) and propionyl aldehyde (0.3 ml) were dissolved in 1,2-dichloroethane (50 ml), and to the solution, triacetoxy sodium borohydride (0.87 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 13) (0.46 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.88 to 1.01 (6H, m), 1.28 to 1.78 (6H, m), 2.89 (2H, t-like), 3.24 to 3.31 (4H, m), 3.54 (2H, t, J=6.6 Hz), 3.79 (2H, t, J=4.9 Hz), 4.13 (2H, t, j=4.9 Hz), 6.43 (1H, s), 6.60 to 6.65 (2H, m), 6.84 to 6.96 (3H, m), 7.12 to 7.27 (2H, m), 7.36 to 7.44 (5H, m), 7.76 to 7.92 (2H, m), 8.05 to 8.06 (1H, m), 8.21 to 8.24 (H, m), 8.50 (1H, s).
IR (KBr) ν: 2957, 2872, 1653, 1607 cm −1 .
Anal calcd for C 39 H 42 F 3 N 3 O 5 .0.5H 2 O: C, 67.03; H, 6.20; N, 6.01. Found: C, 67.40; H, 6.36; N, 6.02.
›Example 14
(Preparation of Compound 14 and Compound 15)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.4 g) was optically resoluted with CHIRALPAK AD 50 mm ID×500 mL and the elution solvent (hexane/ethanol). The fractions were concentrated and dried, and the residue was dissolved in ethanol, and then, was filtered by 0.45 μm filter. The filtrate was concentrated, hexane was added and dried to a solid, to give (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 14) (160 mg, >99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 15) (160 mg, >99.9% ee).
(+) isomer: [α] D =+18.1° (c=0.497%, ethanol solution)
(−) isomer: [α] D =−18.5° (c=0.500%, ethanol solution)
›Example 15
(Preparation of Compound 16 Preparation)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1 g) was dissolved in ethanol (100 ml), and to the solution, sodium borohydride (0.15 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 16) (0.63 g) as yellow crystals.
mp 124 to 128° C.
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.1 Hz), 1.27 to 1.68 (4H, m), 2.23 (3H, s), 2.98 (2H, t-like), 3.49 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.65 (1H, br), 6.38 to 6.43 (2H, m), 6.71 (1H, d, J=8.6 Hz), 6.95 to 7.07 (4H, m), 7.31 to 7.54 (5H, m), 7.82 to 7.95 (3H, m), 8.04 (1H, s), 8.17 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2934, 2847, 1653, 1609, 1499 cm −1 .
Anal calcd. for C 37 H 38 F 3 N 3 O 5 .H 2 O: C, 65.38; H, 5.93; N, 6.18. Found: C, 65.16; H, 5.81; N, 6.17.
›Example 16
(Preparation of Compound 17)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and propionyl aldehyde (0.16 ml) were dissolved in 1,2-dichloroethane (25 ml), and to the solution, triacetoxy sodium borohydride (0.48 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-
1 H-1-benzazepine-4-carboxamide (compound 17) (0.28 g) as yellow crystals.
mp 103 to 105° C.
1 H-NMR (δ, CDCl 3 ) 0.88 to 1.04 (6H, m), 1.22 to 1.82 (6H, m), 2.23 (3H, s), 2.94 (2H, t-like), 3.30 to 3.37 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.37 (1H, d, J=2.2 Hz), 6.43 (1H, s), 6.89 to 7.06 (5H, m), 7.40 to 7.52 (5H, m), 7.85 to 7.96 (3H, m), 8.05 (1H, s), 8.17 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2961, 2932, 2911, 1659, 1607, 1501 cm −1 .
Anal calcd for C 40 H 44 F 3 N 3 O 5 : C, 68.26; H, 6.30; N, 5.97. Found: C, 67.88; H, 6.27; N, 6.11.
›Example 17
(Preparation of Compound 18 and Compound 19)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.11 g) was optically resoluted with CHIRALPAK AD 50 mm ID×500 mL and the elution solvent (hexane/ethanol). The fractions were concentrated and dried, and the residue was dissolved in ethanol, and then, was filtered by 0.45 μm filter. The filtrate was concentrated, hexane was added and dried to a solid, to give (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-
1 H-1-benzazepine-4-carboxamide (compound 18) (54 mg, >99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 19) (53 mg, >99.9% ee).
(+) isomer: [α] D =+36.0° (c=0.491%, ethanol solution).
(−) isomer: [α] D =−30.5° (c=0.118%, ethanol solution).
›Example 18
(Preparation of Compound 20)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (25 ml), and to the solution, triacetoxy sodium borohydride (0.48 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 20) (0.3 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 1.00 (9H, m), 1.22 to 1.68 (4H, m), 2.05 to 2.12 (1H, m), 2.23 (3H, s), 2.95 (2H, t-like), 3.20 (2H, d, J=7.2 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.37 (1H, d, J=2.2 Hz), 6.44 (1H, s), 6.91 to 7.06 (5H, m), 7.40 to 7.51 (5H, m), 7.90 to 7.93 (3H, m), 8.06 (1H, s), 8.17 (1H, d, J=6.6 Hz).
IR (KBr) ν: 2957, 2870, 1651, 1607, 1520, 1499 cm −1 .
Anal calcd for C 41 H 46 F 3 N 3 O 5 .0.5H 2 O: C, 67.75; H, 6.52; N, 5.78. Found: C, 67.93; H, 6.74; N, 5.67.
›Example 19
(Preparation of Compound 21)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.7 g) was dissolved in ethanol (150 ml), and to the solution, sodium borohydride (0.24 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The solvent was distilled off, and to the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 21) (1 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.93 (3H, t, J=7.3 Hz), 1.22 to 1.68 (4H, m), 2.94 (2H, t-like), 3.47 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 4.33 to 4.44 (2H, m), 4.63 (1H, br), 6.24 (H, d, J=6.6 Hz), 6.70 (1H, d, J=8.4 Hz), 6.89 (1H, dd, J=1.8, 8.4 Hz), 6.95 to 7.01 (3H, m), 7.14 to 7.34 (5H, m), 7.42 to 7.47 (3H, m), 7.75 to 7.79 (2H, m), 7.72 (H, d, J=1.8 Hz), 8.17-8.20 (1H, m).
IR (KBr) ν: 3326, 2934, 1651, 1609, 1501 cm −1 .
Anal calcd for C 37 H 38 F 3 N 3 O 6 .0.5H 2 O: C, 64.71; H, 5.72; N, 6.12. Found: C, 64.70; H, 5.79; N, 5.84.
›Example 20
(Preparation of Compound 22)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g) and propionyl aldehyde (0.27 ml) were dissolved in 1,2-dichloroethane (25 ml), and to the solution, triacetoxy sodium borohydride (0.78 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 22) (0.49 g) as pale yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 1.03 (6H, m), 1.22 to 1.81 (6H, m), 2.91 (2H, t-like), 3.29 to 3.36 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.33 to 4.45 (2H, m), 6.24 (1H, d, J=7.0 Hz), 6.85 to 7.03 (5H, m), 7.14 to 7.32 (3H, m), 7.40 to 7.50 (5H, m), 7.70 (1H, s), 7.78 (1H, d, J=8.4 Hz), 7.88 (1H, s), 8.18 to 8.20 (1H, m).
IR (KBr) ν: 2961, 2934, 2872, 1651, 1605, 1499 cm −1 .
Anal calcd for C 40 H 44 F 3 N 3 O 6 .0.5H 2 O: C, 65.92; H, 6.22; N, 5.77. Found: C, 66.16; H, 6.00; N, 5.78.
›Example 21
(Preparation of Compound 23)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) and isobutylaldehyde (0.32 ml) were dissolved in 1,2-dichloroethane (15 ml), and to the solution, triacetoxy sodium borohydride (0.7 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was neutralized with solution of sodium bicarbonate, concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 23) (0.44 g) as yellow crystals.
mp 118 to 123° C.
1 H-NMR (δ, CDCl 3 ) 0.86 to 0.99 (9H, m), 1.26 to 1.68 (4H, m), 1.95 to 2.15 (1H, m), 2.91 (2H, t-like), 3.20 (2H, d, J=6.8 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.34 to 4.46 (2H, m), 6.25 (1H, d, J=7.0 Hz), 6.87 to 7.04 (5H, m), 7.19 to 7.30 (3H, m), 7.40 to 7.51 (5H, m), 7.70 (1H, s), 7.79 (1H, d, J=8.0 Hz), 7.89 (1H, d, J=2.2 Hz), 8.20 (1H, d, J=6.0 Hz).
IR (KBr) ν: 2955, 2870, 1651, 1605, 1499 cm −1 .
Anal calcd for C 41 H 46 F 3 N 3 O 6 : C, 67.11; H, 6.32; N, 5.73. Found: C, 66.75; H, 6.35; N, 5.46.
›Example 22
(Preparation of Compound 24)
To 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.62 g), 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.24 g) and potassium carbonate (0.5 g), N,N-dimethylformamide (15 ml) was added and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 24) (0.48 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 1.06 (6H, m), 1.25 to 1.80 (6H, m), 2.90 (2H, t-like), 3.25 to 3.38 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 (3H, s), 3.80 (2H, t, J=4.8 Hz), 4.15 (2H, t, J=4.8 Hz), 5.29 (2H, s), 6.87 to 7.03 (5H, m), 7.40 to 7.58 (8H, m), 8.11 (1H, s).
IR (KBr) ν: 2957, 2930, 2872, 1501 cm −1 .
Anal calcd for C 36 H 43 N 5 O 4 .0.25H 2 O: C, 70.39; H, 7.14; N, 11.40. Found: C, 70.35; H, 7.46; N, 11.46.
›Example 23
(Preparation of Compound 25)
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 2-chloromethyl-1-propylimidazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (15 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(1-propylimidazole-2-yl) methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 25) (0.51 g) as pale yellow crystals.
mp 118 to 120° C.
1 H-NMR (δ, CDCl 3 ) 0.89 to 0.98 (12H, m), 1.30 to 1.69 (4H, m), 1.77 to 1.88 (2H, m), 2.04 to 2.10 (1H, m), 2.91 (2H, t-like), 3.18 (2H, d, J=7.2 Hz), 3.36 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.97 (2H, t, J=7.3 Hz), 4.16 (2H, t, J=5.0 Hz), 5.14 (2H, s), 6.89 to 7.04 (7H, m), 7.37 to 7.51 (8H, m).
IR (KBr) ν: 2957, 2934, 2870, 1647, 1605, 1499, 1510 cm −1
Anal calcd for C 40 H 50 N 4 O 4 .0.25H 2 O: C, 73.31; H, 7.77; N, 8.55. Found: C, 73.07; H, 7.67; N, 8.44.
›Example 24
(Preparation of Compound 26)
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (10 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 26) (0.47 g) as pale yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.89 to 1.01 (12H, m), 1.23 to 1.56 (4H, m), 1.80 to 1.91 (2H, m), 2.00 to 2.18 (1H, m), 2.91 (2H, t-like), 3.18 (2H, d, J=7.2 Hz), 3.36 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.03 (2H, t, J=7.3 Hz), 4.16 (2H, t, J=5.0 Hz), 5.28 (2H, s), 6.89 to 7.03 (5H, m), 7.38 to 7.59 (8H, m), 8.15 (1H, s).
IR (KBr) ν: 2957, 2868, 1647, 1605, 1507 cm −1 .
Anal calcd for C 39 H 49 N 5 O 4 .0.25H 2 O: C, 71.37; H, 7.60; N, 10.67. Found: C, 71.12; H, 7.58; N, 10.88.
›Example 25
(Preparation of Compound 27)
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g), 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.15 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (5 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 27) (0.31 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.85 to 1.00 (15H, m), 1.26 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.00 to 2.16 (2H, m), 2.91 (2H, t-like), 3.17 (2H, d, J=7.2 Hz), 3.34 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.86 (4H, m), 4.13 to 4.17 (2H, m), 5.25 (2H, s), 6.88 to 7.01 (5H, m), 7.36 to 7.56 (7H, m), 7.85 (1H, br), 8.09 (1H, s).
IR (KBr) ν: 2950, 2880, 1650, 1600, 1507 cm −1 .
›Example 26
(Preparation of Compound 28)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (15 ml), and to the solution, thionyl chloride (0.25 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (25 ml), and the solution was added dropwise to a solution of S-(4-aminophenyl) O-benzyl thiocarbonate (0.6 g) and triethylamine (1 ml) in tetrahydrofuran (15 ml) under ice-cooling. The mixture was stirred overnight under nitrogen atmosphere at room temperature. To the mixture, methanol (15 ml) and 1N sodium hydroxide solution (15 ml) were added, and the mixture was stirred for 30 minutes. To the mixture, 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.53 g) was added, and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 28) (0.6 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.88 to 1.01 (15H, m), 1.17 to 1.68 (4H, m), 1.70 to 2.15 (2H, m), 2.91 (2H, t-like), 3.18 (2H, d, J=7.0 Hz), 3.34 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.69 (2H, d, J=7.2 Hz), 3.80 (2H, t, J=5.0 Hz), 4.07 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.90 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.28 to 7.46 (7H, m), 7.60 (2H, d, J=8.8 Hz), 7.94 (1H, s), 8.37 (H, br).
IR (KBr) ν: 2959, 2932, 2870, 1651, 1607, 1588, 1497 cm −1
Anal calcd for C 40 H 51 N 5 O 3 S.0.75H 2 O: C, 69.08; H, 7.01; N, 10.07. Found: C, 68.84; H, 7.80; N, 10.39.
›Example 27
(Preparation of Compound 29)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) was dissolved in dichloromethane (20 ml). The solution was cooled to −78° C., and a solution of 3-chloroperbenzoic acid (0.45 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 29) (0.3 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.83 to 1.09 (15H, m), 1.22 to 1.48 (2H, m), 1.54 to 1.65 (2H, m), 1.80 to 1.95 (1H, m), 1.95 to 2.15 (1H, m), 2.95 (2H, t-like), 3.20 (2H, d, J=6.6 Hz), 3.63 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.74 (2H, d, J=7.0 Hz), 3.80 (2H, t, J=5.0 Hz), 4.03 to 4.22 (4H, m), 6.90 to 6.99 (3H, m), 7.15 to 7.45 (7H, m), 7.84 (2H, d, J=8.8 Hz), 8.02 (1H, s), 8.51 (1H, br).
IR (KBr) ν: 2959, 2932, 2872, 1661, 1588, 1518, 1499 cm −1 .
›Example 28
(Preparation of Compound 30 and Compound 31)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) was optically resoluted with CHIRALPAK AD 50 mm ID×500 mL and the elution solvent (hexane/ethanol). The fractions were concentrated and dried, and the residue was dissolved in ethanol, and then, was filtered by 0.45 μm filter. The filtrate was concentrated, hexane was added and dried to a solid, to give (+)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 30) (0.13 g, >99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 31) (0.12 g, >99.9% ee) was obtained.
(+) isomer: [α] D =+119.2° (c=0.492%, ethanol solution).
(−) isomer: [α] D =−114.1° (c=0.499%, ethanol solution)
›Example 29
(Preparation of Compound 32)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.97 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.25 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (10 ml), and the solution was added dropwise to a solution of S-(4-aminophenyl) O-benzyl thiocarbonate (0.6 g) and triethylamine (1 ml) in tetrahydrofuran (10 ml) under ice-cooling. The mixture was stirred for 2.5 hours under nitrogen atmosphere at room temperature, methanol (15 ml) and 1N sodium hydroxide solution (15 ml) were added, and stirred for 30 minutes 3-chloromethyl-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.53 g) was added to the reaction mixture, and stirred for 2 hours at room temperature. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 32) (1.2 g) as pale yellow crystals.
mp 130 to 132° C.
1 H-NMR (δ, CDCl 3 ) 0.85 to 1.03 (12H, m), 1.34 to 1.49 (2H, m), 1.54 to 1.80 (4H, m), 1.93 to 2.07 (1H, m), 2.91 (2H, t-like), 3.28 to 3.34 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.68 (2H, d, J=7.4 Hz), 3.80 (2H, t, J=5.0 Hz), 4.06 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.87 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.8 Hz), 7.26 to 7.46 (7H, m), 7.60 (2H, d, J=8.8 Hz), 7.94 (1H, s), 8.41 (H, br).
IR (KBr) ν: 2961, 2932, 2872, 1655, 1605, 1588, 1499 cm −1 .
Anal calcd for C 39 H 49 N 5 O 3 S: C, 70.13; H, 7.39; N, 10.49. Found: C, 69.89; H, 7.52; N, 10.46.
›Example 30
(Preparation of Compound 33)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml). The solution was cooled to −78° C., and a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (extraction solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-((4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 33) (0.57 g) as yellow crystals.
mp 186 to 190° C. (dec.).
1 H-NMR (δ, CDCl 3 ) 0.82 (6H, d, J=6.6 Hz), 0.93 (3H, t, J=7.1 Hz), 1.02 (3H, t, J=7.3 Hz), 1.30 to 1.48 (2H, m), 1.54 to 1.89 (5H, m), 2.96 (2H, br), 3.31 to 3.34 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.70 (2H, d, J=7.4 Hz), 3.80 (2H, t, J=4.7 Hz), 3.95 to 4.17 (4H, m), 6.89 (H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.27 to 7.43 (7H, m), 7.86 (2H, d, J=8.8 Hz), 8.01 (1H, s), 8.68 (1H, br).
IR (KBr) ν: 2961, 2930, 2872, 1661, 1607, 1590, 1520, 1499 cm −1 .
Anal calcd for C 39 H 49 N 5 O 4 S: C, 68.49; H, 7.22; N, 10.24. Found: C, 68.17; H, 7.02; N, 10.17.
›Example 31
(Preparation of Compound 34 and Compound 35)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.27 g) was optically resoluted with CHIRAL PAK AD 50 mm ID×500 mL and the elution solvent (hexane/isopropanol). The fractions were concentrated and dried, and the residue was dissolved in ethanol, and then, was filtered by 0.45 μm filter. The filtrate was concentrated, hexane was added and dried to a solid, to give (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol111-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 34) (0.12 g, >99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-isobutyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 35) (0.12 g, 99.6% ee).
(+) isomer: [α]D=. +131.9° (c=0.457%, ethanol solution)
(−) isomer: [α] D =−137.6° (c=0.493%, ethanol solution)
›Example 32
(Preparation of Compound 36)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.25 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (10 ml) and the solution was added dropwise to a solution of 4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylthio]aniline (0.59 g) and triethylamine (1 ml) in tetrahydrofuran (5 ml) under ice-cooling. The mixture was stirred overnight under nitrogen atmosphere at room temperature, the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 36) (0.46 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.90 to 0.98 (9H, m), 1.29 to 1.49-(2H, m), 1.54 to 1.69 (2H, m), 2.04 to 2.10 (1H, m), 2.47 (3H, s), 2.60 (3H, s), 2.90 (2H, t-like), 3.17 (2H, d, J=7.2 Hz), 3.34 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.14 (2H, t, J=5.0 Hz), 4.33 (2H, s), 6.87 to 6.99 (3H, m), 7.35 to 7.54 (9H, m), 7.85 (1H, br).
IR (KBr) ν: 2959, 2867, 1653, 1607, 1586, 1499 cm −1 .
›Example 33
(Preparation of Compound 37)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (100 ml). The solution was cooled to −78° C., and to the solution, a solution of 3-chloroperbenzoic acid (0.14 g) in dichloromethane (3 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and to the mixture was added sodium thiosulfate solution, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5,6-dimethyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 37) (0.20 g) as yellow crystals.
mp 178 to 183° C. (dec.).
1 H-NMR (δ, CDCl 3 ) 0.88 to 1.09 (9H, m), 1.22 to 1.69 (4H, m), 2.00 to 2.15 (1H, m), 2.51 (3H, s), 2.67 (3H, s), 2.93 (2H, t-like), 3.20 (2H, d, J=7.2 Hz), 3.38 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.36 (1H, d, J=12.6 Hz), 4.53 (1H, d, J=12.6 Hz), 6.91 to 7.00 (3H, m), 7.37 to 7.49 (5H, m), 7.61 (2H, d, J=8.4 Hz), 7.74 to 7.82 (3H, m).
IR (KBr) ν: 2955, 2928, 2868, 1653, 1607, 1588, 1518, 1499 cm −1 .
Anal calcd for C 39 H 49 N 5 O 4 S.0.25H 2 O: C, 68.49; H, 7.22; N, 10.24. Found: C, 68.17; H, 7.02; N, 10.17.
›Example 34
(Preparation of Compound 38)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.9 g) was dissolved in tetrahydrofuran (15 ml), and to the solution, thionyl chloride (0.23 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise under ice-cooling to a solution of 4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]aniline (0.47 g) and triethylamine (0.86 ml) in tetrahydrofuran (10 ml). The mixture was stirred overnight under nitrogen atmosphere at room temperature, the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 38) (1.1 g) as yellow amorphous.
1 H-NMR (δ, CDCl 3 ) 0.89 to 0.98 (9H, m), 1.34 to 1.45 (2H, m), 1.54 to 1.72 (2H, m), 1.94 to 2.05 (1H, m), 2.51 (3H, s), 2.89 (2H, t-like), 3.17 (2H, d, J=7.4 Hz), 3.33 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.14 (2H, t, J=4.9 Hz), 4.36 (2H, s), 6.90 (1H, d, J=9.6 Hz), 6.97 (2H, d, J=8.8 Hz), 7.34 to 7.55 (9H, m), 7.92 (1H, br), 8.93 (1H, s).
IR (KBr) ν: 2953, 2867, 1659 cm −1 .
›Example 35
(Preparation of Compound 39)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was suspended in dichloromethane (100 ml). The suspension was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.38 g) in dichloromethane (7 ml) was added dropwise to the suspension. The mixture was stirred for 1.5 hours at −78° C. To the mixure was added sodium thiosulfate solution, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 39) (0.50 g) as yellow crystals.
1 H-NMR (δ, CDCl 3 ) 0.89 to 1.05 (9H, m), 1.27 to 1.49 (2H, m), 1.54 to 1.68 (2H, m), 1.98 to 2.15 (1H, m), 2.56 (3H, s), 2.92 (2H, t-like), 3.20 (2H, d, J=7.2 Hz), 3.37 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.40 (1H, d, J=12.6 Hz), 4.58 (1H, d, J=12.6 Hz), 6.90 to 7.00 (3H, m), 7.39 to 7.49 (5H, m), 7.59 (2H, d, J=8.6 Hz), 7.76 (2H, d, J=8.6 Hz), 7.81 (1H, s), 9.03 (1H, s).
IR (KBr) ν: 2957, 2899, 1663, 1588, 1518, 1499 cm −1 .
›Example 36
(Preparation of Compound 40)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (3 g) was dissolved in tetrahydrofuran (15 ml), and to the solution under ice-cooling, thionyl chloride (0.8 ml) and N,N-dimethylformamide (catalytic amout) were added at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off to give the acid chloride. Benzyl chloroformate (0.9 ml) was added dropwise to a solution of 4-mercapto-3-methylaniline (0.9 g) and triethylamine (4.5 ml) in tetrahydrofuran (50 ml) at −78° C., and the mixture was stirred for 1.5 hours. Then, a solution of the foremetioned acid chloride in tetrahydrofuran (15 ml) was added dropwise to the solution under ice-cooling, and the mixture was stirred for 1 hour at room temperature. To the mixture, 1N aqueous sodium hydroxide solution (40 ml) and methanol (40 ml) were added and the mixture was stirred for 30 minutes at room temperature. 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (1.3 g) was added to the mixture and the mixture was stirred overnight at room temperature. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by basic silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 40) (1.9 g) as yellow crystals.
mp 104 to 107° C.
1 H-NMR (dppm, CDCl 3 ) 0.90 to 0.99 (12H, m), 1.27 to 1.45 (2H, m), 1.49 to 1.65 (2H, m), 1.72 to 1.85 (2H, m), 2.00 to 2.18 (1H, m), 2.33 (3H, s), 2.91 (2H, t-like), 3.18 (2H, d, J=7.4 Hz), 3.35 (2H, t-like), 3.56 (2H, t, J=6.6 Hz), 3.78 to 3.91 (4H, m), 4.05 (2H, s), 4.16 (2H, t, J=4.9 Hz), 6.91 (1H, d, J=9.2 Hz), 6.97 (2H, d, J=8.4 Hz), 7.29 to 7.47 (7H, m), 7.57 (1H, s), 8.01 (1H, s), 8.07(1H, br).
IR (KBr) n: 2959, 2870, 1659, 1607, 1580, 1518, 1499 cm −1
Anal calcd for C 40 H 51 N 5 O 3 S.0.25H 2 O: C, 69.99; H, 7.56; N, 10.20. Found: C, 69.98; H, 7.55; N, 10.00.
›Example 37
(Preparation of Compound 41)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was suspended in dichloromethane (100 ml) and the suspension was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.35 g) in dichloromethane (5 ml) was added dropwise to the suspension. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 41) (0.54 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 1.02 (12H, m), 1.22 to 1.75 (6H, m), 2.05 to 2.18 (1H, m), 2.29 (3H, s), 2.85 to 2.98 (2H, m), 3.18 to 3.28 (2H, m), 3.30 to 3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.89 to 3.95 (2H, m), 4.08 to 4.17 (2H, tm), 6.89 to 6.98 (3H, m), 7.31 to 7.65 (7H, m), 7.72 (1H, d, J=8.4 Hz), 8.04 (1H, s), 8.46 (1H, br).
IR (KBr) n: 2959, 2932, 2870, 1661, 1405, 1520, 1499 cm −1 .
›Example 38
(Preparation of Compound 42)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.14 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.05 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (10 ml), and the solution was added dropwise under ice-cooling to a solution of 4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]-3-trifluoromethylaniline (0.1 g) and 4-dimethylaminopyridine (catalytic amout) in pyridine (5 ml). The mixture was stirred for 1.5 hours at room temperature, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-trifluoromethyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 42) (0.23 g) as yellow crystals.
mp 131 to 133° C.
1 H-NMR (dppm, CDCl 3 ) 0.84 to 1.01 (12H, m), 1.27 to 1.69 (6H, m), 2.00 to 2.15 (1H, m), 2.96 (2H, t-like), 3.20 (2H, d, J=7.0 Hz), 3.34 (2H, t-like), 3.56 (2H, t, J=6.6 Hz), 3.70 (2H, t, J=7.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.86 (2H, s), 4.15 (2H, t, J=5.0 Hz), 6.87 to 6.97 (3H, m), 7.11 (1H, s), 7.24 (1H, s), 7.36 to 7.43 (4H, m), 7.84 (1H, dd, J=2.2, 8.8 Hz), 7.90 (1H, s), 8.18 (1H, d, J=2.2 Hz), 9.46 (1H, br).
IR (KBr) n: 2963, 2934, 2870, 1661, 1607, 1518, 1499 cm −1 .
Anal calcd for C 40 H 48 F 3 N 5 O 3 S.0.25H 2 O: C, 64.89; H, 6.66; N, 9.46. Found: C, 64.70; H, 6.49; N, 9.65.
›Example 39
(Preparation of Compound 43)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-trifluoromethyl-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.38 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.14 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 2 hours at −78° C., and sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-trifluoromethyl-4-[(4-propyl-4H-1,2,4-triazo-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 43) (0.35 g) as yellow crystals.
mp 169 to 172° C.
1 H-NMR (dppm, CDCl 3 ) 0.82 (3H, t, J=7.3 Hz), 0.94 (3H, t, J=7.2 Hz), 1.05 (6H, d, J=6.6 Hz), 1.31 to 1.72 (6H, m), 2.06 to 2.15 (1H, m), 2.85 to 3.52 (6H, m), 3.56 (2H, t, J=6.6 Hz), 3.60 to 3.78 (2H, m), 3.80 (2H, t, J=4.8 Hz), 3.88 (2H, s), 4.14 (2H, t, J=4.8 Hz), 6.84 to 6.94 (4H, m), 7.08 (1H, s), 7.30 to 7.41 (4H, m), 7.92 (1H, s), 8.13 (1H, s), 8.28 to 8.32 (1H, m), 10.14 (1H, br).
