Purine derivatives and medicaments comprising the same as active ingredient

This application is a continuation of application Ser. No. 09/554,077, filed Nov. 12, 1998, which is a National Stage Application of International Application No. PCT/JP98/05092, filed Nov. 12, 1998, which was not published in English under PCT Article 21(2), entering the national stage on May 11, 2000, and which claims priority of Japanese Application No. 9/310365, filed Nov. 12, 1997. The entire disclosure of application Ser. No. 09/554,077 is considered as being part of the disclosure of this application, and the entire disclosure of application Ser. No. 09/554,077 is expressly incorporated by reference herein in its entirety.

The present invention relates to novel purine derivatives. More precisely, it relates to purine derivatives having inhibitory activity against phosphodiesterase IV. The present invention also relates to synthetic intermediates for the preparation of said novel purine derivatives.

Cyclic AMP (cAMP) is an important second messenger which is involved in relaxation of respiratory tract smooth muscles and control of inflammatory cells, and the messenger is decomposed by phosphodiesterase (hereinafter abbreviated as “PDE” in the specification) to be converted into inactive 5′-AMP. Therefore, it is believed that suppression of the decomposition of cAMP by PDE may increase the concentration of cAMP, thereby bronchodilatation and anti-inflammatory action can be achieved. For this reason, PDE inhibitors having inhibitory action against the decomposition of cAMP have been focused as medicaments for the treatment of asthma. In addition, five PDE isozymes (PDE I, II, III, IV and V) have recently been isolated, and their specific tissue distributions have been revealed (Adv. Second Messenger Phosphoprotein Res., 22, 1 (1988); Trends Pharm., Sci., 11, 150 (1990)).

Among inhibitors for these isozymes, in particular, inhibitors specific for PDE IV have been suggested to be possibly useful for the treatment of asthma (Thorax 46, 512 (1991)). As a compound having specific inhibitory activity against PDE IV, for example, the compound disclosed in Japanese Patent Unexamined Publication (Kokai) No. 50-157360/1975 (Rolipram) has been known.

Although various compounds have been known as PDE IV inhibitors (for example, compounds disclosed in Japanese Patent Unexamined Publication (Kokai) No. 4-253945/1992, International Patent Publication in Japanese (Kohyo) Nos. 6-504782/1994, 7-504442/1995, 8-501318/1996 and 9-500376/1997 and so forth), they have not been used clinically so far, and development of novel compounds having PDE IV inhibitory activity has been desired.

An object of the present invention is to provide a novel compound having specific inhibitory activity against PDE IV, of which possible usefulness for treatment of asthma has been suggested. Another object of the present invention is to provide a medicament comprising a compound that has the aforementioned characteristic as an active ingredient. A further object of the present invention is to provide a synthetic intermediate useful for efficient preparation of the aforementioned compound.

The inventors of the present invention earnestly conducted researches to achieve the foregoing objects. As a result, they found that particular class of purine derivatives represented by the following formula had excellent inhibitory activity against PDE IV. They also found that these compounds were useful as active ingredients of medicaments, and they were extremely useful as, for example, as active ingredients of antiasthmatic agents. The present invention was achieved on the basis of these findings.

The present invention thus provides purine derivatives represented by the following formula (I), salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof:

wherein R 1 represents a C 1 -C 4 alkyl group or difluoromethyl group; R 2 represents tetrahydrofuranyl group, a C 1 -C 7 alkyl group, a C 1 -C 1 haloalkyl group, a C 2 -C 7 alkenyl group, bicyclo[2,2,1]hept-2-yl group, or a C 3 -C 8 cycloalkyl group; X represents hydrogen atom, a halogen atom, or nitro group; and A represents a group represented by the following formula:

wherein R 3 represents hydrogen atom, a halogen atom, hydroxyl group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group, or a C 2 -C 8 dialkylamino group; R 4 and R 5 each independently represent hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group, pyrrolidinyl group, morpholino group, a C 2 -C 8 dialkylamino group, or a group represented by —Y—(CH 2 ) n —B {Y represents —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group), n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted},

provided that either R 4 or R 5 represents —Y—(CH 2 ) n —B {Y represents —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group)} when X represents hydrogen atom, and

(i) n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted when Y represents —O—, —S—, or —NHCO—, or

(ii) n represents an integer of from 1 to 4, and B represents a heterocyclic residue when Y represents —N(R 6 )—.

