Compounds and medicinal use thereof

This invention relates to compounds that inhibit the activity of transcription factor AP-1, salts thereof, agents containing these compounds and/or useful for preventing and treating the diseases into which an overexpression of AP-1 participates, AP-1 inhibitor, and a method for inhibiting the AP-1 activity.

DNA constituting the essentiality of gene is regulated by various factors and thereby its genetic information is controlled. That is, the transcription from DNA to mRNA is controlled and regulated by a plurality of DNA binding proteins which recognize the sequence of several to dozens of bases on the gene and combine thereto. AP-1 known as one of such DNA binding proteins was identified as an important transcription factor dealing with proliferation of cells (Biochem. Biophys. Acta, Vol. 1072, Pages 129-157, 1991). Further, in some succeeding studies, it became apparent that AP-1 extensively participates in the induction of the expression of many genes and in the control and regulation of biological phenomena.

When AP-1 binds to AP-1 binding sequence (5′-TGAGTCA-3′) on genes, it exhibits a function as a transcription factor. As substances having such a sequence on the gene, proteins such as collagenases, stromelysin, metallothionein, interleukin-2 and the like and viruses such as SV40, polyoma virus and the like are known (Cell, Vol. 49, Pages 729-739, 1987).

Hitherto, as therapeutic drugs for may diseases, therapeutic drugs for controlling the function of proteins participating in the pathology such as enzymes and receptors have been developed. It is considered that, however, in the diseases caused by a quantitative abnormality of functional molecules existing in cells or on cell membranes, a treatment in the true sense is to control the quantity of transcription of the genes of the functional molecule and normalize the quantity of its expression rather than to control the activity of the functional molecules.

The gene expression and production of these functional proteins are controlled by a plurality of transcription factors. Since a transcription binding AP-1 sequence is common to exist in the promoter region of many genes, it is expected that various diseases may be effectively treated by controlling the AP-1 activity.

Up to today, it has been disclosed that glucocorticoids (Cell, Vol. 82. Pages 1189-1204, 1990) and retinoid derivatives (Nature, Vol. 372, Pages 107-111, 1994) can suppress the activity of AP-1. The action mechanism is considered as follows at the present time. Thus, these substances can form a complex together with respective receptor, and association of the complex with AP-1 can suppress of the binding of AP-1 to gene.

Steroidal agents used as therapeutic drugs for various diseases are known to exhibit a controlling action at the stage of expression of gene through intermediation of a glucocorticoid receptor. In fact, it has been reported that steroidal agents inhibit the activity of AP-1 and suppresses the production of cytokines and other proteins (Cell, Vol. 62, Pages 1189-1204, 1990). On the other hand, the use of steroidal agents are restricted from the viewpoint of hormone actions and side effects, and their side effects have a problem when they are administered excessively and/or for a long period of time.

In the recent years, a novel chemical drug is usually developed by a rational drug design base on the three-dimensional structure of biopolymers such as proteins (e.g., receptors and enzymes) and nucleic acid, which play an important physiological role (Shin Seikagaku Jikken Koza, Vol. 13, Pages 291-337, Tokyo Kagaku Dojin, 1993).

For applying this method, it is indispensably necessary to know the three-dimensional structure of the target bipolymer. The three-dimensional structure of the complex of transcription factor AP-1 and the complexes of its binding sequence have been elucidated by X ray crystallographic analysis (Nature, Vol. 373, Pages 257-261, 1995).

Accordingly, it has been desired to develop an agent for prevention and/or treatment of diseases in which overexpression of AP-1 participates, which suppresses the excessive expression of a wide variety of genes on the basis of AP-1 inhibitory action with lessened side reactions.

In the above-mentioned state of things, the present inventors have conducted extensive studies to find that compounds comprising the atom corresponding to N 3 and the two or more atoms selected from N 1 , N 2 , N 4 and N 5 said atoms constitute the pharmacophore represented by the following formula:

wherein N 1 represents an atom to which a donative hydrogen atom in a hydrogen-bond donating group is bonded or a hydrogen-bond accepting atom in a hydrogen-bond accepting group; N 3 represents a hydrogen-bond accepting atom in a hydrogen bond accepting group; and N 2 , N 4 and N 5 independently represent an arbitrary carbon atom constituting a hydrophobic group and the distance between N 1 and N 2 is not less than 5 angstroms and not more than 12 angstroms, the distance between N 1 and N 3 is not less than 9 angstroms and not more than 15 angstroms, the distance between N 1 and N 4 is not less than 3 angstroms and not more than 13 angstroms, the distance between N 1 and N 5 is not less than 8 angstroms and not more than 16 angstroms, the distance between N 2 and N 3 is not less than 3 angstroms and not more than 10 angstroms, the distance between N 2 and N 4 is not less than 6 angstroms and not more than 14 angstroms, the distance between N 2 and N 5 is not less than 9 angstroms and not more than 14 angstroms, the distance between N 3 and N 4 is not less than 4 angstroms and not more than 11 angstroms, the distance between N 3 and N 5 is not less than 3 angstroms and not more than 10 angstroms, and the distance between N 4 and N 5 is not less than 4 angstroms and not more than 9 angstroms; and, in the optimized three-dimensional structure thereof, the distances between the atom corresponding to N 3 and the two or more atoms selected from N 1 , N 2 , N 4 and N 5 are the interatomic distances in the pharmacophore; or salts thereof; inhibit activity on transcription factor AP-1, and are useful for prevention and treatment of diseases into which an overexpression of AP-1 participates. Further, it has also been found that specific compounds conforming to the above-mentioned definition of pharmacophore, having an inhibitory activity upon transcription factor AP-1 and useful as an agent for prevention and treatment of the diseases into which an overexpression of AP-1 participates include the following:

a peptide having 10 residues represented by the following amino acid sequence:

Ac-Cys 1 -Gly 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Gly 9 -Cys 10 -NH 2   [2; SEQ ID NO:1]

wherein Ac represents an acetyl group, AA 3 represents a polar amino acid residue, AA 4 , AA 6 and AA 7 independently represent a hydrophobic amino acid residue, AA 5 represents an amino acid residue having carboxyl group or hydroxyl group on side chain thereof, and AA 8 represents an arbitrary amino acid residue; and having a disulfide linkage between the first and tenth cysteine residues; or salts thereof;

a peptide having 10 or 11 residues represented by the following amino acid sequence:

Ac-aa 0 -Cys 1 -Gly 2 -aa 3 -aa 4 -aa 5 -aa 6 -aa 7 -Gly 8 -aa 9 -Cys 10 -NH 2   [2b, SEQ ID NO:2]

wherein Ac represents an acetyl group, aa 0 represents an arbitrary amino acid residue or a bonding unit, aa 3 represents a polar amino acid residue, aa 4 , aa 5 and aa 7 independently represent a hydrophobic amino acid residue, aa 6 represents an arbitrary amino acid residue, and aa 9 represents an amino acid residue having carboxyl group or hydroxyl group on side chain thereof; provided that when aa 0 is a bonding unit, a disulfide linkage exists between the 2nd and 11th cysteine residues; or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 1 represents halogen atom, cyano group, nitro group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 3 represents halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group, carbamoyl group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 4 represents hydrogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group;

X 1 represents —C(O)—, —CH(OH)—, —CH 2 — or a group of any one of the following formulas:

wherein R 21 represents unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl or heterocycle-lower alkyl group; R 22 and R 23 may be the same or different and independently represent hydrogen atom, unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, carbamoyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; R 24 and R 25 may be the same or different and independently represent hydrogen atom, halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; and the double line in which one line is a broken line represents a single bond or a double bond; and W represents —Z—COR 26 , —Z—COOR 2 , —O—CH 2 COOR 2 or —O—CH 2 CH 2 COOR 2 , wherein Z is —(CH 2 ) n — (n is 0, 1, 2 or 3), —CH 2 CH(CH 3 )—, —CH═CH— or —CH 2 CH═CH—; R 2 represents hydrogen atom or a protecting group for carboxyl group; and R 26 represents —NHR 27 or NHSO 2 R 28 (R 27 and R 28 independently represent unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group); or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 5 represents hydrogen atom, halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 6 represents hydrogen atom or a protecting group for carboxyl group; X 2 represents —C(O)—; m represents 0, 1 or 2; ring A represents a group represented by the following formula:

in which R 7 represents hydrogen atom, halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 8 represents hydrogen atom, unprotected or protected amino group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; or a group represented by the following formula:

wherein R 9 and R 10 may be the same or different and independently represent halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, alkanoyloxy, arylsulfonylamino or heterocyclic group; or salts thereof;

benzene derivatives represented by the following formula:

wherein R 15 and R 16 may be the same or different and independently represent hydrogen atom, halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; X 3 represents —C(O)—; and ring B represents a group of the following formula:

in which R 17 represents hydrogen atom or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylsulfonyl or heterocyclic group; R 18 represents hydrogen atom or a protecting group for carboxyl group; and p represents 0, 1 or 2; or salts thereof;

benzene derivatives represented by the following formula:

wherein R 1a represents halogen atom, cyano group, nitro group, unprotected or protected hydroxyl group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 3a and R 4a may be the same or different and independently represent halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; X 1a represents —C(O)—, —CH(OH)—, —CH 2 — or a group of the following formula:

in which R 21a represents unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl or heterocycle-lower alkyl group; R 22a and R 23a may be the same or different and independently represent hydrogen atom, or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, carbamoyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl or heterocyclic group; and R 24a and R 25a may be the same or different and independently represent hydrogen atom, halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; and the double line in which one line is a broken line represents a single bond or a double bond; and W a represents —Z a —COR 26a , —Z a —COOR 2a , —O—CH 2 COOR 2a or —O—CH 2 CH 2 COOR 2a ; in which Z a represents —(CH 2 ) n a (n a represents 0, 1, 2 or 3), CH 2 CH(CH 3 )—, —CH═CH— or —CH 2 CH═CH—; R 2a represents hydrogen atom or a protecting group for carboxyl group; and R 26a represents —NHR 27a or —NHSO 2 R 28a (R 27a and R 28a independently represent unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group); or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 1b represents halogen atom, cyano group, nitro group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 2b represents hydrogen atom or a protecting group for carboxyl group; R 3b and R 4b may be the same or different and independently represent cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; and X 1b represents —C(O)—, —CH(OH)— or —CH 2 —; and Z b represents —(CH 2 ) n b — (n b represents 0, 1 or 2) or —CH═CH—; or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 1c represents halogen atom, cyano group, nitro group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 2c represents hydrogen atom or a protecting group for carboxyl group; R 3c and R 4c may be the same or different and independently represent halogen atom, cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; X 1c represents —C(O)—, —CH(OH)— or —CH 2 —; and Z c represents —(CH 2 ) n c (n c represents 0, 1 or 2) or —CH═CH— or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 1d represents halogen atom, cyano group, nitro group, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 2d represents hydrogen atom or a protecting group for carboxyl group; R 3d represents hydrogen atom or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group; R 4d represents alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, alkylsulfonylamino or arylsulfonylamino group; X 1d represents —C(O)—, —CH(OH)— or —CH 2 —; and Z d represents —(CH 2 ) n d — (n d represents 0, 1 or 2) or —CH═CH—; or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 0e represents hydrogen atom, halogen atom, nitro group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonylamino or arylsulfonylamino group; R 1e represents unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl group; R 2e represents hydrogen atom or a protecting group for carboxyl group; R 3e and R 4e may be the same or different and independently represent hydrogen atom, halogen atom, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; X 1e represents —C(O)—, —CH(OH)— or —CH 2 —; and Z e represents —(CH 2 ) n e — (n e represents 0, 1 or 2) or —CH═CH—; or salts thereof;

benzene derivatives represented by the following general formula:

wherein R 1f represents halogen atom, unprotected or protected hydroxyl group, unprotected or protected amino group, mercapto group or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 2f represents hydrogen atom or a protecting group for carboxyl group; R 3f and R 4f may be the same or different and independently represent hydrogen atom or unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group; X 1f represents —C(O)—, —CH(OH)— or —CH 2 —; and Z f represents —(CH 2 ) n f — (n f represents 1 or 2) or —CH═CH—; or salts thereof; and

benzene derivatives represented by the following general formula:

wherein R 1g and R 4g may be the same or different and independently represent unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group; X 1g represents —C(O)—, —CH(OH)— or —CH 2 —; Z g represents —(CH 2 ) n g — (n g represents 1 or 2); and R 2g represents hydrogen atom or a protecting group for carboxyl group; or salts thereof;

and agents comprising the above-mentioned compounds.

Based on these findings, this invention has been accomplished.

First, the present inventors took out only the three-dimensional structure of transcription factor AP-1 from the three-dimensional structure of a partial structure containing the DNA binding site of AP-1 and its binding sequence (oligonucleotide containing 5′-TGAGTCA-3′) (Nature, Vol. 373, Pages 257-261, 1995) by using the molecular modeling software “SYBYL” (TRIPOS Co., USA), and searched for a compound binding to AP-1 and antagonistic to the AP-1 binding sequence. As its result, it was found that a peptide of the following formula:

can bind to with AP-1 and have an antagonistic activity to the AP-1 binding sequence.

Subsequently, a three-dimensional structure of a complex compound of peptide [2a; SEQ ID NO:3] and a partial structure containing the DNA binding site of AP-1 were prepared by the use of SYBYL, and a molecular dynamics simulation was carried out according to the molecular dynamics calculation program AMBER (Oxford Molecular Co., GB) (Fundamentals of Protein Engineering Physics and Chemistry, published by Kyoritsu Shuppan, Page 192, 1991) by using the three-dimensional structure obtained above as an initial structure to obtain a plurality of three-dimensional structures of AP-1-cyclic peptide [2a; SEQ ID NO:3] complex in water.

On the other hand, nuclear magnetic resonance (NMR) spectrum of peptide [2a; SEQ ID NO:3] was measured, and the result was treated according to a structural analysis software X-PLOR (MSI Co., USA) to obtain a plurality of three-dimensional structures of peptide [2a; SEQ ID NO:3] in water experimentally (Shinsei Kagaku Jikken Koza I, Proteins III, Pages 139-147, 1990, published by Tokyo Kagaku Dojin).

The experimentally obtained three-dimensional structures were compared with the three-dimensional structures of cyclic peptide [2a; SEQ ID NO:3] in the complex obtained from the molecular dynamics simulation. As a result, a high level of similarity was found out between eleven of the experimentally confirmed three-dimensional structures and fourteen of the three-dimensional structures obtained from molecular dynamics simulation in the partial three-dimensional structure of Gln-Leu-Asp-Leu-Ala [SEQ ID NO:4]. Based on this finding, it could be confirmed that the five atoms N 1 , N 2 , N 3 , N 4 and N 5 expressed by the following formula:

wherein N 1 represents an atom to which a donative hydrogen atom in a hydrogen-bond donating group is bonded or a hydrogen-bond accepting atom in a hydrogen-bond accepting group; N 3 represents a hydrogen-bond accepting atom in a hydrogen-bond accepting group; and N 2 , N 4 and N 5 independently represent an arbitrary carbon atom constituting a hydrophobic group, constitute a pharmacophore necessary for the binding to AP-1 and the expression of an antagonistic activity to AP-1 binding sequence (Souyaku Kagaku, Kagaku Dojin, Pages 11-13, 1995).