IR (KBr) n: 2961, 2934, 2870, 1663, 1599, 1539, 1520, 1501 cm −1 .
Anal calcd for C 40 H 48 F 3 N 5 O 4 S: C, 63.90; H, 6.43; N, 9.31. Found: C, 63.63; H, 6.31; N, 9.55.
›Example 40
(Preparation of Compound 44)
7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.14 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, to obtain acid chloride. Benzyl chloroformate (0.18 ml) was added dropwise at −78° C. to a solution of 4-mercapto-3-chloroaniline (0.2 g) and triethylamine (0.87 ml) in tetrahydrofuran (10 ml), and the mixture was stirred for 1 hour. Then, a solution of the above acid chloride in tetrahydrofuran (10 ml) was added dropwise to the solution under ice-cooling, and the mixture was stirred overnight at room temperature. 1N aqueous sodium hydroxide solution (8.5 ml) and methanol (10 ml) were added to the mixture and the mixture was stirred for 30 minutes at room temperature. 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.25 g) was added to the mixture and the mixture was stirred overnight at room temperature. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-chloro-4-[(4-propyl-4H-1,2,4-triazol-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 44) (0.37 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.82 to 1.00 (12H, m), 1.17 to 1.66 (6H, m), 2.04 to 2.15 (1H, m), 2.94 (2H, t-like), 3.18 (2H, d, J=7.6 Hz), 3.32 (2H, t-like), 3.56 (2H, t, J=6.5 Hz), 3.67 (2H, t, J=7.7 Hz), 3.79 to 3.83 (4H, m), 4.14 (2H, t, J=5.0 Hz), 6.85 to 7.03 (4H, m), 7.17 (1H, s), 7.31 to 7.40 (4H, m), 7.53 (1H, dd, J=2.2, 8.4 Hz), 7.84 (H, s), 8.06 (1H, d, J=2.2 Hz), 9.70 (1H, br).
IR (KBr) n: 2957, 2934, 2868, 1653, 1607, 1580, 1499 cm −1 .
›Example 41
(Preparation of Compound 45)
One droplet of DMF was added to a solution of 7-[4-(2-propoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.5 g) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.35 ml) was added under nitrogen atmosphere and the mixture was stirred for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the obtained residue was dissolved in THF (15 ml). This solution was added dropwise to a solution of S-(4-aminophenyl) O-benzyl carbonothioate (950 mg) and triethylamine (2.6 ml) in THF (15 ml) at 0° C. under argon atmosphere. After finishing the dropping, the mixture was allowed to be at room temperature, and stirred overnight under argon atmosphere, and then, methanol (30 ml) was added to the mixture. Further, 1N aqueous solution of sodium hydroxide (18.3 ml) was added to the mixture, and the mixture was stirred for 30 minutes under argon atmosphere. Then, 5-chloromethyl-1-propylimidazole hydrochloride (928 mg) was added to the mixture, and the mixture was stirred for 1.5 hours under argon atmosphere. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate), which was recrystallized from ethyl acetate, to give 7-[4-(2-propoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.63 g)(Compound 45) as yellow crystals.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.91 to 1.01 (9H, m), 1.53 to 1.93 (6H, m), 2.85 to-2.95 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.28 to 3.36 (4H, m), 3.51 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.4 Hz), 3.93 (2H, t, J=7.4 Hz), 3.99 (2H, s), 4.16 (2H, t, J=4.4 Hz), 6.70 (1H, s), 6.90 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.25 to 7.30 (2H, m), 7.36 to 7.55 (8H, m), 7.63 (1H, s).
Elemental Analysis for C 38 H 46 N 4 O 3 S.0.25H 2 Calcd. C, 70.94; H, 7.28; N, 8.71. Found: C, 70.93; H, 7.22; N, 8.69.
›Example 42
(Preparation of Compound 46, 47)
To a solution of 7-[4-(2-propoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.0 g) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (579 mg) in dichloromethane (15 ml) was added dropwise at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-propoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (693 mg)(Compound 46) and 7-[4-(2-propoxyethoxy)phenyl]-1-propyl-N-[4-[[[1-propylimidazol-5-yl]methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (48 mg)(Compound 47) as yellow amorphous.
Compound 46
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 1.03 (9H, m), 1.56 to 1.81 (6H, m), 2.90 to 2.95 (2H, m), 3.30 to 3.40 (4H, m), 3.51 (2H, t, J=6.6 Hz), 3.74 to 3.84 (4H, m), 4.02 (1H, d, J=13.2 Hz), 4.07 to 4.19 (3H, m), 6.57 (1H, s), 6.91 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.37 to 7.51 (8H, m), 7.74 (2H, d, J=8.8, Hz), 7.87 (1H, s) Elemental Analysis for C 38 H 46 N 4 O 4 S.0.25H 2 O Calcd. C, 69.22; H, 7.11; N, 8.50. Found: C, 69.03; H, 6.97; N, 8.47.
Compound 47
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 1.03 (9H, m), 1.59 to 1.81 (6H, m), 2.85 to 2.95 (2H, m), 3.25 to 3.40 (4H, m), 3.51 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.4 Hz), 3.95 (2H, t, J=7.6 Hz), 4.16 (2H, t, J=4.4 Hz), 4.32 (2H, s), 6.53 (1H, s), 6.90 (H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.40 to 7.50 (6H, m), 7.60 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 8.02 (1H, s).
Elemental Analysis for C 38 H 46 N 4 O 5 S Calcd. C, 68.03; H, 6.91; N, 8.35. Found: C, 67.73; H, 6.85; N, 8.13.
›Example 43
(Preparation of Compound 48)
One droplet of DMF was added to a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (600 mg) in tetrahydrofuran (15 ml). Then, thionyl chloride (0.13 ml) was added to the mixture under nitrogen atmosphere and the mixture was stirred for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the obtained residue was dissolved in THF (15 ml). This solution was added dropwise to a solution of 4-[(1-methylimidazol-2-yl) thio]aniline (365 mg) and triethylamine (1.3 ml) in THF (15 ml) at 0° C. under nitrogen atmosphere. After finishing the dropping, the mixture was allowed to be at room temperature, and stirred overnight under nitrogen atmosphere, and water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was isolated and purified by basic silica gel column chromatography (hexane-ethyl acetate=1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (716 mg) (Compound 48) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 0.98 (9H, m), 1.30 to 1.50 (2H, m), 1.55 to 1.75 (2H, m), 1.95 to 2.15 (1H, m), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.63 (3H, s), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.05 (1H, d, J=1.4 Hz), 7.16 to 7.21 (3H, m), 7.37 to 7.53 (7H, m), 7.64 (1H, s).
Elemental Analysis for C 37 H 44 N 4 O 3 S Calcd. C, 71.12; H, 7.10; N, 8.97. Found: C, 70.81; H, 7.07; N, 8.89.
›Example 44
(Preparation of Compound 49)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.26 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (10 ml), and the mixture was added dropwise under ice-cooling to a solution of 4-[2-(4-propyl-4H-1,2,4-triazol-3-yl) ethylthio]aniline (0.6 g) in pyridine (10 ml). The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elutionsolvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 49) (1.49 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 0.98 (12H, m), 1.33 to 1.45 (2H, m), 1.54 to 1.77 (4H, m), 1.98 to 2.58 (1H, m), 2.91 to 2.98 (4H, m), 3.17 (2H, d, J=7.2 Hz), 3.32 to 3.40 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.71 (2H, t, J=7.3 Hz), 3.80 (2H, t, J=4.7 Hz), 4.15 (2H, t, J=4.7 Hz), 6.88 to 6.99 (3H, m), 7.34 to 7.47 (7H, m), 7.61 (2H, d, J=8.8 Hz), 8.00 (1H, s), 8.04 (1H, s).
IR (KBr) n: 2959, 2930, 2870, 1659, 1588, 1499 cm −1 .
›Example 45
(Preparation of Compound 50)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.1 g) was dissolved in dichloromethane (40 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.6 g) in dichloromethane (10 ml) was added dropwise to the mixture. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 50) (0.94 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.86 to 0.99 (12H, m), 1.30 to 1.45 (2H, m), 1.58 to 1.77 (4H, m), 1.95 to 2.15 (1H, m), 2.87 to 3.05 (3H, m), 3.10 to 3.35 (4H, m), 3.37 (2H, t-like), 3.45 to 3.65 (3H, m), 3.78 to 3.83 (4H, m), 4.14 to 4.18 (2H, m), 6.90 to 7.00 (3H, m), 7.39 to 7.48 (5H, m), 7.61 (2H, d, J=8.6 Hz), 7.83 (2H, d, J=8.6 Hz), 8.02 (1H, s), 8.15 (1H, br).
IR (KBr) n: 2961, 2932, 2872, 1661, 1590, 1518, 1499 cm −1 .
›Example 46
(Preparation of Compound 51)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.7 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.18 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off and the residue was dissolved in tetrahydrofuran (20 ml). To the solution, a solution of 4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]aniline (0.43 g) in pyridine (10 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 51) (0.9 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.88 to 1.03 (9H, m), 1.30 to 1.45 (2H, m), 1.54 to 1.81 (6H, m), 2.91 to 3.02 (4H, m), 3.28 to 3.43 (6H, m), 3.55 (2H, t, J=6.6 Hz), 3.72 to 3.83 (4H, m), 4.16 (2H, t, J=4.9 Hz), 6.90 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.36 to 7.48 (7H, m), 7.57 (2H, d, J=8.8 Hz), 7.67 (1H, br), 8.03 (1H, s).
IR (KBr) n: 2963, 2934, 2876, 1655, 1499 cm −1 .
›Example 47
(Preparation of Compound 52)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the mixture, a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 52) (0.43 g) as pale yellow crystals.
mp 93 to 101° C.
1 H-NMR (dppm, CDCl 3 ) 0.91 to 1.02 (9H, m), 1.36 to 1.43 (2H, m), 1.56 to 1.66 (2H, m), 1.72 to 1.80 (4H, m), 2.91 to 2.99 (3H, m), 3.19 to 3.37 (6H, m), 3.53 to 3.57 (3H, m), 3.79 to 3.86 (4H, m), 4.16 (2H, t, J=5.9 Hz), 6.90 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.7 Hz), 7.40 to 7.49 (5H, m), 7.62 (2H, d, J=9.0 Hz), 7.81 (2H, d, J=8.7 Hz), 7.93 (1H, br), 8.04 (1H, s).
IR (KBr) n: 2963, 2932, 2870, 1661, 1590, 1520, 1499 cm −1 .
Anal calcd for C 39 H 49 N 5 O 4 S.0.25H 2 O: C, 68.04; H, 7.25; N, 10.17. Found: C, 67.82; H, 7.24; N, 10.13.
›Example 48
(Preparation of Compound 53)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.79 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.2 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise under ice-cooling to a solution of 5-amino-2-(4-propyl-4H-1,2,4-triazol-3-yl) methylthiopyridine (0.45 g) in pyridine (10 ml). The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elutionsolvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 53) (1.1 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.84 to 1.22 (12H, m), 1.54 to 1.85 (4H, m), 2.03 to 2.14 (1H, m), 2.92 (2H, t-like), 3.18 (2H, d, J=7.4 Hz), 3.34 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.90 (4H, m), 4.13 to 4.17 (2H, m), 4.54 (2H, s), 6.88 to 6.99 (3H, m), 7.18 (1H, d, J=8.8 Hz), 7.36 to 7.46 (5H, m), 7.93 (H, dd, J=2.6, 8.4 Hz), 7.98 (1H, s), 8.58 (1H, br), 8.75 (1H, s).
IR (KBr) n: 2959, 2932, 2870, 1659, 1499 cm −1 .
›Example 49
(Preparation of Compound 54)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the solution, a solution of 3-chloroperbenzoic acid (0.31 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 2 hours at −78° C. and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 54) (0.70 g) as yellow crystals.
mp 135 to 138° C.
1 H-NMR (dppm, CDCl 3 ) 0.77 (3H, t, J=7.6 Hz), 0.93 (3H, t, J=7.1 Hz), 1.06 (6H, d, J=6.2 Hz), 1.34 to 1.68 (6H, m), 2.05 to 2.25 (1H, m), 2.85 to 3.40 (5H, m), 3.45 to 3.75 (3H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, j=5.0 Hz), 3.82 to 4.07 (2H, m), 4.14 (2H, t, J=5.0 Hz), 6.85 to 6.94 (4H, m), 7.24 to 7.40 (5H, m), 7.92 (1H, s), 8.00 (H, d, J=8.4 Hz), 9.61 (1H, s), 10.17 (1H, br).
IR (KBr) n: 2959, 2934, 2870, 1667, 1607, 1574, 1518, 1499 cm −1 .
Anal calcd for C 38 H 48 N 6 O 4 S: C, 66.64; H, 7.06; N, 12.27. Found: C, 66.33; H, 6.88; N, 12.21.
›Example 50
(Preparation of Compound 55, Compound 56)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.39 g) was optically resoluted with CHIRAL PAK AD (ethanol/isopropylalcohol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 55) (0.18 g, 99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 56) (0.18 g, 99.8% ee).
(+)-isomer: [α] D =+235.0° (C=0.500%, ethanol solution)
(−)-isomer: [α] D =−238.9° (C=0.493%, ethanol solution)
›Example 51
(Preparation of Compound 57)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.76 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.2 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise under ice-cooling to a solution of 5-amino-2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridine (0.45 g) in pyridine (10 ml). The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 57) (1.1 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.86 to 1.02 (9H, m), 1.30 to 1.45 (2H, m), 1.54 to 1.80 (6H, m), 2.91 (2H, t-like), 3.28 to 3.35 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.91 (4H, m), 4.15 (2H, t, J=4.8 Hz), 4.56 (2H, s), 6.18 (1H, d, J=9.2 Hz), 6.97 (2H, d, J=8.8 Hz), 7.19 (1H, d, J=8.4 Hz), 7.38 to 7.46 (5H, m), 7.92 (1H, dd, J=2.6, 8.8 Hz), 8.00 (1H, br), 8.72 (1H, d, J=2.4 Hz).
IR (KBr) n: 2961, 2934, 2872, 1659, 1501 cm −1 .
›Example 52
(Preparation of Compound 58)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-
4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.60 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the solution, a solution of 3-chloroperbenzoic acid (0.27 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 1.5 hours at −78° C. and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 58) (0.50 g) as yellow crystals.
1 H-NMR (dppm, CDCl 3 ) 0.78 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 1.06 (3H, t, J=7.4 Hz), 1.30 to 1.88 (10H, m), 2.90 to 3.71 (8H, m), 3.55 (2H, t, J=6.6 Hz), 3.79 (2H, t, J=5.0 Hz), 3.90 (1H, d, J=14.2 Hz), 4.03 (1H, d, J=14.2 Hz), 4.13 (2H, t, J=5.0 Hz), 6.86 to 6.94 (4H, m), 7.25 to 7.46 (5H, m), 7.93 (1H, s), 7.99 (1H, dd, J=2.0, 8.8 Hz), 9.60 (1H, d, J=2.0 Hz), (1H, s), 10.06 (1H, s).
IR (KBr) n: 2959, 2932, 2872, 1669, 1607, 1518, 1499 cm −1 .
Anal calcd for C 37 H 46 N 6 O 4 S: C, 66.24; H, 6.91; N, 12.53. Found: C, 66.06; H, 6.96; N, 12.29.
›Example 53
(Preparation of Compound 59, Compound 60)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.39 g) was optically resoluted with CHIRALPAK AD (ethanol/isopropylalcohol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 59) (0.16 g, >99.9% ee), (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 60) (0.16 g, 99.4% ee).
(+)-isomer: [α] D =+245.5° (C=0.473%, ethanol solution)
(−)-isomer: [α] D =−254.6° (C=0.491%, ethanol solution)
›Example 54
(Preparation of Compound 61)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.13 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (10 ml). The solution was added dropwise under ice-cooling to a solution of 4-[2-(1-propylimidazol-2-yl)ethyl]aniline (0.27 g) and triethylamine (0.82 ml) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate) and basic silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(1-propylimidazol-2-yl)ethyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 61) (0.36 g) as pale yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 1.03 (9H, m), 1.30 to 1.45 (2H, m), 1.54 to 1.81 (6H, m), 2.87 to 2.95 (4H, m), 3.05 to 3.13 (2H, m), 3.28 to 3.32 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.67 (2H, t, J=7.1 Hz), 3.80 (2H, t, J=5.0 Hz), 4.14 (2H, t, J=5.0 Hz), 6.80 (1H, s), 6.90 (1H, d, J=8.8 Hz), 6.95 to 7.01 (3H, m), 7.16 (2H, d, J=8.4 Hz), 7.38 to 7.54 (8H, m).
IR (KBr) n: 2961, 2938, 2870, 1655, 1605, 1516 cm −1 .
›Example 55
(Preparation of Compound 62)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.52 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.13 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (15 ml). The solution was added dropwise under ice-cooling to a solution of 4-[N-methyl-N-[(1-propylimidazol-2-yl)methyl]amino]aniline (0.3 g) and triethylamine (0.86 ml) in tetrahydrofuran (10 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[N-methyl-N-[(1-propylimidazol-2-yl)methyl]amino]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 62) (0.51 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.83 to 1.02 (9H, m), 1.34 to 1.45 (2H, m), 1.54 to 1.80 (6H, m), 2.81 (3H, s), 2.85 to 2.95 (2H, m), 3.27 to 3.35 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.87 (4H, m), 4.13 to 4.15 (2H, m), 4.46 (2H, s), 6.86 to 6.99 (7H, m), 7.37 to 7.55 (8H, m).
IR (KBr) n: 2959, 2872, 1651, 1607, 1520, 1499 cm −1 .
›Example 56
(Preparation of Compound 63)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.13 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (25 ml). The solution was added dropwise under ice-cooling to a solution of 4-[3-(4H-1,2,4-triazol-4-yl) propyl]aniline (0.23 g) and 4-dimethylaminopyridine (catalytic amout) in pyridine (10 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[3-(4H-1,2,4-triazol-4-yl)propyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 63) (0.51 g) as yellow crystals.
mp 165 to 167° C.
1 H-NMR (dppm, CDCl 3 ) 0.89 to 0.99 (9H, m), 1.26 to 1.65 (4H, m), 2.05 to 2.19 (3H, m), 2.64 (2H, t, J=7.1 Hz), 2.92 (2H, t-like), 3.19 (2H, d, J=7.2 Hz), 3.37 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.1 Hz), 3.99 (2H, t, J=7.2 Hz), 4.16 (2H, t, J=5.1 Hz), 6.90 to 7.00 (3H, m), 7.13 (2H, d, J=8.4 Hz), 7.39 to 7.61 (7H, m), 8.14 (2H, s).
IR (KBr) n: 2953, 1651, 1607, 1516, 1499 cm −1 .
Anal calcd for C 38 H 47 N 5 O 3 : C, 73.40; H, 7.62; N, 11.26. Found: C, 73.10; H, 7.47; N, 11.28.
›Example 57
(Preparation of Compound 64)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) was dissolved in tetrahydrofuran (7.5 ml), and to the solution under ice-cooling, thionyl chloride (0.15 ml) and N,N-dimethylformamide. (catalytic amout) were added, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off and the residue was dissolved in tetrahydrofuran (20 ml). The solution was added dropwise under ice-cooling to a solution of 4-[3-(4H-1,2,4-triazol-4-yl)propyl]aniline (0.24 g) and 4-dimethylaminopyridine (catalytic amout) in pyridine (5 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[3-(4H-1,2,4-triazol-4-yl)propyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 64) (0.53 g) as pale yellow crystals.
mp 191 to 194° C.
1 H-NMR (dppm, CDCl 3 ) 0.90 to 1.03 (6H, m), 1.30 to 1.48 (2H, m), 1.54 to 1.81 (4H, m), 2.09 to 2.23 (2H, m), 2.64 (2H, t, j=7.4 Hz), 2.92 (2H, t-like), 3.29 to 3.35 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.00 (2H, t, j=7.2 Hz), 4.16 (2H, t, J=5.0 Hz), 6.90 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.38 to 7.57 (8H, m), 8.14 (2H, s).
IR (KBr) n: 2959, 1653, 1605, 1516, 1501 cm −1 .
Anal calcd for C 37 H 45 N 5 O 3 : C, 73.12; H, 7.46; N, 11.52. Found: C, 72.76; H, 7.53; N, 11.33.
›Example 58
(Preparation of Compound 65)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.61 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.15 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 3 hours. The solvent was distilled off, the residue was dissolved in tetrahydrofuran (25 ml). The solution was added dropwise under ice-cooling to a solution of 4-[(4-propyl-1H-1,2,4-triazole-5-on-3-yl)methylthio]aniline (0.35 g) in pyridine (10 ml). The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 65) (0.69 g) as pale yellow crystals.
mp 98 to 101° C.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 0.99 (12H, m), 1.22 to 1.48 (2H, m), 1.54 to 1.82 (4H, m), 1.95 to 2.15 (1H, m), 2.88 (2H, t-like), 3.16 (2H, d, J=7.2 Hz), 3.32 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.67 to 3.85 (6H, m), 4.15 (2H, t, J=5.0 Hz), 6.87 to 6.98 (3H, m), 7.31 to 7.46 (7H, m), 7.57 (2H, d, J=8.8 Hz), 7.83 (1H, s), 9.31 (1H, s).
IR (KBr) n: 2959, 2934, 2868, 1703, 1499 cm −1 .
Anal calcd for C 39 H 49 N 5 O 4 S: C, 68.49; H, 7.22; N, 10.24. Found: C, 68.21; H, 7.17; N, 10.10.
›Example 59
(Preparation of Compound 66)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.50 g) was dissolved in dichloromethane (30 ml), and the mixture was cooled to −78° C. To the solution, 3-chloroperbenzoic acid (0.22 g) in dichloromethane solution (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-propyl-1H-1,2,4-triazol-5-on-3-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 66) (0.45 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 1.04 (12H, m), 1.22 to 1.70 (6H, m), 2.00 to 2.15 (1H, m), 2.90 (2H, t-like), 3.18 (2H, d, J=7.2 Hz), 3.35 (2H, t-like), 3.52 to 3.61 (4H, m), 3.80 (2H, t-like), 3.97 (2H, s), 4.15 (2H, t, J=4.9 Hz), 6.89 to 6.99 (3H, m), 7.36 to 7.52 (7H, m), 7.29 (2H, d, J=8.8 Hz), 8.03 (1H, s), 9.53 (1H, s).
IR (KBr) n: 2959, 2936, 2874, 1705 cm −1 .
Anal calcd for C 39 H 49 N 5 O 5 S.0.25H 2 O: C, 66.50; H, 7.08; N, 9.94. Found: C, 66.18; H, 6.93; N, 9.93.
›Example 60
(Preparation of Compound 67)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-
1 H-1-benzazepine-4-carboxylic acid (0.95 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.23 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (10 ml). The solution was added dropwise under ice-cooling to a solution of 3-amino-6-[(4-propyl-1H-1,2,4-triazol-3-yl)methylthio]pyridazine (0.52 g) in pyridine (20 ml). The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(4-propyl-1H-1,2,4-triazol-3-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 67) (0.22 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.86 to 0.99 (12H, m), 1.34 to 1.46 (2H, m), 1.57 to 1.66 (2H, m), 1.79 to 1.89 (2H, m), 2.05 to 2.11 (1H, m), 2.93 (2H, t-like), 3.21 (2H, d, J=7.2 Hz), 3.39 (2H, t-like), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.04 (2H, t, J=7.2 Hz), 4.17 (2H, t, J=5.0 Hz), 4.78 (2H, s), 6.93 (1H, d, J=8.7 Hz), 6.99 (2H, d, J=9.0 Hz), 7.41 to 7.49 (4H, m), 7.53 (1H, d, J=2.1 Hz), 7.60 (1H, s), 8.12 (1H, s), 8.46 (1H, d, J=9.6 Hz), 8.60 (1H, s).
IR (KBr) n: 2957, 2934, 2872, 1663, 1605, 1499 cm −1 .
›Example 61
(Preparation of Compound 68)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(4-propyl-1H-1,2,4-triazol-3-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.18 g) was dissolved in dichloromethane (20 ml), and the mixture was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.08 g) in dichloromethane (5 ml) was added dropwise to the solution. The mixture was stirred for 2 hours at −78° C. and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(4-propyl-1H-1,2,4-triazol-3-yl) methylsulfinyl]pyridazin-3-yl]-2,3-dihydro-
1 H-1-benzazepine-4-carboxamide (Compound 68) (0.14 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.86 to 1.08 (12H, m), 1.29 to 1.48 (2H, m), 1.54 to 1.67 (2H, m), 1.72 to 1.90 (2H, m), 2.04 to 2.15 (1H, m), 2.94 (2H, br), 3.19 (2H, d, J=7.4 Hz), 3.37 (2H, br), 3.54 (2H, t, J=6.5 Hz), 3.80 (2H, t, J=4.8 Hz), 3.95 to 4.18 (4H, m), 4.44 (1H, d, J=14.2 Hz), 4.66 (H, d, J=14.2 Hz), 6.89 to 7.00 (3H, m), 7.34 to 7.51 (4H, m), 7.67 (2H, d, J=9.6 Hz), 8.14 (1H, s), 8.67 (1H, d, J=9.0 Hz), 9.62 (1H, s).
IR (KBr) n: 2950, 2872, 1671 cm −1 .
›Example 62
(Preparation of Compound 69)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.92 g) was dissolved in tetrahydrofuran (10 ml), and to the solution, thionyl chloride (0.22 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off, and the residue was dissolved in tetrahydrofuran (10 ml). The solution was added dropwise under ice-cooling to a solution of 3-amino-6-[(3-propylimidazol-4-yl)methylthio]pyridazine (0.5 g) in pyridine (15 ml). The mixture was stirred at room temperature overnight and the solvent was distilled off. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with iN citric acid solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 69) (0.3 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.91 to 0.99 (12H, m), 1.34 to 1.46 (2H, m), 1.56 to 1.66 (2H, m), 1.78 to 1.87 (2H, m), 2.05 to 2.11 (1H, m), 2.94 (2H, t, J=4.5 Hz), 3.20 (2H, d, J=7.5 Hz), 3.39 (2H, t, J=4.5 Hz), 3.55 (2H, t, J=6.8 Hz), 3.81 (2H, t, J=5.0 Hz), 3.93 (2H, t, J=7.2 Hz), 4.16 (2H, t, J=5.0 Hz), 4.58 (2H, s), 6.91 to 7.04 (4H, m), 7.31 (1H, d, J=9.5 Hz), 7.41 to 7.53 (5H, m), 7.62 (1H, s), 8.42 (1H, d, J=9.5 Hz), 8.78 (1H, br).
IR (KBr) n: 2959, 2870, 1661, 1499 cm −1 .
›Example 63
(Preparation of Compound 70)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylthio]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 0.3-chloroperbenzoic acid (0.38 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred at −78° C. for 4 hours and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(3-propylimidazol-4-yl)methylsulfinyl]pyridazin-3-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 70) (0.14 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.89 to 1.00 (12H, m), 1.34 to 1.44 (2H, m), 1.54 to 1.81 (4H, m), 2.05 to 2.13 (1H, m), 2.96 (2H, t-like), 3.21 (2H, d, J=7.4 Hz), 3.40 (2H, t-like), 3.55 (2H, t, J=6.5 Hz), 3.80 (2H, t, J=5.0 Hz), 3.88 to 4.01 (2H, m), 4.17 (2H, t, j=5.0 Hz), 4.23 (1H, d, J=7.4 Hz), 4.50 (1H, d, J=7.4 Hz), 6.52 (1H, d, J=0.6 Hz), 6.91 to 7.02 (3H, m), 7.41 to 7.53 (5H, m), 7.63 (1H, s), 7.72 (1H, d, J=9.5 Hz), 8.69 (1H, d, J=9.5 Hz), 9.37 (1H, br).