According to preferred embodiments of the present invention, there are provided the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein A is a group represented by the following formula:

wherein R 3 is hydrogen atom, a halogen atom, hydroxyl group, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group or a C 2 -C 8 dialkylamino group; one of R 4 and R 5 is hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group, pyrrolidinyl group, morpholino group, or a C 2 -C 8 dialkylamino group, and the other is —Y—(CH 2 ) n —B (Y is —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group), n is an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted);

the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R 1 is a C 1 -C 4 alkyl group; R 2 is tetrahydrofuranyl group, a C 1 -C 6 alkyl group, a C 1 -C 3 haloalkyl group or a C 3 -C 8 cycloalkyl group, and A is a group represented by the following formula:

wherein R 3 is hydrogen atom, a halogen atom, hydroxyl group, a C 1 -C 4 alkyl group, or a C 1 -C 4 alkoxyl group; R 4 is hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, a C 1 -C 4 alkylamino group, or a C 2 -C 8 dialkylamino group, R 5 is —Y—(CH 2 ) n —B (Y is —O—, —S—, or —NHCO—, n is an integer of from 1 to 4, and B represents a heterocyclic residue which may be substituted); and

the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R 1 is a C 1 -C 3 alkyl group; R 2 is a C 3 -C 8 cycloalkyl group, and A is a group represented by the following formula:

wherein R 3 is hydrogen atom, a C 1 -C 3 alkyl group, or a C 1 -C 3 alkoxyl group; R 4 is a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxyl group or a C 1 -C 3 alkylamino group; R 5 is —Y—(CH 2 ) n —B (Y is —O—, n is an integer of from 1 to 4, and B is a heterocyclic residue which may be substituted).

According to another aspect of the present invention, medicaments are provided which contain a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof as an active ingredient. These medicaments are preferably provided as pharmaceutical compositions which contain the aforementioned active ingredient and an additive for pharmaceutical preparation, and they can be used as, for example, antiasthmatic agents for preventive and/or therapeutic treatment of asthma.

According to further aspects of the present invention, there are provided use of a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof for the manufacture of the aforementioned medicaments; methods for preventive and/or therapeutic treatment of asthma which comprise the step of administering an effective amount of a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof to a mammal including human; and phosphodiesterase IV inhibitors which comprise a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof.

According to further aspects of the present invention, there are provided compounds represented by the following formula (A):

wherein R 1 represents a C 1 -C 4 alkyl group or difluoromethyl group; R 2 represents tetrahydrofuranyl group, a C 1 -C 7 alkyl group, a C 1 -C 7 haloalkyl group, a C 2 -C 7 alkenyl group, bicyclo[2,2,1]hept-2-yl group or a C 3 -C 8 cycloalkyl group; R 4 represents hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group, pyrrolidinyl group, morpholino group, a C 2 -C 8 dialkylamino group or —Y—(CH 2 ) n —B {Y represents —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group), n represents an integer of from 0 to 4, B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, and X 2 represents a halogen atom, and compounds represented by the following formula (B):

wherein R 1 represents a C 1 -C 4 alkyl group or difluoromethyl group; R 2 represents tetrahydrofuranyl group, a C 1 -C 7 alkyl group, a C 1 -C 7 haloalkyl group, a C 2 -C 7 alkenyl group, bicyclo[2,2,1]hept-2-yl group, or a C 3 -C 8 cycloalkyl group; R 4 represents hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, amino group, a C 1 -C 4 alkylamino group, pyrrolidinyl group, morpholino group, a C 2 -C 8 dialkylamino group, or —Y—(CH 2 ) n —B {Y represents —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group), n represents an integer of from 0 to 4, B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, and X 2 represents a halogen atom. These compounds are useful as synthetic intermediates for preparation of the compounds represented by the aforementioned formula (I).

According to preferred embodiments of the synthetic intermediates represented by the formula (A) or (B), there are provided those wherein R 1 is a C 1 -C 4 alkyl group, R 2 is tetrahydrofuranyl group, a C 1 -C 6 alkyl group, a C 1 -C 3 haloalkyl group, or a C 3 -C 8 cycloalkyl group, R 4 is hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, a C 1 -C 4 alkylamino group or a C 2 -C 8 dialkylamino group.