Further, distances between five atoms N 1 , N 2 , N 3 , N 4 and N 5 , which are selected therefrom in these 25 three-dimensional structures, and which constitute the pharmacophore necessary for the binding to AP-1 and the expression of the antagonistic activity to AP-1 binding sequence were measured. As N 1 , the nitrogen atom or oxygen atom of amide group was taken into consideration. As N 2 , the four carbon atoms of isobutyl group were taken into consideration. As N 3 , the two oxygen atoms of carboxyl group were taken into consideration. As N 4 , the four carbon atoms of isobutyl group were taken into consideration. As N 5 , the carbon atom of methyl group was taken into consideration. On all the possible combinations of the five atoms, distances were measured. As a result, it was found that the condition represented by the following formula:

wherein N 1 represents an atom to which to a donative hydrogen atom in the hydrogen-bond donating group is bonded or a hydrogen-bond accepting atom in the hydrogen-bond accepting group, N 3 represents a hydrogen-bond accepting atom in the hydrogen-bond accepting group, and N 2 , N 4 and N 5 independently represent an arbitrary carbon atom constituting a hydrophobic group, and the distance between N 1 and N 2 is not less than 5 angstroms and not more than 12 angstroms, the distance between N 1 and N 3 is not less than 9 angstroms and not more than 15 angstroms, the distance between N 1 and N 4 is not less than 3 angstroms and not more than 13 angstroms, the distance between N 1 and N 5 is not less than 8 angstroms and not more than 16 angstroms, the distance between N 2 and N 3 is not less than 3 angstroms and not more than 10 angstroms, the distance between N 2 and N 4 is not less than 6 angstroms and not more than 14 angstroms, the distance between N 2 and N 5 is not less than 9 angstroms and not more than 14 angstroms, the distance between N 3 and N 4 is not less than 4 angstroms and not more than 11 angstroms, the distance between N 3 and N 5 is not less than 3 angstroms and not more than 10 angstroms, and the distance between N 4 and N 5 is not less than 4 angstroms and not more than 9 angstroms are necessary for binding to AP-1 and expressing the antagonistic activity to AP-1 binding sequence. Based on these findings, the pharmacophore model was completed.

Further, compounds conforming to the above-mentioned pharmacophore model were extensively searched to find out non-peptide compounds which can bind to AP-1 and have the antagonistic activity to AP-1 binding sequence. It was found that compounds comprising the atom corresponding to N 3 and the two or more atoms selected from N 1 , N 2 , N 4 and N 5 , said atoms constitute the pharmacophore represented by the following formula:

wherein N 1 represents an atom bonded to a donative hydrogen atom in the hydrogen-bond donating group or a hydrogen-bond accepting atom in the hydrogen-bond accepting group, N 3 represents a hydrogen-bond accepting atom in the hydrogen bond-accepting group, and N 2 , N 4 and N 5 independently represent an arbitrary carbon atom constituting a hydrophobic group, and the distance between N 1 and N 2 is not less than 5 angstroms and not more than 12 angstroms, the distance between N 1 and N 3 is not less than 9 angstroms and not more than 15 angstroms, the distance between N 1 and N 4 is not less than 3 angstroms and not more than 13 angstroms, the distance between N 1 and N 5 is not less than 8 angstroms and not more than 16 angstroms, the distance between N 2 and N 3 is not less than 3 angstroms and not more than 10 angstroms, the distance between N 2 and N 4 is not less than 6 angstroms and not more than 14 angstroms, the distance between N 2 and N 5 is not less than 9 angstroms and not more than 14 angstroms, the distance between N 3 and N 4 is not less than 4 angstroms and not more than 11 angstroms, the distance between N 3 and N 5 is not less than 3 angstroms and not more than 10 angstroms, and the distance between N 4 and N 5 is not less than 4 angstroms and not more than 9 angstroms, and in the optimized three-dimensional structure thereof, the distances between the atom corresponding to N 3 and the two or more atoms selected from N 1 , N 2 , N 4 and N 5 are the interatomic distances in the pharmacophore; or salts thereof inhibit the activity of transcription factor AP-1 and are useful as an agent for preventing and treating the diseases into which overexpression of AP-1 participates.

The compounds of this invention inhibit the binding activity of transcription factor AP-1. That is, the compounds of this invention antagonistically inhibit the bind of AP-1 to the AP-1-recognizing sequence on DNA, and thereby suppress the transcription of AP-1-related DNA, and thereby can reduce the expression of protein corresponding to said genes having AP-1 binding sequence. Accordingly, the compounds of this invention can suppress the expression of gene in tissue-destroying enzymes such as collagenase, stromelysin, gelatinases and the like; cytokines such as interleukin-1, interleukin-2, interleukin-3, interleukin-6, interleukin-8, TNFα, granulocyte-macrophage colony stimulating factor (GM-CSF), monocyte chemotactic factor (MCP-1) and the like; cell surface molecule groups such as interleukin-2 receptor, immunoglobulins, major histocompatibility complex (MHC) class II, vascular cell adhesion molecule-1 (VCAM-1), fibroblast growth factor (FGF) receptors and the like; growth factors such as monocyte growth factor, insulin-like growth factor (IGF), nervous growth factor (NGF) and the like; proteins such as metallothionein, collagens, osteocalcin, amyloid precursor proteins, apolipoprotein-1 and the like; and viruses such as SV40, polyoma virus and the like, and thereby can prevent and treat the diseases related with these genes. As the diseases to which these genes relate, for instance, various autoimmune diseases such as rheumatoid arthritis, systemic erythematosus, scleroderma, Behchet's disease, rheumatic fever, polymyositis, polyarteritis nodosa, Sjoegren's syndrome, active chronic hepatitis, glomerulonephritis and the like; various intractable diseases basically with inflammations such as osteoarthritis, gout, atherosclerosis, psoriasis, atopic dermatitis, lung diseases with granuloma, various encephalitis, and the like; lung diseases with granuloma such as pneumonitis; endotoxin shock; sepsis; inflammatory colitis; diabetes mellitus; acute myeloblastic leukemia; encephalomyelitis; acute hepatitis; chronic hepatitis; drug-induced hepatitis; alcoholic hepatitis; viral hepatitis; jaundice; cirrhosis; liver failure; atrial myxoma; Castleman's syndrome; multiple myeloma; cancer; metastases of cancer; AIDS; epilepsy; ischemic heart disease; hemangio-endothelial hyperplasia (arteriosclerosis); Alzheimer's disease; ischemia-nerve cell death; etc. The compounds of this invention are expected to be effective for prevention and treatment of these diseases.

The compounds of this invention will be detailed below.

Unless otherwise defined, the term “halogen atom” used in this specification means fluorine atom, chlorine atom, bromine atom and iodine atom; “alkyl group” means straight or branched chain C 1-2 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl and the like; “lower alkyl group” means straight or branched chain C 1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and the like; “halogeno lower alkyl group” means straight or branched chain halogeno-C 1-6 alkyl groups such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl and the like; “lower alkoxy lower alkyl group” means straight or branched chain C 1-6 alkoxy-C 1-6 alkyl groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, methoxyethyl, ethoxyethyl and the like; “hydroxy lower alkyl group” means straight or branched chain hydroxy-C 1-6 alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl and the like; “amino lower alkyl group” means amino-C 1-6 alkyl groups such as aminomethyl, aminoethyl, aminopropyl and the like;

“alkenyl group” means straight or branched chain C 2-12 alkenyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl and the like; “lower alkenyl group” means straight or branched chain C 2-6 alkenyl groups such as vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl and the like; “cycloalkyl group” means C 3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; “ar-lower alkyl group” means ar-C 1-6 alkyl groups such as benzyl, diphenylmethyl, trityl, phenethyl and the like;

“aryl group” means phenyl, tolyl, naphthyl and the like; “aralkyl group” means benzyl, diphenylmethyl, trityl, phenethyl, 4-methylbenzyl, naphthylmethyl and the like; “aryloxy group” means phenoxy, naphthoxy and the like; “aryloxycarbonyl group” means phenoxycarbonyl, naphthoxycarbonyl and the like;

“alkoxy group” means straight or branched chain C 1-12 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy and the like; “lower alkoxy group” means straight or branched chain C 1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butyoxy, pentyloxy, isopentyloxy and the like; “alkoxycarbonyl group” means straight or branched chain C 1-12 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like; “lower alkoxycarbonyl group” means straight or branched chain C 1-6 alkyloxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like;

“lower alkoxycarbonyl lower alkyl group” means straight or branched chain C 1-6 alkoxycarbonyl-C 1-6 alkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl and the like; “lower alkoxyimino group” means straight or branched chain C 1-6 alkoxyimino groups such as methoxyimino, ethoxyimino and the like; “alkylamino group” means straight or branched chain C 1-12 alkylamino groups such as methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino and the like; “lower alkylamino group” means straight or branched chain mono- or di-C 1-6 alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino and the like; “lower alkylamino lower alkyl group” means mono- or di-C 1-6 alkylamino-C 1-6 alkyl groups such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminopropyl, propylaminoethyl, dimethylaminomethyl, diethylamino-methyl, diethylaminoethyl, dimethylaminopropyl and the like; “lower alkylidene group” means C 1-6 alkylidene groups such as methylene, ethylidene, propylidene, isopropylidene and the like;

“acyl group” inclusively means straight or branched chain C 2-12 alkanoyl groups such as formyl, acetyl, isovaleryl, propionyl and the like, aralkylcarbonyl groups such as benzylcarbonyl and the like, aroyl groups such as benzoyl, naphthoyl and the like, and heterocycle-carbonyl groups such as nicotinoyl, thenoyl, pyrrolidinocarbonyl, furoylcarbonyl and the like; “acylamino group” means C 1-6 acylamino groups such as formylamino, acetylamino, propionylamino, butyrylamino and the like; “alkanoyloxy group” means C 2-12 alkanoyloxy groups such as acetyloxy, propionyloxy and the like;

“cyclic amino group” may be any of saturated cyclic amino groups and unsaturated cyclic amino groups, and may contain one or more hetero atoms such as nitrogen atoms, oxygen atoms, sulfur atoms and the like and carbonyl carbon atoms additionally in the ring thereof, and may be any of monocyclic, bicyclic and tricyclic groups, which more specifically include saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups having one nitrogen atom such as aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, pyrrolin-1-yl, pyrrol-1-yl, dihydropyridin-1-yl, piperidino, dihydroazepin-1-yl, perhydroazepin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups having 2 nitrogen atoms such as imidazol-1-yl, imidazolidin-1-yl, imidazolin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, 1,4-dihydropyrazin-1-yl, 1,2-dihydropyrimidin-1-yl, perhydropyrazin-1-yl, homopiperazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups having 3 or more nitrogen atoms such as 1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,2-dihydro-1,2,4-triazin-1-yl, perhydro-s-triazin-1-yl and the like; saturated or unsaturated, monocyclic, 3- to 7-membered cyclic amino groups having 1 to 4 hetero atoms selected from the group consisting of oxygen atom and sulfur atom in addition to nitrogen atoms such as oxazolidin-3-yl, isoxazolidin-2-yl, morpholino, thiazolidin-3-yl, isothiazolidin-2-yl, thiomorpholino, homothiomorpholin-4-yl, 1,2,4-thiadiazolin-2-yl and the like; saturated or unsaturated, 2- or 3-membered cyclic amino groups such as isoindolin-2-yl, indolin-1-yl, 1H-indazol-1-yl, purin-7-yl, tetrahydroquinolin-1-yl and the like; and spiro type or crosslinked type of saturated or unsaturated, 5- to 12-membered cyclic amino groups such as 5-azaspiro[2.4]heptan-5-yl, 2,8-diazabicyclo[4.3.0]nonan-8-yl, 3-azabicyclo[3.1.0]-hexan-3-yl, 2-oxa-5,8-diazabicyclo[4.3.0]nonan-8-yl, 2,8-diazaspiro[4.4]nonan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl and the like;

“alkylthio group” means straight or branched chain C 1-12 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio, heptylthio, octylthio and the like; “lower alkylthio group” means straight or branched chain C 1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio and the like; “alkylsulfinyl group” means straight or branched chain C 1-12 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl, isopentylsulfinyl, hexylsulfinyl, heptylsulfinyl, octylsulfinyl and the like; “alkylsulfonyl group” means straight or branched chain C 1-12 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octylsulfonyl and the like; “alkylsulfonylamino group” means straight or branched chain C 1-12 alkylsulfonylamino groups such as methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, isopentylsulfonylamino, hexylsulfonylamino, heptylsulfonylamino, octylsulfonylamino and the like; “arylsulfonylamino group” means aryl-SO 2 NH— groups such as phenylsulfonylamino, naphthylsulfonylamino and the like; and

“heterocycle-lower alkyl group” means heterocycle-CH 2 — group and the like such as pyrrolidinylmethyl, piperidylmethyl, piperazinylmethyl, pyrazolylmethyl, tetrahydropyridylmethyl, morpholinylmethyl, thiomorpholinylmethyl, tetrahydro-quinolinylmethyl, tetrahydroisoquinolinylmethyl, quinacridinylmethyl, tetrazolylmethyl, thiadiazolylmethyl, pyrazolidinylmethyl, purinylmethyl, indazolylmethyl, 2-thienylmethyl, 2-furfurylmethyl, 2-pyranylmethyl, 1-isobenzofurylmethyl, 2-pyrrolylmethyl, 1-imidazolylmethyl, 1-pyrazolylmethyl, 3-isothiazolylmethyl, 3-isoxazolylmethyl, 2-pyridylmethyl, 2-pyrazinylmethyl, 2-pyrimidinylmethyl, 2-pyridazinylmethyl, 1-isoindolylmethyl, 2-indolylmethyl, 1-isoquinolylmethyl, 2-quinolylmethyl, 1-phthalazinylmethyl, 2-naphthyridinylmethyl, 2-quinoxalinylmethyl, 2-quinazolinylmethyl, 3-cinnolinylmethyl, 2-oxazolylmethyl, 2-thiazolylmethyl, 2-benzo[b]furylmethyl, 2-benzo[b]thienylmethyl, 2-benz[d]imidazolylmethyl, 2-benz[d]oxazolylmethyl and the like.

“Nitrogen-containing heterocyclic group” means 5- or 6-membered ring, fused ring or crosslinked ring type heterocyclic groups which contain at least one nitrogen atoms as hetero atoms constituting the ring and may contain at least one oxygen atom or sulfur atom in addition to said nitrogen atoms, such as pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyrazolyl, pyridyl, tetrahydropyridyl, pyrimidinyl, morpholinyl, thiomorpholinyl, quinolyl, quinolizinyl, tetrahydroquinolinyl, tetrahydro-isoquinolinyl, quinacridinyl, thiazolyl, tetrazolyl, thiadiazolyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, purinyl, indazolyl and the like; and “heterocyclic group” inclusively means the above-mentioned nitrogen-containing heterocyclic groups and 5- or 6-membered ring, fused ring or crosslinked ring type heterocyclic groups which may contain at least one oxygen atoms or sulfur atoms as hetero atoms constituting the ring and contain at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, such as furyl, thienyl, benzothienyl, pyranyl, isobenzofuranyl, oxazolyl, benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinoxalyl, dihydroquinoxalinyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzopyrrolyl, 2,3-dihydro-4H-1-thianaphthyl, 2,3-dihydrobenzofuranyl, benzo[b]dioxanyl, imidazo[2.3-a]pyridyl, benzo[b]piperazinyl, chromenyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, isoindolyl, isoquinolyl and the like.