IR (KBr) n: 2961, 2930, 2870, 1667, 1607, 1559, 1499 cm −1 .
›Example 64
(Preparation of Compound 71)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.6 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.15 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling at room temperature, and the mixture was stirred for 1.5 hours. The solvent was distilled off and the residue was dissolved in tetrahydrofuran (5 ml). The solution was added dropwise under ice-cooling to a solution of S-(4-aminophenyl)-o-benzylthiocarbonate (0.36 g) and triethylamine (1 ml) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 4 hours. 1N aqueous sodium hydroxide solution (7 ml) and methanol (7 ml) were added to the mixture and the mixture was stirred for 1 hour at room temperature. Then, 4-chloromethyl-3-methylimidazole hydrochloride (0.24 g) was added to the mixture and the mixture was stirred overnight at room temperature. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-methylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 71) (0.61 g) as pale yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.89 to 0.99 (9H, m), 1.33 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.00 to 2.10 (1H, m), 2.91 (2H, t-like), 3.19 (2H, d, J=7.2 Hz), 3.35 (2H, t-like), 3.55 (2H, t, J=6.8 Hz), 3.65 (3H, s), 3.80 (2H, t, J=4.8 Hz), 3.99 (2H, s), 4.16 (2H, t, J=4.9 Hz), 6.71 (1H, s), 6.89 to 7.00 (3H, m), 7.25 to 7.29 (2H, m), 7.40 to 7.56 (8H, m), 7.65 (1H, br).
IR (KBr) n: 2955, 2867, 1655, 1605, 1586, 1499 cm −1 .
›Example 65
(Preparation of Compound 72)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-methylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.53 g) was dissolved in dichloromethane (5 ml), and the mixture was cooled to −78° C. 3-chloroperbenzoic acid (0.31 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-methylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 72) (0.36 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.89 to 0.99 (9H, m), 1.30 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.05 to 2.15 (1H, m), 2.93 (2H, t-like), 3.19 (2H, d, J=7.0 Hz), 3.36 (2H, t-like), 3.44 (3H, s), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.95 (1H, d, J=7.2 Hz), 4.14 to 4.17 (3H, m), 6.60 (1H, s), 6.92 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.4 Hz), 7.30 to 7.47 (8H, m), 7.77 (2H, d, J=8.8 Hz), 8.28 (H, br).
IR (KBr) n: 2955, 2930, 2870, 1663, 1605, 1588, 1499 cm −1 .
›Example 66
(Preparation of Compound 73)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1 g) was dissolved in tetrahydrofuran (5 ml), and to the solution, thionyl chloride (0.25 ml) and N,N-dimethylformamide (catalytic amout) were added under ice-cooling, and the mixture was stirred for 1 hour at room temperature. The solvent was distilled off and the residue was dissolved in tetrahydrofuran (10 ml). The solution was added dropwise under ice-cooling to a solution of S-(4-aminophenyl)-o-benzylthiocarbonate (0.6 g) and triethylamine (1 ml) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 4 hours and 1N aqueous sodium hydroxide solution (12.5 ml), methanol (25 ml) and tetrahydrofuran (15 ml) were added to the mixture. The mixture was stirred at room temperature for 4 hours. Then, 4-chloromethyl-3-cyclopropylimidazole hydrochloride (0.57 g) was added to the mixture and the mixture was stirred overnight at room temperature. The mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 73) (0.34 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.90 to 1.06 (13H, m), 1.30 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.05 to 2.10 (1H, m), 2.91 (2H, t-like), 3.19 (2H, d, J=7.6 Hz), 3.21 to 3.34 (1H, m), 3.36 (2H, t-like), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.07 to 4.18 (4H, m), 6.67 (1H, s), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz), 7.38 to 7.57 (8H, m), 7.72 (1H, br).
IR (KBr) n: 2957, 2928, 2870, 1657, 1605, 1588, 1497 cm −1 .
›Example 67
(Preparation of Compound 74)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) was dissolved in dichloromethane (10 ml), and the mixture was cooled to −78° C. 3-chloroperbenzoic acid (0.17 g) in dichloromethane solution (5 ml) was added dropwise to the solution. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-cyclopropylimidazol-4-yl)methylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 74) (0.22 g) as yellow amorphous.
1 H-NMR (dppm, CDCl 3 ) 0.85 to 1.07 (13H, m), 1.33 to 1.46 (2H, m), 1.56 to 1.66 (2H, m), 1.98 to 2.11 (1H, m), 2.93 to 3.00 (3H, m), 3.19 (2H, d, J=6.9 Hz), 3.36 (2H, s), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.09 to 4.26 (4H, m), 6.57 (1H, s), 6.92 (1H, d, J=8.7 Hz), 6.98 (2H, d, J=8.4 Hz), 7.37 to 7.48 (8H, m), 7.77 (2H, d, J=8.1 Hz), 8.06 (1H, br).
IR (KBr) n: 2959, 2930, 2870, 1663, 1607, 1588, 1518, 1499 cm −1 .
›Example 68
(Preparation of Compound 75)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg) and 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g) was added at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, a solution of (S)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.28 ml) in DMF (10 ml) were added dropwise. The mixture was stirred for 4 days at room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 75) (247 mg) as pale yellow crystals.
m.p. 130 to 134° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.30 to 1.48 (2H, m), 1.53 to 1.68 (2H, m), 3.02 (2H, t, J=5.5 Hz), 3.56 (2H, t, J=6.4 Hz), 3.82 (2H, t, J=5.0 Hz), 3.91 (2H, t, J=5.5 Hz), 4.18 (2H, t, J=5.0 Hz), 5.32 (1H, d, J=4.1 Hz), 5.75 (1H, d, J=4.1 Hz), 7.02 (2H, d, J=8.4 Hz), 7.12 to 7.24 (3H, m), 7.36 to 7.67 (11H, m), 8.54 (1H, s), 8.56 to 8.59 (1H, m).
IR (KBr) 3343, 1664, 1601, 1597, 1514, 1497, 1360, 1314, 1248, 1190, 824 cm −1
Elemental Analysis for C 36 H 37 N 3 O 5 Calcd. C, 73.08; H, 6.30; N, 7.10. Found: C, 72.72; H, 6.27; N, 7.04.
›Example 69
(Preparation of Compound 76)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg) and 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g) was added at room temperature, and the mixture was stirred for 0.5 hour. To the reaction solution, a solution of (R)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.28 ml) in DMF (10 ml) was added dropwise. The mixture was stirred for 3 days at room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 76) (154.5 mg) as pale yellow crystals.
m.p. 110 to 112° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.30 to 1.48 (2H, m), 1.53 to 1.68 (2H, m), 3.02 (2H, t, J=5.5 Hz), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=5.0 Hz), 3.91 (2H, t, J=5.5 Hz), 4.18 (2H, t, J=5.0 Hz), 5.32 (1H, d, J=4.4 Hz), 5.75 (1H, d, J=4.4 Hz), 7.02 (2H, d, J=8.4 Hz), 7.12 to 7.24 (3H, m), 7.36 to 7.67 (11H, m), 8.54 (1H, s), 8.56 to 8.59 (1H, m).
IR (KBr) 3357, 1663, 1601, 1597, 1514, 1497, 1360, 1314, 1248, 1190, 822 cm −1
Elemental Analysis for C 36 H 37 N 3 O 5 .0.25H 2 O Calcd. C, 72.52; H, 6.34; N, 7.05. Found: C, 72.45; H, 6.35; N, 7.10.
›Example 70
(Preparation of Compound 77)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy (2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (225.3 mg) in dichloromethane (20 ml), 3-chloroperbenzoic acid (70%, 113 mg) was added at 0° C., and the mixture was stirred at room temperature for 20 hours. To the reaction solution, sodium thiosulfate solution was added, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give, as pale yellow crystals 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 77) (125.5 mg).
m.p. 120 to 125° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.28 to 1.47 (2H, m), 1.53 to 1.68 (2H, m), 3.03 (2H, t, J=5.5 Hz), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=5.0 Hz), 3.93 (2H, t, J=5.5 Hz), 4.18 (2H, t, J=5.0 Hz), 6.07 (1H, d, J=4.8 Hz), 6.43 (1H, d, J=4.8 Hz), 6.91 to 7.01 (1H, m), 7.03 (2H, d, J=8.8 Hz), 7.16 to 7.28 (2H, m), 7.46 to 7.79 (10H, m), 8.25 to 8.29 (1H, m), 8.55 (1H, s).
IR (KBr) 3248, 1665, 1607, 1518, 1499, 1314, 1246, 1186 cm −1
Elemental Analysis for C 36 H 37 N 3 O 6 .1.0H 2 O Calcd. C, 69.10; H, 6.28; N, 6.72. Found: C, 68.78; H, 6.20; N, 6.78.
›Example 71
(Preparation of Compound 78)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (130 mg) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (70%, 65 mg) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the-reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 78) (68.2 mg) as pale yellow crystals.
m.p. 104 to 106° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.28 to 1.47 (2H, m), 1.53 to 1.68 (2H, m), 3.03 (2H, t, J=5.5 Hz), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.91 (2H, t, J=5.5 Hz), 4.17 (2H, t, J=5.0 Hz), 6.06 (1H, d, J=4.2 Hz), 6.39 (1H, d, J=4.2 Hz), 6.91 to 7.01 (1H, m), 7.03 (2H, d, J=8.8 Hz), 7.16 to 7.28 (2H, m), 7.44 to 7.67 (9H, m), 7.75 (1H, s), 8.23-8.27 (1H, m), 8.53 (1H, s).
IR (KBr) 3263, 1667, 1607, 1518, 1497, 1316, 1248, 1188 cm −1
Elemental Analysis for C 36 H 37 N 3 O 6 .1.0H 2 O Calcd. C, 69.10; H, 6.28; N, 6.72. Found: C, 69.31; H, 6.17; N, 6.85.
›Example 72
(Preparation of Compound 79)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (463 mg) and triethylamine (0.51 ml) in acetonitrile (25 ml), trifluoroacetic acid anhydride (0.43 ml) was added at 0° C., and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue and 1-hydroxybenzotriazole (0.33 g) in DMF (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.46 g) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution, a solution of (S)-(4-aminophenyl)-(2-pyridyl)methanol (267 mg) and triethylamine (0.67 ml) in DMF (5 ml) was added dropwise. The mixture was stirred at room temperature for 20 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate), which was recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 79) (316 mg) as pale yellow crystals.
m.p. 100 to 102° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 1.32 to 1.48 (2H, m), 1.51 to 1.66 (2H, m), 2.86 to 3.27 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.74 to 4.89 (1H, m), 5.34 (1H, d, J=3.0 Hz), 5.75 (1H, d, J=3.0 Hz), 7.03 (2H, d, J=8.8 Hz), 7.13 to 7.27 (3H, m), 7.30 to 7.42 (4H, m), 7.51 to 7.69 (7H, m), 8.5 to 8.62 (1H, m).
IR (KBr) 3356, 1694, 1653, 1595, 1520, 1499., 1314, 1208, 1179, 1155, 826 cm −1
Elemental Analysis for C 37 H 36 N 3 O 5 F 3 .0.25H 2 O Calcd. C, 66.91; H, 5.54; N, 6.33. Found: C, 66.93; H, 5.60; N, 6.32.
›Example 73
(Preparation of Compound 80)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (285 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 127 mg) was added at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethanol-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (Compound 80) (220.9 mg) as pale yellow crystals.
m.p. 107 to 110° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.29 to 1.48 (2H, m), 1.51 to 1.67 (2H, m), 2.86 to 3.34 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.76 to 4.91 (1H, m), 6.07 (1H, d, J=3.8 Hz), 6.41 (H, d, J=3.8 Hz), 6.91 to 7.05 (3H, m), 7.20 to 7.38 (4H, m), 7.45 to 7.67 (9H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3044, 1696, 1650, 1607, 1499, 1435, 1316, 1252, 1206, 1181, 1155, 825 cm −1
Elemental Analysis for C 37 H 36 N 3 O 6 F 3 .0.5H 2 O Calcd. C, 64.90; H, 5.45; N, 6.14. Found: C, 64.97; H, 5.37; N, 6.10.
›Example 74
(Preparation of Compound 81)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (300 mg) in THF (10 ml) were added thionyl chloride (0.13 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and a solution of the residue in THF (15 ml) was added dropwise at 0° C. to a solution of (S)-(4-aminophenyl)-(2-pyridyl)methanol (156 mg) and triethylamine (0.59 ml) in THF (5 ml). The mixture was stirred at room temperature for 18 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane 2:1→4:1), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 81) (316 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.99 (3H, t, J=7.3 Hz), 1.29 to 1.47 (2H, m), 1.50 to 1.82 (4H, m), 2.86 to 2.95 (2H, m), 3.25 to 3.39 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 5.27 to 5.37 (1H, m), 5.74 (1H, br s), 6.89 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.12 to 7.26 (2H, m), 7.34 to 7.67 (11H, m), 8.56 to 8.58 (1H, m).
IR (KBr) 3350, 1651, 1607, 1516, 1499, 1314, 1242, 1179 cm −1
Elemental Analysis For C 38 H 43 N 3 O 4 .0.25H 2 O Calcd. C, 74.79; H, 7.1.8; N, 6.89. Found: C, 74.82; H, 7.29; N, 6.93.
›Example 75
(Preparation of Compound 82)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (180 mg) in ethanol (30 ml) was added sodium borohydride (10.0 mg) at room temperature and stirred for 2 hours. To the reaction solution was further added sodium borohydride (10.0 mg), and the mixture was stirred for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 82) (141.4 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.28 to 1.48 (2H, m), 1.51 to 1.68 (2H, m), 2.89 to 3.01 (2H, m), 3.41 to 3.51 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.07 (1H, br s), 6.31-6.45 (1H, m), 6.71 (1H, d, J=8.0 Hz), 6.92-6.99 (3H, m), 7.20 to 7.36 (5H, m), 7.39 to 7.52 (4H, m), 7.62 to 7.66 (3H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3293, 1651, 1609, 1499, 1435, 1408, 1316, 1246, 1181, 820 cm −1
Elemental Analysis for C 35 H 37 N 3 O 5 .1.5H 2 O Calcd. C, 69.27; H, 6.65; N, 6.93. Found: C, 69.05; H, 6.31; N, 6.67.
›Example 76
(Preparation of Compound 83)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (120 mg) and propionaldehyde (0.15 ml) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) at room temperature, and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 83) (105.4 mg) as yellow crystals.
m.p. 87 to 89° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.00 (3H, t, J=7.0 Hz), 1.29 to 1.48 (2H, m), 1.53 to 1.82 (4H, m), 2.86 to 2.96 (2H, m), 3.25 to 3.40 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.06 (1H, br s), 6.35 to 6.45 (1H, m), 6.88 to 7.00 (4H, m), 7.23 to 7.28 (2H, m), 7.38 to 7.51 (7H, m), 7.62 to 7.67 (3H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3296, 1651, 1607, 1516, 1499, 1313, 1242, 1181, 814 cm −1
Elemental Analysis for C 38 H 43 N 3 O 5 .0.5H 2 O Calcd. C, 72.36; H, 7.03; N, 6.66. Found: C, 72.07; H, 7.01; N, 6.51.
›Example 77
(Preparation of Compound 84)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (142.6 mg) and cyclopropane carboxyaldehyde (0.17 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) at room temperature and the mixture was stirred for 64 hours. To the reaction solution were added cyclopropane carboxyaldehyde (0.1 g) and sodium triacetoxyborohydride (0.13 g), and the mixture was further stirred for 4 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethanol:ethyl acetate 1:4), which was recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-cyclopropylmethyl-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 84) (120.7 mg) as yellow crystals.
m.p. 85 to 88° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.24-0.35 (2H, m), 0.60 to 0.70 (2H, m), 0.93 (3H, t, J=7.1 Hz), 1.02 to 1.22 (1H, m), 1.30 to 1.46 (2H, m), 1.53 to 1.66 (2H, m), 2.91 to 3.02 (2H, m), 3.26 (2H, d, J=6.2 Hz), 3.43 to 3.50 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.04 to 6.09 (1H, m), 6.36 to 6.46 (1H, m), 6.91 to 7.00 (4H, m), 7.24 to 7.28 (2H, m), 7.39 to 7.52 (7H, m), 7.63 to 7.67 (3H, m), 8.25 to 8.29 (1H, m).
IR (KBr) 3270, 1653, 1605, 1516, 1499, 1244, 1181, 837 cm −1
Elemental Analysis for C 39 H 43 N 3 O 5 .1.0H 2 O Calcd. C, 71.87; H, 6.96; N, 6.45. Found: C, 72.10; H, 6.93; N, 6.50.
›Example 78
(Preparation of Compound 85)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and isobutylaldehyde (0.15 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.22 g) at room temperature and the mixture was stirred for 4 days. To the reaction solution were added isobutylaldehyde (0.15 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 5 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethanol:ethyl acetate 1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 85) (155.2 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.98 (6H, d, J=6.6 Hz), 1.27 to 1.47 (2H, m), 1.53 to 1.68 (2H, m), 1.98 to 2.18 (1H, m), 2.89 to 2.98 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.32 to 3.42 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.07 (1H, d, J=4.1 Hz), 6.42 (1H, d, J=4.1 Hz), 6.90 to 7.00 (4H, m), 7.23 to 7.28 (2H, m), 7.38 to 7.52 (7H, m), 7.63 to 7.68 (3H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3230, 1653, 1605, 1516, 1499, 1240, 1181, 839 cm-1
Elemental Analysis for C 39 H 45 N 3 O 5 .0.75H 2 O Calcd. C, 72.14; H, 7.22; N, 6.47. Found: C, 72.22; H, 7.29; N, 6.57.
›Example 79
(Preparation of Compound 86)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-formylthiazole (0.24 g) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.22 g) at room temperature and the mixture was stirred for 4 days. To the reaction solution were added 2-formylthiazole (0.24 g), sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethanol:ethyl acetate 1:4→1:3), which was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(thiazol-2-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 86) (113.6 mg) as yellow crystals.
m.p. 164 to 165° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.29 to 1.47 (2H, m), 1.54 to 1.68 (2H, m), 2.90 to 2.99 (2H, m), 3.43 to 3.50 (2H, m), 3.55 (2H, t, J=6.8 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 4.87 (2H, s), 6.06 (H, d, J=4.4 Hz), 6.42 (1H, d, J=4.4 Hz), 6.92 to 7.03 (4H, m), 7.23 to 7.27 (2H, m), 7.32 (1H, d, J=5=3.2 Hz), 7.37 to 7.54 (7H, m), 7.65 (2H, d, J=8.4 Hz), 7.76 (1H, s), 7.79 (1H, d, J=3.2 Hz), 8.23-8.27 (1H, m).
IR (KBr) 3263, 1634, 1595, 1537, 1499, 1435, 1406, 1318, 1244, 1188, 1126, 814 cm −1
Elemental Analysis for C 39 H 40 N 4 O 5 S Calcd. C, 69.21; H, 5.96; N, 8.28. Found: C, 68.93; H, 5.84; N, 8.20.
›Example 80
(Preparation of Compound 87)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 4-formyl-1-methylpyrazole (0.4 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethanol:ethyl acetate 1:3→1:2) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-4-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 87) (96.1 mg) as yellow crystals.
m.p. 94 to 97° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.32 to 1.46 (2H, m), 1.51 to 1.68 (2H, m), 2.80 to 2.89 (2H, m), 3.29 to 3.39 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.90 (3H, s), 4.16 (2H, t, j=5.0 Hz), 4.44 (2H, s), 6.07 (1H, d, J=4.4 Hz), 6.43 (1H, d, J=4.4 Hz), 6.91 to 7.00 (4H, m), 7.24 to 7.28 (2H, m), 7.32 (1H, s), 7.38 to 7.63 (8H, m), 7.62 to 7.67 (3H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3274, 1653, 1605, 1516, 1499, 1433, 1404, 1316, 1240, 1184, 1123, 818 cm −1
Elemental Analysis for C 40 H 43 N 5 O 5 .0.75H 2 O Calcd. C, 69.90; H, 6.53; N, 10.19. Found: C, 69.98; H, 6.77; N, 9.90.
›Example 81
(Preparation of Compound 88)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and thiophene-3-carboxaldehyde (0.5 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 20 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-(3-thienylmethyl)-2,3-dihydro-1-1H-1-benzazepine-4-carboxamide (Compound 88) (171.4 mg) as yellow crystals.
m.p. 110 to 112° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.29 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.90 to 2.90 (2H, m), 3.31 to 3.42 (2H, m), 3.55 (2H, t, J=6.8 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.58 (2H, s), 6.07 (1H, d, J=4.2 Hz), 6.42 (1H, d, J=4.2 Hz), 6.91 to 7.07 (5H, m), 7.12 to 7.18 (1H, m), 7.23 to 7.27 (2H, m), 7.34 to 7.49 (7H, m), 7.54 (1H, d, J=2.2 Hz), 7.63 to 7.68 (3H, m), 8.24 to 8.28 (1H, m).
IR (KBr) 3262, 1636, 1595, 1499, 1435, 1406, 1316, 1242, 1186, 1128, 810 cm −1
Elemental Analysis for C 40 H 41 N 3 O 5 S.0.25H 2 O Calcd. C, 70.62; H, 6.15; N, 6.18. Found: C, 70.61; H, 6.22; N, 6.21.
›Example 82
(Preparation of Compound 89)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-1-methylpyrazole (0.23 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 5 days. To the reaction solution, 5-formyl-1-methylpyrazole (0.23 g) and sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) were added, and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:3) and further recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-(1-methylpyrazol-5-ylmethyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 89) (140.1 mg) as yellow crystals.
m.p. 109 to 111° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.30 to 1.48 (2H, m), 1.52 to 1.68 (2H, m), 2.62-2.70 (2H, m), 3.29 to 3.39 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.78 to 3.83 (5H, m), 4.17 (2H, t, J=5.0 Hz), 4.55 (2H, s), 6.07 (1H, d, J=4.3 Hz), 6.25 (1H, d, J=1.8 Hz), 6.43 (1H, d, J=4.3 Hz), 6.91 to 7.02 (4H, m), 7.24 to 7.28 (2H, m), 7.42 to 7.67 (11H, m), 8.25 to 8.28 (1H, m).
IR (KBr) 3260, 1636, 1597, 1499, 1437, 1406, 1318, 1246, 1188, 1128, 810 cm −1
Elemental Analysis for C 40 H 43 N 5 O 5 .1.0H 2 O Calcd. C, 69.44; H, 6.56; N, 10.12. Found: C, 69.34; H, 6.72; N, 10.07.
›Example 83
(Preparation of Compound 90)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and benzaldehyde (0.22 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution were added benzaldehyde (0.22 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 1-benzyl-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 90) (168.0 mg) as yellow crystals.
m.p. 89 to 93° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.28 to 1.48 (2H, m), 1.51 to 1.67 (2H, m), 2.81 to 2.89 (2H, m), 3.32 to 3.42 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.62 (2H, s), 6.07 (1H, d, J=4.3 Hz), 6.41 (1H, d, J=4.9 Hz), 6.88 to 7.06 (4H, m), 7.24 to 7.67 (17H, m), 8.25 to 8.28 (1H, m).
IR (KBr) 3275, 1653, 1603, 1499, 1454, 1433, 1406, 1314, 1244, 1184, 1123, 812 cm −1
Elemental Analysis for C 42 H 43 N 3 O 5 .1.0H 2 O Calcd. C, 73.34; H, 6.59; N, 6.11. Found: C, 73.70; H, 6.66; N, 5.99.
›Example 84
(Preparation of Compound 91)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 2-furaldehyde (0.2 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 20 hours. To the reaction solution were added 2-furaldehyde (0.2 g) and sodium triacetoxyborohydride (0.22 g), and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-furyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 91) (150.0 mg) as yellow crystals.
m.p. 117 to 119° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.29 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.81 to 2.88 (2H, m), 3.31 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.51 (2H, s), 6.06 (1H, d, J=4.4 Hz), 6.30 (H, d, J=3.6 Hz), 6.37 to 6.42 (2H, m), 6.91 to 7.06 (3H, m), 7.08 (H, d, J=8.4 Hz), 7.23 to 7.27 (2H, m), 7.40 to 7.53 (8H, m), 7.64 (2H, d, J=8.4 Hz), 7.68 (1H, s), 8.23-8.27 (1H, m).
IR (KBr) 3281, 1644, 1597, 1499, 1435, 1408, 1316, 1244, 1186, 1123, 812 cm −1
Elemental Analysis for C 40 H 41 N 3 O 6 .0.25H 2 O Calcd. C, 72.32; H, 6.30; N, 6.33. Found: C, 72.36; H, 6.33; N, 6.10.
›Example 85
(Preparation of Compound 92)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (200 mg) and 5-formyl-3-methyl isothiazole (0.44 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.22 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added sodium triacetoxyborohydride (0.22 g) was added to the mixture, and the mixture was further stirred for 3 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methyl-isothiazol-5-ylmethyl)-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 92) (154.0 mg) as yellow crystals.
m.p. 93 to 96° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.29 to 1.47 (2H, m), 1.52 to 1.68 (2H, m), 2.49 (3H, s), 2.88 to 2.98 (2H, m), 3.35 to 3.45 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 4.79 (2H, s), 6.07 (1H, d, J=4.4 Hz), 6.43 (1H, d, J=4.4 Hz), 6.91 to 7.01 (5H, m), 7.24 to 7.28 (2H, m), 7.39 to 7.49 (6H, m), 7.52 to 7.58 (1H, m), 7.63 to 7.68 (3H, m), 8.25 to 8.29 (1H, m).
IR (KBr) 3314, 1655, 1605, 1514, 1499, 1433, 1406, 1314, 1244, 1182, 1120, 814 cm −1
Elemental Analysis for C 40 H 42 N 4 O 5 S.1.0H 2 O Calcd. C, 67.77; H, 6.26; N, 7.90. Found: C, 67.73; H, 6.12; N, 7.90.
›Example 86
(Preparation of Compound 93)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.50 g) in THF (10 ml) were added thionyl chloride (0.12 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, a solution of the residue in THF (20 ml) was added dropwise at 0° C. to a solution of (S)-(+)-(4-aminophenyl)(2-pyridyl)methanol (0.24 g) and triethylamine (0.6 ml) in THF (5 ml), and the mixture was stirred for 18 hours at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 93) (542.7 mg) as colorless crystals.
m.p. 158 to 160° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.32 to 1.45 (2H, m), 1.52 to 1.67 (2H, m), 2.88 (3H, s), 3.05 to 3.15 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 3.88 to 3.94 (2H, m), 4.17 (2H, t, J=4.9 Hz), 5.29-5.36 (1H, m), 5.72-5.79 (1H, m), 7.01 (2H, d, J=8.8 Hz), 7.12 to 7.26 (2H, m), 7.39 (2H, d, J=8.8 Hz), 7.48 to 7.68 (10H, m), 8.56 to 8.59 (1H, m).
IR (KBr) 3362, 1651, 1597, 1518, 1493, 1341, 1242, 1154, 966, 822 cm −1
Elemental Analysis for C 36 H 39 N 3 O 6 S Calcd. C, 67.37; H, 6.13; N, 6.55. Found: C, 67.21; H, 5.85; N, 6.67.