R 1 represents a linear or branched C 1 -C 4 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), or difluoromethyl group. R 1 preferably represents a C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group, further preferably methyl group or ethyl group, and most preferably methyl group.

R 2 represents tetrahydrofuranyl group, a C 1 -C 7 linear or branched alkyl group (methyl group R 2 represents, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, n-pentyl group, 1,2-dimethylpropyl group, 1,1-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1,2,2-trimethylpropyl group, heptyl group, 5-methylhexyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 4,4-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,2,3-trimethylbutyl group, 1,1,2-trimethylbutyl group, 1,1,3-trimethylbutyl group and the like), a C 1 -C 7 haloalkyl group (chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 3-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, trifluoromethyl group and the like), a C 2 -C 7 alkenyl group (vinyl group, allyl group, 2-propenyl group, isopropenyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group and the like), bicyclo[2,2,1]hept-2-yl group, or a C 3 -C 8 cycloalkyl group (cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like). R 2 preferably represents tetrahydrofuranyl group, a C 1 -C 6 alkyl group, a C 1 -C 3 haloalkyl group, or a C 3 -C 8 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, further preferably a C 4 -C 6 cycloalkyl group, and most preferably cyclopentyl group.

X represents hydrogen atom, a halogen atom (when a halogen is referred to in the specification, the halogen may be any of fluorine, chlorine, bromine, and iodine), or nitro group, preferably hydrogen atom. As symbol “A”, a group represented by the following formula is preferred.

In the above formula, R 3 represents hydrogen atom, a halogen atom, hydroxyl group, a linear or branched C 1 -C 4 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a linear or branched C 1 -C 4 alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), amino group, a linear or branched C 1 -C 4 alkylamino group (methylamino group, n-propylamino group, isopropylamino group, butylamino group and the like) or a linear or branched C 2 -C 8 dialkylamino group (dimethyl amino group, diethylamino group, dipropylamino group, dibutylamino group and the like). R 3 preferably represents hydrogen atom, a halogen atom, hydroxyl group, a linear or branched C 1 -C 4 alkyl group, a C 1 -C 4 linear or branched alkoxyl group, more preferably hydrogen atom, a C 1 -C 3 alkyl group or a C 1 -C 3 alkoxyl group.

In the aforementioned formula, R 4 and R 5 each independently represent hydrogen atom, halogen atom, a linear or branched C 1 -C 4 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a linear or branched C 1 -C 4 alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), amino group, a linear or branched C 1 -C 4 alkylamino group (methylamino group, n-propylamino group, isopropylamino group, butylamino group and the like), pyrrolidinyl group, morpholino group, a linear or branched C 2 -C 8 dialkylamino groups (dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group and the like) or —Y—(CH 2 ) n —B {Y is —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 is hydrogen atom or a linear or branched C 1 -C 4 alkyl group (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), and Y is preferably —O—)}. Symbol “n” represents an integer of from 0 to 4, preferably an integer of from 1 to 3.

B represents a phenyl group, a naphthyl group, or a heterocyclic residue. Each of these groups may have, on their rings, one or more substituents selected from the group consisting of a halogen atom, a linear or branched C 1 -C 4 alkyl groups (methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group and the like), a C 1 -C 4 haloalkyl group (chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, difluoromethyl group, trifluoromethyl group and the like), a linear or branched C 1 -C 4 alkoxyl group (methoxy group, isopropoxy group, butoxy group and the like), a linear or branched C 1 -C 4 haloalkoxyl group (trifluoromethoxy group, difluoromethoxy group, 2,2,2-trifluoromethoxy group, 3-chloropropoxy group and the like), cyano group, nitro group, amino group, hydroxy group, carboxy group, a C 1 -C 4 acyl groups (formyl group, acetyl group, propionyl group and the like), a C 2 -C 4 alkoxycarbonyl group (methoxycarbonyl group, ethoxycarbonyl group and the like), a linear or branched C 1 -C 4 alkylamino group (methylamino group, isopropylamino group, butylamino group etc.), and a linear or branched C 2 -C 6 dialkylamino group (dimethylamino group, diethylamino group and the like), preferably one or more substituents selected from the group consisting of a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, a C 1 -C 4 haloalkoxyl group, carboxy group, and a C 2 -C 4 alkoxycarbonyl group.