As the protecting group for carboxyl group, all the groups which can conventionally be used as a protecting group for carboxyl group can be referred to. Examples thereof include alkyl groups such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acyl-alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-alkyl groups such as 2,2,2-trichloroethyl and the like; alkylsilylalkyl groups such as 2-(trimethylsilyl)ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocycle-alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; alkoxy-alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)-ethoxymethyl and the like; ar-alkoxy-alkyl groups such as benzyloxymethyl and the like; alkylthio-alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthioalkyl groups such as phenylthiomethyl and the like; alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethyliso-propylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

As the protecting group for amino group, all the groups which can conventionally be used as a protecting group for amino group can be referred to. Examples thereof include acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di- and tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(phenylazo)-benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; dialkylamino-alkylidene groups such as N,N-dimethylaminomethylene and the like; aralkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclo-hexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- or dialkyl-phosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; and substituted silyl groups such as trimethylsilyl and the like.

As protecting group for hydroxyl group, all the groups which can conventionally be used as a protecting group for hydroxyl group can be referred to. Examples thereof include acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)-ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the like; alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; alkenyl groups such as allyl and the like; aralkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; alkoxy-alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl and the like; alkyl- and aryl-sulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; and substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

The term “amino acid residue” means a structure —NHCHRCO— which appears when an amino acid is incorporated into a protein or peptide while forming a peptide bond with loss of a water molecule, wherein R represents an amino acid side chain. As used herein, the term “amino acid” means an L-amino acid and a D-amino acid, namely compounds having carboxyl group and amino group in one molecule, unless otherwise defined. Examples of said amino acid include glycine, alanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, lysine, arginine, histidine, methionine, tyrosine, phenylalanine, tryptophan, proline, cysteine, homocysteine, β-alanine, γ-aminobutyric acid, ornithine, 3,4-dihydroxyphenylalanine and the like. For expression of amino acids and amino acid residues, the three letters expression prescribed by IUPAC and IUB is used.

The term “polar amino acid”, means amino acids such as asparagine, glutamine, aspartic acid, glutamic acid, serine, threonine, tyrosine, lysine, arginine, histidine, citrulline, homocitrulline, homoserine, hydroxyproline, β-hydroxyvaline, ornithine and the like, for example.

The term “hydrophobic amino acid” means amino acids such as leucine, isoleucine, valine, alanine, glycine, methionine, proline, phenylalanine, tryptophan, norleucine, norvaline, γ-aminobutyric acid, β-cyclohexylalanine and the like, for example.

As the salt of compound in the compound conforming to the pharmacophore of formula 1, the compounds of general formulas [2], [2b], [3], [4], [5], [a], [b], [c], [d], [e], [f] and [g] or salts thereof, conventionally known salts at the site of basic group such as amino group and the like and conventionally known salts at the site of acidic group such as hydroxyl group, carboxyl group and the like can be referred to. As the salts at the site of basic group, for example, salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, salts of organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like, and salts of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like can be referred to. As the salts at the site of acidic group, for example, salts of alkali metals such as sodium, potassium and the like, salts of alkaline earth metals such as calcium, magnesium and the like, ammonium salts, and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, N,N′-dibenzylethylenediamine and the like can be referred to. Further, among the salts mentioned above, preferable salts of the compound conforming to the pharmacophore of formula 1 and the compounds of formulas [2], [2b], [3], [4], [5], [a], [b], [c], [d], [e], [f] and [g], pharmacologically acceptable ones can be referred to.

As the “atom to which a donative hydrogen atom in the hydrogen-bond donating group is bonded”, the nitrogen atom of unsubstituted or substituted amino, ammonium, amido, thioamido, ureido, isoureido, amidino, guanidino, thioureido, hydrazino or hydrazono group to which one or more hydrogen atoms are bonded, the carbon atom of ethenyl group to which a hydrogen atom is bonded, the nitrogen atom of imino group to which a hydrogen atom is bonded, the oxygen atom of hydroxyl group, the nitrogen atom to which the hydrogen atom of an unsubstituted or substituted nitrogen-containing heterocyclic group is bonded, and the like can be referred to.

The “hydrogen-bond accepting atom in hydrogen-bond accepting group” may be any atom, so far as it has an unshared electron pair. Examples thereof include the oxygen atom of carbonyl group, the sulfur atom of thiocarbonyl group, the nitrogen atom of unsubstituted or substituted imino group, the oxygen atom of sulfonic group, the oxygen atom of sulfonyl group, the oxygen atom of sulfinyl group, the oxygen atom of sulfonyloxy group, the oxygen atom of carboxyl group, the oxygen atom of ether, the sulfur atom of thioether, the oxygen atom of hydroxyl group, the oxygen atom of ester, the nitrogen atom to which no hydrogen atom is bonded in an unsubstituted or substituted nitrogen-containing heterocyclic group, the nitrogen atom of sulfonamido group, the nitrogen atom of acylsulfonamido group, etc.

As the “arbitrary carbon atom constituting a hydrophobic group”, the carbon atom of alkyl group, the carbon atom of alkenyl group, the carbon atom of aryl group, the carbon atom of alkoxy group and the like can be referred to, and preferably the carbon atom of branched chain-like alkyl group, the carbon atom of alkenyl group and the carbon atom of alkoxy group can be referred to.

The term “optimized structure” means the energy-minimized structure obtained by a usual geometry optimization calculation (Keisan kagaku Njumon, Kodansha, Page 55, 1994) according to a calculation program such as SYBYL (TRIPOS, USA) or the like.

The alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonyl-amino, arylsulfonylamino or heterocyclic group in R 1 , R 1a , R 1b , R 1c , rd, R 3a , R 3b , R 4 , R 4a , R 4b , R 5 , R 7 , R 8 , R 9 , R 10 , R 15 , R 16 , R 24 , R 24a , R 25 and R 25a ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group in R 1f , R 3e and R 4e ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl-amino or arylsulfonylamino group in R 0e ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl group in R 1e the alkoxy group in R 1g and R 4g ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group in R 3 ; the alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group in R 3c and R 4c ; the alkyl, alkenyl, cycloalkyl, aryl or aralkyl group in R 3d , R 3f and R 4f ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl, alkylsulfonylamino or arylsulfonylamino group in R 4d ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylsulfonyl or heterocyclic group in R 17 ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl or heterocycle-lower alkyl group in R 21 and R 21a ; the alkyl, aralkyl or heterocycle-lower alkyl group in R 21a′ ; the alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, carbamoyl, alkylsulfinyl, alkylsulfonyl, arylsulfonyl or heterocyclic group in R 22 , R 22a , R 23 and R 23a ; the alkyl, alkoxycarbonyl, aryloxycarbonyl or carbamoyl group in R 24a′ and R 25a′ ; the alkyl, alkenyl, cycloalkyl, aryl or aralkyl group in R 27 , R 27a , R 28 and R 28a ; and the alkyl group in R 28′ and R 28a′ may additionally be substituted with at least one groups selected from the following substituents:

substituents: cyano group, nitro group, unprotected or protected carboxyl group, unprotected or protected hydroxyl group, unprotected or protected amino group, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, acyl group, aryl group, cycloalkyl group, lower alkenyl group, aralkyl group, lower alkylidene group, mercapto group, lower alkylthio group, halogeno-lower alkyl group, lower alkoxy-lower alkyl group, unprotected or protected hydroxy-lower alkyl group, unprotected or protected amino-lower alkyl group, lower alkoxycarbonyl-lower alkyl group, unprotected or protected cyclic amino group, unprotected or protected lower alkylamino group, lower alkoxyimino group, and unprotected or protected lower alkylamino-lower alkyl group.

Among the compounds conforming to the pharmacophore of formula 1 of this invention, preferred are compounds conforming to a pharmacophore in which the distances between the atoms constituting the pharmacophore are as follows, namely the distance between N 1 and N 2 is not less than 5.09 angstroms and not more than 11.67 angstroms, the distance between N 1 and N 3 is not less than 9.47 angstroms and not more than 14.30 angstroms, the distance between N 1 and N 4 is not less than 3.48 angstroms and not more than 12.60 angstroms, the distance between N 1 and N 5 is not less than 8.77 angstroms and not more than 15.67 angstroms, the distance between N 2 and N 3 is not less than 3.78 angstroms and not more than 9.78 angstroms, the distance between N 2 and N 4 is not less than 6.97 angstroms and not more than 13.26 angstroms, the distance between N 2 and N 5 is not less than 9.37 angstroms and not more than 13.32 angstroms, the distance between N 3 and N 4 is not less than 4.83 angstroms and not more than 10.51 angstroms, the distance between N 3 and N 5 is not less than 3.31 angstroms and not more than 9,97 angstroms, and the distance between N 4 and N 5 is not less than 4.32 angstroms and not more than 8.25 angstroms, and more preferred are compounds conforming to a pharmacophore in which N 1 constituting the pharmacophore is a nitrogen atom of unsubstituted or substituted amino, ammonium, amido, thioamido, ureido, isoureido, amidino, guanidino, thioureido, hydrazino or hydrazono group to which one or more hydrogen atoms are bonded, a carbon atom of ethenyl group to which a hydrogen atom is bonded, an oxygen atom of carbonyl group, a sulfur atom of thiocarbonyl group, a nitrogen atom of unsubstituted or substituted imino group, an oxygen atom of sulfonyl group, an oxygen atom of sulfonyloxy group, an oxygen atom of sulfonic group, an oxygen atom of sulfinyl group, an oxygen atom of carboxyl group, an oxygen atom of ether, a sulfur atom of thioether, a sulfur atom of mercapto group, an oxygen atom of hydroxyl group, an oxygen atom of ester, or a nitrogen atom of unsubstituted or substituted nitrogen-containing heterocyclic group; N 3 is an oxygen atom of carbonyl group, a sulfur atom of thiocarbonyl group, a nitrogen atom of imino group, an oxygen atom of sulfo group, an oxygen atom of sulfonyl group, an oxygen atom of sulfinyl group, an oxygen atom of sulfonyloxy group, an oxygen atom of carboxyl group, an oxygen atom of ether, a sulfur atom of thioether, an oxygen atom of hydroxyl group, an oxygen atom of ester, a nitrogen atom of unsubstituted or substituted nitrogen-containing heterocyclic group to which no hydrogen atom is bonded, a nitrogen atom of sulfonamido group or a nitrogen atom of acylsulfonamido group; and each of N 2 , N 4 and N 5 is arbitrary carbon atom constituting a carbon atom of alkyl group, a carbon atom of alkenyl group, a carbon atom of aryl group and a carbon atom of alkoxy group; and further preferred are compounds having an activity on the binding reaction between AP-1 and its recognition sequence.

Among the compounds of general formula [2] of this invention, preferred are those in which AA 3 is L-asparagine residue or L-glutamine residue; AA 4 , AA 6 and AA 7 are L-leucine residue, L-isoleucine residue, L-alanine residue or L-valine residue; and AA 5 is L-aspartic acid residue, L-glutamic acid residue, L-serine residue or L-threonine residue.

Among the compounds of general formula [2b] of this invention, preferred are those in which aa 3 is L-asparagine residue or L-glutamine residue; aa 4 , aa 5 and aa 7 are L-leucine residue, L-isoleucine residue, L-alanine residue or L-valine residue; and aa 9 is L-aspartic acid residue, L-glutamic acid residue, L-serine residue or L-threonine residue.

Among the compounds of general formula [3] of this invention, preferred are those in which W is —Z′—COOR 2 —, —Z′—CONH—SO 2 R 28′ —, —CONH—CH 2 COOR 2′ — or —CONH—CH 2 CH 2 COOR 2′ (in these formulas, Z′ represents —(CH 2 ) n′ — in which n′ is 0, 1 or 2 or —CH═CH—, R 28′ represents unsubstituted or substituted alkyl group, R 2′ represents hydrogen atom or a protecting group for carboxyl group, and X 1 represents —C(O)—, —CH(OH)— or —CH 2 —; more preferred are those in which R 1 is unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group, R 3 is unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group, and R 4 is unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group; further preferred are those in which R 3 is alkoxy group, hydroxyl group or alkylcarbonyloxy group, and X 1 is —C(O)—; and yet further preferred are those in which R 1 is alkoxy group and R 4 is alkoxy group.

Among the compounds of general formula [4] of this invention, preferred are those in which R 5 is alkoxy group or acylamino group, and ring A is a group represented by the following formula:

wherein R 11 is alkyl or alkoxycarbonyl group and R 12 is alkyl group, or a group represented by the following formula:

wherein R 13 is alkyl or alkoxycarbonyl group and R 14 is alkoxy or alkanoyloxy group.

Among the compounds of general formula [5] of this invention, preferred are those in which R 15 and R 16 are the same or different and represent alkoxy group, and ring B represents the following formula:

wherein R 19 represents acyl group, and R 20 represents a protecting group for carboxyl group and p represents 0, 1 or 2.

Among the compounds of general formula [a] of this invention, preferred are those in which R 1a is unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group, R 3a and R 4a are the same or different and represent unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group, X 1a represents —C(O)—, —CH(OH)—, —CH 2 — or the following formulas:

wherein R 21a′ represents unsubstituted or substituted alkyl, aralkyl or heterocycle-lower alkyl group, R 24a′ and R 25a′ are the same or different and represent hydrogen atom, unprotected or protected carboxyl group or unsubstituted or substituted alkyl, alkoxycarbonyl, aryloxycarbonyl or carbamoyl group, W a represents —Z a′ —COR 26a′ , —Z a′ —COOR 2a′ , —O—CH 2 COOR 2a′ , —O—CH 2 CH 2 —COOR 2a′ , —CONH—CH 2 COOR 2a′ or —CONH—CH 2 CH 2 COOR 2a′ (in these formulas, Z a′ represents —(CH 2 ) n a′ wherein n a′ is 0, 1, 2 or 3, —CH 2 CH(CH 3 )—, —CH═CH— or —CH 2 CH═CH—, R 2a′ represents hydrogen atom or a protecting group for carboxyl group, and R 26a′ represents —NHSO 2 R 28a′ wherein R 28a′ is unsubstituted or substituted alkyl group.

Among the compounds of general formula [b] of this invention, preferred are those in which R 1b represents unsubstituted or substituted alkoxy group, R 3b and R 4b are the same or different and represent unprotected or protected hydroxyl group or unsubstituted or substituted alkoxy group, X 1b is —C(O)—, and Z b is —(CH 2 ) 2 —.

Among the compounds of general formula [c] of this invention, preferred are those in which R 1c represents unsubstituted or substituted alkoxy group; R 2c represents hydrogen atom or a protecting group for carboxyl group; R 3c and R 4c may be the same or different and represent unsubstituted or substituted alkoxy group; X 1c is —C(O)—; and Z c is —(CH 2 ) 2 —.

Among the compounds of general formula [d] of this invention, preferred are those in which R 1 1d is unsubstituted or substituted alkoxy group; R 3d is unsubstituted or substituted alkyl group; R 4d is unsubstituted or substituted acyl group; X 1d is —C(O)—; and Z d is —(CH 2 ) 2 —.

Among the compounds of general formula [e] of this invention, preferred are those in which R 0e is hydrogen atom or halogen atom; R 1e is unsubstituted or substituted alkyl group; R 3e and R 4e independently represent unsubstituted or substituted alkoxy group; X 1e is —C(O)—; and Z e is a bonding unit.