›Example 87
(Preparation of Compound 94)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C. and the mixture was stirred for 20 hours at room temperature. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 94) (292.1 mg) as colorless crystals.
m.p. 118 to 120° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.29 to 1.46 (2H, m), 1.51 to 1.68 (2H, m), 2.90 (3H, s), 3.08 to 3.19 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 3.86 to 3.96 (2H, m), 4.18 (2H, t, J=4.9 Hz), 6.03 to 6.09 (1H, m), 6.38 to 6.45 (1H, m), 6.94 to 7.00 (1H, m), 7.02 (2H, d, J=8.6 Hz), 7.25 to 7.29 (2H, m), 7.46 to 7.57 (6H, m), 7.63 to 7.72 (5H, m), 8.25 to 8.28 (1H, m).
IR (KBr) 3250, 1657, 1607, 1518, 1493, 1341, 1246, 1154, 1103, 1061, 966, 824 cm −1
Elemental Analysis for C 36 H 39 N 3 O 7 S.0.75H 2 O Calcd. C, 64.41; H, 6.08; N, 6.26. Found: C, 64.39; H, 6.22; N, 6.05.
›Example 88
(Preparation of Compound 95)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid 0.5 g (1.05 mmole) and 1-hydroxybenzotriazole (0.35 g) in DMF (10 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.50 g) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution were added a solution of (4-aminophenyl)(6-methylpyridin-2-yl)methanol (0.29 g) and triethylamine (0.60 ml) in DMF (5 ml) and 4-dimethylaminopyridine (1 flake) and the mixture was stirred for 20 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 95) (378.9 mg) as pale yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.29 to 1.48 (2H, m), 1.52 to 1.70 (2H, m), 2.60 (3H, s), 2.88 to 3.26 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.74 to 4.89 (1H, m), 5.64 to 5.76 (2H, m), 6.89 (1H, d, J=7.6 Hz), 7.00 to 7.07 (3H, m), 7.30 to 7.65 (12H, m).
IR (KBr) 3343, 1692, 1597, 1518, 1497, 1460, 1406, 1314, 1250, 1208, 1179, 1155, 828 cm −1
Elemental Analysis for C 38 H 38 N 3 O 5 F 3 .0.25H 2 O Calcd. C, 67.29; H, 5.72; N, 6.20. Found: C, 67.25; H, 5.58; N, 6.35.
›Example 89
(Preparation of Compound 96)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (340 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.15 g) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 96) (262 mg) as colorless crystals.
m.p. 170 to 173° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.94 (3H, t, J=7.2 Hz), 1.29 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 2.57 (3H, s), 2.93 to 3.27 (3H, m), 3.56 (2H, t, J=6.8 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.76 to 4.91 (1H, m), 6.06 (1H, d, J=4.6 Hz), 6.68 (1H, d, J=4.6 Hz), 6.78 to 6.84 (1H, m), 7.03 (2H, d, J=8.8 Hz), 7.13 to 7.36 (3H, m), 7.46 to 7.66 (10H, m).
IR (KBr) 3296, 1694, 1647, 1597, 1530, 1497, 1316, 1248, 1206, 1179, 1154, 847, 828 cm −1
Elemental Analysis for C 38 H 38 N 3 O 6 F 3 Calcd. C, 66.17; H, 5.55; N, 6.09. Found: C, 65.97; H, 5.48; N, 6.10.
›Example 90
(Preparation of Compound 97)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (230 mg) in ethanol (20 ml) was added sodium borohydride (63 mg) at room temperature and the mixture was stirred for 3 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 97) (120.5 mg) as yellow crystals.
m.p. 175 to 177° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.28 to 1.44 (2H, m), 1.48 to 1.68 (2H, m), 2.56 (3H, s), 2.92 to 3.01 (2H, m), 3.41 to 3.49 (2H, m), 3.55 (2H, t, J=6.8 Hz), 3.80 (2H, t, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.46 to 4.72 (H, m), 6.06 (1H, s), 6.70 (1H, d, J=8.4 Hz), 6.78 to 6.84 (1H, m), 6.97 (2H, d, J=8.8 Hz), 7.11 to 7.18 (1H, m), 7.20 to 7.34 (3H, m), 7.43 to 7.47 (5H, m), 7.61 to 7.65 (3H, m).
IR (KBr) 3283, 1661, 1645, 1599, 1499, 1321, 1248, 1181, 826 cm −1
Elemental Analysis for C 36 H 39 N 3 O 5 .1.0H 2 O Calcd. C, 70.68; H, 6.76; N, 6.87. Found: C, 70.53; H, 6.15; N, 6.93.
›Example 91
(Preparation of Compound 98)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (154 mg) and isobutylaldehyde (0.12 g) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.17 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 24 hours. To the reaction solution were further added isobutylaldehyde (0.12 g) and sodium triacetoxyborohydride (0.17 g), and the mixture was further stirred for 4 days. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(6-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 98) (122.3 mg) as yellow crystals.
m.p. 114 to 116° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (6H, d, J=6.6 Hz), 1.30 to 1.46 (2H, m), 1.50 to 1.71 (2H, m), 1.98 to 2.16 (1H, m), 2.57 (3H, s), 2.88 to 2.97 (2H, m), 3.19 (2H, d, J=6.6 Hz), 3.33 to 3.43 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.07 (1H, s), 6.77 to 6.84 (1H, m), 6.91 to 7.00 (3H, m), 7.15 (1H, t, J=7.7 Hz), 7.37 to 7.51 (8H, m), 7.63 to 7.70 (3H, m).
IR (KBr) 3282, 1641, 1598, 1499, 1315, 1246, 1182, 1065, 838, 815 cm −1
Elemental Analysis for C 40 H 47 N 3 O 5 Calcd. C, 73.93; H, 7.29; N, 6.47. Found: C, 73.83; H, 7.21; N, 6.45.
›Example 92
(Preparation of Compound 99)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) and 1-hydroxybenzotriazole (0.28 g) in DMF (10 ml), was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution were added a solution of (4-aminophenyl)(3-methylpyridin-2-yl)methanol (0.27 g) and triethylamine (0.60 ml) in DMF (5 ml) and 4-dimethylaminopyridine (1 flake), and the mixture was stirred for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:3→1:2→1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 99) (319.2 mg) as colorless amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 1.30 to 1.48 (2H, m), 1.51 to 1.68 (2H, m), 2.09 (3H, s), 2.87 to 3.34 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.75 to 4.88 (1H, m), 5.73 (1H, d, J=5.9 Hz), 6.06 (1H, d, J=5.9 Hz), 7.02 (2H, d, J=8.8 Hz), 7.17 to 7.35 (5H, m), 7.42 to 7.43 (1H, m), 7.47 to 7.54 (6H, m), 7.62 to 7.66 (1H, m), 8.45 to 8.50 (1H, m).
IR (KBr) 3314, 1693, 1607, 1520, 1497, 1414, 1314, 1250, 1206, 1179, 1155, 1042, 828 cm −1
Elemental Analysis for C 38 H 38 N 3 O 5 F 3 0.25H 2 O Calcd. C, 67.29; H, 5.72; N, 6.20. Found: C, 67.13; H, 5.56; N, 6.05.
›Example 93
(Preparation of Compound 100)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(3-methylpyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (291 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 128 mg) at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) and further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 100) (210.9 mg) as pale yellow crystals.
m.p. 109 to 112° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.29 to 1.48 (2H, m), 1.55 to 1.68 (2H, m), 2.46 (3H, s), 2.88 to 3.30 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.72 to 4.88 (1H, m), 6.03 (1H, d, J=10.2 Hz), 7.02 (2H, d, J=8.8 Hz), 7.15 to 7.64 (13H, m), 7.90 to 8.02 (1H, m), 8.08 to 8.11 (1H, m).
IR (KBr) 3284, 1696, 1609, 1520, 1499, 1248, 1206, 1181, 1155, 1061, 1040, 828 cm −1
Elemental Analysis for C 38 H 38 N 3 O 6 F 3 .1.0H 2 O Calcd. C, 64.49; H, 5.70; N, 5.94. Found: C, 64.75; H, 5.42; N, 5.75.
›Example 94
(Preparation of Compound 101)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (180 mg) in ethanol (10 ml) was added sodium borohydride (49 mg) at room temperature and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (49 mg), and the mixture was stirred for 2 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. After the organic layer was concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridins-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 101) (86.1 mg) as yellow crystals.
m.p. 101 to 104° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.28 to 1.47 (2H, m), 1.52 to 1.89 (2H, m), 2.46 (3H, s), 2.90 to 2.97 (2H, m), 3.39 to 3.49 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.52 to 4.64 (1H, m), 6.03 (1H, d, J=11.2 Hz), 6.69 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.8 Hz), 7.15 to 7.58 (12H, m), 8.00 (1H, d, J=11.2 Hz), 8.08 to 8.11 (1H, m).
IR (KBr) 3295, 1651, 1609, 1499, 1454, 1316, 1246, 1179, 1121, 1040, 824 cm −1
Elemental Analysis for C 36 H 39 N 3 O 5 .1.0H 2 O Calcd. C, 70.68; H, 6.76; N, 6.87. Found: C, 70.72; H, 6.43; N, 6.86.
›Example 95
(Preparation of Compound 102)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (70 mg) and isobutylaldehyde (0.09 ml) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (64 mg) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 18 hours. To the reaction solution were further added isobutylaldehyde (0.09 ml) and sodium triacetoxyborohydride (64 mg) and the mixture was stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 102) (28.5 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.30 to 1.48 (2H, m), 1.50 to 1.70 (2H, m), 1.96 to 2.17 (1H, m), 2.46 (3H, s), 2.84 to 2.95 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.29 to 3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.03 (1H, d, J=10.8 Hz), 6.91 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=9.2 Hz), 7.15 to 7.24 (2H, m), 7.38 to 7.58 (10H, m), 8.01 (1H, d, J=10.8 Hz), 8.08 to 8.11 (1H, m).
IR (KBr) 3295, 1657, 1607, 1514, 1499, 1454, 1244, 1181, 1117, 1061, 816 cm −1
Elemental Analysis for C 40 H 47 N 3 O 5 .1.25H 2 O Calcd. C, 71.46; H, 7.42; N, 6.25. Found: C, 71.50; H, 7.32; N, 6.00.
›Example 96
(Preparation of Compound 103)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g), 1-hydroxybenzotriazole (0.28 g), (4-aminophenyl)(5-methylpyridin-2-yl)methanol (0.29 g) and triethylamine (0.60 ml) in DMF (10 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and 4-dimethylaminopyridine (1 flake) at room temperature and the mixture was stirred for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1) and further recrystallized to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 103) (529.9 mg) as pale yellow crystals.
m.p. 110 to 113° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.28 to 1.48 (2H, m), 1.53 to 1.68 (2H, m), 2.33 (3H, s), 2.85 to 3.31 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 4.18 (2H, t, J=4.8 Hz), 4.74 to 4.89 (1H, m), 5.31 (1H, d, J=4.2 Hz), 5.71 (1H, d, J=4.2 Hz), 7.01 to 7.05 (3H, m), 7.31 to 7.57 (11H, m), 7.62 to 7.67 (1H, m), 8.36 to 8.42 (1H, m).
IR (KBr) 3364, 1692, 1651, 1609, 1518, 1499, 1314, 1250, 1208, 1181, 1154, 828 cm −1
Elemental Analysis for C 38 H 38 N 3 O 5 F 3 Calcd. C, 67.74; H, 5.69; N, 6.24. Found: C, 67.43; H, 5.76; N, 6.01.
›Example 97
(Preparation of Compound 104)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-5-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C. and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methyl-1-oxideopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 104) (386.8 mg) as colorless crystals.
m.p. 201 to 204° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.94 (3H, t, J=7.2 Hz), 1.30 to 1.49 (2H, m), 1.54 to 1.70 (2H, m), 2.32 (3H, s), 2.89 to 3.35 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.78 to 4.97 (H, m), 6.03 (1H, d, J=4.2 Hz), 6.52 (1H, d, J=4.2 Hz), 6.81 (1H, d, J=8.2 Hz), 7.01 to 7.10 (3H, m), 7.26 to 7.36 (1H, m), 7.44 to 7.66 (10H, m), 8.11 (1H, s).
IR (KBr) 3248, 1686, 1647, 1609, 1597, 1314, 1250, 1209, 1181, 1157, 1144, 826 cm −1
Elemental Analysis for C 38 H 38 N 3 O 6 F 3 . Calcd. C, 66.17; H, 5.55; N, 6.09. Found: C, 66.11; H, 5.40; N, 6.21.
›Example 98
(Preparation of Compound 105)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (320 mg) in ethanol (10 ml) was added sodium borohydride (88 mg) at room temperature and the mixture was stirred for 2 hours. To the reaction solution was added sodium borohydride (88 mg), and the mixture was stirred for 1 hour. Sodium borohydride (88 mg) was further added to the mixture and the mixture was stirred for 13 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, the obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methyl-1-oxidpyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 105) (256.8 mg) as yellow crystals.
m.p. 119 to 121° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.29 to 1.46 (2H, m), 1.53 to 1.70 (2H, m), 2.30 (3H, s), 2.90 to 3.01 (2H, m), 3.21 to 3.50 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.56 to 4.65 (1H, m), 6.03 (1H, br s), 6.45 to 6.54 (1H, m), 6.70 (1H, d, J=8.0 Hz), 6.79 (1H, d, J=8.0 Hz), 6.97 (2H, d, J=8.8 Hz), 6.99 to 7.07 (1H, m), 7.29 to 7.33 (2H, m), 7.41 to 7.47 (5H, m), 7.64 (2H, d, J=8.4 Hz), 7.74 (1H, s), 8.10 (1H, s).
IR (KBr) 3252, 1647, 1599, 1499, 1318, 1250, 1181, 1123, 822 cm −1
Elemental Analysis for C 36 H 39 N 3 O 5 .0.5H 2 O Calcd. C, 71.74; H, 6.69; N, 6.97. Found: C, 71.76; H, 6.98; N, 6.91.
›Example 99
(Preparation of Compound 106)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (180 mg) and isobutylaldehyde (0.17 ml) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.19 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 16 hours. To the reaction solution were further added isobutylaldehyde (0.17 ml) and sodium triacetoxyborohydride (0.19 g), and the mixture was further stirred for 24 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 106) (130.6 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (6H, d, J=6.6 Hz), 1.30 to 1.46 (2H, m), 1.52 to 1.68 (2H, m), 1.98 to 2.16 (H, m), 2.31 (3H, s), 2.89 to 2.97 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.31 to 3.42 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.03 (1H, s), 6.79 (1H, d, J=8.0 Hz), 6.90 to 7.08 (4H, m), 7.38 to 7.52 (7H, m), 7.64 (2H, d, J=8.4 Hz), 7.65 (1H, s), 8.11 (1H, s).
IR (KBr) 3250, 1647, 1607, 1499, 1314, 1244, 1182, 1119, 1065, 1049, 818 cm −1
Elemental Analysis for C 40 H 47 N 3 O 5 .0.5H 2 O Calcd. C, 71.94; H, 7.40; N, 6.29. Found: C, 71.90; H, 7.53; N, 6.13.
›Example 100
(Preparation of Compound 107)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g), 1-hydroxybenzotriazole (0.28 g), (4-aminophenyl)(5-chloropyridin-2-yl)methanol (0.32 g) and triethylamine (0.60 ml) in DMF (10 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and 4-dimethylaminopyridine (1 flake) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1) and further separated and purified by basic silica gel column chromatography (ethyl acetate:hexane 1:1→2:1→3:1), and the residue was recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloropyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 106) (365.8 mg) as pale yellow crystals.
m.p. 144 to 146° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 1.29 to 1.47 (2H, m), 1.54 to 1.68 (2H, m), 2.90 to 3.25 (3H, m), 3.56 (2H, t, J=6.8 Hz), 3.82 (2H, t, J=4.9 Hz), 4.18 (2H, t, J=4.9 Hz), 4.75 to 4.89 (2H, m), 5.75 (H, d, J=4.0 Hz), 7.02 (2H, d, J=8.8 Hz), 7.14 (H, d, J=8.4 Hz), 7.32 to 7.43 (4H, m), 7.50 to 7.65 (8H, m), 8.53 (1H, d, J=2.6 Hz).
IR (KBr) 3343, 1694, 1651, 1595, 1518, 1497, 1312, 1244, 1213, 1182, 1152, 1111, 828 cm −1
Elemental Analysis for C 37 H 35 N 3 O 5 ClF 3 Calcd. C, 64.02; H, 5.08; N, 6.05. Found: C, 64.02; H, 5.20; N, 6.03.
›Example 101
(Preparation of Compound 108)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloropyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (682 mg) in dichloromethane (15 ml) was added 3-chloroperbenzoic acid (70%, 0.29 g) at 0° C. and the mixture was stirred for 24 hours at room temperature. 3-chloroperbenzoic acid (70%, 0.29 g) was further added to the mixture at room temperature and the mixture was stirred for 18 hours. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 108) (233.8 mg) as colorless crystals.
m.p. 200 to 203° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 1.34 to 1.45 (2H, m), 1.52 to 1.67 (2H, m), 2.86 to 3.34 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 4.18 (2H, t, J=4.8 Hz), 4.78 to 4.92 (1H, m), 5.75 (1H, d, J=4.2 Hz), 6.05 (1H, d, J=4.2 Hz), 6.91 (H, d, J=8.6 Hz), 7.03 (2H, d, J=8.4 Hz), 7.22 to 7.37 (2H, m), 7.43 to 7.67 (10H, m), 8.16 (1H, d, J=1.6 Hz).
IR (KBr) 3279, 1688, 1651, 1597, 1497, 1408, 1314, 1252, 1211, 1181, 1142, 924, 828 cm −1
Elemental Analysis for C 37 H 35 N 3 O 6 ClF 3 Calcd. C, 62.58; H, 4.97; N, 5.92. Found: C, 62.36; H, 5.01; N, 5.89.
›Example 102
(Preparation of Compound 109)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.20 g) in ethanol (30 ml), sodium borohydride (50 mg) was added at room temperature and the mixture was stirred for 2.5 hours. To the reaction solution was added sodium borohydride (50 mg), and the mixture was stirred for 2.5 hours. Sodium borohydride (50 mg) was further added to the mixture and the mixture was stirred for 1 hour. Sodium borohydride (50 mg) was further added to the mixture, and the mixture was stirred for 13 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 109) (53 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.34 to 1.49 (2H, m), 1.51 to 1.68 (2H, m), 2.91 to 3.00 (2H, m), 3.42 to 3.50 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.45 to 4.69 (1H, m), 5.71-5.78 (1H, m), 6.02-6.06 (1H, m), 6.71 (1H, d, J=8.4 Hz), 6.88 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.17 to 7.22 (1H, m), 7.28 to 7.36 (2H, m), 7.42 to 7.48 (5H, m), 7.50 to 7.67 (2H, m), 8.30 (1H, d, J=1.8 Hz).
›Example 103
(Preparation of Compound 110)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (40 mg) and isobutylaldehyde (0.1 ml) in 1,2-dichloroethane (5 ml) were added sodium triacetoxyborohydride (60 mg) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 14 hours. To the reaction solution was further added sodium triacetoxyborohydride (40 mg), and the mixture was stirred for 6 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(5-chloro-1-oxidopyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 110) (26.6 mg) as yellow crystals.
m.p. 137-139° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (6H, d, J=6.6 Hz), 1.29 to 1.46 (2H, m), 1.52 to 1.68 (2H, m), 1.94 to 2.17 (1H, m), 2.86 to 2.99 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.31 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 5.76 (1H, d, J=3.9 Hz), 6.04 (1H, d, J=3.9 Hz), 6.87 to 6.94 (2H, m), 6.98 (2H, d, J=8.8 Hz), 7.20 to 7.26 (1H, m), 7.35 to 7.52 (7H, m), 7.63 to 7.67 (3H, m), 8.29 (1H, d, J=1.8 Hz).
IR (KBr) 3290, 1644, 1597, 1499, 1318, 1244, 1182, 924, 813 cm −1 .
›Example 104
(Preparation of Compound 111)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.5 g) and 1-hydroxybenzotriazole (0.30 g), (4-aminophenyl)(3-propoxypyridin-2-yl)methanol (0.30 g) in DMF (10 ml) were added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g), triethylamine (0.6 ml) and 4-dimethylaminopyridine (1 flake) at room temperature and the mixture was stirred for 24 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 111) (528.7 mg) as pale yellow crystals.
m.p. 154 to 157° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.6 Hz), 0.99 (3H, t, J=7.4 Hz), 1.31 to 1.48 (2H, m), 1.51 to 1.66 (2H, m), 1.71 to 1.83 (2H, m), 2.83 to 3.26 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.79 to 3.89 (2H, m), 4.18 (2H, t, J=4.8 Hz), 4.74 to 4.95 (H, m), 5.59 (1H, d, J=6.6 Hz), 5.93 (1H, d, J=6.6 Hz), 7.02 (2H, d, J=8.8 Hz), 7.08 to 7.24 (2H, m), 7.29 to 7.41 (4H, m), 7.46 to 7.58 (6H, m), 7.64 (1H, br s), 8.16 to 8.18 (1H, m).
IR (KBr) 3324, 1698, 1671, 1609, 1522, 1499, 1453, 1406, 1316, 1281, 1250, 1208, 1179, 1144, 1042, 828 cm −1
Elemental Anaylsis for C 40 H 42 N 3 O 6 F 3 Calcd. C, 66.93; H, 5.90; N, 5.85. Found: C, 66.72; H, 6.09; N, 5.80.
›Example 105
(Preparation of Compound 112)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.2 g) at 0° C. and the mixture was stirred for 30 hours at room temperature. To the reaction solution was added sodium thiosulfate solution and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 112) (370 mg) as colorless crystals.
m.p. 144 to 146° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.09 (3H, t, J=7.3 Hz), 1.31 to 1.47 (2H, m), 1.51 to 1.67 (2H, m), 1.82 to 1.97 (2H, m), 2.86 to 3.24 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.93 to 4.13 (2H, m), 4.18 (2H, t, J=5.0 Hz), 4.72 to 4.89 (1H, m), 6.36 (1H, d, J=11.0 Hz), 6.95 (1H, d, J=7.6 Hz), 7.02 (2H, d, J=8.8 Hz), 7.12 to 7.19 (1H, m), 7.28 to 7.41 (2H, m), 7.45 to 7.64 (9H, m), 7.81 to 7.84 (1H, m), 7.90 to 7.96 (1H, m).
IR (KBr) 3318, 1694, 1674, 1599, 1532, 1514, 1499, 1319, 1291, 1250, 1181, 1146, 1074, 1042, 826 cm −1
Elemental Analysis for C 40 H 42 N 3 O 7 F 3 Calcd. C, 65.47; H, 5.77; N, 5.73. Found: C, 65.23; H, 5.60; N, 5.51.
›Example 106
(Preparation of Compound 113)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (330 mg) in ethanol (20 ml) was added sodium borohydride (85 mg) at room temperature and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 2 hours. To the reaction solution was further added sodium borohydride (85 mg), and the mixture was stirred for 14 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridine-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 113) (230.7 mg) as yellow crystals.
m.p. 148 to 149° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.09 (3H, t, J=7.3 Hz), 1.28 to 1.49 (2H, m), 1.52 to 1.67 (2H, m), 1.81 to 2.00 (2H, m), 2.88 to 2.97 (2H, m), 3.41 to 3.52 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, t, J=4.9 Hz), 3.95 to 4.10 (2H, m), 4.15 (2H, t, J=4.9 Hz), 4.48 to 4.67 (1H, m), 6.31-6.41 (1H, m), 6.92-6.99 (3H, m), 7.11 to 7.19 (1H, m), 7.26 to 7.33 (3H, m), 7.43 to 7.47 (3H, m), 7.50 to 7.56 (4H, m), 7.82 (1H, m, J=6.6 Hz), 7.84 to 8.02 (1H, m).
IR (KBr) 3308, 1657, 1601, 1507, 1498, 1317, 1244, 1181, 1040, 831 cm −1
Elemental Analysis for C 38 H 43 N 3 O 6 Calcd. C, 71.56; H, 6.80; N, 6.59. Found: C, 71.37; H, 6.82; N, 6.42.
›Example 107
(Preparation of Compound 114)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (190 mg) and isobutylaldehyde (0.27 ml) in 1,2-dichloroethane (10 ml) were added sodium triacetoxyborohydride (0.19 g) and acetic acid (1 droplet) at room temperature and the mixture was stirred for 15 hours. To the reaction solution were further added isobutylaldehyde (0.27 ml) and sodium triacetoxyborohydride (0.19 g), and the mixture was stirred for 6 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxido-3-propoxypyridin-2-yl)methyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 114) (143.3 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.09 (3H, t, J=7.3 Hz), 1.32 to 1.72 (4H, m), 1.81 to 2.13 (3H, m), 2.84 to 2.93 (2H, m), 3.18 (2H, d, J=7.8 Hz), 3.30 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.98 to 4.11 (2H, m), 4.16 (2H, t, J=5.0 Hz), 6.36 (1H, s), 6.89 to 7.00 (4H, m), 7.12 to 7.19 (1H, m), 7.37 to 7.60 (11H, m), 7.81 to 7.84 (1H, m).
IR (KBr) 3301, 1653, 1607, 1514, 1499, 1468, 1314, 1244, 1181, 1073, 818 cm −1
Elemental Analysis for C 42 H 51 N 3 O 6 .1.0H 2 O Calcd. C, 70.86; H, 7.50; N, 5.90. Found: C, 70.87; H, 7.33; N, 5.80.
›Example 108
(Preparation of Compound 115)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) were added thionyl chloride (0.1 ml) and pyridine (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The solvent was removed under reduced pressure, to a solution of the residue in ethanol (20 ml) was added triethylamine (2.0 ml) and 2-mercapto-1,3,4-thiadiazole (0.12 g) at 50° C. and the mixture was stirred for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:2→1:1) and further recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1,3,4-thiadiazol-2-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 115) (373.1 mg) as yellow crystals.
m.p. 77 to 79° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.30 to 1.46 (2H, m), 1.52 to 1.68 (2H, m), 1.96 to 2.11 (1H, m), 2.86 to 2.97 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.30 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.58 (2H, s), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.34 to 7.61 (10H, m), 9.00 (1H, s).
IR (KBr) 3299, 1640, 1605, 1595, 1516, 1499, 1408, 1368, 1316, 1246, 1181, 1123, 1061, 816 cm −1
Elemental Analysis for C 36 H 42 N 4 O 3 S 2 Calcd. C, 67.26; H, 6.59; N, 8.72. Found: C, 67.07; H, 6.37; N, 8.53.
›Example 109
(Preparation of Compound 116)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) were added thionyl chloride (0.1 ml) and pyridine (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and to a solution of the residue in DMF (10 ml) was added potassium carbonate (0.51 g) and potassium 5-methyl-2-mercapto-1,3,4-oxadiazole (0.18 g), and the mixture was stirred at 50° C. for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1) and further recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-methyl-1,3,4-oxadiazol-2-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 116) (469.8 mg) as yellow crystals.
m.p. 107 to 109° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.29 to 1.48 (2H, m), 1.54 to 1.67 (2H, m), 1.97 to 2.16 (1H, m), 2.49 (3H, s), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.33 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 4.43 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.37 to 7.50 (7H, m), 7.57 (2H, d, J=8.4 Hz), 7.63 (1H, s).
IR (KBr) 3345, 1645, 1605, 1591, 1518, 1499, 1487, 1246, 1161, 808 cm −1
Elemental Analysis for C 37 H 44 N 4 O 4 S Calcd. C, 69.35; H, 6.92; N, 8.74. Found: C, 69.12; H, 6.84; N, 8.93.