As the heterocyclic residue, a heterocyclic residue having 1 to 5 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom and having 5 to 10 ring-constituting atoms may be used, such as thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group tetrazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, pyrrolidinyl group pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, benzimidazolyl group, indolyl group, quinolyl group, naphthylidinyl group, quinazolinyl group and the like, preferably thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, benzimidazolyl group and the like, more preferably a 6-membered heterocyclic residue having one or two nitrogen atoms as the hetero atom(s), for example, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group and the like. B represents a heterocyclic residue which may be substituted, and most preferably an unsubstituted heterocyclic residue.

As for R 4 and R 5 , R 4 preferably represents hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, a C 1 -C 4 alkylamino group, or a C 2 -C 8 dialkylamino group, more preferably a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxyl group, or a C 1 -C 3 alkylamino group, and R 5 represents —Y—(CH 2 ) n —B (Y, n, and B have the same meanings as already defined above).

When X represents hydrogen atom, either of R 4 or R 5 represents —Y—(CH 2 ) n —B. In this case, Y represents —O—, —S—, —NHCO—, or —N(R 6 )— (R 6 represents hydrogen atom or a C 1 -C 4 alkyl group), and (i) when Y represents —O—, —S—, or —NHCO—, n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted, or (ii) when Y represents —N(R 6 )—, n represents an integer of from 1 to 4, and B represents a heterocyclic residue.

When R 4 or R 5 in the compounds represented by the aforementioned formula (I) represents —Y(CH 2 ) n —B wherein B is a heterocyclic residue which has at least one nitrogen atom as the hetero atom, the compounds may exist as N-oxide compounds. The N-oxide compounds also fall within the scope of the present invention.

Specific examples of the compounds of the present invention are shown in Table 1 below. In the table, Me represents methyl group, Et represents ethyl group, and n-Pr represents normal propyl group.

Examples of particularly preferred compounds of the present invention include the following compounds. However, the compounds of the present invention are not limited to these examples.

2-chloro-9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-methoxypurine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-(pyridazinylmethyloxy)purine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-[4-pyridylmethyloxy]purine;

4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8dimethylpurin]-2-yl-oxymethyl]-pyridine N-oxide;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-[2-(4-pyridyl)ethyloxy]purine;

4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-2-oxyethyl]-pyridine N-oxide;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6-methylamino-2-(3-pyridazinylmethyloxy)purine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-[2-(4-pyridyl)ethylamino]-purine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-[(4-pyridyl)methylamino]purine;

9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethyl-2-[3-(4-pyridyl)propyloxy]purine; and

4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]-pyridine N-oxide.

As the salts of the compounds represented by the aforementioned formula (I), physiologically acceptable salts are preferred. Examples include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates and phosphates, and organic acid salts such as oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, methanesulfonates and p-toluenesulfonates. The compounds of the formula (I), N-oxide derivatives, and salts thereof may exist in the forms of hydrates or solvates, and such hydrates and solvates are also fall within the scope of the present invention. As solvents constituting such solvates, examples include, for example, methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride.

Among the compounds of the present invention, those wherein R 2 represents tetrahydrofuranyl group or bicyclo[2,2,1]hept-2-yl group may exist as optical enantiomers. Moreover, depending on the types of substituents, they may have one or more asymmetric carbons, and hence stereoisomers such as optical enantiomers and diastereoisomers based on the asymmetric carbon(s) may exist. Any stereoisomers in a pure form, any mixtures thereof, any racemates thereof and the like fall within the scope of the present invention.

According to the present invention, there are provided the compound represented by the aforementioned formulas (A) and (B). These compounds are useful as synthetic intermediates for the preparation of the aforementioned purine derivatives represented by formula (I). In the compounds represented by the formulas (A) and (B), R 1 , R 2 and R 4 have the same meanings as R 1 , R 2 and R 4 defined for the compounds of the aforementioned formula (I). R 1 is preferably a C 1 -C 4 alkyl group, more preferably a C 1 -C 3 alkyl group, further preferably methyl group or ethyl group, and most preferably methyl group. R 2 is preferably tetrahydrofuranyl group, a C 1 -C 6 alkyl group, a C 1 -C 3 haloalkyl group, or a C 3 -C 8 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, further preferably a C 4 -C 6 cycloalkyl group, and most preferably cyclopentyl group. R 4 is preferably hydrogen atom, a halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxyl group, a C 1 -C 4 alkylamino group, or a C 2 -C 8 dialkylamino group, and more preferably a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxyl group, or a C 1 -C 3 alkylamino group. X 2 represents a halogen atom, and preferably chlorine atom.