Among the compounds of general formula [f] of this invention, preferred are those in which R 1f is unsubstituted or substituted alkoxy group; R 3f and R 4f independently represent unsubstituted or substituted alkyl group; X 1f is —C(O)—; and Z f is —CH 2 —.

As typical compounds of this invention, the following compounds can be referred to, for example, provided that Ac represents an acetyl group.

Ac-Cys-Gly-Gln-Leu-Asp-Leu-Ala-Leu-Gly-Cys-NH 2 [SEQ ID NO:5] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Gln-Leu-Ser-Leu-Ala-Leu-Gly-Cys-NH 2 [SEQ ID NO:6] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Gln-Leu-Asp-Leu-Ala-Gly-Gly-Cys-NH 2 [SEQ ID NO:7] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Gln-Leu-Asp-Leu-Ala-Asn-Gly-Cys-NH 2 [SEQ ID NO:8] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Gln-Leu-Ser-Leu-Ala-Asp-Gly-Cys-NH 2 [SEQ ID NO:9] (having a disulfide linkage between the first and tenth cysteine residues)

Ac-Cys-Gly-Asn-Leu-Asp-Leu-Ala-Asp-Gly-Cys-NH 2 [SEQ ID NO:3] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Asn-Cys-Gly-Asn-Leu-Leu-Ala-Leu-Gly-Ser-Cys-NH 2 [SEQ ID NO:10] (having a disulfide linkage between the second and eleventh L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ala-Leu-Gly-Ser-Cys-NH 2 [SEQ ID NO:11] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Asn-Cys-Gly-Asn-Ala-Leu-Ala-Leu-Gly-Ser-Cys-NH 2 [SEQ ID NO:12] (having a disulfide linkage between the second and eleventh L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ala-Leu-Gly-Asp-Cys-NH 2 [SEQ ID NO:13] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ser-Leu-Gly-Asp-Cys-NH 2 [SEQ ID NO:14] (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ala-Leu-Gly-Ser-Cys-NH 2 (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Asn-Cys-Gly-Asn-Ala-Leu-Ala-Leu-Gly-Ser-Cys-NH 2 (having a disulfide linkage between the second and eleventh L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ala-Leu-Gly-Asp-Cys-NH 2 (having a disulfide linkage between the first and tenth L-cysteine residues)

Ac-Cys-Gly-Asn-Leu-Leu-Ser-Leu-Gly-Asp-Cys-NH 2 (having a disulfide linkage between the first and tenth L-cysteine residues)

(3S)-8-(3-methylbutylidene)-4-(4-methylpentanoyl)-1-thia-4-azaspiro[4.5]-deecane-3-carboxylic acid 2-[(2S)-4-(2,4-diisobutoxybenzoyl)-1-(3-methylbutanoyl)-3-oxohexahydro-2-pyrazinyl]-acetic acid 2-(2-isobutoxy-5-{[(2S,4R)-4-(isobutyryloxy)-2-(isopropoxycarbonyl)tetrahydro-1H-1-pyrrolyl]carbonyl}-phenyl)-acetic acid 2-(2-isobutoxy-5-{[(2S)-4-isopentyl-2-(isopropoxycarbonyl)-3-oxohexahydro-1-pyrazinyl]carbonyl}-phenyl)-acetic acid 2-(5-{[(2R)-2,4-diisopentyl-3-oxohexahydro-1-pyrazinyl]-carbonyl}-2-isobutoxyphenyl)-acetic acid

Further, the compounds of the following Tables 1 to 37 can also be referred to.

In the tables, meanings of the abbreviations are as follows:

Me: CH 3 ; Et: C 2 H 5 ; nPr: CH 2 CH 2 CH 3 ; iPr: CHCH 3 ) 2 ; iBu: CH 2 CH(CH 3 ) 2 ; iAm: CH 2 CH 2 CH(CH 3 ) 2 ; Ph: phenyl; Py: pyridyl

In cases where the compounds conforming to the pharmacophore of formula 1, the compounds of general formulas [2], [2b], [3], [4], [5], [a], [b], [c], [d], [e], [f] and [g] or salts of these compounds have isomers such as optical isomers, geometrical isomers and tautomers, this invention involves these isomers, too, and involves solvated products, hydrated products and crystal of various forms, too.

Next, processes for producing the compounds of this invention will be explained.

The compound of this invention are produced by combining the processes which are well known in themselves, and, for example, according to the Production Processes 1 to 20.

wherein AA 3 and AA 8 are as defined above, Ac is acetyl group, Y 1 is an optionally used protecting group for cysteine, and Y 3 and Y 8 independently represent a protecting group for functional group in the side chain of amino acid, provided that amino acid residues are expressed according to the three letters expression prescribed in IUPAC and IUB.

The peptide of this invention is produced by a liquid phase method or a solid phase method according to a combination of methods which are well known in themselves (Izumiya et al., Fundamentals and Experiments of Peptide Syntheses, Pages 194-283, published by Maruzen Shuppan).

The peptide-bonded resin of general formula [7; SEQ ID NO:1] can be obtained by subjecting the resin of general formula [6] to a solid phase method. The construction of peptide chain by solid phase method is carried out by repeating a condensation of amino acid having an amino acid functional group protected with appropriate protecting group and de-protection of the protecting group of α-amino acid. Condensation of amino acid is carried out successively one by one from the terminal amino acid according to the order of amino acids in the sequence to be synthesized. The procedure of the solid phase method will be mentioned below. A series of reactions used therein are preferably carried out in an atmosphere of nitrogen. Any of the manual method and the method of using an automatic synthesizing apparatus may be adopted.

(1) A peptide-bonded resin having a protected N terminal can be obtained by condensing a resin with an amino acid derivative. Concretely speaking, a resin is introduced into a reactor, and a solvent is added to swell the resin. After filtering off the solvent, an amino acid derivative and a condensing agent are added, a solvent is again added, and a reaction is carried out.

As the resin of general formula [6] used in this reaction, those resins which are conventionally used in the solid phase method can be referred to. Examples thereof include benzhydrylamine resin, 4-methylbenzhydrylamine resin, Rink amide resin and the like. The solvents used in this reaction include N,N-dimethylformamide, dichloromethane, chloroform, N-methylpyrrolidone and the like. Although the amount of the solvent is not critical, it is 5-100 ml and preferably 5-20 ml per gram of resin when the solvent is used for swelling a resin, and the amount of solvent is 5-100 ml and preferably 5-50 ml per gram of resin when the solvent is used for reaction. The amino acid derivatives used in this reaction are those in which α-amino acid is protected with t-butyloxycarbonyl group (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) or the like. The protecting groups for functional group in side chain are as follows. Thus, for protecting the side chain carboxyl group of aspartic acid and glutamic acid, t-butyl ester group, benzyl ester group, cyclohexyl ester group and the like are used. For protecting the side chain hydroxyl group of serine, threonine and tyrosine, t-butyl group, benzyl group, 2,6-dibromobenzyl group and the like are used. For protecting the side chain thiol group of cysteine, trityl group, acetamidomethyl group, t-butyl group and the like are used. Preferable amino acid derivative is Fmoc-amino acid. As the condensing agents which can be used in this reaction, dicyclohexylcarbodiimide, diisopropylcarbodiimide, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBROP) and the like can be referred to. The condensing agent may be used in an amount of 1-10 equivalents per equivalent of amino group in the resin. When PyBOP or PyBROP is used, an amine such as diisopropylethylamine, triethylamine or the like may be added in an amount of 1-5 equivalents per equivalent of the condensing agent. Further, an active ester-forming agent such as N-hydroxybenzotriazole, N-hydroxy-7-azabenzotriazole or the like may be added in an amount of 0.5-2 equivalents per equivalent of the condensing agent. The reaction is carried out usually at 10-40° C. and preferably 20-30° C., for a period of 5-120 minutes.

(2) The peptide of which N terminal is de-protected can be obtained by reacting the α-amino protecting group of peptide-bonded resin having a protected N terminal in the presence of de-protecting agent to eliminate the protecting group. Concretely speaking, a peptide-bonded resin of which N terminal is protected is reacted with an acid or a base in the presence or absence of a solvent.

The de-protecting agent used in this reaction is appropriately selected in accordance with the kind of α-amino protecting group. When the protecting group of α-amino group is Boc group, an acid such as trifluoroacetic acid, methanesulfonic acid or the like is used. When the protecting group is Fmoc group, a base such as piperidine, 1,8-diazabicyclo[5.4.0]undec-7-ene or the like is used. The solvents used in this reaction are not limited so far as they exercise no adverse influence upon the reaction. When an acid is used, dichloromethane, dichloroethane and the like are used. When a base is used, N,N-dimethylformamide, N-methylpyrrolidone and the like are used. In a case where a solvent is used, the solvent is used in an amount of 5-20 ml per gram of the resin. The reaction is carried out usually at 10-40° C. and preferably 20-30° C., for a period of 5-120 minutes.

(3) Peptide-bonded resins having ten residues can be obtained by repeating the procedure of (1) or (2) ten times on the peptide-bonded resin obtained above.

(4) The peptide of general formula (7; SEQ ID NO:1) can be obtained by acetylating a peptide-bonded resin having 10 residues. Concretely, it can be obtained by reacting a peptide-bonded resin of 10 residues with acetic anhydride in the presence or absence of an amine.

In this reaction, acetic anhydride is used in an amount of 1-20 equivalents and preferably 5-10 equivalents per equivalent of amino group in the resin. As the amine used in this reaction according to the need, diisopropylamine, triethylamine and the like can be referred to, and the amount thereof is 0.2-2 equivalents per equivalent of acetic anhydride. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence upon the reaction, N,N-dimethylformamide, dichloromethane, chloroform, N-methylpyrrolidone and the like are used. These solvents may be used either alone or in the form of mixture of two or more. Although the amount of the solvent is not particularly limited, the solvent may be used in an amount of 5-20 ml per gram of resin. The reaction is carried out at 10-40° C. and preferably 20-30° C., for a period of 10-120 minutes.

The peptide of general formula [8; SEQ ID NO:1] can be obtained by removing the protecting group of amino side chain and the resin from the protected peptide resin of general formula [7; SEQ ID NO:1] in the presence of an acid.

The acid used in this reaction can appropriately be selected in accordance with combination of the resin used and the protecting group for amino group. For example, trifluoromethanesulfonic acid, anhydrous hydrogen fluoride, trifluoroacetic acid and the like can be used as said acid. When the resin is benzhydrylamine resin, 4-methylbenzhydrylamine resin or the like and the protecting group for amino acid side chain is a group selected from benzyl ester group, cyclohexyl ester group, benzyl group and 2,6-dibromobenzyl group, trifluoromethanesulfonic acid, anhydrous hydrogen fluoride or the like may be used as said acid. When the resin is Rink amide resin or the like and the protecting group for amino acid side chain is a group selected from t-butyl ester group, t-butyl group and trityl group, trifluoroacetic acid and the like may be used as said acid. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, dichloromethane may be used, for example, as said acid. Although amount of the solvent is not critical, it may be 5-100 ml per gram of resin. In this reaction, anisole, thioanisole, m-cresol, p-cresol, ethanedithiol, water, etc. may be added, and the amount thereof is preferably 0.1-20% by volume based on the solvent used. A combined use of these compounds is also allowable, if desired. This reaction is carried out at −10° C. to 40° C. and preferably 0-20° C., for a period of 30-300 minutes.

The cyclic peptide of general formula [2; SEQ ID NO:1] can be obtained by forming a disulfide linkage between the cysteine side chains of the peptide of general formula [8; SEQ ID NO:1]. The formation of intramolecular disulfide linkage between two cysteine residues can be effected according to a known method.

Concretely speaking, when the side chain thiol group of cysteine is not protected, air oxidation in a dilute aqueous ammonia solution, or the method of using 5-20% dimethyl sulfoxide/trifluoroacetic acid solution may be used. When the side chain thiol group of cysteine is protected with triacetamidomethyl group or the like, the iodine oxidation method or the method of de-protection using silver tetrafluoroborate followed by air oxidation may be used. When the side chain thiol group of cysteine is protected with t-butyl, the silyl chloride-diphenyl sulfoxide method may be used (Development of Pharmaceuticals, Peptide syntheses, Hirokawa Shoten, Pages 233-258).

The cyclic peptides of general formula [2; SEQ ID NO:1] or salts thereof thus obtained can be isolated and purified according to conventional methods such as extraction, crystallization, gel filtration, liquid chromatography and/or column chromatography. For example, the isolation and purification can be effected by the gel filtration method using a gel filter such as Sephadex G-10, G-25 or the like, the column chromatography using a reverse phase type synthetic polymer resin or a chemically modified silica gel carrier and/or a high performance liquid chromatography, or the like.

[Production Process 1a]

The cyclic peptide of general formula [2b; SEQ ID NO:2] can be obtained by the same method as Production Process 1.

wherein R 1 , R 2 (hydrogen atom is excepted), R 3 , R 4 , R 5 , R 6 (hydrogen atom is excepted), R 7 , R 8 , R 9 , R 10 , R 15 , R 16 , R 17 , R 18 (hydrogen atom is excepted), Z, n, m and p are as defined above.

[Production Process 2]

The compound of general formula [10] can be obtained by reacting a compound of general formula [9] and a formylating agent in the presence of an acid. As the acid used in this reaction, titanium tetrachloride, stannic chloride, aluminum chloride, phosphorus oxychloride and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of formula [9]. As the formylating agent, α,α-dichloromethyl methyl ether, N,N-dimethylformamide, ethyl orthoformate and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [9]. As the solvent used in this reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like and aliphatic hydrocarbons such as n-hexane, cyclohexane and the like can be referred to, and these solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [12] can be obtained by reacting a compound of general formula [10] with an oxidant in the presence or absence of an acid or a base.

As the acid which can be used in this reaction according to need, hydrochloric acid, sulfuric acid, acetic acid, sulfamic acid and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [10]. As the base which can be used according to need, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like and pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [10]. As the oxidant used in this reaction, sodium chlorite, sodium hypochlorite, chromic acid, potassium permanganate, hydrogen peroxide, ruthenium oxide, nickel oxide, silver oxide, silver nitrate and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-3 mol per mol of the compound of general formula [10]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, ethers such as tetrahydrofuran, ethyl ether, dioxane and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitrites such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, aromatic hydrocarbons such as toluene, benzene and the like, dimethyl sulfoxide, pyridine, water, etc. can be referred to. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the solvent for a period of 30 minutes to 24 hours.

The compound of general formula [12] can be obtained by reacting a compound of general formula [11] with an oxidant in the presence or absence of an acid or a base.

As the acid which can be used in this reaction according to the need, sulfuric acid, acetic acid and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [11]. As the base which can be used in this reaction according to the need, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like and pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [11]. As the oxidant used in this reaction, chromic acid, potassium permanganate and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [11]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, pyridine, water and the like can be referred to, for example, and these solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the solvent, for a period of 30 minutes to 24 hours.

The compound of general formula [3a] can be obtained by subjecting an acid chloride or an acid anhydride of a compound of general formula [12] and a compound of general formula [13] to Friedel-Crafts reaction in the presence of an acid.