›Example 110
(Preparation of Compound 117)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-isobutyl-1H-1-benzazepine-4-carboxamide (0.50 g) in THF (10 ml) were added thionyl chloride (0.1 ml) and pyridine (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction solution was concentrated under reduced pressure, and a solution of the residue in ethanol (20 ml) was added to triethylamine (2.0 ml) and 2-mercapto-4-methyl-1,2,4-triazole (0.14 g) at 50° C. and the mixture was stirred for 16 hours. To the reaction solution was added 1,8-diazabicyclo[5,4,0]-7-undecene (1.0 ml), and the mixture was further stirred at 60° C. for 4 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethanol:ethyl acetate 1:10) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 117) (312.9 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, =6.6 Hz), 1.31 to 1.46 (2H, m), 1.51 to 1.66 (2H, m), 1.93 to 2.15 (1H, m), 2.85 to 2.94 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.30 to 3.38 (5H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.34 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.22 to 7.26 (2H, m), 7.37 to 7.54 (7H, m), 7.62 (1H, s), 8.08 (1H, s).
IR (KBr) 3275, 1655, 1605, 1516, 1499, 1408, 1316, 1244, 1181, 1123, 1065, 835, 816 cm −1
Elemental Analysis for C 37 H 45 N 5 O 3 S.0.5H 2 O Calcd. C, 68.49; H, 7.15; N, 10.79. Found: C, 68.45; H, 7.22; N, 10.68.
›Example 111
(Preparation of Compound 118)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.26 g) in dichloromethane (10 ml) was added a solution of 3-chloroperbenzoic acid (70%, 0.26 g) in dichloromethane (10 ml) at −78° C. and the mixture was stirred at −10 to −15° C. for 1.5 hours. To the reaction solution was added magnesium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylsulfinylmethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 118) (73.8 mg) as yellow crystals.
m.p. 87 to 89° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.26 to 1.45 (2H, m), 1.48 to 1.67 (2H, m), 1.98 to 2.12 (1H, m), 2.85 to 2.96 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.30 to 3.43 (5H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.37 (1H, d, J=13.4 Hz), 4.65 (1H, d, J=13.4 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.6 Hz), 7.34 to 7.64 (8H, m), 8.05 (1H, s).
IR (KBr) 3267, 1655, 1607, 1516, 1499, 1410, 1314, 1246, 1182, 1125, 1063, 820 cm −1
Elemental Analysis for C 37 H 45 N 5 O 4 S.1.0H 2 O Calcd. C, 65.95; H, 7.03; N, 10.39. Found: C, 65.55; H, 6.79; N, 10.34.
›Example 112
(Preparation of Compound 119)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1,3,4-thiadiazol-2-ylthiomethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (480 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.28 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred at −10° C. for 4 hours, and to the reaction solution was added sodium thiosulfate solution and the mixture was further stirred at room temperature for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:2→1:1) to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1,3,4-thiadiazol-2-ylsulfinylmethyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 119) (33 mg) as yellow crystals.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.30 to 1.49 (2H, m), 1.53 to 1.68 (2H, m), 1.98 to 2.13 (1H, m), 2.85 to 2.96 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.30 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.31 (1H, d, J=13.2 Hz), 4.54 (1H, d, J=13.2 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.4 Hz), 7.35 to 7.56 (7H, m), 7.62 (H, s), 9.21 (1H, s).
IR (KBr) 3306, 1653, 1607, 1516, 1499, 1410, 1316, 1244, 1182, 1117, 1071, 820 cm −1
Elemental Analysis for C 36 H 42 N 4 O 4 S 2 .0.5H 2 O Calcd. C, 64.74; H, 6.49; N, 8.39. Found: C, 64.75; H, 6.48; N, 8.50.
›Example 113
(Preparation of Compound 120)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (700 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, to the solution was added thionyl chloride (0.15 ml) at 0° C., and the mixture was allowed to be at room temperature and stirred for 1 hour under nitrogen atmosphere. This solution was added to a solution of 4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]aniline (515 mg) and triethylamine (5.8 ml) in tetrahydrofuran (15 ml) at 0° C. The mixture was stirred for 1 hour at room temperature under nitrogen atmosphere, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3→ethyl acetate), which was recrystallized from ethanol-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (417 mg)(Compound 120) as yellow crystals.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (9H, m), 1.30 to 1.45 (8H, m), 1.55 to 1.70 (2H, m), 1.95 to 2.10 (1H, m), 2.90 (2H, t, J=4.8 Hz), 3.18 (2H, d, J=7.0 Hz), 3.35 (2H, t, J=4.8 Hz), 3.56 (2H, t, J=7.0 Hz), 3.80 (2H, t, J=4.4 Hz), 4.13 to 4.18 (4H, m), 4.40 to 4.60 (1H, m), 6.89 to 7.00 (5H, m), 7.32 to 7.55 (9H, m), 7.75 (1H, s).
Elemental Analysis for C 40 H 50 N 4 O 3 S.0.25H 2 O Calcd. C, 71.55; H, 7.58; N, 8.34. Found: C, 71.32; H, 7.52; N, 8.17.
›Example 114
(Preparation of Compound 121, Compound 122)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (111 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added sodium thiosulfate solution, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (methanol:ethyl acetate=1:9) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isopropylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (89.0 mg)(Compound 121) as yellow amorphous, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isopropylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (29 mg)(Compound 122) as yellow crystals.
Compound 121
1H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (9H, m), 1.22 to 1.49 (8H, m), 1.54 to 1.75 (2H, m), 2.00 to 2.20 (H, m), 2.90 to 3.00 (2H, m), 3.20 (2H, d, J=7.6 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, t, J=7.6 Hz), 3.80 (2H, t, J=4.4 Hz), 4.10 to 4.30 (4H, m), 4.40 to 4.50 (1H, m), 6.90 to 7.02 (5H, m), 7.38 to 7.48 (7H, m), 7.73 (2H, d, J=8.8 Hz), 7.88 (1H, s).
Elemental Analysis for C 40 H 50 N 404 S.0.3H 2 O Calcd. C, 69.80; H, 7.41; N, 8.14. Found: C, 69.56; H, 7.18; N, 7.91.
Compound 122
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 1.02 (9H, m), 1.34 to 1.65 (10H, m), 2.00 to 2.20 (1H, m), 2.90 to 3.00 (2H, m), 3.21 (2H, d, J=7.4 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, t, J=7.0 Hz), 3.80 (2H, t, J=5.2 Hz), 4.15 (2H, t, J=5.2 Hz), 4.42 (2H, s), 4.60 to 4.70 (1H, m), 6.89 to 7.03 (5H, m), 7.31 to 7.38 (5H, m), 7.55 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 8.52 (1H, s).
Elemental Analysis for C 40 H 50 N 4 O 5 S.0.5H 2 O Calcd. C, 67.86; H, 7.26; N, 7.91. Found: C, 67.61; H, 7.07; N, 7.76.
›Example 115
(Preparation of Compound 123)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.25 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain acid chloride. To a solution of 4-aminothiophenol (0.29 g) and triethylamine (1.6 ml) in THF (10 ml) was added benzyl chlorocarbonate (0.35 ml) at 0° C., and the mixture was stirred at 0° C. for 0.5 hour and at room temperature for 0.5 hour. To the mixture was added a solution of the previously prepared acid chloride in THF (20 ml) dropwise at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. A solution of the residue in THF-methanol (30-30 ml) was added to 1N aqueous solution of sodium hydroxide (10 ml) at room temperature, and the mixture was stirred for 0.5 hour. To the reaction solution was added 5-chloromethyl-1-methyl-1H-1,2,4-triazole hydrochloride (0.39 g), and the mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→3:2→2:1), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 123) (639 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.30 to 1.48 (2H, m), 1.51 to 1.68 (2H, m), 1.98 to 2.16 (1H, m), 2.85 to 2.95 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.33 to 3.78 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.74 (3H, s), 3.80 (2H, t, J=5.0 Hz), 4.12 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.92 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.31 to 7.49 (7H, m), 7.55 (2H, d, J=8.8 Hz), 7.62 (1H, s), 7.76 (1H, s).
IR (KBr) 3300, 1651, 1607, 1586, 1497, 1395, 1312, 1285, 1244, 1181, 1119, 822 cm −1
Elemental Analysis for C 37 H 45 N 5 O 3 S0.5H 2 O Calcd. C, 68.49; H, 7.15; N, 10.79. Found: C, 68.62; H, 7.14; N, 11.00.
›Example 116
(Preparation of Compound 124)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (565 mg) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.32 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the reaction solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:19→1:9) and further recrystallized from ethyl acetate-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(1-methyl-1H-1,2,4-triazol-5-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 124) (515 mg) as yellow crystals.
m.p. 135 to 138° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (6H, d, J=6.6 Hz), 1.35 to 1.47 (2H, m), 1.52 to 1.68 (2H, m), 1.96 to 2.17 (1H, m), 2.87 to 2.97 (2H, m), 3.20 (2H, d, J=7.4 Hz), 3.32 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.76 (3H, s), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.19 (H, d, J=13.6 Hz), 4.28 (1H, d, J=13.6 Hz), 6.91 to 7.01 (3H, m), 7.36 to 7.52 (7H, m), 7.74 (1H, br s), 7.78 (2H, d, J=8.8 Hz), 7.83 (1H, s).
IR (KBr) 3382, 1655, 1613, 1591, 1520, 1497, 1393, 1318, 1246, 1184, 1121, 1036, 820 cm −1
Elemental Analysis for C 37 H 45 N 5 O 4 S Calcd. C, 67.76; H, 6.92; N, 10.68. Found: C, 67.52; H, 6.76; N, 10.43.
›Example 117
(Preparation of Compound 125)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and a solution of the residue in THF (30 ml), was added dropwise to a solution of S-(4-aminophenyl)O-benzyl thiocarbonate (0.64 g) and triethylamine (1.3 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-1-methyl-1H-1,2,4-triazole hydrochloride (0.44 g), and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 125) (1.00 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.32 to 1.50 (2H, m), 1.53 to 1.69 (2H, m), 1.96 to 2.15 (1H, m), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.33 to 3.38 (2H, m), 3.55 (1H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.86 (3H, s), 4.13 to 4.18 (4H, m), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.38 to 7.55 (10H, m), 7.94 (1H, s).
IR (KBr) 3300, 1653, 1605, 1586, 1499, 1312, 1285, 1244, 1181, 1123, 820 cm −1
Elemental Analysis for C 37 H 45 N 5 O 3 S.0.5H 2 O Calcd. C, 68.49; H, 7.15; N, 10.79. Found: C, 68.18; H, 6.85; N, 11.09.
›Example 118
(Preparation of Compound 126, Compound 127)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.8 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.46 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 0.5 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:3), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 126) (678.9 mg) as yellow crystals.
In addition, at the same time, 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-methyl-1H-1,2,4-triazol-3-ylmethylsulfonyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 127) (22.2 mg) was obtained.
Compound 126
m.p. 112 to 114° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (6H, d, J=6.6 Hz), 1.30 to 1.44 (2H, m), 1.50 to 1.66 (2H, m), 1.96 to 2.15 (1H, m), 2.86 to 2.97 (2H, m), 3.20 (2H, d, J=7.0 Hz), 3.32 to 3.41 (2H, m), 3.55 (1H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 3.89 (3H, s), 4.09 (1H, d, J=13.2 Hz), 4.16 (2H, t, J=4.8 Hz), 4.28 (1H, d, J=13.2 Hz), 6.93 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=9.2 Hz), 7.36 to 7.50 (5H, m), 7.58 (2H, d, J=8.8 Hz), 7.69 (1H, s), 7.75 (2H, d, J=8.8 Hz), 7.97 (1H, s).
IR (KBr) 3104, 1661, 1607, 1590, 1518, 1499, 1314, 1246, 1179, 1125, 1046, 835 cm −1
Elemental Analysis for C 37 H 45 N 5 O 4 S.0.25H 2 O Calcd. C, 67.30; H, 6.94; N, 10.61. Found: C, 67.16; H, 6.89; N, 10.61.
Compound 127
m.p. 205 to 208° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.28 to 1.46 (2H, m), 1.52 to 1.68 (2H, m), 1.96 to 2.13 (H, m), 2.86 to 2.96 (2H, m), 3.20 (2H, d, J=7.0 Hz), 3.31 to 3.42 (2H, m), 3.55 (1H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.89 (3H, s), 4.16 (2H, t, J=4.8 Hz), 4.52 (2H, s), 6.91 to 7.00 (3H, m), 7.39 to 7.50 (5H, m), 7.77 to 7.81 (5H, m), 7.95 (H, s).
IR (KBr) 3240, 1672, 1609, 1590, 1520, 1501, 1402, 1318, 1240, 1182, 1146, 808 cm −1
Elemental Analysis for C 37 H 45 N 5 O 5 S.0.5H 2 O Calcd. C, 65.27; H, 6.81; N, 10.29. Found: C, 65.17; H, 6.72; N, 10.16.
›Example 119
(Preparation of Compound 128)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.21 ml) and DMF (1 droplet) at room temperature, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 4-(1,2,4-oxadiazol-3-ylmethylthio) aniline (0.43 g) and triethylamine (1.6 ml) in THF (2 ml) at 0° C. The mixture was stirred at room temperature for 4 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate:hexane 1:2→1:1), and was further recrystalized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 128) (855.7 mg) as yellow crystals.
m.p. 112 to 115° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.28 to 1.48 (2H, m), 1.54 to 1.68 (2H, m), 1.94 to 2.18 (1H, m), 2.84 to 2.95 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.33 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.13 to 4.18 (4H, m), 6.92 (H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.38 to 7.58 (10H, m), 8.67 (1H, s).
IR (KBr) 3337, 1647, 1605, 1584, 1551, 1501, 1397, 1337, 1310, 1240, 1109, 828, 810 cm −1
Elemental Analysis for C 36 H 42 N 4 O 4 S Calcd. C, 68.98; H, 6.75; N, 8.94. Found: C, 68.95; H, 6.94; N, 8.97.
›Example 120
(Preparation of Compound 129)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.60 g) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (5 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→4:1), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1,2,4-oxadiazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 129) (534.9 mg) as yellow crystals.
m.p. 142 to 144° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.34 to 1.49 (2H, m), 1.54 to 1.71 (2H, m), 1.96 to 2.16 (1H, m), 2.86 to 2.95 (2H, m), 3.20 (2H, d, J=7.2 Hz), 3.31 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.21 (1H, d, J=13.2 Hz), 4.32 (1H, d, J=13.2 Hz), 6.91 to 7.00 (3H, m), 7.39 to 7.50 (5H, m), 7.59 (2H, d, J=8.8 Hz), 7.77 to 7.81 (3H, m), 8.71 (1H, s).
IR (KBr) 3222, 1649, 1607, 1588, 1499, 1397, 1343, 1314, 1246, 1181, 1128, 1047, 828, 808 cm −1
Elemental Analysis for C 36 H 42 N 4 O 5 S Calcd. C, 67.26; H, 6.59; N, 8.72. Found: C, 67.24; H, 6.60; N, 8.66.
›Example 121
(Preparation of Compound 130)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.50 g) in THF (10 ml) were added thionyl chloride (0.13 ml) and DMF (1 droplet) at room temperature, and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain acid chloride. Separately, to a solution of 4-aminothiophenol (0.16 g) and triethylamine (0.70 ml) in THF (10 ml) was added benzyl chlorocarbonate (0.19 ml) at −78° C., and the mixture was stirred at −78° C. for 10 minutes, at 0° C. for 0.5 hour and at room temperature for 0.5 hour. A solution of the previously prepared acid chloride in THF (10 ml) was added dropwise to the solution at 0° C., and the mixture was stirred for 1 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4→1:3) to give yellow amorphous. To a solution of the obtained compound (0.54 g) in THF-methanol (10 −10 ml) was added 1N aqueous solution of sodium hydroxide (32 ml) at room temperature, and the mixture was stirred for 1 hour. To the reaction solution was added 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.15 g), and the mixture was stirred for 0.5 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:10→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 130) (352.8 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.98 (6H, d, J=6.6 Hz), 1.29 to 1.48 (2H, m), 1.51 to 1.68 (2H, m), 1.97 to 2.18 (1H, m), 2.86 to 2.96 (2H, m), 3.19 (2H, d, J=6.6 Hz), 3.28 to 3.39 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.60 (3H, s), 3.81 (2H, t, J=5.0 Hz), 4.11 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.89 to 7.00 (3H, m), 7.29 to 7.43 (6H, m), 7.46 (2H, d, J=8.4 Hz), 7.57 (2H, d, J=8.4 Hz), 7.97 (1H, s), 806 (1H, br s).
IR (KBr) 3282, 1655, 1607, 1586, 1499, 1312, 1242, 1181, 1123, 820 cm −1
›Example 122
(Preparation of Compound 131)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.30 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.17 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 0.5 hour at −78° C. and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 131) (204 mg) as yellow crystals.
m.p. 103 to 105° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.01 (6H, d, J=6.2 Hz), 1.29 to 1.47 (2H, m), 1.53 to 1.72 (2H, m), 1.96 to 2.17 (1H, m), 2.89 to 3.01 (2H, m), 3.22 (2H, d, J=7.8 Hz), 3.30 to 3.40 (2H, m), 3.53 to 3.61 (5H, m), 3.81 (2H, t, J=4.9 Hz), 3.96 (1H, d, J=14.0 Hz), 4.11 (1H, d, J=14.0 Hz), 4.16 (2H, t, J=4.9 Hz), 6.89 to 6.99 (3H, m), 7.16 to 7.22 (2H, m), 7.34 to 7.48 (5H, m), 7.85 (2H, d, J=8.4 Hz), 8.00 (1H, s), 8.64 (1H, br s).
IR (KBr) 3298, 1655, 1607, 1588, 1520, 1499, 1314, 1246, 1181, 1125, 1090, 1047, 833 cm −1
›Example 123
(Preparation of Compound 132)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain acid chloride. In addition, to a solution of 4-aminothiophenol (0.30 g) and triethylamine (2.0 ml) in THF (5 ml) was added benzyl chlorocarbonate (0.36 ml) at −78° C. and the mixture was stirred at −78° C. for 20 minutes and at 0° C. for 20 minutes. To the mixture was added dropwise a solution of the previously prepared acid chloride in THF (20 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction solution were added methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml), and the mixture was stirred for 20 minutes. To the reaction solution was added 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.41 g), and the mixture was stirred for 0.5 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:10→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 132) (836.4 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 1.00 (3H, t, J=7.3 Hz), 1.30 to 1.46 (2H, m), 1.51 to 1.82 (4H, m), 2.85 to 2.96 (2H, m), 3.24 to 3.38 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.57 (3H, s), 3.81 (2H, t, J=4.9 Hz), 4.07 (2H, s), 4.16 (2H, t, J=4.9 Hz), 6.88 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=9.2 Hz), 7.31 to 7.47 (7H, m), 7.58 (2H, d, J=8.8 Hz), 7.94 (1H, s), 8.26 (1H, s).
IR (KBr) 3268, 1655, 1605, 1586, 1499, 1397, 1310, 1242, 1179, 1119, 816 cm −1
›Example 124
(Preparation of Compound 133)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (5 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., and to the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (ethanol:ethyl acetate ˜1:9), and was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 133) (613.2 mg) as yellow crystals.
m.p. 101 to 103° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.03 (3H, t, J=7.3 Hz), 1.30 to 1.46 (2H, m), 1.52 to 1.88 (4H, m), 2.89 to 3.00 (2H, m), 3.28 to 3.41 (4H, m), 3.48 (3H, s), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.87 (1H, d, J=14.0 Hz), 4.04 (1H, d, J=14.0 Hz), 4.13 (2H, t, J=4.8 Hz), 6.89 (1H, d, J=8.6 Hz), 6.96 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.4 Hz), 7.30 to 7.43 (5H, m), 7.86 (2H, d, J=8.8 Hz), 7.96 (1H, s), 8.88 (1H, br s).
IR (KBr) 3262, 1653, 1590, 1520, 1501, 1316, 1246, 1179, 1123, 1051, 835 cm −1
›Example 125
(Preparation of Compound 134)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure, and a solution of the residue in THF (35 ml), was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.59 g) and triethylamine (2.0 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-4-ethyl-4H-1,2,4-triazole hydrochloride (0.46 g), and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 134) (1.14 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.31 to 1.46 (5H, m), 1.55 to 1.67 (2H, m), 1.97 to 2.17 (1H, m), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.27 to 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.92 (2H, q, J=7.5 Hz), 4.06 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.89 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.26 to 7.41 (5H, m), 7.43 (2H, d, J=8.8 Hz), 7.60 (2H, d, J=8.8 Hz), 8.00 (1H, s), 8.43 (1H, s).
IR (KBr) 3264, 1659, 1605, 1588, 1514, 1499, 1244, 1182, 1125, 818 cm −1
Elemental Analysis for C 38 H 47 N 5 O 3 S.0.25H 2 O Calcd. C, 69.32; H, 7.27; N, 10.64. Found: C, 69.28; H, 7.49; N, 10.50.
›Example 126
(Preparation of Compound 135)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.94 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.53 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:9), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 135) (858.7 mg) as yellow crystals.
m.p. 102 to 104° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.99 (6H, d, J=6.6 Hz), 1.30 to 1.48 (5H, m), 1.51 to 1.68 (2H, m), 1.96 to 2.19 (1H, m), 2.89 to 2.99 (2H, m), 3.21 (2H, d, J=6.6 Hz), 3.32 to 3.42 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 3.93 to 4.26 (6H, m), 6.90 to 7.00 (3H, m), 7.37 to 7.46 (7H, m), 7.81 (2H, d, J=8.8 Hz), 8.09 to 8.17 (2H, m).
IR (KBr) 3218, 1655, 1605, 1590, 1520, 1499, 1314, 1244, 1181, 1090, 1053, 835 cm −1
Elemental Analysis for C 38 H 47 N 5 O 4 S.0.5H 2 O Calcd. C, 67.23; H, 7.13; N, 10.32. Found: C, 66.91; H, 7.06; N, 10.03.
›Example 127
(Preparation of Compound 136)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (35 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.62 g) and triethylamine (2.0 ml) in THF (5 ml) at 0° C. The mixture was stirred for 16 hours at room temperature, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-4-ethyl-4H-1,2,4-triazole hydrochloride (0.47 g), and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 136) (1.15 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.00 (3H, t, J=7.3 Hz), 1.26 to 1.47 (5H, m), 1.52 to 1.82 (4H, m), 2.85 to 2.96 (2H, m), 3.27 to 3.37 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.92 (2H, q, J=7.4 Hz), 4.05 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.87 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.8 Hz), 7.27 to 7.32 (4H, m), 7.36 to 7.46 (3H, m), 7.60 (2H, d, J=8.4 Hz), 8.00 (1H, s), 8.45 (1H, br s).
IR (KBr) 3223, 1657, 1605, 1588, 1499, 1310, 1240, 1181, 1121, 816 cm −1
Elemental Analysis for C 37 H 45 N 5 O 3 S.0.5H 2 O Calcd. C, 68.49; H, 7.15; N, 10.79. Found: C, 68.52; H, 7.20; N, 11.14.
›Example 128
(Preparation of Compound 137)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1, 2, 4-triazol-3-ylmethylthio) phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.93 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.54 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:3→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 137) (694.7 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 1.02 (3H, t, J=7.3 Hz), 1.29 to 1.50 (5H, m), 1.53 to 1.86 (4H, m), 2.92-2.99 (2H, m), 3.25 to 3.40 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 3.87 to 4.01 (3H, m), 4.08 to 4.17 (3H, m), 6.89 (1H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.23 to 7.43 (7H, m), 7.85 (2H, d, J=8.8 Hz), 8.08 (1H, s), 8.62 (1H, br s).
IR (KBr) 3104, 1661, 1607, 1588, 1518, 1499, 1397, 1314, 1244, 1179, 1123, 1090, 833 cm −1
Elemental Analysis for C 37 H 45 N 5 O 4 S—H 2 O Calcd. C, 65.95; H, 7.03; N, 10.39. Found: C, 65.78; H, 7.10; N, 10.52.
›Example 129
(Preparation of Compound 138)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.64 g) and triethylamine (1.3 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, and methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.51 g), and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 138) (987 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 2.99 (12H, m), 1.29 to 1.49 (2H, m), 1.53 to 1.85 (4H, m), 1.96 to 2.17 (1H, m), 2.86 to 2.96 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.28 to 3.38 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.79 to 3.86 (4H, m), 4.06 (2H, s), 4.16 (2H, t, J=4.9 Hz), 6.90 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.31 to 7.46 (7H, m), 7.60 (2H, d, J=8.8 Hz), 7.97 (1H, s), 8.42 (1H, br s).
IR (KBr) 3264, 1659, 1607, 1588, 1497, 1397, 1312, 1242, 1181, 1123, 816 cm −1
Elemental Analysis for C 39 H 49 N 5 O 3 S.0.5H 2 O Calcd. C, 69.20; H, 7.45; N, 10.35. Found: C, 69.12; H, 7.58; N, 10.41.
›Example 130
(Preparation of Compound 139)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (826 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.46 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethanol:ethyl acetate 1:5→1:3), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 139) (628.7 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.88 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.1 Hz), 1.01 (6H, d, J=6.6 Hz), 1.28 to 1.47 (2H, m), 1.51 to 1.78 (4H, m), 1.95 to 2.18 (1H, m), 2.90 to 3.01 (2H, m), 3.21 (2H, d, J=7.2 Hz), 3.31 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.76 to 3.86 (4H, m), 3.97 (1H, d, J=14.2 Hz), 4.11 (1H, d, J=14.2 Hz), 4.15 (2H, t, J=4.9 Hz), 6.91 (1H, d, J=8.8 Hz), 6.96 (2H, d, J=8.4 Hz), 7.27 to 7.43 (7H, m), 7.85 (2H, d, J=8.8 Hz), 8.04 (1H, s), 8.70 (1H, br s).
IR (KBr) 3282, 1661, 1607, 1588, 1518, 1499, 1397, 1314, 1244, 1181, 1125, 1051, 835 cm −1
Elemental Analysis for C 39 H 49 N 5 O 4 S.0.5H 2 O Calcd. C, 67.60; H, 7.27; N, 10.11. Found: C, 67.25; H, 7.28; N, 9.82.
›Example 131
(Preparation of Compound 140)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.64 g) and triethylamine (2.0 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (0.50 g), and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 140) (1.00 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 1.03 (9H, m), 1.28 to 1.47 (2H, m), 1.51 to 1.88 (6H, m), 2.85 to 2.96 (2H, m), 3.23 to 3.36 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.77 to 3.84 (4H, m), 4.04 (2H, s), 4.16 (2H, t, J=4.8 Hz), 6.87 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.26 to 7.45 (7H, m), 7.60 (2H, d, J=8.8 Hz), 7.96 (1H, s), 8.52 (1H, s).
IR (KBr) 3280, 1655, 1607, 1588, 1499, 1456, 1397, 1310, 1287, 1242, 1181, 1121, 818 cm −1
Elemental Analysis for C 38 H 47 N 5 O 3 S Calcd. C, 68.85; H, 7.30; N, 10.56. Found: C, 68.54; H, 7.41; N, 10.70.
›Example 132
(Preparation of Compound 141)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (843.7 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.48 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 141) (490.8 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 (3H, t, J=7.2 Hz), 0.93 (3H, t, J=7.4 Hz), 1.02 (3H, d, J=7.3 Hz), 1.27 to 1.48 (2H, m), 1.51 to 1.86 (6H, m), 2.89 to 3.00 (2H, m), 3.28 to 3.41 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.89 (4H, m), 4.00 (1H, d, J=14.4 Hz), 4.12 to 4.19 (3H, m), 6.90 (1H, d, J=8.4 Hz), 6.96 (2H, d, J=9.2 Hz), 7.27 to 7.44 (7H, m), 7.84 (2H, d, J=8.4 Hz), 8.06 (1H, s), 8.54 (1H, br s).