Examples of particularly preferred compounds represented by the formula (A) include the following compounds.

4(3-cyclopentyloxy-4-methoxybenzylamino)-2-fluoro-5-nitro-6-methylpyrimidine;

2-chloro-4-(3-cyclopentyloxy-4-methoxybenzylamino)-5-nitro-6-methylpyrimidine;

2-bromo-4-(3-cyclopentyloxy-4-methoxybenzylamino)-5-nitro-6-methylpyrimidine; and

4-(3-cyclopentyloxy-4-methoxybenzylamino)-2-iodide-5-nitro-6-methylpyrimidine.

Examples of particularly preferred compounds represented by the formula (B) include the following compounds.

5-amino-4-(3-cyclopentyloxy-4-methoxybenzylamino)-2-fluoro-6-methylpyrimidine;

5-amino-2chloro-4-(3-cyclopentyloxy-4-methoxybenzylamino)-6-methylpyrimidine;

5-amino-2-bromo-4-(3-cyclopentyloxy-4-methoxybenzylamino)-6-methylpyrimidine; and

5-amino-4-(3-cyclopentyloxy-4-methoxybenzylamino)-2-iodide-6-methylpyrimidine.

Methods for preparing the compounds of the present invention are not particularly limited. For example, they can be prepared by the following methods.

When A is a group represented by the following formula:

a compound of the following formula (III) can be prepared by the following-preparing method 1 or 2.

<Preparation Method 1>

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , and X have the same meanings as those defined above, and X 1 represents a halogen atom.

The above reaction is performed at a temperature within the range of from 0 to 150° C. without a solvent or in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran, and in the presence or absence of an organic base such as triethylamine, pyridine, and N,N-diethylaniline, or an inorganic base such as sodium carbonate and sodium hydride.

A compound of the aforementioned formula (II) as the starting material of the above reaction can be prepared according to the following scheme.

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , X and X 1 have the same meanings as already defined above.

<Preparation Method 2>

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , and X have the same meanings as those defined above, and X 2 represents a halogen atom.

A compound of the formula (III) can be prepared by carrying out condensation of a compound of the formula (VII) and a compound represented by R 5 —H according to the aforementioned reaction. A compound represented by R 5 —H is added to a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran or a mixed solvent thereof, and the mixture is added with 1 to 5 equivalents of an organic base such as triethylamine, pyridine or N,N-diethylaniline, or an inorganic base such as sodium carbonate or sodium hydride. Then, the mixture is reacted with a compound of the formula (VII) to obtain the target compound of the formula (III). The reaction is usually performed at from −20 to 150° C. under a nitrogen or argon flow. A compound of the aforementioned formula (VII) as the starting material of the aforementioned reaction can be prepared by any one of the following three methods.

Preparation Method (1)

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , X, and X 2 have the same meanings as those defined above.

Preparation Method (2)

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , X, X 1 , and X 2 have the same meanings as those defined above.

Preparation Method (3)

When X 2 is a halogen atom, a compound of the formula (VII) can also be prepared according to the following reaction formula.

In the scheme, R 1 , R 2 , R 3 , R 4 , R 5 , and X have the same meanings as those defined above, and X 2 represents a halogen atom.

In the above reaction, a compound of the formula (XI) and a compound of the formula (XII) are first condensed to prepare a compound of the formula (XIII). The compound of the formula (XI) and the compound of the formula (XII) are added to a suitable solvent such as N,N-dimethylformamide, tetrahydrofuran, methylene chloride or water, or a mixed solvent comprising a combination of these solvents, and the mixture is then added with 1 to 5 equivalents of an organic base such as triethylamine, pyridine or N,N-diethylaniline, or an inorganic base such as sodium carbonate or sodium hydride to obtain the target compound of the formula (XIII). The reaction is usually performed at −20 to 150° C. under a nitrogen or argon flow.