The acid chloride or acid anhydride of the compound of general formula [12] used in this reaction can be obtained by reacting a compound of general formula [12] with an activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride, ethyl chloroformate or the like, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the acid used in this reaction, stannic chloride, aluminum chloride, boron trifluoride, zinc chloride and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [12]. The compound of general formula [13] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the solvent used in this reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, nitrobenzene, carbon disulfide and the like can be referred to, and these solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [3b] can be obtained by subjecting a compound of general formula [3a] to a de-protecting reaction such as a hydrolysis using an acid or a base, a de-esterification reaction using a salt, a reductive de-esterification reaction including hydrogenation in the presence of metallic catalyst, etc. As the acid which can be used in this reaction, formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminum chloride, trimethyliodosilane and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3a]. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, tetrabutylammonium fluoride and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-50 mol per mol of the compound of general formula [3a]. As the salt used in this reaction, lithium iodide, sodium chloride and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [3a]. As the catalyst used in the reductive de-esterification reaction, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001 to 1 mol and preferably 0.01 to 0.5 mol per one mol of the compound of general formula [3a]. As the reductant, hydrogen, formic acid, cyclohexene, zinc and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [3a]. Although the solvent which can be used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol, isopropyl alcohol and the like, ethers such as tetrahydrofuran, ethyl ether, dioxane, anisole and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitrites such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at −78° C. to 100° C. and preferably 5-80° C., for a period of 10 minutes to 24 hours.

The compound of general formula [3c] can be obtained by reacting a compound of general formula [3b] with a reductant in the presence or absence of an acid, a base or a salt. As the acid which can be used in this reaction according to need, hydrochloric acid, sulfuric acid, trifluoroacetic acid, aluminum chloride, boron trifluoride and the like can be referred, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [3b]. As the base which can be used according to the need, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like and pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3b]. As the salt which can be used according to the need, lithium chloride, magnesium chloride, calcium chloride and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [3b]. As the reductant, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride and the like can be used, and amount thereof is 0.25-10 mol and preferably 1-8 mol per mol of the compound of general formula [3b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, ethers such as tetrahydrofuran, ethyl ether and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, dimethyl sulfoxide, N,N-dimethylformamide, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at −78° C. to 70° C., for a period of 30 minutes to 24 hours.

The compound of general formula [3d] can be obtained by subjecting a compound of general formula [3b] or [3c] to reduction including hydrogenation using a metallic catalyst, in the presence or absence of an acid, a base or a salt. As the acid which can be used in this reaction according to need, hydrochloric acid, sulfuric acid, trifluoroacetic acid, aluminum chloride, boron trifluoride and the like can be referred, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [3b] or [3c]. As the base which can be used according to the need, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like and pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3b] or [3c]. As the salt which can be used according to the need, lithium chloride, magnesium chloride, calcium chloride and the like can be referred to, and amount thereof is 1-50 mol and preferably 1-10 mol per mol of the compound of general formula [3b] or [3c]. As the reductant, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, triethylsilane, hydrogen, cyclohexene and the like can be used, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [3b] or [3c]. As the catalyst, palladium-carbon, palladium-black, palladium hydroxide and the like can be used, and amount thereof is 0.001-1 mol and preferably 0.01-0.5 mol per mol of the compound of general formula [3b] or [3c]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, ethers such as tetrahydrofuran, ethyl ether and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, N,N-dimethylformamide, acetic acid, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

[Production Process 3]

The compound of general formula [4a] or [4b] can be obtained by reacting a compound of general formula [14] with a compound of general formula [15] or [16] by the use of a condensing agent in the presence or absence of an acid or a base. Otherwise, it can be obtained by reacting an acid chloride or acid anhydride of a compound of general formula [14] with a compound of general formula [15] or [16].

The acid chloride or acid anhydride of the compound of general formula [14] used in this reaction can be obtained by reacting a compound of general formula [14] with an activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride, ethyl chloroformate and the like. The activating agent is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [14]. As the acid used in this reaction according to the need, toluenesulfonic acid, N-hydroxysuccinimide and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [14]. As the base which can be used according to the need, N,N-dimethylaminopyridine, pyridine, triethylamine and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [14]. As the condensing agent used in this reaction, dicyclohexylcarbodiimide, diphenylphosphoryl acid azide, N,N′-carbonyldiimidazole and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [14]. The compound of general formula [15] or [16] is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [14]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, ethers such as tetrahydrofuran, ethyl ether and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitriles such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, ketones such as acetone and the like, pyridine, N,N-dimethylformamide, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [4c] or [4d] can be obtained by subjecting a compound of general formula [4a] or [4b] to a de-protection reaction such as hydrolysis using an acid or a base, a de-esterification reaction using a salt, a reductive de-esterification reaction including hydrogenation using a metallic catalyst, or the like.

As the acid used in this reaction, formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminum chloride, trimethyliodosilane and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [4a] or [4b]. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, tetrabutylammonium fluoride and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-30 mol per mol of the compound of general formula [4a] or [4b]. As the salt used in this reaction, lithium iodide, sodium chloride and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [4a] or [4b]. As the catalyst used in the de-esterification reaction, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001-1 mol and preferably 0.01-0.5 mol per mol of the compound of general formula [4a] or [4b]. As the reductant used in this reaction, hydrogen, formic acid, cyclohexene, zinc and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [4a] or [4b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol, isopropyl alcohol and the like, ethers such as tetrahydrofuran, ethyl ether, dioxane, anisole and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitrites such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene, benzene, and the like, dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine, water, etc. can be used, and these solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature ranging from 0° C. to reflux temperature of the solvent and preferably at 5-60° C., for a period of 10 minutes to 24 hours.

[Production Process 4]

The compound of general formula [18] can be obtained by reacting a compound of general formula [17] with an acid chloride in the presence or absence of an acid or a base. Otherwise, it can be obtained by reacting a compound of general formula [17] with a carboxylic acid by the use of a condensing agent.

As the acid used in this reaction according to the need, toluenesulfonic acid, N-hydroxysuccinic acid and the like can be referred to, and amount thereof is 1-10 mol per mol of the compound of general formula [17]. As the base used in this reaction according to the need, N,N-dimethylaminopyridine, pyridine, triethylamine and the like can be referred to, and amount thereof is 1-10 mol per mol of the compound of general formula [17]. The acid chloride or carboxylic acid is used in an amount of 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [17]. As the condensing agent, dicyclohexylcarbodiimide, diphenylphosphoryl acid azide, N,N′-carbonyldiimidazole and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [17]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, ethers such as tetrahydrofuran, ethyl ether and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitrites such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, ketones such as acetone and the like, pyridine, N,N-dimethylformamide, etc. can be referred to. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

Further, it is also possible to obtain the compound of general formula [18] by subjecting a compound of general formula [17] to alkylation, amidation or sulfonamidation in the presence or absence of a base.

As the alkylating agent used in this reaction, methyl iodide, benzyl bromide and the like can be referred to. As the amidating agent, acid anhydrides such as acetic anhydride and the like and acyl halogenides such as acetyl chloride, benzoyl chloride and the like can be referred to. As the sulfonamidating agent, sulfonyl halides such as methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. These reagents are used in an amount of 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [17]. As the base used in this reaction according to the need, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like, and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [17]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as toluene, benzene, xylene and the like, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like, esters such as methyl acetate, ethyl acetate and the like, nitriles such as acetonitrile and the like, amides such as N,N-dimethylformamide and the like, and halogenated hydrocarbons such as chloroform, methylene chloride and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at 0-200° C. and preferably 10-150° C., for a period of 10 minutes to 24 hours. It is also possible to effect carbamoylation by reacting a compound of general formula [17] with triphosgene in the presence of a base and then treating the resulting active intermediate with aqueous ammonia. The triphosgen is used in an amount of 0.3-20 mol and preferably 1-4 mol per mol of the compound of general formula [17]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [17]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as chloroform, methylene chloride and the like can be used, for example. This reaction is carried out usually at 0-70° C. and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

After the reaction, the reaction mixture is treated with 1-50 v/w, preferably 5-15 v/w, of 25% aqueous ammonia to obtain a carbamoylated product. This reaction is carried out usually at 0-100° C. and preferably 0-30° C., for a period of 10 minutes to 24 hours.

The compound of general formula [5a] can be obtained by reacting a compound of general formula [18] and a compound of general formula [19] by the use of a condensing agent, in the presence or absence of an acid or a base. Otherwise, it is also possible to obtain the compound of general formula [5a] by reacting an acid chloride or acid anhydride of the compound of general formula [19] with a compound of general formula [18].

The acid chloride or acid anhydride of the compound of general formula [19] used in this reaction can be obtained by reacting a compound of general formula [19] with an activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride, ethyl chloroformate or the like, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [19]. As the acid used in this reaction according to the need, toluenesulfonic acid, N-hydroxysuccinimide and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [19]. As the base which can be used in this reaction according to need, N,N-dimethylaminopyridine, pyridine, triethylamine and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [19]. As the condensing agent used in this reaction, dicyclohexylcarbodiimide, diphenylphosphoryl acid azide, N,N′-carbonyldiimidazole and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [19]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, ethers such as tetrahydrofuran, ethyl ether and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitriles such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, ketones such as acetone and the like, pyridine, N,N-dimethylformamide, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out at a temperature ranging from −78° C. to the reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [5b] can be obtained by subjecting a compound of general formula [5a] to a de-protecting reaction such as hydrolysis using an acid or a base, de-esterification using a base or reductive de-esterification including hydrogenation using a metallic catalyst. As the acid which can be used in this reaction, formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminum chloride, trimethyliodosilane and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [5a]. As the base, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, tetrabutylammonium fluoride and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-30 mol per mol of the compound of general formula [5a]. As the salt used in this reaction, lithium chloride, sodium chloride and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [5a]. As the catalyst used in the reductive de-esterification reaction, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001 to 1 mol and preferably 0.01 to 0.5 mol per one mol of the compound of general formula [5a]. As the reductant, hydrogen, formic acid, cyclohexene, zinc and the like can be referred to, and amount thereof is 1-100 mol per mol of the compound of general formula [5a]. Although the solvent which can be used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol, isopropyl alcohol and the like, ethers such as tetrahydrofuran, ethyl ether, dioxane, anisole and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitriles such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at 0° C. to reflux temperature of the solvent and preferably 5-60° C., for a period of 10 minutes to 24 hours.

wherein R 1 , R 2 (hydrogen atom is excepted), R 3 , R 4 and Z are as defined above.

The reaction for obtaining a compound of general formula [3a] from a compound of general formula [9e] may be carried out by the same procedure as that of the reaction for obtaining a compound of general formula [3a] from a compound of general formula [12] described in Production Process 2.

wherein R 29 , R 30 and R 31 may be the same or different and independently represent unsubstituted or substituted alkyl, cycloalkyl or aralkyl group; X represents halogen atom, alkylsulfonyloxy group or arylsulfonyloxy group; and R 1 , R 2 (hydrogen atom is excepted) and Z are as defined above.

The compound of general formula [20a] can be obtained by subjecting an acid chloride or acid anhydride of a compound of general formula [12] and a compound of general formula [13′] to Friedel-Crafts reaction in the presence of an acid.

The acid chloride or acid anhydride of the compound of general formula [12] used in this reaction can be obtained by reacting a compound of general formula [12] with an activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, acetic anhydride, ethyl chloroformate or the like, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [12]. As the acid used in this reaction, stannic chloride, aluminum chloride, boron trifluoride, zinc chloride and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 0.9-6 mol per mol of the compound of general formula [12]. The compound of general formula [13′] is used in an amount of 0.1-10 mol and preferably 0.3-3 mol per mol of the compound of general formula [12]. As the solvent used in this reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, nitrobenzene, carbon disulfide and the like can be referred to, and these solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at −30° C. to 30° C., for a period of 10 minutes to 24 hours.

It is also possible to obtain a compound of general formula [20b] directly by this reaction while controlling the reaction conditions such as amount of acid, reaction temperature and/or amount of reaction solvent, etc.

The compound of general formula [20b] can be obtained by subjecting a compound of general formula [20a] to a de-alkylation reaction in the presence of an acid, a base or a salt.

As the acids which can be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like, organic acids such as trifluoroacetic acid, thiophenol and the like, and trimethyliodosilane, aluminum chloride, boron trifluoride, zinc chloride and the like can be referred to. As the bases which can be used in this reaction, sodium salt of ethylmercaptan, lithium diisopropylamide and the like can be referred to. As the salts which can be used in this reaction, sodium cyamide, lithium iodide, pyridine hydrochloride and the like can be referred to. Each of the acids, bases and salts is used in an amount of 1-50 mol and preferably 2-20 mol per mol of the compound of general formula [20a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. When a mineral acid is used, water may also be used, if desired. These solvents may be used either alone or in the form of mixture of two or more.

This reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-110° C., for a period of 30 minutes to 24 hours.

The compound of general formula [20c] can be obtained by subjecting a compound of general formula [20b] to an alkylation reaction with a compound of general formula [47] in the presence of a base.

In this reaction, the compound of general formula [47] is used in an amount of 1-20 mol and preferably 1-5 mol per mol of the compound of general formula [20b]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; alkali metal hydrides such as sodium hydride and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-5 mol per mol of the compound of general formula [20b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at 0-200° C. and preferably at 25-150° C., for a period of 10 minutes to 24 hours.

The compound of general formula [20d] can be obtained by subjecting a compound of general formula [20c] to a de-protecting reaction such as hydrolysis using an acid or a base, de-esterification reaction using a salt, reductive de-esterification reaction including hydrogenation in the presence of metallic catalyst, etc.

As the acid which can be used in this reaction, formic acid, hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, aluminum chloride, trimethyliodosilane and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [20c]. As the base used in this reaction, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and the like, tetrabutylammonium fluoride and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-10 mol per mol of the compound of general formula [20c]. As the salt used in this reaction, lithium iodide, sodium chloride and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [20c]. As the catalyst used in the reductive de-esterification reaction, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001 to 1 mol and preferably 0.01 to 0.5 mol per mol of the compound of general formula [20c]. As the reductant, hydrogen, formic acid, cyclohexene, zinc and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [20c]. Although the solvent which can be used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol, isopropyl alcohol and the like, ethers such as tetrahydrofuran, ethyl ether, dioxane, anisole and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitriles such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more.

The reaction is carried out usually at −78° C. to 100° C. and preferably 5-60° C., for a period of 10 minutes to 24 hours.

The reaction for obtaining a compound of general formula [20e] from the compound of general formula [20b] may be effected in the same manner as the procedure for obtaining compound [20d] from compound [20c] in Production Process 5. If desired, the compound of general formula [20e] can be subjected to the same treatment for producing compound [28c] from compound [28b] in the Production Process 9 to acylate or alkylate the hydroxyl group thereof.

wherein R 1 , R 3 , R 4 , Z, X 1 , R 27 and R 28 are as defined above.

The compound of general formula [21b] can be obtained by subjecting a compound of general formula [21a] to a reaction with a compound of general formula [48].

This reaction can be carried out by a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. For example, in the method using a base, a condensing agent and an additive, the compound of general formula [48] used in this reaction is selected from methanesulfonamide, benzenesulfonamide and the like, and amount thereof is 1-10 mol and preferably 1-3 mol per mol of the compound of general formula [21a]. As the base used in this reaction, organic amines such as dimethylaminopyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, pyridine, N-methylmorpholine and the like, and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [21a]. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide, 1,1′-carbonyldiimidazole, diphenylphosphoryl azide and the like can be used. As the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be used, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [21a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [21c] can be obtained by subjecting a compound of general formula [21a] and a compound of general formula [22] to an amidation reaction.