IR (KBr) 3284, 1661, 1607, 1588, 1518, 1499, 1397, 1314, 1244, 1179, 1088, 1051, 835 cm −1
Elemental Analysis for C 38 H 47 N 5 O 4 S Calcd. C, 66.35; H, 7.18; N, 10.18. Found: C, 65.95; H, 7.23; N, 10.53.
›Example 133
(Preparation of Compound 142)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.59 g) and triethylamine (2.0 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (0.51 g), and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 142) (1.34 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (12H, m), 1.22 to 1.48 (4H, m), 1.52 to 1.83 (4H, m), 1.98 to 2.18 (1H, m), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.6 Hz), 3.29 to 3.39 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.89 (2H, t. J=7.5 Hz), 4.09 (2H, s), 4.16 (2H, t, J=4.8 Hz), 6.88 to 6.99 (3H, m), 7.29 to 7.47 (7H, m), 7.58 (2H, d, J=8.8 Hz), 8.00 (1H, s), 8.21 (1H, s).
IR (KBr) 3227, 1653, 1605, 1588, 1518, 1497, 1312, 1242, 1181, 1121, 820 cm −1
Elemental Analysis for C 40 H 51 N 5 O 3 S.0.5H 2 O Calcd. C, 69.53; H, 7.59; N, 10.14. Found: C, 69.29; H, 7.57; N, 10.41.
›Example 134
(Preparation of Compound 143)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.01 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 143) (794.5 mg) as yellow crystals.
m.p. 178 to 180°
1 H-NMR (200 MHz, CDCl 3 ) δ 0.88 to 1.07 (12H, m), 1.20 to 1.69 (8H, m), 1.99 to 2.19 (1H, m), 2.91 to 2.99 (2H, m), 3.20 (2H, d, J=7.0 Hz), 3.31 to 3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.93 (4H, m), 4.03 (1H, d, J=14.0 Hz), 4.12 to 4.18 (3H, m), 6.90 to 6.99 (3H, m), 7.27 to 7.45 (7H, m), 7.83 (2H, d, J=8.8 Hz), 8.06 (1H, s), 8.46 (1H, s).
IR (KBr) 3297, 1653, 1607, 1588, 1520, 1499, 1397, 1310, 1240, 1181, 1028, 833 cm −1
Elemental Analysis for C 40 H 51 N 5 O 4 S.0.25H 2 O Calcd. C, 68.39; H, 7.39; N, 9.97. Found: C, 68.22; H, 7.34; N, 10.04.
›Example 135
(Preparation of Compound 144)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.61 g) and triethylamine (2.0 ml) in THF (5 ml) at 0° C. The mixture was stirred for 64 hours at room temperature, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (15 ml) were added to the mixture and the mixture was stirred for 0.5 hour. To the reaction solution was added 4-n-butyl-3-chloromethyl-4H-1,2,4-triazole hydrochloride (0.52 g), and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 144) (1.23 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 1.03 (9H, m), 1.23 to 1.45 (4H, m), 1.53 to 1.82 (6H, m), 2.87 to 2.96 (2H, m), 3.25 to 3.36 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 3.87 (2H, t, J=7.3 Hz), 4.08 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.88 (1H, d, J=8.6 Hz), 6.97 (2H, d, J=8.4 Hz), 7.26 to 7.46 (7H, m), 7.59 (2H, d, J=8.4 Hz), 7.98 (1H, s), 8.32 (1H, br s).
IR (KBr) 3218, 1655, 1605, 1587, 1499, 1397, 1310, 1242, 1179, 1119, 833 cm −1
Elemental Analysis for C 39 H 49 N 5 O 3 S.0.75H 2 O. Calcd. C, 68.74; H, 7.47; N, 10.28. Found: C, 68.79; H, 7.15; N, 10.68.
›Example 136
(Preparation of Compound 145)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.00 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.55 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), and was recrystalized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 145) (614.2 mg) as yellow crystals.
m.p. 157 to 160° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.86 to 0.97 (6H, m), 1.02 (3H, t, J=7.3 Hz), 1.18 to 1.84 (10H, m), 2.89 to 2.99 (2H, m), 3.26 to 3.40 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.97 (5H, m), 4.06 to 4.17 (3H, m), 6.89 (H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.24 to 7.42 (7H, m), 7.85 (2H, d, J=8.8 Hz), 8.03 (1H, s), 8.73 (1H, s).
IR (KBr) 3295, 1655, 1607, 1588, 1518, 1499, 1318, 1242, 1181, 1028, 835 cm −1
Elemental Analysis for C 39 H 49 N 5 O 4 S.0.5H 2 O Calcd. C, 67.60; H, 7.27; N, 10.11. Found: C, 67.46; H, 7.03; N, 10.33.
›Example 137
(Preparation of Compound 146)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.21 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.48 g) and triethylamine (1.5 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 2 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (9 ml) were added and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-5-ethylthio-4-isobutyl-4H-1,2,4-triazole hydrochloride (0.54 g), and the mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 146) (845.4 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 (6H, d, J=7.0 Hz), 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.26 to 1.44 (5H, m), 1.54 to 1.68 (2H, m), 1.94 to 2.16 (2H, m), 2.84 to 2.95 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.21 (2H, q, J=7.4 Hz), 3.28 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.74 (2H, d, J=8.0 Hz), 3.80 (2H, t, J=5.0 Hz), 4.12 (2H, s), 4.16 (2H, t, J=5.0 Hz), 6.90 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.31 to 7.47 (7H, m), 7.56 (2H, d, J=8.4 Hz), 7.93 (1H, s).
IR (KBr) 3083, 1659, 1607, 1588, 1499, 1468, 1397, 1312, 1242, 1181, 1125, 831 cm −1
Elemental Analysis for C 42 H 55 N 5 O 3 S 2 .0.25H 2 O Calcd. C, 67.57; H, 7.49; N, 9.38. Found: C, 67.37; H, 7.50; N, 9.30.
›Example 138
(Preparation of Compound 147)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (697 mg) in dichloromethane (15 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.35 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 4:1→9:1 →ethyl acetate→ethanol:ethyl acetate 1:19), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(5-ethylthio-4-isobutyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 147) (574.6 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.84 to 1.00 (15H, m), 1.28 to 1.48 (5H, m), 1.52 to 1.68 (2H, m), 1.84 to 2.18 (2H, m), 2.89 to 2.98 (2H, m), 3.16 to 3.31 (4H, m), 3.34 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.66 to 3.84 (4H, m), 4.08 to 4.28 (4H, m), 6.91 to 7.00 (3H, m), 7.35 to 7.52 (7H, m), 7.79 (2H, d, J=8.8 Hz), 7.92 (1H, s).
IR (KBr) 3268, 1663, 1607, 1588, 1518, 1499, 1468, 1397, 1312, 1244, 1179, 1125, 1090, 835 cm −1
Elemental Analysis for C 42 H 55 N 5 O 4 S 2 .0.5H 2 O Calcd. C, 65.76; H, 7.36; N, 9.13. Found: C, 65.85; H, 7.47; N, 9.19.
›Example 139
(Preparation of Compound 148)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.21 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of S-(4-aminophenyl)O-benzylcarbonate (0.48 g) and triethylamine (1.5 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 4 hours, methanol (50 ml) and 1N aqueous solution of sodium hydroxide (12 ml) were added to the mixture, and the mixture was stirred for 0.5 hour. To the reaction solution was added 3-chloromethyl-5-methylthio-4-propyl-4H-1,2,4-triazole hydrochloride (0.47 g), and the mixture was stirred for 1 hour. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 148) (931 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (12H, m), 1.25 to 1.48 (2H, m), 1.52 to 1.81 (4H, m), 1.94 to 2.17 (1H, m), 2.68 (3H, s), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.29 to 3.39 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.86 (4H, m), 4.11 (2H, s), 4.16 (2H, t, J=4.9 Hz), 6.91 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.32 to 7.47 (7H, m), 7.57 (2H, d, J=8.8 Hz), 7.97 (1H, s).
IR (KBr) 3270, 1659, 1607, 1588, 1499, 1470, 1397, 1312, 1244, 1181, 1125, 816 cm −1
Elemental Analysis for C 40 H 51 N 5 O 3 S 2 .0.25H 2 O Calcd. C, 66.87; H, 7.22; N, 9.75. Found: C, 66.82; H, 7.11; N, 9.82.
›Example 140
(Preparation of Compound 149)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), which was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 149) (617.6 mg) as yellow crystals.
m.p. 150 to 152° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.88 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.3 Hz), 0.99 (6H, d, J=6.6 Hz), 1.29 to 1.45 (2H, m), 1.48 to 1.73 (4H, m), 1.96 to 2.19 (1H, m), 2.70 (3H, s), 2.89 to 3.01 (2H, m), 3.20 (2H, d, J=7.0 Hz), 3.31 to 3.43 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.89 (4H, m), 4.02 (1H, d, J=13.8 Hz), 4.13 to 4.20 (3H, m), 6.89 to 6.99 (3H, m), 7.36 to 7.47 (7H, m), 7.83 (2H, d, J=8.8 Hz), 8.22 (1H, s).
IR (KBr) 3164, 1659, 1603, 1590, 1518, 1499, 1476, 1395, 1312, 1242, 1179, 1125, 1053, 833 cm −1
Elemental Analysis for C 40 H 51 N 5 O 4 S 2 Calcd. C, 65.81; H, 7.04; N, 9.59. Found: C, 65.64; H, 7.00; N, 9.52.
›Example 141
(Preparation of Compound 150)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml) were added thionyl chloride (0.075 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (10 ml) was added dropwise to a solution of 4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]aniline (0.18 g) in pyridine (2 ml) at 0° C. The mixture was stirred at room temperature for 18 hours. To the reaction solution was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), and was further recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 150) (210.4 mg) as yellow crystals.
m.p. 134 to 136° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.84-0.98 (12H, m), 1.31 to 1.46 (2H, m), 1.52 to 1.86 (4H, m), 1.95 to 2.13 (1H, m), 2.84 (3H, s), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.28 to 3.38 (2H, m), 3.55 (2H, t, J=6.5 Hz), 3.78 to 3.90 (4H, m), 4.10 to 4.17 (2H, m), 4.56 (2H, s), 6.88 to 7.00 (5H, m), 7.36 to 7.54 (7H, m), 7.62 to 7.81 (1H, m), 8.10 (1H, s).
IR (KBr) 3287, 1655, 1605, 1518, 1499, 1248, 1186, 1121, 1067, 820 cm −1
Elemental Analysis for C 40 H 52 N 6 O 3 Calcd. C, 72.26; H, 7.88; N, 12.64. Found: C, 71.96; H, 7.89; N, 12.49.
›Example 142
(Preparation of Compound 151)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml) were added thionyl chloride (0.077 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (10 ml) was added dropwise to a solution of 4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]aniline (0.19 g) in pyridine (7 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4), and was further recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[methyl(4-propyl-4H-1,2,4-triazol-3-ylmethyl)amino]phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 151) (240.2 mg) as yellow crystals.
m.p. 131 to 133° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.1 Hz), 0.99 (3H, t, J=7.3 Hz), 1.28 to 1.47 (2H, m), 1.52 to 1.80 (6H, m), 2.85 (3H, s), 2.86 to 2.95 (2H, m), 3.26 to 3.38 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.89 (2H, t, J=7.3 Hz), 4.16 (2H, t, J=5.0 Hz), 4.59 (2H, s), 6.88 to 7.00 (5H, m), 7.34 to 7.52 (8H, m), 8.11 (1H, s).
IR (KBr) 3303, 1640, 1605, 1518, 1501, 1306, 1246, 119, 1175, 1128, 833, 821 cm −1
Elemental Analysis for C 39 H 50 N 6 O 3 .0.25H 2 O Calcd. C, 71.48; H, 7.77; N, 12.82. Found: C, 71.51; H, 7.74; N, 12.54.
›Example 143
(Preparation of Compound 152)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml) were added thionyl chloride (0.075 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethyl]aniline (0.17 g) and pyridine (2 ml) in THF (7 ml) at 0° C. The mixture was stirred at room temperature for 64 hours, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:9→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 152) (219.5 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.86 to 0.98 (12H, m), 1.33 to 1.48 (2H, m), 1.51 to 1.79 (2H, m), 1.96 to 2.15 (1H, m), 2.82 to 3.03 (4H, m), 3.05 to 3.22 (4H, m), 3.27 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.63 (2H, t, J=7.2 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.4 Hz), 7.37 to 7.55 (7H, m), 7.65 to 7.86 (1H, m), 8.03 (1H, s).
IR (KBr) 3090, 1655, 1605, 1516, 1499, 1246, 1182, 1123, 1067, 820 cm −1
Elemental Analysis for C 40 H 51 N 5 O 3 .0.5H 2 O Calcd. C, 72.92; H, 7.95; N, 10.63. Found: C, 72.88; H, 7.78; N, 10.56.
›Example 144
(Preparation of Compound 153)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.30 g) in THF (10 ml) were added thionyl chloride (0.077 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (10 ml) was added dropwise to a solution of 4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethyl]aniline (0.18 g) in pyridine (7 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:9→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethyl]phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 153) (378.3 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 (3H, t, J=7.2 Hz), 0.93 (3H, t, J=7.4 Hz), 0.99 (3H, t, J=7.4 Hz), 1.28 to 1.48 (2H, m), 1.54 to 1.81 (6H, m), 2.86 to 3.03 (4H, m), 3.10 to 3.22 (2H, m), 3.24 to 3.39 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.65 (2H, t, J=7.3 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.90 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.35 to 7.54 (7H, m), 7.62 (1H, s), 8.03 (1H, s).
IR (KBr) 3260, 1655, 1605, 1516, 1499, 1454, 1408, 1316, 1244, 1179, 1123, 1067, 818 cm −1
Elemental Analysis for C 39 H 49 N 5 O 3 .0.5H 2 O Calcd. C, 72.64; H, 7.82; N, 10.86. Found: C, 72.70; H, 7.74; N, 10.74.
›Example 145
(Preparation of Compound 154)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.20 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 4-[2-(4-aminophenylthio)ethyl]-4H-1,2,4-triazole (0.44 g) in pyridine (20 ml) at 1° C. The mixture was stirred at room temperature for 2 days, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:4→1:3), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 154) (1.06 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 6 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.28 to 1.48 (2H, m), 1.51 to 1.67 (2H, m), 1.92 to 2.18 (1H, m), 2.86 to 2.96 (2H, m), 3.15 to 3.22 (4H, m), 3.31 to 3.41 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.10 to 4.19 (4H, m), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.35 to 7.50 (7H, m), 7.61 (2H, d, J=8.4 Hz), 7.73 (1H, s), 8.15 (2H, s).
IR (KBr) 3092, 1659, 1607, 1497, 1456, 1395, 1310, 1285, 1242, 1182, 1123, 1071, 818 cm −1
Elemental Analysis for C 37 H 45 N 5 O 3 S.0.25H 2 O Calcd. C, 68.97; H, 7.12; N, 10.87. Found: C, 68.94; H, 7.12; N, 11.03.
›Example 146
(Preparation of Compound 155)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.37 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:19), and was recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 155) (681.4 mg) as yellow crystals.
m.p. 168 to 170° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.92 (3H, t, J=7.4 Hz), 0.97 (6H, d, J=6.2 Hz), 1.25 to 1.48 (2H, m), 1.53 to 1.68 (2H, m), 1.95 to 2.19 (1H, m), 2.86 to 2.95 (2H, m), 2.97 to 3.41 (6H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.22 to 4.37 (1H, m), 4.47 to 4.61 (1H, m), 6.90 to 6.99 (3H, m), 7.38 to 7.57 (7H, m), 7.83 (2H, d, J=8.6 Hz), 8.06 (1H, s), 8.17 (2H, s).
IR (KBr) 3225, 1663, 1605, 1590, 1534, 1501, 1316, 1246, 1182, 1040, 828 cm −1
Elemental Analysis for C 37 H 45 N 5 O 4 S Calcd. C, 67.76; H, 6.92; N, 10.68. Found: C, 67.49; H, 6.89; N, 10.51.
›Example 147
(Preparation of Compound 156)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.26 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (30 ml) was added dropwise to a solution of 4-[2-(4-aminophenylthio)ethyl]-4H-1,2,4-triazole (0.57 g) in pyridine (20 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:5→1:3), and was further recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 156) (1.34 g) as yellow crystals.
m.p. 114 to 115° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.00 (3H, t, J=7.4 Hz), 1.31 to 1.45 (2H, m), 1.52 to 1.84 (4H, m), 2.87 to 2.96 (2H, m), 3.20 (2H, t, J=6.6 Hz), 3.26 to 3.40 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.14 (4H, m), 6.91 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.36 to 7.49 (7H, m), 7.57 to 7.62 (3H, m), 8.16 (2H, s).
IR (KBr) 3243, 1647, 1609, 1591, 1526, 1501, 1397, 1319, 1275, 1246, 1182, 1123, 808 cm −1
Elemental Analysis for C 36 H 43 N 5 O 3 S.0.5H 2 O Calcd. C, 68.11; H, 6.99; N, 11.03. Found: C, 67.98; H, 7.07; N, 10.95.
›Example 148
(Preparation of Compound 157)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (1.0 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethanol:ethyl acetate 1:20→1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4H-1,2,4-triazol-4-ylethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 157) (0.90 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.99 (3H, t, J=7.2 Hz), 1.29 to 1.47 (2H, m), 1.52 to 1.86 (4H, m), 2.84 to 2.95 (2H, m), 2.98 to 3.39 (6H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.21 to 4.36 (1H, m), 4.46 to 4.61 (1H, m), 6.90 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.39 to 7.55 (7H, m), 7.82 (2H, d, J=8.8 Hz), 8.09 (1H, s), 8.16 (2H, s).
IR (KBr) 3112, 1661, 1607, 1588, 1516, 1499, 1397, 1312, 1242, 1181, 1046, 836 cm −1
Elemental Analysis for C 36 H 43 N 5 O 4 S.0.5H 2 Calcd. C, 66.44; H, 6.81; N, 10.76. Found: C, 66.34; H, 6.80; N, 10.62.
›Example 149
(Preparation of Compound 158)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.50 g) in THF (10 ml) were added thionyl chloride (0.13 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was contcentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 3-[(4-aminobenzyl)methylamino]-4-propyl-4H-1,2,4-triazole (0.34 g) in pyridine (10 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[methyl(4-n-propyl-4H-1,2,4-triazol-3-yl)aminomethyl]phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 158) (243 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (12H, m), 1.29 to 1.50 (2H, m), 1.52 to 1.68 (2H, m), 1.71 to 1.90 (2H, m), 1.97 to 2.18 (1H, m), 2.77 (3H, s), 2.87 to 2.96 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.30 to 3.42 (2H, m), 3.55 (2H, d, J=6.6 Hz), 3.71 to 3.83 (4H, m), 4.16 (2H, t, J=4.9 Hz), 4.24 (2H, s), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.27 to 7.50 (7H, m), 7.58 (2H, d, J=8.6 Hz), 7.66 (1H, s), 7.93 (1H, s).
IR (KBr) 3163, 1657, 1603, 1516, 1499, 1406, 1314, 1244, 1181, 1119, 816 cm −1
Elemental Analysis for C 40 H 52 N 6 O 3 .0.25H 2 O Calcd. C, 71.77; H, 7.91; N, 12.55. Found: C, 71.66; H, 7.91; N, 12.37.
›Example 150
(Preparation of Compound 159)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.48 g) in THF (10 ml) were added thionyl chloride (0.12 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 3-[(4-aminobenzyl)methylamino]-4-propyl-4H-1,2,4-triazole (0.31 g) in pyridine (10 ml) at 0° C. The mixture was stirred at room temperature for 16 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate→ethanol:ethyl acetate 1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[methyl(4-n-propyl-4H-1,2,4-triazol-3-yl)aminomethyl]phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 159) (120 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 1.03 (9H, m), 1.31 to 1.49 (2H, m), 1.51 to 1.85 (6H, m), 2.77 (3H, s), 2.86 to 2.97 (2H, m), 3.25 to 3.39 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.72 to 3.83 (4H, m), 4.16 (2H, t, J=4.9 Hz), 4.24 (2H, s), 6.90 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.29 to 7.55 (7H, m), 7.57 (2H, d, J=8.6 Hz), 7.62 (1H, s), 7.94 (1H, s).
IR (KBr) 3036, 1657, 1605, 1516, 1499, 1454, 1406, 1314, 1244, 1177, 818 cm −1
Elemental Analysis for C 39 H 50 N 6 O 3 .0.25H 2 O Calcd. C, 71.48; H, 7.77; N, 12.82. Found: C, 71.29; H, 7.63; N, 12.53.
›Example 151
(Preparation of Compound 160)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (355 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and sodium thiosulfate solution was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (246 mg) (Compound 160) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 0.98 (9H, m), 1.30 to 1.50 (2H, m), 1.55 to 1.75 (2H, m), 1.95 to 2.15 (1H, m), 2.85 to 2.95 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.63 (3H, s), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.91 (H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.05 (1H, d, J=1.4 Hz), 7.16 to 7.21 (3H, m), 7.37 to 7.53 (7H, m), 7.64 (1H, s).
Elemental Analysis for C 37 H 44 N 4 O 4 S Calcd. C, 71.12; H, 7.10; N, 8.97. Found: C, 70.81; H, 7.07; N, 8.89.
›Example 152
(Preparation of Compound 161)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (400 mg) in tetrahydrofuran (15 ml) was added one droplet of DMF. Then, thionyl chloride (0.09 ml) was added to the mixture under nitrogen atmosphere and the mixture was stirred for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure, and the obtained residue was dissolved in THF (15 ml). This solution was added dropwise to a solution of 4-[(4-methyl-1,2,4-triazol-3-yl)thio]aniline (189 mg) in pyridine (15 ml) at 0° C. under nitrogen atmosphere. After finishing the dropping, the mixture was allowed to be at room temperature under nitrogen atmosphere. The mixture was stirred for 1.5 hours, and water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by basic silica gel column chromatography (hexane-ethyl acetate=1:3), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-methyl-1,2,4-triazol-3-yl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (376 mg) (Compound 161) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.90 to 0.99 (9H, m), 1.34 to 1.45 (2H, m), 1.50 to 1.70 (2H, m), 1.95 to 2.15 (1H, m), 2.90 to 3.00 (2H, m), 3.20 (2H, d, J=7.2 Hz), 3.30 to 3.45 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.66 (3H, s), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.93 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.6 Hz), 7.39 to 7.53 (5H, m), 7.67 to 7.76 (3H, m), 7.90 (1H, s), 8.00 (2H, d, J=8.8 Hz).
Elemental Analysis for C 36 H 43 N 5 O 3 S.0.25H 2 O Calcd. C, 68.86; H, 6.95; N, 8.68. Found: C, 68.82; H, 6.98; N, 8.55.
›Example 153
(Preparation of Compound 162)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.20 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 3-(4-aminophenylthiomethyl)-2-methylimidazol[1,2-a]pyridine (0.54 g) in pyridine (7 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 162) (1.03 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.96 (6H, d, J=6.6 Hz), 1.29 to 1.48 (2H, m), 1.52 to 1.69 (2H, m), 1.94 to 2.17 (4H, m), 2.84 to 2.95 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.32 to 3.37 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.25 (2H, s), 6.81 to 6.85 (1H, m), 6.90 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.12 to 7.23 (3H, m), 7.36 to 7.55 (8H, m), 7.83 (1H, s), 8.00 to 8.06 (1H, m).
IR (KBr) 3032, 1655, 1607, 1586, 1499, 1397, 1350, 1285, 1242, 1179, 912, 818, 743 cm −1
Elemental Analysis for C 42 H 48 N 4 O 3 S.0.5H 2 O Calcd. C, 72.28; H, 7.08; N, 8.03. Found: C, 72.45; H, 7.58; N, 7.95.
›Example 154
(Preparation of Compound 163)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.43 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetatehexane 3:1→ethyl acetate), and was recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 163) (456.5 mg) as yellow crystals.
m.p. 130 to 133° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.97 (6H, d, J=6.6 Hz), 1.29 to 1.49 (2H, m), 1.53 to 1.68 (2H, m), 1.90 (3H, s), 1.95 to 2.18 (1H, m), 2.84 to 2.96 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.30 to 3.40 (2H, m), 3.56 (2H, d, J=6.8 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.27 (1H, d, J=14.1 Hz), 4.45 (1H, d, J=14.1 Hz), 6.72 to 6.79 (1H, m), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.12 to 7.21 (1H, m), 7.31 (1H, s), 7.38 to 7.50 (7H, m), 7.71 (2H, d, H=8.8 Hz), 8.04 (1H, s), 8.07 to 8.11 (1H, m).
IR (KBr) 3032, 1661, 1607, 1588, 1518, 1499, 13797, 1350, 1312, 1244, 1179, 912, 747 cm −1
Elemental Analysis for C 42 H 48 N 4 O 4 S.0.5H 2 O Calcd. C, 70.66; H, 6.92; N, 7.85. Found: C, 70.79; H, 6.87; N, 7.78.
›Example 155
(Preparation of Compound 164)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.21 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 3-(4-aminophenylthiomethyl)-2-methylimidazol[1,2-a]pyridine (0.56 g) in pyridine (7 ml) at 0° C. The mixture was stirred for 3 days at room temperature, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 2:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazol[1,2-a]pyridin-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 164) (1.17 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.99 (3H, t, J=7.5 Hz), 1.28 to 1.48 (2H, m), 1.53 to 1.84 (4H, m), 2.07 (3H, s), 2.84 to 2.93 (2H, m), 3.25 to 3.36 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.7 Hz), 4.16 (2H, t, J=4.7 Hz), 4.26 (2H, s), 6.81 to 6.95 (2H, m), 6.97 (2H, d, J=8.8 Hz), 7.13 to 7.23 (3H, m), 7.39 to 7.54 (8H, m), 7.72 (1H, s), 8.03 to 8.07 (1H, m).
IR (KBr) 3077, 1659, 1607, 1586, 1499, 1397, 1352, 1308, 1242, 1177, 1119, 818, 737 cm −1
Elemental Analysis for C 41 H 46 N 4 O 3 S.0.5H 2 O Calcd. C, 72.00; H, 6.93; N, 8.19. Found: C, 72.18; H, 6.89; N, 8.03.
›Example 156
(Preparation of Compound 165)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.96 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.52 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), and was further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 165) (663.1 mg) as yellow crystals.
m.p. 134 to 137° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 1.00 (3H, t, J=7.3 Hz), 1.28 to 1.49 (2H, m), 1.51 to 1.84 (4H, m), 1.94 (3H, s), 2.86 to 2.96 (2H, m), 3.27 to 3.39 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.30 (1H, d, J=14.4 Hz), 4.47 (1H, d, J=14.4 Hz), 6.73-6.79 (1H, m), 6.90 (H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.13 to 7.21 (1H, m), 7.30 (2H, d, J=8.8 Hz), 7.40 to 7.53 (1H, m), 7.69 (2H, d, J=8.8 Hz), 7.73 to 7.79 (1H, m), 8.09 (1H, d, J=7.0 Hz).
IR (KBr) 3228, 1661, 1607, 1588, 1518, 1499, 1312, 1244, 1179, 1042, 833 cm −1
Elemental Analysis for C 41 H 46 N 4 O 4 S.0.5H 2 O Calcd. C, 70.36; H, 6.77; N, 8.00. Found: C, 70.63; H, 6.96; N, 8.06.
›Example 157
(Preparation of Compound 166)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.20 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 3-(4-aminophenylthiomethyl)imidazo[1,2-a]pyridine (0.51 g) in pyridine (7 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 166) (0.98 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.30 to 1.47 (2H, m), 1.55 to 1.76 (2H, m), 1.96 to 2.17 (1H, m), 2.84 to 2.96 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.32 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.32 (2H, s), 6.86 to 6.93 (2H, m), 6.97 (2H, d, J=8.8 Hz), 7.18 to 7.29 (5H, m), 7.37 to 7.52 (6H, m), 7.58 to 7.64 (1H, m), 7.72 (1H, s), 8.13 to 8.17 (1H, m).