Then, a compound of the formula (XIV) can be obtained by reducing the compound of the formula (XIII). The reduction can be performed by dissolving the compound of the formula (XIII) in a solvent such as methanol, ethanol or tetrahydrofuran, or a mixed solvent comprising a combination of such solvents, adding 10 to 100% by weight of a catalyst such as Raney Nickel, palladium/carbon, hydroxylated palladium/carbon or platinum to the solution, and then performing the reaction at a temperature of from room temperature to 60° C. under a hydrogen flow or under pressure. A compound of the formula (VII) can be obtained by allowing a compound of the formula (XIV) to react with 1 to 5 equivalents of a regent such as triethyl orthoformate or triethyl orthoacetate in the absence of a solvent or in the presence of 1 to 5 equivalents of an organic acid such as acetic acid, trifluoroacetic acid or p-toluenesulfonic acid, or an inorganic acid such as hydrochloric acid. The reaction can generally be performed at a temperature of from room temperature to 250° C. The compounds of the formula (A) and the formula (B), useful as synthetic intermediates of the compounds of the formula (I), correspond to the compounds of the formula (XIII) and formula (XIV) wherein X is hydrogen atom, respectively.

<Preparation Method 3>

When A is a group represented by the following formula:

a compound of the following formula (XV) can be prepared by a method similar to Preparation Methods 1 and 2 using a compound of the aforementioned formula (VI) or a compound of the formula (IX).

In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , and X have the same meanings as those defined above.

N-oxide compounds can be prepared by oxidizing a starting material by an ordinarily used method.

When the compounds of present invention are used as active ingredients of the medicaments, the compounds, per se, may be administered, or they may be administered as pharmaceutical compositions which are prepared by using pharmaceutically acceptable additives for pharmaceutical preparations. The composition of the pharmaceutical compositions may be chosen depending on solubility and chemical properties of the aforementioned compounds as active ingredients, as well as administration route and schedule. For example, the composition may be orally administered in the forms of granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or intravenously, intramuscularly or subcutaneously administered as injections. The composition may be prepared as powders for injection, and administered as injection prepared just before use.

For the manufacture of pharmaceutical compositions suitable for oral, enteral, parenteral, or topical administration, organic or inorganic pharmaceutical additives can be used. These additives may be a solid or liquid, and examples include carriers and diluents for pharmaceutical formulations and the like. As excipients used for the manufacture of solid pharmaceutical compositions, for example, lactose, sucrose, starch, talc, cellulose, dextrin and the like can be used. For the manufacture of liquid pharmaceutical compositions for oral administration such as emulsions, syrups, suspensions and solutions, commonly used inactive diluents, for example, water, vegetable oils and the like can be used. The pharmaceutical compositions may contain, for example, wetting agents, suspension aids, sweeteners, aromatics, colorants, preservatives and the like as auxiliaries, as well as inactive diluents. A liquid preparation may be prepared and filled in capsules made of a material that can be disintegrated in body such as gelatin. As solvents or suspending agents used for the manufacture pharmaceutical compositions for parenteral administration such as injections, examples include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecitin and the like. Method for preparing the pharmaceutical compositions are not particularly limited, and any methods for preparing formulations available in the art can be utilized.

The medicaments of the present invention can be used as, for example, antiasthmatic agents for therapeutic and/or preventive treatment of asthma. Doses of the medicaments of the present invention for oral administration are generally 0.01 to 1000 mg (as a weight of an active ingredient), preferably 0.01 to 100 mg, per day for an adult. Preferably, the aforementioned doses are suitably increased or decreased depending on various conditions including the age, conditions and symptoms of a patient, and the presence or absence of a medicament simultaneously administered and the like. The aforementioned daily dose may be administered once a day or twice or three times a day as divided portions with suitable intervals, or intermittently administered every several days. When the medicaments are used as injections or drip infusions, they are preferably administered continuously or intermittently in a dose of from 0.001 to 100 mg (a weight of an active ingredient) per day for an adult.

The present invention will be explained more specifically with reference to examples and test examples. However, the scope of present invention is not limited by the examples and test examples.

The compounds of the present invention represented by the formula (I) have excellent PDE IV inhibitory activity, and are useful as active ingredients of medicaments for therapeutic and/or preventive treatment of asthma and the like. The compounds represented by the formulas (A) and (B) are useful as synthetic intermediates for preparation of the compounds represented by the aforementioned formula (I).