This reaction can be effected according to the conventional procedure of amidation. For example, it can be carried out by a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In the method using a base, a condensing agent and an additive, the compound of general formula [22] is used in an amount of 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [21a]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [21a]. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide, diphenylphosphoryl azide and the like can be used, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [21a]. As the additive, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be used, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [21a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

In cases where X 1 and R 27 in the Production Process 6 mentioned above has a group which has to be protected, such as carboxyl group or the like, the objective compound can be obtained by appropriately protecting the group to be protected before the reaction and carrying out de-protection after completion of the reaction.

wherein Ac is acetyl group; Z″ is —CH 2 — or —CH 2 CH 2 —; and R 1 , R 2 (hydrogen atom is excepted), R 3 , R 4 and X are as defined above.

The reaction for obtaining a compound of general formula [24] from a compound of general formula [23] is carried out by the same procedure as that for obtaining a compound of formula [20a] from a compound of formula [12] in Production Process 5.

The compound of general formula [25] can be obtained by subjecting a compound of general formula [24] to a de-protection reaction in the presence or absence of an acid or a base.

As the acid used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like can be referred to, and amount thereof is 1-50 mol and preferably 10-30 mol per mol of the compound of general formula [24]. As the base which can be used in this reaction according to the need, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxides and the like can be referred to, and the amount thereof is 1-50 mol and preferably 1-30 mol per mol of the compound of general formula [24]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; acetic acid; water; and sulfoxides such as dimethyl sulfoxide and the like can be used. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of 0° C. to 150° C. and preferably at 25-120° C., for a period of 30 minutes to 24 hours.

The reaction for obtaining a compound of general formula [26a] from a compound of general formula [25] is carried out by the same procedure as that for obtaining a compound of formula [20c] from a compound of formula [20b] in Production Process 5.

The reaction for obtaining a compound of general formula [26b] from a compound of general formula [26a] is carried out by the same procedure as that for obtaining a compound of formula [20d] from a compound of formula [20c] in Production Process 5.

The reaction for obtaining a compound of general formula [26a] from a compound of general formula [12c] is carried out by the same procedure as that for obtaining a compound of formula [24] from a compound of formula [23] in Production Process 7.

wherein R 1 , R 2 (hydrogen atom is excepted), R 3 and R 4 are as defined above.

The compound of general formula [27b] can be obtained by reacting a compound of general formula [27a] with methyl iodide, methyl bromide or the like in the presence of a base.

As the base used for this reaction, organolithium compounds such as lithium diisopropyl-amide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to. The base is used in an amount of 1-20 mol and preferably 1-10 mol per mol of the compound of general formula [27a]. Methyl iodide, methyl bromide and the like are used in an amount of 1-50 mol and preferably 1-20 mol per mol of the compound of general formula [27a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −78° C. to 150° C. and preferably at −60° C. to 120° C., for a period of 30 minutes to 24 hours.

The reaction for forming the compound of general formula [27c] from the compound of [27b] is carried out by the same procedure as that for obtaining compound [20d] from compound [20c] in Production Process 5.

wherein R 32 is a protecting group for carboxyl group; R 33 and R 34 may be the same or different and independently represent hydrogen atom or alkyl, cycloalkyl, aralkyl, aryl or heterocyclic group; and R 1 , R 2 (hydrogen atom is excepted), R 3 and Z are as defined above.

The reaction for forming the compound of general formula [49] from the compound of [9f] is carried out by the same procedure as that for obtaining compound [20a] from compound [12] in Production Process 5.

The reaction for forming the compound of general formula [50a] from the compound of [49] is carried out by the same procedure as that for obtaining compound [20d] from compound [20c] in Production Process 5.

The compound of general formula [50b] can be obtained by subjecting a compound of general formula [50a] to an esterification reaction.

This reaction can be effected according to the conventional procedure of esterification, and the methods for performing it include a method via an acid chloride, a method via an acid anhydride, a method using a base and alkyl halide, a method using a condensing agent and an additive, etc. When a base and an alkyl halide are used, the bases which can be used in this reaction include, for example, organic amines such as dimethylaminopyridine, triethylamine, N-methylmorpholine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like. The amount of said base is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50a]. As the alkyl halide used in this invention, methyl iodide, ethyl iodide, benzyl bromide and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. This reaction is carried out usually at a temperature of 0-200° C. and preferably at 5-100° C., for a period of 10 minutes to 24 hours. When a condensing agent and an additive are used, the intended product can be obtained by subjecting an alcohol such as methanol, ethanol, benzyl alcohol or the like to a condensation reaction with a condensing agent and an additive. As the condensing agent used in this reaction, for example, 1,1′-carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide, diphenyl-phosphoryl azide and the like can be referred to. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. In this reaction, each of the alcohol, condensing agent and additive is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl-acetate, ethyl acetate and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. The reaction is carried out usually at 0-200° C. and preferably at 5-100° C., for a period of 10 minutes to 24 hours.

The compound of general formula [50c] can be obtained by subjecting a compound of general formula [50b] to amidation reaction.

This reaction is a conventional amidation reaction, and includes a method via an acid chloride, a method via an acid anhydride, a method using a base, a condensing agent and an additive, etc. In the method of using a base, a condensing agent and an additive, the amines used in this reaction include primary amines such as ammonia, methylamine, benzylamine, aniline, phenethylamine, isopropylamine, aminothiazole and the like; and secondary amines such as dimethylamine, diethylamine, di-n-propylamine and the like, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50b]. As the base used in this reaction, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50b]. As the condensing agent, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide, diphenylphosphoryl azide and the like can be referred to, and amount thereof is 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50b]. As the additive used in this reaction, for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide and the like can be referred to. In this reaction, each of the condensing agent and additive is used in an amount of 0.5-10 mol and preferably 1-3 mol per mol of the compound of general formula [50b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; esters such as methyl acetate, ethyl acetate and the like; nitrites such as acetonitrile and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used. The reaction is carried out usually at −20° C. to 150° C. and preferably at 0-120° C., for a period of 30 minutes to 24 hours.

The reaction for forming the compound of general formula [50d] from the compound of [50c] is carried out by the same procedure as that for obtaining compound [20d] from compound [20c] in Production Process 5.

wherein R 1 , W, R 3 , R 4 , R 21 , R 22 , R 23 and X are as defined above.

The compound of general formula [28b] can be obtained by reacting a compound of general formula [28a] with hydroxylamine hydrochloride in the presence or absence of a base.

In this reaction, hydroxylamine hydrochloride is used in an amount of 1-10 mol and preferably 1-5 mol per mol of the compound [28a]. As the base used in this reaction, alkali metal hydroxides such as sodium hydroxide and the like, organic amines such as dimethylaminopyridine, triethylamine, pyridine, N-methylmorpholine and the like, and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and the amount thereof is 0.5-20 mol and preferably 1-10 mol per mol of the compound of general formula [28a]. Although the solvent which can be used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, alcohols such as methanol, ethanol, isopropyl alcohol and the like, ethers such as tetrahydrofuran, ethyl ether, dioxane, anisole and the like, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, nitriles such as acetonitrile and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, dimethyl sulfoxide, N,N-dimethylformamide, nitromethane, pyridine, water, etc. can be used. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at −20° C. to 150° C. and preferably 0-120° C., for a period of 30 minutes to 24 hours.

The compound of general formula [28c] can be obtained by subjecting a compound of general formula [28b] to an O-alkylating reaction or acylation reaction with a compound of general formula [47a] in the presence of base.

In this reaction, the compound of general formula [47a] is used in an amount of 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [28b]. As the base used in this reaction, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; alkali metal hydrides such as sodium hydride and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 2-20 mol and preferably 1-4 mol per mol of the compound of general formula [28b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like, esters such as methyl acetate, ethyl acetate and the like, nitrites such as acetonitrile and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, amides such as N,N-dimethylformamide and the like, halogenated hydrocarbons such as chloroform, methylene chloride and the like, and sulfoxides such as dimethyl sulfoxide and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at 0-200° C. and preferably 10-150° C., for a period of 10 minutes to 24 hours.

The compound of general formula [28e] can be obtained by subjecting a compound of general formula [28b] to reduction including hydrogenation using a metallic catalyst in the presence or absence of an acid, a base or a salt.

As the acid used in this reaction according to the need, hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, nickel chloride, aluminum chloride and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [28b]. As the base used in this reaction according to the need, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, ammonia, pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-10 mol per mol of the compound of general formula [28b]. As the salt used in this reaction according to the need, lithium chloride, magnesium chloride, ammonium acetate and the like can be referred to, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [28b]. As the reductant, sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, triethylsilane, hydrogen, cyclohexene, diborane, sodium amalgam, Raney nickel and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-10 mol per mol of the compound of general formula [28b]. As the catalyst, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001-1 mol per mol of the compound [28b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like, ethers such as tetrahydrofuran, ethyl ether and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, aromatic hydrocarbons such as toluene, benzene, xylene and the like, aliphatic hydrocarbons such as n-hexane, cyclohexane and the like, esters such as ethyl acetate and the like, N,N-dimethylformamide, acetic acid, pyridine water, etc. can be referred to, for example, and these solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

The compound of general formula [28f] can be obtained by subjecting a compound of general formula [28e] to alkylation, amidation or sulfonamidation reaction in the presence of a base.

As the alkylating agent used in this reaction, for example, methyl iodide and benzyl bromide can be referred to. As the amidating agent, for example, acid anhydrides such as acetic anhydride and the like and acyl halides such as acetyl chloride, benzoyl chloride and the like can be referred to. As the sulfonamidating agent, sulfonyl halides such as methanesulfonyl chloride, benzenesulfonyl chloride and the like can be referred to. These reagents are used in an amount of 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [28e]. As the base used in this reaction, for example, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like; and alkali metal carbonates such as potassium carbonate, sodium carbonate and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound [28e]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like, esters such as methyl acetate, ethyl acetate and the like, nitriles such as acetonitrile and the like, alcohols such as methanol, ethanol, isopropyl alcohol and the like, amides such as N,N-dimethylformamide and the like, and halogenated hydrocarbons such as chloroform, methylene chloride and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at 0-200° C. and preferably 10-150° C., for a period of 10 minutes to 24 hours. It is also possible to carry out carbamoylation by reacting a compound of general formula [28e] with triphosgene and then treating the active intermediate thus obtained with aqueous ammonia. The amount of triphosgene used in this reaction is 0.3-20 mol and preferably 1-4 mol per mol of the compound of general formula [28e]. As the base used in this reaction, organic amines such as dimethylaminopyridine, triethylamine, pyridine and the like can be referred to, and amount thereof is 1-20 mol and preferably 1-4 mol per mol of the compound of general formula [28e]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, halogenated hydrocarbons such as chloroform, methylene chloride and the like are used, for example. This reaction is carried out usually at 0-70° C. and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

Thereafter, the compound of general formula [28e] is treated with 1-50 v/w, preferably 5-15 v/w, of 25% aqueous ammonia to obtain a carbamoyl compound. This reaction is carried out usually at 0-100° C. and preferably at 0-30° C., for a period of 10 minutes to 24 hours.

In cases where the compounds mentioned in Production Process 9 have a group which has to be protected, such as a carboxyl group or the like, the objective compound can be obtained by first appropriately protecting the group before the reaction and removing the protecting group after completion of the reaction.

wherein R 1 , W, R 3 , R 4 , R 24 and R 25 are as defined above.

The compound of general formula [3e] can be a obtained by reacting a compound of general formula [3b] with Wittig reagent or Horner-Wadsworth-Emmons reagent.

Concretely speaking, the compound of general formula [3e] can be obtained by reacting a compound of general formula [3b] with Wittig reagent synthesized according to the method described in Organic Syntheses Collective Volume, Vol. 5, Pages 751-754 (1973) or Horner-Wadsworth-Emmons reagent synthesized according to the method described in Organic Syntheses Collective Volume, Vol. 5, Pages 509-513 (1973).

The Wittig reagent and Horner-Wadsworth-Emmons reagent used in this reaction are used in an amount of 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [3b].

Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene and the like, ethers such as dioxane, tetrahydrofuran, diethyl ether and the like, esters such as ethyl acetate, butyl acetate and the like, nitrites such as acetonitrile and the like, amides such as N,N-dimethylformamide N,N-dimethylacetamide and the like, halogenated hydrocarbons such as chloroform, methylene chloride and the like, sulfones such as sulfolane and the like, and sulfoxides such as dimethyl sulfoxide and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −78° C. to reflux temperature of the solvent and preferably 0-150° C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in the atmosphere of an inert gas such as argon or nitrogen.

The compound of general formula [3f] can be obtained by subjecting a compound of general formula [3b] to Grignard reaction.

Concretely speaking, the compound [3f] can be obtained by reacting a compound of general formula [3b] with a Grignard reagent synthesized according to the method described in Organic Syntheses Collective Volume, Vol. 1, Pages 188-190 (1956).

In this reaction, the Grignard reagent is used in an amount of 1-100 mol and preferably 1-10 mol per mol of the compound of general formula [3b].

Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene and the like, ethers such as dioxane, tetrahydrofuran, diethyl ether and the like, and sulfones such as sulfolane and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −78° C. to reflux temperature of the solvent and preferably 0-150° C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in the atmosphere of an inert gas such as argon or nitrogen.

The compound of general formula [3e] can be obtained by dehydrating a compound of general formula [3f] in the presence or absence of an acid, a base or a dehydrating agent.

As the acid used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like; and organic acids such as p-toluenesulfonic acid, trifluoroacetic acid and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3f]. As the base used in this reaction, alkali metal hydroxides such as sodium hydroxide and the like; and organic amines such as triethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3f]. As the dehydrating agent used in this reaction, diphosphorus pentoxide, polyphosphoric acid and the like can be referred to, and amount thereof 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3f].

Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene and the like, ethers such as dioxane, tetrahydrofuran, diethyl ether and the like, esters such as ethyl acetate, butyl acetate and the like, nitriles such as acetonitrile and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, halogenated hydrocarbons such as chloroform, methylene chloride and the like, sulfones such as sulfolane and the like, and sulfoxides such as dimethyl sulfoxide and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. This reaction is carried out usually at a temperature of −78° C. to reflux temperature of the solvent and preferably 0-150° C., for a period of 30 minutes to 24 hours. If desired, this reaction may be carried out in the atmosphere of an inert gas such as argon or nitrogen.

The compound of general formula [3g] can be obtained by subjecting a compound of general formula [3e] or general formula [3f] to a reduction including hydrogenation using a metallic catalyst, in the presence or absence of an acid, a base or a salt.