IR (KBr) 3165, 1657, 1607, 1588, 1499, 1310, 1242, 1181, 1128, 741, cm −1
Elemental Analysis for C 41 H 46 N 4 O 3 S.0.25H 2 O Calcd. C, 72.48; H, 6.90; N, 8.25. Found: C, 72.36; H, 6.98; N, 8.31.
›Example 158
(Preparation of Compound 167)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.44 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 167) (642 mg) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.97 (6H, d, J=6.6 Hz), 1.29 to 1.48 (2H, m), 1.52 to 1.74 (2H, m), 1.96 to 2.15 (1H, m), 2.88 to 2.98 (2H, m), 3.20 (2H, d, J=7.8 Hz), 3.30 to 3.42 (2H, m), 3.56 (2H, d, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.29 (1H, d, J=14.3 Hz), 4.48 (1H, d, J=14.3 Hz), 6.76 to 6.85 (1H, m), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.13 to 7.23 (2H, m), 7.32 to 7.48 (7H, m), 7.56 to 7.60 (1H, m), 7.71 (2H, d, H=8.8 Hz), 7.92 (1H, s), 8.15-8.18 (1H, m).
IR (KBr) 3088, 1661, 1607, 1588, 1518, 1499, 1397, 1312, 1244, 1179, 1123, 833 cm −1
Elemental Analysis for C 41 H 46 N 4 O 4 S.0.5H 2 O Calcd. C, 70.36; H, 6.77; N, 8.00. Found: C, 70.1; H, 6.80; N, 7.94.
›Example 159
(Preparation of Compound 168)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (1.0 g) in THF (10 ml) were added thionyl chloride (0.25 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (20 ml) was added dropwise to a solution of 5-(4-aminophenylthio)imidazo[1,2-a]pyridine (0.61 g) in pyridine (7 ml) at 0° C. The mixture was stirred at room temperature for 20 hours, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 168) (1.27 g) as yellow amorphous.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.3 Hz), 0.96 (6H, d, J=6.6 Hz), 1.30 to 1.48 (2H, m), 1.51 to 1.69 (2H, m), 1.94 to 2.13 (1H, m), 2.86 to 2.96 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, d, J=6.8 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.89 to 7.00 (4H, m), 7.12 to 7.20 (1H, m), 7.31 to 7.49 (7H, m), 7.58 to 7.68 (6H, m).
IR (KBr) 3223, 1655, 1609, 1588, 1499, 1397, 1310, 1289, 1244, 1179, 1121, 820 cm −1
Elemental Analysis for C 40 H 44 N 4 O 3 S.0.25H 2 O Calcd. C, 72.20; H, 6.74; N, 8.42. Found: C, 72.14; H, 6.67; N, 8.35.
›Example 160
(Preparation of Compound 169)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (1.0 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.56 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 5 hours at −20° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:1→3:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(imidazo[1,2-a]pyridin-5-ylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 169) (259 mg) as yellow crystals.
m.p. 162 to 164° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.96 (6H, d, J=6.6 Hz), 1.28 to 1.50 (2H, m), 1.52 to 1.70 (2H, m), 1.94 to 2.15 (1H, m), 2.84 to 2.93 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.28 to 3.39 (2H, m), 3.55 (2H, d, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.6 Hz), 7.31 to 7.53 (7H, m), 7.63 to 7.83 (8H, m).
IR (KBr) 3297, 1672, 1609, 1593, 1534, 1497, 1393, 1321, 1289, 1246, 1184, 1140, 138, 820 cm −1
Elemental Analysis for C 40 H 44 N 4 O 4 S Calcd. C, 70.98; H, 6.55; N, 8.28. Found: C, 70.72; H, 6.26; N, 8.30.
›Example 161
(Preparation of Compound 170)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-benzazepine-4-carboxylic acid (0.80 g) in THF (10 ml) were added thionyl chloride (0.20 ml) and DMF (1 droplet) at room temperature and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and a solution of the residue in THF (25 ml) was added dropwise to a solution of 5-(4-aminophenylthio)-2-methylimidazo[1,2-a]pyridine (0.52 g) in pyridine (10 ml) at 0° C. The mixture was stirred at room temperature for 3 days, and water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 170) (574 mg) as yellow crystals.
m.p. 164 to 166° C.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.1 Hz), 0.97 (6H, d, J=6.6 Hz), 1.27 to 1.46 (2H, m), 1.51 to 1.67 (2H, m), 1.96 to 2.14 (1H, m), 2.43 (3H, s), 2.85 to 2.94 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.30 to 3.40 (2H, m), 3.55 (2H, d, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.87-6.94 (2H, m), 6.97 (2H, d, J=8.8 Hz), 7.07 to 7.15 (1H, m), 7.30 (2H, d, J=8.8 Hz), 7.38 to 7.62 (10H, m).
IR (KBr) 3274, 1638, 1607, 1586, 1499, 1397, 1314, 1244, 1181, 1121, 814 cm −1
Elemental Analysis for C 41 H 46 N 4 O 3 S Calcd. C, 72.97; H, 6.87; N, 8.30. Found: C, 72.73; H, 6.96; N, 8.37.
›Example 162
(Preparation of Compound 171)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazo[1,2-a]pyridin-5-ylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.50 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.27 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred at −20° C. for 18 hours, sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 1:1→2:1), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(2-methylimidazo[1,2-a]pyridin-5-ylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 171) (110.5 mg) as yellow crystals.
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.96 (6H, d, J=6.6 Hz), 1.38 to 1.48-(2H, m), 1.51 to 1.67 (2H, m), 1.93 to 2.14 (1H, m), 2.40 (3H, s), 2.83 to 2.92 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.30 to 3.40 (2H,), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 6.91 (1H, d, J=9.2 Hz), 6.97 (2H, d, J=8.8 Hz), 7.26 to 7.34 (1H, m), 7.35 to 7.47 (6H, m), 7.58 to 7.78 (7H, m).
IR (KBr) 3300, 1671, 1609, 1591, 1532, 1499, 1318, 1246, 1184, 1121, 1042, 808 cm −1
Elemental Analysis for C 41 H 46 N 4 O 4 S.0.25H 2 O Calcd. C, 70.81; H, 6.74; N, 8.06. Found: C, 70.75; H, 6.53; N, 7.73.
›Example 163
(Preparation of Compound 172, Compound 173)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 133) was optically resoluted with CHIRALPAK AD(50 mm ID×500 mmL, hexane:ethanol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 172) (141 mg, 99.9% ee) and (−)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-methyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 173) (142 mg, 99.9% ee).
Compound 172
[α] D =+137.5° (C=0.504, ethanol solution)
Compound 173
[α] D =−137.9° (C=0.504, ethanol solution)
›Example 164
(Preparation of Compound 174, Compound 175)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 139) (387 mg) was optically resoluted with CHIRALPAK AD(50 mm ID×500 mmL, hexane:ethanol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 174) (170 mg, 99.9% ee) and (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 175) (171 mg, 99.9% ee).
Compound 174
[α] D =+146.6° (C=0.498, ethanol solution)
Compound 175
[α] D =−147.0° (C=0.506, ethanol solution)
›Example 165
(Preparation of Compound 176, Compound 177)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 141) was optically resoluted with CHIRALPAK AD(50 mm ID×500 mmL, hexane:ethanol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 176) (6.61 g, 99.9% ee) and (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 177) (6.85 g, 99.8% ee).
Compound 176
[α] D =+141.8° (C=0.495, ethanol solution)
Compound 177
[α] D =−140.8° (C=0.504, ethanol solution)
›Example 166
(Preparation of Compound 178, Compound 179)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 143) was optically resoluted with CHIRALPAK AD(50 mm ID×500 mmL, hexane:ethanol), to give (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 178) (220 mg, 99.9% ee) and (−)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-n-butyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 179) (200 mg, 99.8% ee).
Compound 178
[α] D =+133.1° (C=0.504, ethanol solution)
Compound 179
[α] D =−132.4° (C=0.5005, ethanol solution)
›Example 167
(Preparation of Compound 180)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the solution, thionyl chloride (0.34 ml) was added to the solution, and the solution was stirred at room temperature for 1 hour. The solution was added dropwise to the solution of 4-[(2-pyridinylsulfanyl)methyl]aniline (0.56 g) and triethylamine (1.97 ml) in THF (20 ml) under ice-cooling at room temperature and the mixture was stirred for 2 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 180) (0.56 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=6.8 Hz), 0.98(3H, t, J=7.4 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.80 (4H, m), 2.89 (2H, m), 3.26 to 3.34(4H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.12 to 4.18 (2H, m), 4.41 (2H, s), 6.88 (1H, d, J=8.4 Hz), 6.94 to 7.02 (2H, m), 6.97 (2H, d, J=8.8 Hz), 7.15 (1H, d, J=8.0 Hz), 7.35 to 7.56 (10H, m), 8.45 (1H, d, J=5.2 Hz).
IR (KBr) 3339, 2959, 1642, 1607, 1497, 1412, 1250, 1127, 924, 829 cm −1
›Example 168
(Preparation of Compound 181)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.30 g) was dissolved in methylene chloride (15 ml), m-chloroperbenzoic acid (83 mg) was added to the solution at −30° C., and the mixture was stirred for 1 hour at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 181) (97 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.98 (3H, t, J=7.4 Hz), 1.33 to 1.45 (2H, m), 1.55 to 1.76 (4H, m), 2.89 (2H, m), 3.26 to 3.34 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 (2H, t, J=4.8 Hz), 4.05 (1H, d, J=13.2 Hz), 4.12 to 4.18 (2H, m), 4.34 (H, d, J=13.2 Hz), 6.86 to 6.89 (5H, m), 7.32 to 7.59 (9H, m), 7.70 to 7.76 (2H, m), 8.64 to 8.68 (H, m)
IR (KBr) 2955, 1655, 1607, 1499, 1246, 1181, 1125, 1038 cm −1
›Example 169
(Preparation of Compound 182)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the mixture, and thionyl chloride (0.34 ml) was added to the mixture. The mixture was stirred at room temperature for 1 hour, and the mixture was added dropwise to the solution of 4-(2-pyridinylsulfanyl) aniline (0.53 g) and triethylamine (1.97 ml) in THF (20 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfanyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 182) (0.57 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 1.00 (3H, t, J=7.2 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.77 (4H, m), 2.93 (2H, m), 3.28 to 3.36 (4H, m), 3.51 to 3.59 (2H, m), 3.80 (2H, t, J=4.8 Hz), 4.13 to 4.18 (2H, m), 6.85 (1H, d, J=8.0 Hz), 6.90 (2H, t, J=8.8 Hz), 6.95 to 7.00 (3H, m), 7.40 to 7.50 (6H, m), 7.58 (2H, d, J=8.8 Hz), 7.66 to 7.71 (10H, m), 8.40 to 8.43 (1H, m).
IR (KBr) 3283, 2957, 1651, 1607, 1499, 1242, 1177, 1127, 833, 733 cm −1
›Example 170
(Preparation of Compound 183)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfanyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.15 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (95 mg) was added to the solution at 0° C., and the mixture was stirred for 15 minutes at 0° C. To the mixture was m-chloroperbenzoic acid (95 mg) was added, and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(2-pyridinylsulfinyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 183) (30 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.92 (3H, t, J=7.6 Hz), 0.96 (3H, t, J=7.6 Hz), 1.33 to 1.44 (2H, m), 1.43 to 1.82 (4H, m), 2.85 (2H, m), 3.23 to 3.31 (2H, m), 3.54 (2H, t, J=6.6 Hz), 3.76 to 3.82 (2H, m), 3.76 to 3.82 (2H, m), 4.13 (2H, t, J=6.6 Hz), 6.86 (1H, d, J=8.8 Hz), 6.93 (2H, d, J=8.8 Hz), 7.24 to 8.09 (13H, m), 8.52 (1H, d, J=4.0 Hz)
IR (KBr) 3268, 2957, 1663, 1588, 1499, 1244, 1123, 1036, 824, 735 cm −1
›Example 171
(Preparation of Compound 184)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.40 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (20 ml) was added dropwise to a solution of 4-[(2-pyridinylsulfanyl)methyl]aniline (0.54 g) and triethylamine (1.91 ml) in THF (16.2 ml) under ice-cooling and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue washed with hexane/ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 184) (0.65 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.96 (6H, t, J=6.6 Hz), 1.33 to 1.44 (2H, m), 1.54 to 1.69 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.32 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.6 Hz), 4.41 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.95 to 7.02 (3H, m), 7.15 (1H, d, J=8.0 Hz), 7.36 to 7.54 (11H, m), 8.44 to 8.47 (1H, m).
Elemental Analysis for C 39 H 45 N 3 O 3 S Cald. C, 73.67; N, 6.61; H, 7.13. Found: C, 73.50; N, 6.60; H, 7.09
›Example 172
(Preparation of Compound 185)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), and m-chloroperbenzoic acid (217 mg) was added to the solution at 0° C., and the mixture was stirred at 0° C. for 20 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 185) (70 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, t, J=6.6 Hz), 1.26 to 1.49 (2H, m), 1.54 to 1.69 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.35 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.07 (1H, d, J=13.2 Hz), 4.16 (2H, t, J=4.6 Hz), 4.35 (1H, d, J=13.0 Hz), 6.89 (1H, m), 6.91 (2H, d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.31 to 7.60 (10H, m), 7.78 (1H, td, J=7.8, 1.6 Hz), 8.66 to 8.69 (1H, m).
›Example 173
(Preparation of Compound 186)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.21 ml) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-(benzenesulfanylmethyl) aniline (0.36 g) and triethylamine (1.34 ml) in THF (10.7 ml) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give N-[4-(benzenesulfanylmethyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 186) (0.42 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.44 to 1.67 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.32 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.10 (2H, m), 4.12 to 4.18 (2H, m), 6.88 to 7.00 (5H, m), 7.14 to 7.31 (8H, m), 7.36 to 7.56 (5H, m)
›Example 174
(Preparation of Compound 187)
N-[4-(benzenesulfanylmethyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.35 g) was dissolved in methylene chloride (10.5 ml), m-chloroperbenzoic acid (99 mg) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate, to give N-[4-(benzenesulfinylmethyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 187) (164 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=5.6 Hz), 3.20 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 4.02 (2H, d, J=5.2 Hz), 4.13 to 4.18 (2H, m), 6.89 to 7.00 (5H, m), 7.37 to 7.53 (12H, m), 7.56 (1H, s).
IR (KBr) 3337, 2955, 1644, 1609, 1499, 1242, 1040, 831 cm −1
Elemental Analysis for C 40 H 46 N 2 O 4 S Cald. C, 73.81; N, 4.30; H, 7.12. Found: C, 73.60; N, 4.06; H, 7.21
›Example 175
(Preparation of Compound 188)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.30 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (20 ml) was added dropwise to a solution of 4-[(2-pyrimidinylsulfanyl)methyl]aniline (0.55 g) and triethylamine (1.91 ml) in THF (16.5 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 188) (0.30 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.35 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.12 to 4.18 (2H, m), 4.40 (2H, s), 6.89 to 7.00 (4H, m), 7.36 to 7.56 (10H, m), 8.53 (2H, d, J=5.0 Hz).
›Example 176
(Preparation of Compound 189)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfanyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.23 g) was dissolved in methylene chloride (7.5 ml), m-chloroperbenzoic acid (68 mg) was added to the mixture at 0° C., and the mixture was stirred for 15 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidylsulfinyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 189) (90 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.47 (2H, m), 1.55 to 1.69 (2H, m), 2.04 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J=7.4 Hz), 3.30 to 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.13 to 4.18 (2H, m), 4.22 (1H, d, J=13.2 Hz), 4.37 (1H, d, J=13.2 Hz), 6.89 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.07 (2H, d, J=8.4 Hz), 7.31 to 7.55 (8H, m), 7.82 (1H, s), 8.79 (2H, d, J=4.8 Hz).
IR (KBr) 3293, 2957, 1653, 1607, 1499, 1381, 1181, 1065, 816 cm −1
›Example 177
(Preparation of Compound 190)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.0 g) was dissolved in THF (20 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.40 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (20 ml) was added dropwise to a solution of 4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfanyl]methyl]aniline (0.68 g) and triethylamine (1.91 ml) in THF (20.4 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfanyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 0.190) (1.08 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.32 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.15 (2H, t, J=4.8 Hz), 4.45 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.22 to 7.26 (1H, m), 7.37 to 7.56 (10H, m), 7.66 (1H, dd, J=8.0, 2.2 Hz), 8.69(1H, s).
›Example 178
(Preparation of Compound 191)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfanyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) was dissolved in methylene chloride (20.4 ml), m-chloroperbenzoic acid (125 mg) was added to the mixture at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[5-(trifluoromethyl)-2-pyridinyl]sulfinyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 191) (136 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.48 to 1.65 (2H, m), 2.06 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.35 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.09 (1H, d, J=13.4 Hz), 4.13 to 4.18 (2H, m), 4.04 (1H, d, J=13.2 Hz), 6.88 to 7.00 (3H, m), 6.99 (2H, d, J=8.8 Hz), 7.37 to 7.33 (7H, m), 7.63 (1H, s), 7.75 (H, d, J=8.0 Hz), 8.02 (1H, m), 8.92 to 8.94 (H, m).
›Example 179
(Preparation of Compound 192)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (16 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.25 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (16 ml) was added dropwise to a solution of 4-[(2-pyridinylmethyl)sulfanyl]aniline (0.45 g) and triethylamine (2.1 ml) in THF (13.5 ml) under ice-cooling and the mixture was stirred for 1 hour at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was washed with hexane/ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 192) (0.68 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.98 (3H, t, J=6.8 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.76 (4H, m), 2.88 (2H, m), 3.26 to 3.35 (4H, m), 3.51 to 3.58 (2H, m), 3.77 to 3.83 (2H, m), 4.12 to 4.18 (2H, m), 4.21 (2H, s), 6.89 (H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.14 to 7.60 (13H, m), 8.51 to 8.55 (1H, m).
›Example 180
(Preparation of Compound 193)
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.40 g) was dissolved in methylene chloride (12 ml), m-chloroperbenzoic acid (111 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 193) (181 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.99 (3H, t, J=7.0 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.76 (4H, m), 2.90 (2H, m), 3.27 to 3.35 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.13 (1H, d, J=12.2 Hz), 4.15 (2H, m), 4.25 (1H, d, J=12.2 Hz), 6.89 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.12 to 7.25 (2H, m), 7.38 to 7.49 (7H, m), 7.61 (1H, td, J=7.6, 1.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.90 (1H, s).
IR (KBr) 3312, 2932, 2870, 1655, 1615, 1503, 1246, 1181, 1036, 824 cm −1
Elemental Analysis for C 31 H 43 N 3 O 4 S Cald. C, 71.56; N, 6.59; H, 6.80. Found: C, 71.38; N, 6.44; H, 7.06
›Example 181
(Preparation of Compound 194)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.2 g) was dissolved in THF (24 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.48 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (24 ml) was added dropwise to a solution of 4-[(2-pyridinylmethyl)sulfanyl]aniline (0.65 g) and triethylamine (2.3 ml) in THF (19.5 ml) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 194) (0.98 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.68 (2H, m), 2.05 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J=7.4 Hz), 3.31 to 3.36 (2H, m), 3.55 (2H, t, J=6.2 Hz), 3.80 (2H, t, J=4.8 Hz), 4.15 (2H, t, J=4.8 Hz), 4.21 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.10 to 7.17 (1H, m), 7.22 to 7.63 (13H, m), 8.51 to 8.54
(1H, m).
Elemental Analysis for C 39 H 45 N 3 O 3 S Cald. C, 73.67; N, 6.61; H, 7.13. Found: C, 73.78; N, 6.62; H, 7.37
›Example 182
(Preparation of Compound 195 and Compound 196)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.85 g) was dissolved in methylene chloride (25.5 ml), m-chloroperbenzoic acid (277 mg) was added to the mixture at 0° C., and the mixture was stirred for 90 minutes at 0° C. M-chloroperbenzoic acid (230 mg) was further added to the mixture, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 195) (300 mg) and 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 196) (150 mg).
Compound 195: 1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.2 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.62 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.2 Hz), 3.78 to 3.83 (2H, m), 4.13 to 4.19 (2H, m), 4.15 (1H, d, J=12.2 Hz), 4.26 (1H, d, J=12.4 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.14 to 7.26 (2H, m), 7.38 to 7.51 (7H, m), 7.63 (1H, td, J=7.6, 1.8 Hz), 7.69 to 7.78 (3H, m), 8.54 to 8.57 (1H, m).
IR (KBr) 3328, 2955, 1645, 1499, 1246, 1042, 829 cm −1
Compound 196: 1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=6.8 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.08 (1H, m), 2.97 (2H, m), 3.20 (2H, d, J=6.8 Hz), 3.34 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, m), 4.16 (2H, m), 4.54 (2H, s), 6.93 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.20 to 7.26 (2H, m), 7.40 to 7.49 (5H, m), 7.59 to 7.77 (6H, m), 8.43 to 8.46 (1H, m).
IR (KBr) 3310, 2955, 1649, 1501, 1242, 1163, 810 cm −1
Elemental Analysis for C 39 H 45 N 3 O 5 S Cald. C, 70.14; N, 6.29; H, 6.79. Found: C, 70.10; N, 6.39; H, 7.06
›Example 183
(Preparation of Compound 197 and Compound 198)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) was optically resoluted with CHIRALCEL OJ(5 cmφ×50 cm), to give (+)-(7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 197) (78 mg, [α] D =+95.4°) and (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 198) (95 mg).
›Example 184
(Preparation of Compound 199)
7-[4-(2-butoxyethoxy)phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was dissolved in DMF (10 ml), 4-[(2-pyridinylsulfanyl)methyl]aniline (272 mg) and 1-hydroxybenzotriazole (321 mg) were added to the mixture, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chloride (401 mg) and triethylamine (0.44 ml) were added to the mixture, and the mixture was stirred for 16 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 199) (0.36 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 1.33 to 1.46 (2H, m), 1.54 to 1.68 (2H, m), 2.87 to 3.25 (3H, m), 3.55 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 4.10 (2H, s), 4.18 (2H, t, J=4.8 Hz), 4.86 (1H, m), 7.02 (2H, d, J=8.8 Hz), 7.10 to 7.34 (7H, m), 7.42 (1H, s), 7.48 to 7.55 (6H, m), 7.65 (1H, d, J=1.8 Hz).
›Example 185
(Preparation of Compound 200 and Compound 201)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfanyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (0.35 g) was dissolved in methylene chloride (10.5 ml), m-chloroperbenzoic acid (0.28 g) was added to the mixture at 0° C., and the mixture was stirred for 2 hours at room temperature. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 200) (61 mg) and 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 201) (151 mg).
Compound 200: 1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 1.33 to 1.49 (2H, m), 1.58 to 1.69 (2H, m), 2.91 to 3.24 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 4.15 to 4.21 (2H, m), 4.29 (2H, s), 4.75 to 4.88 (1H, m), 7.02 (2H, d, J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz), 7.31 to 7.67 (11H, m).
Compound 201: 1 H-NMR (200 MHz, CDCl 3 ) δ 0.94 (3H, t, J=7.0 Hz), 1.29 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.85 to 3.26 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.6 Hz), 4.02 (2H, s), 4.18 (2H, t, J=4.8 Hz), 4.75 to 4.89 (1H, m), 6.96 (2H, d, J=8.4 Hz), 7.02 (2H, d, J=8.8 Hz), 7.30 to 7.57 (11H, m), 7.63 (1H, s), 7.83 (1H, s).
›Example 186
(Preparation of Compound 202)
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (137 mg) was dissoved in ethanol (4.0 ml), sodium borohydride (36 mg) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (36 mg) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 202) (85 mg).
1 H-NMR (200 MHz, CDCl 3 ) 0.93 (3H, t, J=7.2 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.9.4 (2H, m), 3.46 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 3.98 (1H, d, J=12.8 Hz), 4.07 (1H, d, J=12.4 Hz), 4.13 to 4.18 (2H, m), 4.61 (1H, m), 6.70 (1H, d, J=8.4 Hz), 6.94 (2H, d, J=8.4 Hz), 6.97 (2H, d, J=8.8 Hz), 7.29 to 7.52 (11H, m), 7.64 (1H, s).
IR (KBr) 3318, 2957, 1651, 1609, 1516, 1318, 1246, 1181, 1038, 820 cm −1
Examples 187
(Preparation of Compound 203)
In 1,2-dichloromethane (7.0 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (70 mg), and isobutylaldehyde (51 μl), sodium triacetoxyborohydride (118 mg) and acetic acid (3 droplets) were added to the mixture, and the mixture was stirred for 60 hours at room temperature. Sodium triacetoxyborohydride (118 mg) was added to the mixture, and the mixture was stirred at 50° C. for 40 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 203) (52 mg).
1 H-NMR (200 MHz, CDCl 3 ) 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.4 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.32 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 3.98 (1H, d, J=12.2 Hz), 4.07 (1H, d, J=12.6 Hz), 4.13 to 4.18 (2H, m), 6.89 to 6.94 (3H, m), 6.98 (2H, d, J=8.4 Hz), 7.37 to 7.53 (11H, m), 7.66 (1H, s).
IR (KBr) 3337, 2951, 1640, 1518, 1499, 1246, 1038, 808 cm −1
›Example 188
(Preparation of Compound 204)
In ethanol (4.9 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-1-(trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (49 mg), and sodium borohydride (13 mg) was added to the mixture, and the mixture was stirred at room temperature for 3 hours. Sodium borohydride (13 mg) was further added to the mixture, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 204) (23 mg).
1 H-NMR (200 MHz, CDCl 3 ). δ 0.93 (3H, t, J=7.4 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.62 (2H, m), 2.95 (2H, m), 3.46 (2H, t, J=4.6 Hz), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.07 to 4.20 (2H, m) 4.29 (2H, s), 6.55 (1H, d, J=8.6 Hz), 6.70 (1H, d, J=8.2 Hz), 6.85 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.8 Hz), 7.05 (2H, d, J=8.4 Hz), 7.31 to 7.35 (2H, m), 7.41 to 7.67 (7H, m).
IR (KBr) 3387, 2945, 2861, 1663, 1611, 1526, 1319, 829 cm −1
›Example 189
(Preparation of Compound 205)
In 1,2-dichloromethane (0.85 ml) was dissolved 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-pyridinylsulfonyl)methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (17 mg), and isobutylaldehyde (13 μl), sodium triacetoxyborohydride (29 mg) and acetic acid (3 droplets) were added to the mixture, and the mixture was stirred at 50° C. for 40 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-oxido-2-pyridinyl)sulfonyl]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 205) (6 mg).
1 H-NMR (200 MHz, CDCl 3 ). δ 0.93 (3H, t, J=6.6 Hz), 0.97 (6H, d, J=7.2 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.05 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 4.13 to 4.19 (2H, m), 4.29 (2H, s), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=9.2 Hz), 7.05 (2H, d, J=8.6 Hz), 7.38 to 7.67 (12H, m).
›Example 190
(Preparation of Compound 206)
7-(4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-(benzylsulfanyl) aniline (0.38 g) and triethylamine (1.34 ml) in THF (11.4 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give. N-[4-(benzylsulfanyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 206) (0.70 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.4 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.32 to 3.37 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.06 (2H, s), 4.16 (2H, t, J=4.6 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.25 to 7.32 (7H, m), 7.37 to 7.56 (8H, m).