As the acid used in this reaction, hydrochloric acid, sulfuric acid, hydrobromic acid, aluminum chloride, boron trifluoride, trifluoroacetic acid and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3e] or [3f]. As the base used in this reaction, alkali metal hydroxides such as sodium hydroxide and the like and organic amines such as triethylamine, pyridine and the like can be referred to, and amount thereof is 1-1,000 mol and preferably 1-100 mol per mol of the compound of general formula [3e] or [3f]. As the salt used in this reaction, lithium chloride, calcium chloride and the like can be referred to, and amount thereof is 1-100 mol and preferably 1-10 mol per mol of general formula [3e] or [3f]. As the reductant used in this reaction, sodium borohydride, lithium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, triethylsilane, hydrogen, cyclohexene and the like can be used, and amount thereof is 1-10 mol and preferably 1-5 mol per mol of the compound of general formula [3e] or [3f]. As the catalyst used in this reaction, palladium-carbon, palladium-black, palladium hydroxide and the like can be referred to, and amount thereof is 0.001 to 1 mol and preferably 0.01 to 0.5 mol per mol of the compound of general formula [3e] or [3f]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene and the like, ethers such as dioxane, tetrahydrofuran, diethyl ether and the like, esters such as ethyl acetate, butyl acetate and the like, alcohols such as methanol, ethanol and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like, halogenated hydrocarbons such as chloroform, methylene chloride and the like, sulfones such as sulfolane and the like, aliphatic hydrocarbons such as hexane, cyclohexane and the like, acetic acid, pyridine, water, etc. can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature from −78° C. to reflux temperature of the solvent and preferably at 0-30° C., for a period of 30 minutes to 24 hours.

When R 24 and R 25 referred to in the reaction for obtaining compound [3e], [3f] or [3g] have an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unprotected or protected amino group, the objective compound can be obtained by appropriately carrying out a protecting reaction and a de-protecting reaction.

wherein R 1a , R 2a (hydrogen atom is excepted), R 3a , R 4a and Z a are as defined above.

The reaction for obtaining a compound of general formula [30a] from a compound of general formula [29] can be carried out by the same procedure as that for obtaining a compound of general formula [20a] from compound [12] in Production Process 5.

The reaction for obtaining a compound of general formula [30b] from a compound of general formula [30a] can be carried out by the same procedure as that for obtaining a compound of general formula [20d] from compound [20c] in Production Process 5.

The reaction for obtaining a compound of general formula [30c] from a compound of general formula [30b] can be carried out by the same procedure as that for obtaining a compound of general formula [3c] from compound [3b] in Production Process 2.

The reaction for obtaining a compound of general formula [30d] from a compound of general formula [30b] and [30c] can be carried out by the same procedure as that for obtaining a compound of general formula [3d] from compound [3b] and [3c] in Production Process 2.

wherein R 1a , R 3a , R 4a , R 27a , R 28a , X 1a and Z a are as defined above.

The reaction for obtaining a compound of general formula [31b] from a compound of general formula [31a] can be carried out by the same procedure as that for obtaining a compound of general formula [21b] from compound [21a] in Production Process 6.

The reaction for obtaining a compound of general formula [31c] from a compound of general formula [31a] can be carried out by the same procedure as that for obtaining a compound of general formula [21c] from compound [21a] in Production Process 6.

When X 1a or R 27a described in Production Process 11 has a group which has to be protected such as a carboxyl group, the objective compound can be obtained by appropriately carrying out protection before the reaction and de-protection after completion of the reaction.

wherein Ac represents acetyl group; Z a″ represents —CH 2 — or —CH 2 —CH 2 —; and R 1a , R 2a′ (hydrogen atom is excepted), R 3a , R 4a and X are as defined above.

The reaction for obtaining a compound of general formula [33] from a compound of general formula [32] can be carried out by the same procedure as that for obtaining a compound of general formula [20a] from compound [12] in Production Process 5.

The reaction for obtaining a compound of general formula [34] from a compound of general formula [33] can be carried out by the same procedure as that for obtaining a compound of general formula [25] from compound [24] in Production Process 7.

The reaction for obtaining a compound of general formula [35a] from a compound of general formula [34] can be carried out by the same procedure as that for obtaining a compound of general formula [26a] from compound [25] in Production Process 7.

The reaction for obtaining a compound of general formula [35b] from a compound of general formula [35a] can be carried out by the same procedure as that for obtaining a compound of general formula [26b] from compound [26a] in Production Process 7.

The reaction for obtaining a compound of general formula [35a] from a compound of general formula [12b] can be carried out by the same procedure as that for obtaining a compound of general formula [33] from compound [32] in Production Process 12.

wherein R 1a , R 2a (hydrogen atom is excepted), R 3a and R 4a are as defined above.

The reaction for obtaining a compound of general formula [37b] from a compound of general formula [37a] can be carried out by the same procedure as that for obtaining a compound of general formula [27b] from compound [27a] in Production Process 8a.

The reaction for obtaining a compound of general formula [37c] from a compound of general formula [37b] can be carried out by the same procedure as that for obtaining a compound of general formula [27c] from compound [27b] in Production Process 8a.

wherein R 1a , W a , R 3a , R 4a , R 21a , R 22a , R 23a and X are as defined above.

The reaction for obtaining a compound of general formula [38a] from a compound of general formula [30a] can be carried out by the same procedure as that for obtaining a compound of general formula [28b] from compound [28a] in Production Process 9.

The reaction for obtaining a compound of general formula [38b] from a compound of general formula [38a] can be carried out by the same procedure as that for obtaining a compound of general formula [28c] from compound [28b] in Production Process 9.

The reaction for obtaining a compound of general formula [38d] from a compound of general formula [38a] can be carried out by the same procedure as that for obtaining a compound of general formula [28e] from compound [28b] in Production Process 9.

The reaction for obtaining a compound of general formula [38e] from a compound of general formula [38d] can be carried out by the same procedure as that for obtaining a compound of general formula [28f] from compound [28e] in Production Process 9.

Some of the compounds mentioned in Production Process 14 may have a group which has to be protected, such as carboxyl group. In such a case, the objective compound can be obtained by carrying out protection before the reaction, then carrying out the reaction, and carrying out de-protection after the reaction.

wherein R 1a , W a , R 3a , R 4a , R 24a and R 25a are as defined above.

The reaction for obtaining a compound of general formula [30e] from a compound of general formula [30b] can be carried out by the same procedure as that for obtaining a compound of general formula [3e] from compound [3b] in Production Process 9a.

The reaction for obtaining a compound of general formula [30f] from a compound of general formula [30b] can be carried out by the same procedure as that for obtaining a compound of general formula [3f] from compound [3b] in Production Process 9a.

The reaction for obtaining a compound of general formula [30g] from a compound of general formula [30e] and a compound of [30f] can be carried out by the same procedure as that for obtaining a compound of general formula [3g] from compounds [3e] and [3f] in Production Process 9a.

In some of the reactions for obtaining the compounds of general formulas [30e], [30f] and [30g], R 24a and R 25a may involve an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group or an unprotected or protected amino group. In such a case, the objective compound can be obtained by carrying out protecting and de-protecting reactions appropriately.

wherein R 1b , R 2b (hydrogen atom is excepted), R 3b , R 4b and Z b are as defined above.

The reaction for obtaining a compound of general formula [40a] from a compound of general formula [39] can be carried out by the same procedure as that for obtaining a compound of general formula [30a] from compound [29] in Production Process 10.

The reaction for obtaining a compound of general formula [40b] from a compound of general formula [40a] can be carried out by the same procedure as that for obtaining a compound of general formula [30b] from compound [30a] in Production Process 10.

The reaction for obtaining a compound of general formula [40c] from a compound of general formula [40b] can be carried out by the same procedure as that for obtaining a compound of general formula [30c] from compound [30b] in Production Process 10.

The reaction for obtaining a compound of general formula [40d] from compounds of general formulas [40b] and [40c] can be carried out by the same procedure as that for obtaining a compound of general formula [30d] from compounds [30b] and [30c] in Production Process 10.

wherein R 1c , R 2c (hydrogen atom is excepted), R 3c , R 4c and Z c are as defined above.

The reaction for obtaining a compound of general formula [42a] from a compound of general formula [41] can be carried out by the same procedure as that for obtaining a compound of general formula [30a] from compound [29] in Production Process 10

The reaction for obtaining a compound of general formula [42b] from a compound of general formula [42a] can be carried out by the same procedure as that for obtaining a compound of general formula [30b] from compound [30a] in Production Process 10.

The reaction for obtaining a compound of general formula [42c] from a compound of general formula [42b] can be carried out by the same procedure as that for obtaining a compound of general formula [30c] from compound [30b] in Production Process 10.

The reaction for obtaining a compound of general formula [42d] from compound of general formulas [42b] and [42c] can be carried out by the same procedure as that for obtaining a compound of general formula [30d] from compounds [30b] and [30c] in Production Process 10.

wherein R 1d , R 2d (hydrogen atom is excepted), R 3d , R 4d , Z d and X are as defined above.

wherein R 1d′ represents alkoxyl group; R 35 represents hydrogen atom or acyl group; R 36 represents unsubstituted or substituted alkyl, cycloalkyl or aralkyl group; R 4d′ represents acyl group; and R 2d (hydrogen atom is excepted), R 3d , X and Z d are as defined above.

The compound of general formula [43a] can be obtained by reacting an acid chloride or acid anhydride of a compound of general formula [12a] and a compound of general formula [13d] in the presence of a base.

The acid chloride or acid anhydride of compound [12a] used in this reaction can be obtained by reacting a compound of general formula [12a] with an activating agent such as thionyl chloride, oxalyl chloride, phosphorus pentoxide, acetic anhydride, ethyl chloroformate or the like, and amount thereof is 1-10 mol and preferably 1-2 mol per mol of the compound of general formula [12a]. As used herein, the amount of the compound of general formula [13d] is 1-20 mol and preferably 1-5 mol per mol of the compound of general formula [12a]. As the base used in this reaction, for example, organolithium compounds such as n-butyllithium, methyllithium, lithium diisopropylamide and the like; and organomagnesium compounds such as methyl magnesium bromide and the like can be referred to, and the base is used in an amount of 1-20 mol and preferably 1-3 mol per mol of the compound of general formula [12a]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; and aliphatic hydrocarbons such as hexane, cyclohexane and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more.

This reaction is carried out usually at a temperature of −78° C. to 150° C. and preferably at −78° C. to 30° C., for a period of 30 minutes to 24 hours.

The reaction for obtaining a compound of general formula [43b] from a compound of [43a] can be carried out by the same procedure as that for obtaining a compound of general formula [20a] from a compound of general formula [12] in Production Process 5.

The reaction for obtaining a compound of general formula [43b] from a compound of [12a] can be carried out by the same procedure as that for obtaining a compound of general formula [43a] from a compound of general formula [12a] in Production Process 17.

The compound of general formula [43c] can be obtained by subjecting a compound of general formula [43b] to an alkylation reaction with and a compound of general formula [47c] in the presence of a base.

In this reaction, the compound of general formula [47c] is used in an amount of 1-20 mol and preferably 1-4 mol per mol of the compound of compound [43b]. As the base used in this reaction, organolithium compounds such as n-butyllithium, phenyllithium, lithium diisopropylamide and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal carbonates such as potassium carbonate, sodium carbonate and the like; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like can be referred to, and amount thereof is 2-20 mol and preferably 1-4 mol per mol of the compound of general formula [43b]. Although the solvent used in this reaction is not particularly limited so far as it exercises no adverse influence on the reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitrites such as acetonitrile and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N-dimethylformamide and the like; halogenated hydrocarbons such as chloroform. methylene chloride and the like; and sulfoxides such as dimethyl sulfoxide and the like can be used as the solvent. These solvents may be used either alone or in the form of mixture of two or more. The reaction is carried out usually at a temperature ranging from −78° C. to 200° C. and preferably at −50° C. to 120° C., for a period of 10 minutes to 24 hours.

The reaction for obtaining a compound of general formula [43d] from a compound of general formula [43c] is carried out by the same procedure as that for obtaining compound of general formula [20d] from compound of general formula [20c] in Production Process 5.

The reaction for obtaining a compound of general formula [43e] from a compound of general formula [43d] is carried out by the same procedure as that for obtaining compound of general formula [3c] from compound of general formula [3b] in Production Process 2.

The reaction for obtaining a compound of general formula [43f] from compounds of general formulas [43d] and [43e] is carried out by the same procedure as that for obtaining compound of general formula [3d] from compounds of general formulas of [3b] and [3c] in Production Process 2.

The reaction for obtaining a compound of general formula [43g] from a compound of general formula [43a′] is carried out by the same procedure as that for obtaining compound of general formula [43b] from compound of general formula [43a] in Production Process 17.

The reaction for obtaining a compound of general formula [43h] from a compound of general formula [43g] is carried out by the same procedure as that for obtaining compound of general formula [43c] from compound of general formula [43b] in Production Process 17.

The reaction for obtaining a compound of general formula [43i] from a compound of general formula [43h] is carried out by the same procedure as that for obtaining compound of general formula [43d] from compound of general formula [43c] in Production Process 17.

The compound of general formula [43j] can be obtained by subjecting a compound of general formula [43i] to an O-alkylation reaction.

The reaction for obtaining a compound of general formula [43j] from a compound of general formula [43i] is carried out by the same procedure as that for obtaining compound of general formula [28c] from compound of general formula [28b] in Production Process 9.

The reaction for obtaining a compound of general formula [43k] from a compound of general formula [43j] is carried out by the same procedure as that for obtaining compound of general formula [20d] from compound of general formula [20c] in Production Process 5.

wherein R Oe , R 1e , R 2e (hydrogen atom is excepted), R 3e , R 4e and Z e are as defined above.

The reaction for obtaining a compound of general formula [44a] from a compound of general formula [44] is carried out by the same procedure as that for obtaining compound of general formula [30a] from compound of general formula [29] in Production Process 10.

The reaction for obtaining a compound of general formula [44b] from a compound of general formula [44a] is carried out by the same procedure as that for obtaining compound of general formula [30b] from compound of general formula [30a] in Production Process 10.

The reaction for obtaining a compound of general formula [44c] from a compound of general formula [44b] is carried out by the same procedure as that for obtaining compound of general formula [30c] from compound of general formula [30b] in Production Process 10.

The reaction for obtaining a compound of general formula [44d] from compounds of general formulas [44b] and [44c] is carried out by the same procedure as that for obtaining compound of general formula [30d] from compounds of general formulas [30b] and [30c] in Production Process 10.

wherein R 1f , R 2f (hydrogen atom is excepted), R 3f , R 4f and Z f are as defined above.

The reaction for obtaining a compound of general formula [46a] from a compound of general formula [45] is carried out by the same procedure as that for obtaining a compound of general formula [30a] from a compound of general formula [29] in Production Process 10.

The reaction for obtaining a compound of general formula [46b] from a compound of general formula [46a] is carried out by the same procedure as that for obtaining a compound of general formula [30b] from a compound of general formula [30a] in Production Process 10.

The reaction for obtaining a compound of general formula [46c] from a compound of general formula [46b] is carried out by the same procedure as that for obtaining a compound of general formula [30c] from a compound of general formula [30b] in Production Process 10.

The reaction for obtaining a compound of general formula [46d] from compounds of general formulas [46b] and [46c] is carried out by the same procedure as that for obtaining a compound of general formula [30d] from compounds of general formulas [30b] and [30c] in Production Process 10.

wherein R 1g , R 2g (hydrogen atom is excepted), R 4g and Z g are as defined above.

The reaction for obtaining a compound of general formula [51a] from a compound of general formula [12d] is carried out by the same procedure as that for obtaining a compound of general formula [3a] from a compound of general formula [12] in Production Process 2.

The reaction for obtaining a compound of general formula [51b] from a compound of general formula [51a] is carried out by the same procedure as that for obtaining a compound of general formula [3b] from a compound of general formula [3a] in Production Process 2.

The reaction for obtaining a compound of general formula [51c] from a compound of general formula [51b] is carried out by the same procedure as that for obtaining a compound of general formula [3c] from a compound of general formula [3b] in Production Process 2.

The reaction for obtaining a compound of general formula [51d] from compounds of general formulas [51b] and [51c] is carried out by the same procedure as that for obtaining a compound of general formula [3d] from compounds of general formulas [3b] and [3c] in Production Process 2.

Among the compounds used in the above-mentioned production processes, those which can take a form of salt can be used as a salt. Examples of such salt include the same salts as mentioned in the paragraphs describing the compounds conforming to the pharmacophore of formula 1 and compounds of general formulas [2], [2b], [3], [4], [5], [a], [b], [c], [d], [e], [f] and [g].

Some of the compounds used in the above-mentioned production processes may have isomers such as optical isomers, geometric isomers and tautomers. In such cases, the isomers are also usable. In cases where solvated products, hydrates and various crystal forms of the compounds exist, those solvated products, hydrates and various crystal forms are also usable. Some of the compounds used in the above-mentioned production processes have a substituent which can be protected such as amino group, hydroxyl group, mercapto group, carboxyl group and the like. When such a compound is used, it is also possible to protect these groups with conventional protecting group previously, and after the reaction, to eliminate these protecting groups by methods which are well known in themselves.

When the compound of this invention is used as a medical drug. adjuvants conventionally used for making a preparation such as excipient, carrier, diluent and the like may be incorporated appropriately. The preparations produced in the above-mentioned manner can be administered in the usual manner either orally or non-orally in the form of tablet, capsule, powder, syrup, granule, pill, suspension, emulsion, solution, powdery preparation, suppository, ointment, injection, etc. The method of administration, the dosage and the frequency of administration can be properly selected in accordance with age, body weight and symptoms of the patient. To adult patients, the compound of this invention is given orally or non-orally (for example, by injection, drip infusion, intrarectal administration, etc., at a dosage of 0.1 to 100 mg/kg/day in one portion or several portions.

Next, conformity of typical compounds of this invention to pharmacophore will be mentioned. In the tables presented below, the unit of distance is angstrom.

For example, in a cyclic peptide of Example 3 (5) represented by the following formula:

wherein the framed letters N a 1 , N a 2 , N a 3 , N a 4 and N a 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N a 1 , N a 2 , N a 3 , N a 4 and N a 5 have the characters shown in the following Table 38, and there exists a local minimum structure in which the interatomic distances are as shown in Table 39.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the compound of Example 7 represented by the following formula:

wherein the framed letters N b 2 , N b 3 , N b 4 and N b 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N b 2 , N b 3 , N b 4 and N b 5 have the characters shown in the following Table 40, and there exists a local minimum structure in which the interatomic distances are as shown in Table 41.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 4 represented by the following formula:

wherein the framed letters N c 2 , N c 3 and N c 4 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 and N 4 in formula 1, the N c 2 , N c 3 and N c 4 have the characters shown in the following Table 42, and there exists a locally stabilized structure in which the interatomic distances are as shown in Table 43.

Accordingly, this compound conforms to a pharmacophore at three atoms.

In the cyclic peptide of Example 3 (1) represented by the following formula:

wherein the framed letters N d 1 , N d 2 , N d 3 , N d 4 and N d 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N d 1 , N d 2 , N d 3 , N d 4 and N d 5 have the characters shown in the following Table 44, and there exists a local minimum structure in which the atomic distances are as shown in Table 45.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the cyclic peptide of Example 3 (2) represented by the following formula:

wherein the framed letters N e 1 , N e 2 , N e 3 , N e 4 and N e 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N e 1 , N e 2 , N e 3 , N e 4 and N e 5 have the characters shown in the following Table 46, and there exists a local minimum structure in which the interatomic distances are as shown in Table 47.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the cyclic peptide of Example 3 (3) represented by the following formula:

wherein the framed letters N f 1 , N f 2 , N f 3 , N f 4 and N f 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N f 1 , N f 2 , N f 3 , N f 4 and N f 5 have the characters shown in the following Table 48, and there exists a local minimum structure in which the interatomic distances are as shown in Table 49.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the cyclic peptide of Example 3 (4) represented by the following formula:

wherein the framed letters N g 1 , N g 2 , N g 3 , N g 4 and N g 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N g 1 , N g 2 , N g 3 , N g 4 and N g 5 have the characters shown in the following Table 50, and there exists a local minimum structure in which the interatomic distances are as shown in Table 51.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the cyclic peptide of Example 3 (6) represented by the following formula:

wherein the framed letters N h 1 , N h 2 , N h 3 , N h 4 and N h 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N h 1 , N h 2 , N h 3 , N h 4 and N h 5 have the characters shown in the following Table 52, and there exists a local minimum structure in which the interatomic distances are as shown in Table 53.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the compound of Example 9 represented by the following formula:

wherein the framed letters N i 2 , N i 3 , N i 4 and N i 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N i 2 , N i 3 , N i 4 and N i 5 have the characters shown in the following Table 54, and there exists a local minimum structure in which the interatomic distances are as shown in Table 55.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 12 represented by the following formula:

wherein the framed letters N j 2 , N j 3 , N j 4 and N j 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N j 2 , N j 3 , N j 4 and N j 5 have the characters shown in the following Table 56, and there exists a local minimum structure in which the interatomic distances are as shown in Table 57.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 13 represented by the following formula:

wherein the framed letters N k 2 , N k 3 , N k 4 and N k 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N k 2 , N k 3 , N k 4 and N k 5 have the characters shown in the following Table 58, and there exists a local minimum structure in which the interatomic distances are as shown in Table 59.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the cyclic peptide of Example 3 (10) represented by the following formula:

wherein the framed letters N l 1 , N l 2 , N l 3 , N l 4 and N l 5 , represent the shaded atoms, respectively, to signify the atoms corresponding to N 1 , N 2 , N 3 , N 4 and N 5 in formula 1, the N l 1 , N l 2 , N l 3 , N l 4 and N l 5 have the characters shown in the following Table 60, and there exists a local minimum structure in which the interatomic distances are as shown in Table 61.

Accordingly, this compound conforms to a pharmacophore at five atoms.

In the compound of Example 47 represented by the following formula:

wherein the framed letters N m 2 , N m 3 , N m 4 and N m 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N m 2 , N m 3 , N m 4 and N m 5 have the characters shown in the following Table 62, and there exists a local minimum structure in which the interatomic distances are as shown in Table 63.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 43 represented by the following formula:

wherein the framed letters N n 2 , N n 3 , N n 4 and N n 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N n 2 , N n 3 , N n 4 and N n 5 have the characters shown in the following Table 64, and there exists a local minimum structure in which the interatomic distances are as shown in Table 65.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 41 represented by the following formula:

wherein the framed letters N o 2 , N o 3 , N o 4 and N o 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N o 2 , N o 3 , N o 4 and N o 5 have the characters shown in the following Table 66, and there exists a local minimum structure in which the interatomic distances are as shown in Table 67.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 38 represented by the following formula:

wherein the framed letters N p 2 , N p 3 and N p 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 and N 5 in formula 1, the N p 2 , N p 3 and N p 5 have the characters shown in the following Table 68, and there exists a local minimum structure in which the interatomic distances are as shown in Table 69.

Accordingly, this compound conforms to a pharmacophore at three atoms.

In the compound of Example 88 represented by the following formula:

wherein the framed letters N q 2 , N q 3 , N q 4 and N q 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N q 2 , N q 3 , N q 4 and N q 5 have the characters shown in the following Table 70, and there exists a local minimum structure in which the interatomic distances are as shown in Table 71.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 82 represented by the following formula:

wherein the framed letters N r 2 , N r 3 , N r 4 and N r 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N r 2 , N r 3 , N r 4 and N r 5 have the characters shown in the following Table 72, and there exists a local minimum structure in which the interatomic distances are as shown in Table 73.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 90 represented by the following formula:

wherein the framed letters N s 2 , N s 3 , N s 4 and N s 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 , N 4 and N 5 in formula 1, the N s 2 , N s 3 , N s 4 and N s 5 have the characters shown in the following Table 74, and there exists a local minimum structure in which the interatomic distances are as shown in Table 75.

Accordingly, this compound conforms to a pharmacophore at four atoms.

In the compound of Example 25(8) represented by the following formula:

wherein the framed letters N t 2 , N t 3 and N t 5 represent the shaded atoms, respectively, to signify the atoms corresponding to N 2 , N 3 and N 5 in formula 1, the N t 2 , N t 3 and N t 5 have the characters shown in the following Table 76, and there exists a local minimum structure in which the interatomic distances are as shown in Table 77.

Accordingly, this compound conforms to a pharmacophore at three atoms.

Next, pharmacological activities of typical compounds of this invention will be described.

[Testing Method]

TEST EXAMPLE 1

Activities on AP-1 Binding Reaction to Recognition Sequence (ELISA)

Nuclear extract protein containing transcription factor AP-1 prepared from HeLa cells was coated on 96-well ELISA plate (100 ng/well) in Hepes buffer (20 mM Hepes-potassium hydroxide (pH 7.9), 0,5 mM ethylenediamine-tetraacetic acid, 50 mM potassium chloride, 10% glycerol). After washing, a blocking treatment was carried out with bovine serum albumin, and then used for a binding assay using nuclear extract protein.

On the other hand, Jun peptide and N-terminal biotinylated tetraglycine Fos peptide containing a DNA-binding site [Nature, Vol. 373, Pages 257-261, 1995] were synthesized and separately dissolved in tris buffer (20 mM tris-hydrochloride (pH 7.5), 50 mM potassium chloride, 1 mM ethylenediaminetetraacetic acid, 10 mM magnesium chloride, 1 mM dithiothreitol, 0.5M guanidine hydrochloride, 30% glycerol). Equimolar quantities of both the solutions were mixed together, and the mixture was used as an AP-1 complex (Fos/Jun peptide). The AP-1 complex was added to avidin-coating 96-well ELISA plate (10 pmol/well), washed, and then blocked with bovine serum albumin. The product was used for binding assay using AP-1 complex.

On the basis of the above-mentioned two coated AP-1, a digoxigenin-labeled double stranded oligonucleotide (22-mer) containing an AP-1 binding sequence (3′-TGAGTCA-5′) which has been synthesized elsewhere was reacted in the presence and absence of a sample at room temperature for 30-60 minutes in a binding reaction solution [Hepes buffer or 25 mM tris-hydrochloric acid (pH 7.9), 0.5 mM ethylenediaminetetraacetic acid, 0.05% Nonidet P-40, 10% glycerol]. After of the reaction, unbound labeled oligonucleotide washed out with Hepes buffer solution containing 0.05% of Tween-20. Then, an anti-digoxigenin antibody labeled with peroxidase was added, and reacted with the labeled oligonucleotide bound to AP-1. After washing out the excessive antibody with Hepes buffer containing 0.05% of Tween-20, the residue was reacted for a predetermined period of time in a 100 mM citrate buffer (pH 5.0) containing hydrogen peroxide by using o-phenylenediamine as a substrate. After adding-sulfuric acid solution to each well, absorbance (492 nm) was measured. Taking the absorbance in the absence of sample as 100%, inhibition rate of sample was calculated from the absorbance in the presence of sample.

The results are shown in Table 78 and Table 79.

[Table 78]

The samples of Example No. 12, 15, 25(5) and 43 were converted to sodium salts and then measured according to the procedure of Example 17. In Example 6 8(8), measurement was carried out on the isomer having a lower polarity among the two isomers.

[Table 79]

In this test system, compounds exhibiting an inhibition of 10% or more at 500 μM are preferable when Fos/Jun is used; and compounds exhibiting an inhibition of 10% or more at 100 μM are preferable when nuclear extract protein is used.

TEST EXAMPLE 2

Type II Collagen-Induced Arthritis in Mice

The effect of the compound of Example 12 on the type II collagen-induced arthritis in mice was examined. As the animals, 8 weeks old male DBA/1J mice (Charles River Japan) were used. To 2 mg/mL solution of bovine type II collagen in 0.1 mol/L acetic acid (Kouken) was added an equivalent quantity of Freund complete adjuvant (Nacalai Tesque), and prepared an emulsion. 0.2 ml of the emulsion was subcutaneously injected into the tail root portion. On the 22nd day as counted from the day of first inoculation, the same treatment as above was repeated to induce arthritis. The compound was suspended in 0.5% methyl cellulose solution and administered orally at 100 mg/kg once every day from the 22nd day to the 36th day. To the control group (negative control group), a 0.5% methyl cellulose solution was administered similarly. Severity of the arthritis was evaluated in the following manner:

score 0: no change

score 1: swelling on one or two toes or slight swelling in the foreleg root or hindleg root only;

score 2: swelling and rubor in more joints;

score 3: extensive swelling over whole foreleg or hindleg;

and total of the four legs was calculated. Taking the maximum score as 12, the arthritis score was calculated to evaluate the severity of arthritis. Regarding the destruction of joints and bones, X ray photographs of four paws were taken on the 37th day, and severity of destruction in the second to fifth articulationes interphalangeae, first to fifth articulationes metacarpophalangeae and metatarsophalangeae, and calcaneus was scored by 0 or 1 in accordance with presence or absence of destruction, and the severity of destruction in the carpus and tarsal was scored by 0 to 3. Total score for the four paws was taken as joint and bone destruction score, taking 50 points as maximum score.

The results on the 37th day from the first inoculation was as follows:

Control group: arthritis score 8, joint an bone destruction score 26;

Compound-administered group: arthritis score 3, joint and bone destruction score 10.

That is, the inhibition rate as compared with control group was 63% and 62%, respectively.

Next, this invention is explained by referring to examples. The invention is by no means limited by these examples.

For expression of amino acid residue, the 3-letters expression system prescribed by IUPAC and IUB is used. Unless otherwise defined, an amino acid means L-form. The abbreviations have the following meanings:

Fmoc: 9-fluorenylmethoxycarbonyl PyBOP: benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate HOBt: N-hydroxybenzotriazole monohydrate DMF: N,N-dimethylformamide DIEA: N,N-diisopropylethylamine DCM: dichloromethane TFA: trifluoroacetic acid DMSO: dimethyl sulfoxide Cys(Trt): S-trityl-L-cysteine Asp(tBu): β-tert-butyl L-aspartate Ac: acetyl Me: methyl Et: ethyl nPr: n-propyl iPr: isopropyl iBu: isobutyl iAm: isoamyl Ph: phenyl Py: pyridyl (4-NO 2 )PhCH 2 : p-nitrobenzyl CDCl 3 : heavy chloroform d 6 -DMSO: heavy dimethyl sulfoxide (Cys 1 -Cys 10 ) means that a disulfide linkage is present between the first and 10th Cys residues. (Cys 2 -Cys 11 ) means that a disulfide linkage is present between the second and 11th Cys residues.

HPLC purification was carried out under the following conditions:

Column: YMC PROTEIN-RP (250×20 mm I.D.)

Flow rate: 8.0 ml/min.

Detection wavelength: UV 230 nm

Mobile phase: CH 3 CN (10-30%) in 0.1% TFA-H 2 O (30 min.)

As the carrier for silica gel column chromatography, BW-127ZH (manufactured by Fuji Silicia Kagaku) was used.

This invention relates to a compound having an inhibitory action on the activity of transcription factor AP-1 or a salt thereof, an agent for preventing and treating diseases into which an excessive expression of AP-1 participates which contains said compound or said salt, and an AP-1 inhibiting agent. The compounds and agents of this invention are useful as therapeutic and preventive drugs causing lessened side reactions.