›Example 191
(Preparation of Compound 207, Compound 208)
In methylene chloride (11.4 ml) was dissolved m-chloroperbenzoic acid (0.23 g), and this solution was added dropwise to a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(benzylsulfanyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.57 g) in methylene chloride (17.1 ml) at 0° C. The mixture was stirred for 20 minutes at 0° C., m-chloroperbenzoic acid (0.23 g) was further added to the mixture, and the mixture was stirred for 20 minutes at 0° C. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give. N-[4-(benzylsulfinyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 207) (135 mg) and N-[4-(benzylsulfonyl)phenyl]-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 208) (35 mg).
Compound 207: 1 H-NMR (200 MHz, CDCl 3 ) 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65: (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.17 (2H, d, J=7.0 Hz), 3.34 (2H, m), 3.54 (2H, t, J=6.6 Hz), 3.77 to 3.82 (2H, m), 3.95 (1H, d, J=12.4 Hz), 4.04 to 4.11 (1H, m), 4.11 to 4.17 (2H, m), 6.89 to 6.99 (3H, m), 6.96 (2H, d, J=8.6 Hz), 7.24 to 7.51 (10H, m), 7.69 (2H, d, J=8.8 Hz), 7.92 to 8.15 (1H, m).
IR (KBr) 3331, 2957, 1651, 1499, 1312, 1242, 1038, 828 cm −1
Compound 208: 1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.55 to 1.65 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.20 (2H, d, J=7.6 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 4.16 (2H, t, J=4.6 Hz), 4.30 (2H, s), 6.90 to 6.95 (1H, m), 6.98 (2H, d, J=8.8 Hz), 7.24 to 7.33 (4H, m), 7.40 to 7.76 (9H, m).
IR (KBr) 3314, 2957, 1647, 1499, 1244, 1167, 787 cm −1
›Example 192
(Preparation of Compound 209)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-[(3-pyridinylmethyl)sulfanyl]aniline (0.38 g) and triethylamine (1.34 ml) in THF (11.4 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 209) (0.33 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.07 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.8 Hz), 3.32 to 3.38 (2H, m), 3.55 (2H, t, J=6.2 Hz), 3.80 (2H, t, J=4.8 Hz), 4.01 (2H, s), 4.15 (2H, t, J=4.8 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.15 to 7.29 (3H, m), 7.37 to 7.60 (9H, m), 8.38 (1H, d, J=2.2 Hz), 8.46 (1H, dd, J=4.6, 1.8 Hz).
›Example 193
(Preparation of Compound 210)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.32 g) was dissolved in methylene chloride (9.6 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 210) (98 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.91 (1H, d, J=12.8 Hz), 4.05 to 4.12 (1H, m), 4.16 (2H, t, J=4.8 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.19 to 7.31 (3H, m), 7.39 to 7.51 (6H, m), 7.70 (2H, d, J=8.8 Hz), 7.83 (1H, m), 8.12 (1H, m), 8.52 (0.1H, dd, J=4.8, 1.6 Hz).
IR (KBr) 3333, 2957, 1651, 1499, 1242, 1036, 818 cm −1
›Example 194
(Preparation of Compound 211)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-[(4-pyridinylmethyl)sulfanyl]aniline (0.38 g) and triethylamine (1.34 ml) in THF (11.4 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 211) (0.27 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.06 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.35 (2H, t, J=4.8 Hz), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.82 (2H, m), 3.98 (2H, s), 4.12 to 4.18 (2H, m), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.38 to 7.58 (8H, m), 8.47 to 8.51 (2H, m).
›Example 195
(Preparation of Compound 212)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.24 g) was dissolved in methylene chloride (7.2 ml), m-chloroperbenzoic acid (65 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(4-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 212) (101 mg).
H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.05 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.44 to 3.50 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.92 (1H, d, J=12.4 Hz), 4.05 (1H, d, J=12.8 Hz), 4.13 to 4.18 (2H, m), 6.88 to 6.92 (3H, m), 6.98 (2H, d, J=8.8 Hz), 7.31 to 7.49 (7H, m), 7.69 to 7.82 (3H, m), 8.50 (2H, d, 5.8 Hz).
IR (KBr) 3335, 2957, 1649, 1499, 1242, 1036, 829 cm −1
Elemental Analysis for C 39 H 45 N 3 O 4 S. Cald. C, 71.86; N, 6.45; H, 6.96. Found: C, 71.65; N, 6.56; H, 7.04
›Example 196
(Preparation of Compound 213)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2, 3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-[(3-pyridinylmethyl)sulfanyl]aniline (0.39 g) and triethylamine (1.34 ml) in THF (11.4 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 213) (0.52 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.96 (6H, d, J=6.6 Hz), 1.36 to 1.45 (2H, m), 1.57 to 1.64 (2H, m), 2.05 (1H, m), 2.54 (3H, s), 2.89 (2H, m), 3.17 (2H, t, J=7.2 Hz), 3.34 (2H, t, J=4.4 Hz), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.12 to 4.18 (2H, m), 4.19 (2H, s), 6.91 (1H, d, J=8.6 Hz), 6.97 (2H, d, J=8.8 Hz), 6.95 to 7.07 (2H, m), 7.29 to 7.57 (11H, m).
›Example 197
(Preparation of Compound 214)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.46 g) was dissolved in methylene chloride (13.8 ml), m-chloroperbenzoic acid (87 mg) was added to the mixture at 0° C., and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 214) (157 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.92 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.08 (1H, m), 2.52 (3H, s), 2.92 (2H, m), 3.19 (2H, t, J=7.4 Hz), 3.34 to 3.40 (2H, m), 3.51 to 3.58 (2H, m), 3.78 to 3.83 (2H, m), 4.09 (1H, d, J=12.0 Hz), 4.13 to 4.18 (2H, m), 4.23 (1H, d, J=12.4 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 6.98 to 7.09 (2H, m), 7.38 to 7.55 (8H, m), 7.69 to 7.79 (3H, m).
IR (KBr) 3322, 2965, 1644, 1588, 1499, 1244, 1184, 1044, 924, 829, 750 cm −1
›Example 198
(Preparation of Compound 215)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]aniline (0.42 g) and triethylamine (1.34 ml) in THF (12.6 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4-chloro-2-pyridinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 215) (0.51 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.92 (3H, t, J=7.4 Hz), 0.95 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.53 to 1.64 (2H, m), 2.04 (1H, m), 2.87 (2H, m), 3.15 (2H, d, J=7.0 Hz), 3.29 to 3.34 (2H, m), 3.54 (2H, t, 6.6 Hz), 3.77 to 3.82 (2H, m), 4.09 to 4.15 (2H, m), 4.16 (2H, s), 6.89 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.4 Hz), 7.23 to 7.54 (11H, m), 7.73 (1H, s), 8.40 (1H, d, J=5.2 Hz).
›Example 199
(Preparation of Compound 216)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.51 g) was dissolved in methylene chloride (15.3 ml), and to the mixture was added dropwise a solution of m-chloroperbenzoic acid (0.20 g) in methylene chloride (10.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(6-chloro-2-pyridinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 216) (0.34 g).
1 H-NMR (200 MHz, CDCl 3 ) δ0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.63 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.19 (2H, m), 3.34 to 3.39 (2H, m), 3.55 (2H, m), 3.77 to 3.83 (2H, m), 4.13 to 4.18 (2H, m), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.23 to 7.26 (2H, m), 7.38 to 7.53 (7H, m), 7.72 to 7.81 (3H, m), 8.41 to 8.45 (1H, m).
IR (KBr) 3320, 2957, 1645, 1499, 1244, 1127, 1042, 826 cm −1
Elemental Analysis for C 39 H 44 N 3 O 4 SCl Cald. C, 68.25; N, 6.12; H, 6.46; Cl, 5.17. Found: C, 68.04; N, 6.16; H, 6.43; Cl, 5.05
›Example 200
(Preparation of Compound 217)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.70 g) was dissolved in THF (14 ml), DMF (2 droplets) was added to the mixture, oxalyl chloride (0.28 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (14 ml) was added dropwise to a solution of 4-[[(4-methyl-2-pyridinyl)methyl]sulfanyl]aniline (0.41 g) and triethylamine (1.78 ml) in THF (12.3 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 217) (0.40 g).
1 H-NMR (200 MHz, CDCl 3 ) δ0.93 (3H, t, J=7.2 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.30 (3H, s), 2.89 (2H, m), 3.17 (2H, d, J=7.4 Hz), 3.31 to 3.37 (2H, m), 3.51 to 3.59 (2H, m), 3.77 to 3.83 (2H, m), 4.10 to 4.15 (2H, m), 4.18 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.4 Hz), 7.11 (1H, s), 7.27 to 7.52 (10H, m), 7.63 (1H, s), 7.38 (1H, d, J=5.2 Hz).
›Example 201
(Preparation of Compound 218)
A solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.39 g) in methylene chloride (7.8 ml) was added dropwise to a solution of m-chloroperbenzoic acid (0.21 g) in methylene chloride (7.8 ml) at −40° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(6-methyl-2-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 218) (146 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=6.8 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.68 (2H, m), 2.07 (1H, m), 2.31 (3H, s), 2.91 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.33 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.15 to 4.18 (2H, m), 4.15 (2H, s), 6.92 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 6.95 to 7.05 (2H, m), 7.37 to 7.52 (7H, m), 7.73 (2H, d, J=8.4 Hz), 7.92 (1H, s), 8.40 (1H, d, J=5.2 Hz).
IR (KBr) 3322, 2959, 1644, 1501, 1242, 1184, 828 cm −1
Elemental Analysis for C 40 H 47 N 3 O 4 S.0.3H 2 O. Cald. C, 72.57; N, 6.26; H, 7.15. Found: C, 71.69; N, 6.22; H, 7.28
›Example 202
(Preparation of Compound 219)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (1.2 g) was dissolved in THF (24 ml), DMF (3 droplets) was added to the mixture, oxalyl chloride (0.48 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (24 ml) was added dropwise to a solution of 4-[[2-(methoxymethoxy)benzyl]sulfanyl]aniline (0.83 g) and triethylamine (2.29 ml) in THF (24.9 ml) under ice-cooling and the mixture was stirred at room temperature for 16 hours. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and washed with hexane/ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 219) (1.09 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.55 to 1.65 (2H, m), 2.07 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.33 to 3.38 (2H, m), 3.50 (3H, s), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.4 Hz), 4.12 (2H, S), 4.13 to 4.19 (2H, m), 5.19 (2H, s), 6.84 to 7.52(17H, m).
›Example 203
(Preparation of Compound 220)
A solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.02 g) in methylene chloride (20.4 ml), was added dropwise to a solution of m-chloroperbenzoic acid (0.51 g) in methylene chloride (40.8 ml) at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 220) (820 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.53 to 1.67 (2H, m), 2.07 (1H, m), 2.91 (2H, m), 3.18 (2H, d, J=7.0 Hz), 3.35 (2H, d, J=7.0 Hz), 3.45 (3H, s), 3.54 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.01 (1H, d, J=12.0 Hz), 4.12 to 4.18 (2H, m), 4.29 (1H, d, J=12.2 Hz), 5.06 (2H, s), 6.86 to 7.08 (6H, m), 7.20 to 7.43 (8H, m), 7.68 (2H, d, J=8.8 Hz), 7.87 to 7.98 (1H, m).
IR (KBr) 3335, 2957, 1645, 1588, 1499, 1242, 1182, 926, 828, 760 cm −1
Elemental Analysis for C 42 H 50 N 2 O 6 S Cald. C, 70.96; N, 3.94; H, 7.09. Found: C, 70.93; N, 3.88; H, 7.01
›Example 204
(Preparation of Compound 221)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.69 g) was dissolved in methanol (13.8 ml), 4N hydrochloric acid/ethyl acetate (3.45 ml) was added to the mixture at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-hydroxybenzyl)sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 221) (0.30 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.53 to 1.64 (2H, m), 2.05 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J=7.4 Hz), 3.31 to 3.35 (2H, d, J=6.6 Hz), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 3.96 (1H, d, J=13.8 Hz), 4.10 to 4.17 (2H, m), 4.37 (1H, d, J=13.6 Hz), 6.63-6.72 (2H, m), 6.89 to 7.00 (4H, m), 7.12 to 7.18 (1H, m), 7.37 to 7.48 (7H, m), 7.72 (2H, d, J=7.0 Hz), 7.92 (1H, s), 9.08 (1H, s).
IR (KBr) 2957, 1649, 1607, 1499, 1397, 1246, 1179, 818, 756 cm −1
›Example 205
(Preparation of Compound 222)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, oxalyl chloride (0.24 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in methylene chloride (12 ml) was added dropwise to a solution of 4-amino-N-(2-pyrimidinyl)benzenesulfonamide (0.38 g) and triethylamine (1.53 ml) in methylene chloride (11.4 ml) under ice-cooling and the mixture was stirred for 20 hours at room temperature. The reaction solution was added to water, and extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(2-pyrimidinylamino)sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 222) (113 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=6.8 Hz), 0.93 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.61 (2H, m), 2.05 (1H, m), 2.83 (2H, m), 3.22 (2H, d, J=7.4 Hz), 3.26 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.4 Hz), 4.14 (2H, d, J=4.4 Hz), 6.85 to 7.00 (4H, m), 7.35 to 7.44 (5H, m), 7.74 (2H, d, J=8 Hz), 7.96 to 8.02 (3H, m), 8.64 (2H, d, J=5.0 Hz), 11.33 (1H, br).
IR (KBr) 3312, 2953, 1647, 1581, 1499, 1246, 1165, 941, 839 cm −1
Elemental Analysis for C 37 H 43 N 5 O 5 S Cald. C, 66.34; N, 10.46; H, 6.47. Found: C, 66.18; N, 10.44; H, 6.77
›Example 206
(Preparation of Compound 223)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was dissolved in THF (10 ml), DMF (3 droplets) was added to the mixture, oxalyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (10 ml) was added dropwise to a solution of 3-methyl-4-[(2-pyridinylmethyl)sulfanyl]aniline (0.29 g) and triethylamine (0.96 ml) in THF (8.7 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 223) (0.46 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.34 (3H, s), 2.89 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.32 to 3.37 (2H, m), 3.52 to 3.59 (2H, m), 3.80 (2H, t, J=4.6 Hz), 4.13 to 4.18 (2H, m), 4.16 (2H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.6 Hz), 7.14 to 7.18 (12H, m), 8.51 to 8.55 (1H, m).
›Example 207
(Preparation of Compound 224)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(2-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.45 g) in methylene chloride (13.5 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.16 g) in methylene chloride (9.0 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(2-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 224) (185 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.97 (6H, d, J=6.6 Hz), 1.29 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.07 (1H, m), 2.22 (3H, s), 2.91 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.34 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 4.13 to 4.18 (2H, m), 4.18 (2H, s), 6.89 to 6.95 (1H, m), 6.97 (2H, d, J=8.8 Hz), 7.12 to 7.24 (2H, m), 7.38 to 7.79 (10H, m), 8.53 (1H, d, J=4.4 Hz).
IR (KBr) 3287, 2957, 1661, 1499, 1244, 1180, 910, 818, 733 cm −1
Elemental Analysis for C 40 H 47 N 3 O 4 S Cald. C, 72.15; N, 6.31; H, 7.11. Found: C, 72.20; N, 6.45; H, 7.08
›Example 208
(Preparation of Compound 225)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.50 g) was dissolved in THF (10 ml), DMF (3 droplets) was added to the mixture, oxalyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (10 ml) was added dropwise to a solution of 4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]-3-methylaniline (0.33 g) and triethylamine (0.96 ml) in THF (9.9 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 225) (0.18 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (5H, m), 1.54 to 1.65 (2H, m), 2.05 (1H, m), 2.36 (3H, s), 2.89 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.36 (2H, m), 3.51 to 3.59 (2H, m), 3.80 (2H, t, J=4.8 Hz), 4.12 (2H, s), 4.12 (2H, q, J=7.0 Hz), 6.66 (1H, dd, J=5.6, 2.2 Hz), 6.76 (1H, d, J=2.6 Hz), 6.91 (1H, d, J=8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.30 to 7.48 (8H, m), 8.33 (1H, d, J=5.8 Hz).
›Example 209
(Preparation of Compound 226)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.17 g) in methylene chloride (5.1 ml) was added dropwise a solution of m-chloroperbenzoic acid (55 mg) in methylene chloride (3.4 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-methyl-4-[[(4-ethoxy-2-pyridinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 226) (32 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.89 to 1.00 (6H, m), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.44 (5H, m), 1.54 to 1.65 (2H, m), 2.08 (1H, m), 2.27 (3H, s), 2.91 (2H, m), 3.19 (2H, d, J=7.0 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.01 to 4.18 (4H, m), 4.10 (2H, s), 6.69 to 6.73 (2H, m), 6.90 to 6.95 (2H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.26 to 7.58 (8H, m), 7.77 (1H, d, J=8.2 Hz), 8.31 (1H, d, J=5.2 Hz).
IR (KBr) 3268, 2957, 1661, 1599, 1497, 1238, 1125, 1044, 816, 731 cm −1
›Example 210
(Preparation of Compound 227)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, oxalyl chloride (0.24 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (12 ml) was added dropwise to a solution of 4-[(3-pyridinylmethyl)sulfanyl]-3-methylaniline (0.33 g) and triethylamine (1.15 ml) in THF (9.9 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 227) (0.51 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.0 Hz), 0.96 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.29 (3H, s), 2.89 (2H, t, J=4.0 Hz), 3.17 (2H, d, J=7.2 Hz), 3.31 to 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 3.94 (2H, s), 4.10 to 4.18 (2H, m), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.14 to 7.25 (2H, m), 7.34 to 7.51 (8H, m), 7.63 (1H, s), 8.36 (1H, d, J=2.2 Hz), 8.43 to 8.47 (1H, m).
›Example 211
(Preparation of Compound 228)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) in methylene chloride (15 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.17 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[(3-pyridinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 228) (151 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.06 (1H, m), 2.18 (3H, s), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.34 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 3.90 (1H, d, J=13.0 Hz), 4.02 (1H, d, J=12.8 Hz), 4.12 to 4.17 (2H, m), 6.89 to 6.94 (1H, m), 6.96 (2H, d, J=8.8 Hz), 7.15 to 7.49 (10H, m), 7.71 (1H, s), 8.02 (1H, s), 8.48 to 8.52 (1H, m).
IR (KBr) 3287, 2957, 1655, 1499, 1244, 910, 816, 731 cm −1
›Example 212
(Preparation of Compound 229)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (12 ml) was added dropwise to a solution of 4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfanyl]aniline (0.37 g) and triethylamine (1.53 ml) in THF (11.1 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 229) (0.57 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.4 Hz), 0.97 (6H, d, J=6.6 Hz), 1.36 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.40 (6H, s), 2.90 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.32 to 3.38 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 4.13 (2H, s), 6.69 (1H, s), 6.91 (1H, d, J=9.2 Hz), 6.97 (2H, d, J=8.8 Hz), 7.36 to 7.55 (10H, m).
›Example 213
(Preparation of Compound 230)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (0.56 g) in methylene chloride (16.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.22 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. The mixture was allowed to be warmed up to 0° C., and an aqueous solution of saturated sodium thiosulfate was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[(4,6-dimethyl-2-pyrimidinyl)methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 230) (165 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.05 (1H, m), 2.54 (6H, s), 2.90 (2H, m), 3.18 (2H, d, J=7.4 Hz), 3.35 (2H, t, J=4.4 Hz), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.6 Hz), 4.16 to 4.24 (1H, m), 4.35 (1H, d, J=12.8 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (1H, d, J=8.8 Hz), 7.02 (1H, d, J=8.8 Hz), 7.14 (1H, d, J=8.8 Hz), 7.36 to 7.56 (7H, m), 7.71 (1H, s).
IR (KBr) 3285, 2957, 1651, 1582, 1499, 1244, 1180, 910, 816, 733 cm −1
Elemental Analysis for C 40 H 48 N 4 O 4 S Cald. C, 70.56; N, 8.23; H, 7.11. Found: C, 70.39; N, 8.04; H, 7.08
›Example 214
(Preparation of Compound 231)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (12 ml) was added dropwise to a solution of 4-[[(1-methyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (0.31 g) and triethylamine (1.53 ml) in THF (9.3 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 231) (0.59 g).
1 H-NMR (200 MHz, CDCl 3 ) 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.04 (1H, m), 2.89 (2H, m), 3.17 (2H, d, J=7.4 Hz), 3.32 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.78 to 3.83 (2H, m), 4.10 (2H, s), 4.12 to 4.18 (2H, m), 6.89 (1H, d, J=9.0 Hz), 6.96 (2H, d, J=8.8 Hz), 7.21 to 7.41 (7H, m), 7.58 (2H, d, J=8.8 Hz), 8.08(1H, s).
IR (KBr) 3310, 2957, 1651, 1607, 1499, 1244, 1180, 910, 816, 733 cm −1
›Example 215
(Preparation of Compound 232)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g) in methylene chloride (18 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (12 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 232) (350 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.8 Hz), 0.99 (6H, d, J=7.0 Hz), 1.33 to 1.45 (2H, m), 1.52 to 1.64 (2H, m), 2.08 (1H, m), 2.92 (2H, m), 3.18 (2H, d, J=6.6 Hz), 3.34 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.77 to 3.83 (2H, m), 3.91 to 4.23 (2H, m), 3.92 (3H, s), 4.11 to 4.17 (2H, m), 6.88 to 6.93 (1H, m), 6.95 (2H, d, J=8.4 Hz), 7.30 to 7.40 (7H, m), 7.83 (2H, d, J=8.4 Hz), 8.50 (1H, br).
IR (KBr) 2957, 1647, 1607, 1507, 1316, 1244, 910, 735 cm −1
›Example 216
(Preparation of Compound 233)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (12 ml) was added dropwise to a solution of 4-[[(2-methyl-1,2,3,4-tetrazol-5-yl)methyl]sulfanyl]aniline (0.31 g) and triethylamine (1.53 ml) in THF (9.3 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 233) (0.59 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.57 to 1.65 (2H, m), 2.05 (1H, m), 2.90 (2H, m), 3.18 (2H, d, J=7.2 Hz), 3.35 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.15 (2H, t, 4.8 Hz), 4.27 (2H, s), 4.29 (3H, s), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.36 to 7.62 (10H, m).
IR (KBr) 3285, 2957, 1651, 1607, 1497, 1242, 1181, 1123, 818, 733: cm −1
›Example 217
(Preparation of Compound 234)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.58 g) in methylene chloride (17.4 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (11.6 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 234) (420 mg).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.64 (2H, m), 2.04 (1H, m), 2.92 (2H, m), 3.19 (2H, d, J=7.2 Hz), 3.34 to 3.39 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, 4.6 Hz), 4.32 (2H, s), 4.33 (3H, s), 6.93 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.38 to 7.56 (7H, m), 7.74 to 7.79 (3H, m).
IR (KBr) 3283, 2957, 1661, 1497, 1314, 1124, 1180, 835, 731 cm −1
Elemental Analysis for C 36 H 44 N 6 O 4 S Cald. C, 65.83; N, 12.79; H, 6.75. Found: C, 65.69; N, 12.56; H, 6.76
›Example 218
(Preparation of Compound 235)
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.60 g) was dissolved in THF (12 ml), DMF (3 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure, and a solution of the obtained residue in THF (12 ml) was added dropwise to a solution of 4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)aniline (0.43 g) and triethylamine (1.53 ml) in THF (12.9 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 235) (0.47 g).
1 H-NMR (200 MHz, CDCl 3 ) δ 0.93 (3H, t, J=7.2 Hz), 0.97 (6H, d, J=6.6 Hz), 1.33 to 1.45 (2H, m), 1.54 to 1.65 (2H, m), 2.05 (1H, m), 2.91 (2H, m), 3.19 (2H, d, J=7.4 Hz), 3.36 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.05 (2H, s), 4.13 to 4.18 (2H, m), 6.92 (1H, d, J=8.6 Hz), 6.97 (2H, d, J=8.8 Hz), 7.18 to 7.61 (8H, m), 7.71 (1H, s), 7.73 to 7.79 (1H, m), 7.88 (1H, d, J=2.2 Hz), 8.37 (1H, d, J=2.2 Hz), 8.47 (1H, dd, J=4.6, 1.4 Hz).
›Example 219
(Preparation of Compound 236)
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridinylmethyl)sulfanyl]-3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.11 g) in methylene chloride (7.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixt
›Tables in the description — 7
| zidovudine: | 100 mg |
| didanosine: | 125 to 200 mg |
| zalcitabine: | 0.75 mg |
| lamivudine: | 150 mg |
| stavudine: | 30 to 40 mg |
| saquinavir: | 600 mg |
| ritonavir: | 600 mg |
| indinavir: | 800 mg |
| nelfinavir: | 750 mg. |
| Compound | Binding Inhibitory |
|---|---|
| No. | Ratio (%) |
| 13 | 100 |
| 26 | 97 |
| 40 | 90 |
| 53 | 98 |
| 63 | 96 |
| 68 | 97 |
| 74 | 97 |
| 85 | 92 |
| 87 | 89 |
| 117 | 95 |
| 122 | 97 |
| 130 | 100 |
| 135 | 100 |
| 141 | 100 |
| 152 | 97 |
| 154 | 100 |
| 210 | 97 |
| 230 | 98 |
| 240 | 97 |
| 242 | 94 |
| 251 | 99 |
| 259 | 88 |
| 272 | 98 |
| 308 | 100 |
| 313 | 95 |
| 355 | 99 |
| 363 | 100 |
| 366 | 96 |
| 367 | 96 |
| 371 | 100 |
| 373 | 94 |
| 375 | 92 |
| 378 | 87 |
| 383 | 93 |
| 404 | 85 |
| 411 | 100 |
| 415 | 98 |
| 418 | 92 |
| 424 | 96 |
| 425 | 100 |
| 427 | 100 |
| 436 | 100 |
| 437 | 100 |
| 443 | 100 |
| (1) | (−)-7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4- | 40 mg |
| [[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3- | ||
| dihydro-1-benzazepine-4-carboxamide | ||
| (2) | lactose | 61 mg |
| (3) | microcrystalline cellulose | 18 mg |
| (4) | magnesium stearate | 1 mg |
| Total weight of 1 capsule | 120 mg |
| (1) | (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4- | 40 mg |
| [[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3- | ||
| dihydro-1-benzazepine-4-carboxamide | ||
| (2) | lactose | 61 mg |
| (3) | microcrystalline cellulose | 18 mg |
| (4) | magnesium stearate | 1 mg |
| Total weight of 1 capsule | 120 mg |
| (1) | (−)-7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4- | 40 mg |
| propyl-4h-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3- | ||
| dihydro-1H-1-benzazepine-4-carboxamide | ||
| (2) | lactose | 61 mg |
| (3) | microcrystalline cellulose | 18 mg |
| (4) | magnesium stearate | 1 mg |
| Total weight of 1 capsule | 120 mg |
| (1) | (−)-1-isobutyl-7-[4-(2-propoxyethoxy)phenyl]-N-[4- | 40 mg |
| [[[1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3- | ||
| dihydro-1-benzazepine-4-carboxamide | ||
| (2) | mannitol | 51.2 mg |
| (3) | microcrystalline cellulose | 18 mg |
| (4) | hydroxypropyl cellulose | 3.6 mg |
| (5) | croscarmellose sodium | 6 mg |
| (6) | magnesium stearate | 1.2 mg |
| Total weight of 1 tablet | 120 mg |
| (1) | (+)-7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1- | 40 mg |
| oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-1- | ||
| propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide | ||
| (2) | mannitol | 51.2 mg |
| (3) | microcrystalline cellulose | 18 mg |
| (4) | hydroxypropyl cellulose | 3.6 mg |
| (5) | croscarmellose sodium | 6 mg |
| (6) | magnesium stearate | 1.2 mg |
| Total weight of 1 tablet | 120 mg |
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8 codes- A61K31/55
- A61P43/00
- A61K31/18
- C07D223/16
- C07D417/12
- C07D401/12
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