Novel compounds and pharmaceutical use thereof

Abstract

A compound 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 represents an arbitrary carbon atom constituting a hydrophobic group and defined by the interatomic distances between N 1 , N 2 , N 3 , N 4 and N 5 ; 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 , in the optimized steric structure thereof, are the interatomic distances in a pharmacophore; or a salt thereof; inhibits the activity of transcription factor AP-1 and is useful as an agent for preventing and treating the diseases into which overexpression of AP-1 participates and as an AP-1 inhibitor.

1 - 34 . (canceled) 
     
     
         35 . A peptide compound selected from the group consisting of:
 a peptide of 10 residues represented by the following amino acid sequence:   Ac-Cys 1 -Gly 2 -AA -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Gly 9 -Cys 10 -NH 2      wherein Ac represents an acetyl group, AA 3  represents a polar amino acid residue, each of AA 4 , AA 6  and AA 7  represents a hydrophobic amino acid residue, AA 5  represents an amino acid residue having carboxyl or hydroxyl group in the side chain thereof, and AA 8  represents an arbitrary amino acid residue; said peptide having a disulfide linkage between the first and tenth cysteine residues; or a salt thereof; and   a peptide of 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      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, each of aa 4 , aa 5  and aa 7  represents a hydrophobic amino acid residue, aa 6  represents an arbitrary amino acid residue, and aa 9  represents an amino acid residue having carboxyl or hydroxyl group in the side chain thereof; provided that, when aa 0  is a bonding unit, said peptide has a disulfide linkage between the first and tenth cysteine residues and, when aa 0  is an arbitrary amino acid residue, said peptide has a disulfide linkage between the second and eleventh cysteine residues; or a salt thereof.   
     
     
         36 . The peptide compound of  claim 35 , which a peptide of 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 -Cly 9 -Cys 10 -NH 2      wherein Ac represents an acetyl group, AA 3  represents a polar amino acid residue, each of AA 4 , AA 6  and AA 7  represents a hydrophobic amino acid residue, AA 5  represents an amino acid residue having carboxyl or hydroxyl group in the side chain thereof, and AA 8  represents an arbitrary amino acid residue; said peptide having a disulfide linkage between the first and tenth cysteine residues; or a salt thereof.   
     
     
         37 . The compound of  claim 35 , which consists of Ac-Cys 1 -Gly 2 -AA 3 -AA 4 -AA 5 -AA 6 -AA 7 -AA 8 -Gly 9 -Cys 10 -NH 2 , wherein AA 3  is an L-asparagine residue or an L-glutamine residue; AA 4 , AA 6  and AA 7  are an L-leucine residue, an L-isoleucine residue, an L-alanine residue or an L-valine residue; and AA 5  is an L-aspartic acid residue, an L-glutamic acid residue, an L-serine residue or an L-threonine residue, or a salt thereof.. 
     
     
         38 . The compound of  claim 35 , which is a peptide of 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      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, each of aa 4 , aa 5  and aa 7  represents a hydrophobic amino acid residue, aa 6  represents an arbitrary amino acid residue, and aa 9  represents an amino acid residue having carboxyl or hydroxyl group in the side chain thereof; provided that, when aa 0  is a bonding unit, said peptide has a disulfide linkage between the first and tenth cysteine residues and, when aa 0  is an arbitrary amino acid residue, said peptide has a disulfide linkage between the second and eleventh cysteine residues; or a salt thereof.   
     
     
         39 . The compound according to  claim 35 , which is a peptide of 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      wherein aa 3  is an L-asparagine acid residue or an L-glutamine acid residue; aa 4 , aa 5  and aa 7  are an L-leucine residue, an L-isoleucine residue, an L-alanine residue or an L-valine residue; and aa 9  is an L-aspartic acid residue, an L-glutamic acid residue, an L-serine residue or an L-threonine residue, or a salt thereof.   
     
     
         40 . A composition comprising the compound of  claim 35  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         41 . A method for treating disease or disorder into which an excessive expression of AP-1 participates comprising administering an amount of the compound of  claim 35  sufficient to reduce the expression of AP-1 and ameliorate said disease. 
     
     
         42 . A compound selected from the group consisting of compound of formula (4) and formula (5); wherein
 compound of formula (4) is:   
       
         
           
           
               
               
           
         
         wherein R 5  represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an 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 a hydrogen atom or a protecting group for carboxyl group; X 2  represents —C(O)—; m represents 0, 1 or 2; and ring A represents a group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 7  represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an 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 R 8  represents a hydrogen atom, an unprotected or protected amino group or an 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 of the following fonnula: 
       
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  may be the same or different represent a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino, alkanoyloxy or heterocyclic group; and 
         the compound of formula (5) is: 
       
       
         
           
           
               
               
           
         
         wherein R 15  and R 16  may be the same or different represent a hydrogen atom, a halogen atom, a cyano group, a nitro group, an unprotected or protected carboxyl group, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an 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: 
       
       
         
           
           
               
               
           
         
         wherein R 17  represents a hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, carbamoyl, alkylsulfonyl or heterocyclic group; R 18  represents a hydrogen atom or a protecting group for carboxyl group; and p represents 0, 1 or 2; 
         or a salt thereof. 
       
     
     
         43 . The compound of  claim 42  which is a compound having formula (4) or a salt thereof. 
     
     
         44 . The compound according to  claim 43 , wherein R 5  is an alkoxy group or an acylamino group; X 2  is —C(O)—; and ring A is a group of the following formula: 
       
         
           
           
               
               
           
         
         wherein R 11  is an alkyl or alkoxycarbonyl group; and R 12  is an alkyl group; or a group of the following formula: 
       
       
         
           
           
               
               
           
         
         wherein R 13  is an alkyl or alkoxycarbonyl group; and R 14  is an alkoxy or alkanoyloxy group. 
       
     
     
         45 . A benzene derivative according to  claim 43 , having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 42  which is a compound of formula (5) or a salt thereof. 
     
     
         47 . The compound according to  claim 46 , wherein R 15  and R 16  may be the same or different represent an alkoxy group; and ring B represents a group of the following formula: 
       
         
           
           
               
               
           
         
         wherein R 19  is an acyl group; R 20  is a protecting group for carboxyl group; and p is 0, 1 or 2. 
       
     
     
         48 . The compound according to  claim 46 , having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         49 . A composition comprising the compound of  claim 42  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         50 . A method for treating disease or disorder into which an excessive expression of AP-1 participates comprising administering an amount of the compound of  claim 42  sufficient to reduce the expression of AP-1 and ameliorate said disease. 
     
     
         51 . A compound represented by the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 1d  represents a halogen atom, a cyano group, a nitro group, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an 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 a hydrogen atom or a protecting group for carboxyl group; R 3d  represents a hydrogen atom or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl or aralkyl group; R 4d  represents a halogen atom, a nitro group, an unsubstituted or substituted 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 a salt thereof. 
       
     
     
         52 . The compound according to  claim 51 , wherein R 1d  is an unsubstituted or substituted alkoxy group; R 3d  is an unsubstituted or substituted alkyl group; R 4d  is an unsubstituted or substituted acyl group; X 1d  is —C(O)—; and Z d  is —(CH 2 ) 2 —. 
     
     
         53 . The benzene derivative according to  claim 51 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         54 . A composition comprising the compound of  claim 51  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         55 . A method for treating disease or disorder into which an excessive expression of AP-1 participates comprising administering an amount of the compound of  claim 51  sufficient to reduce the expression of AP-1 and ameliorate said disease. 
     
     
         56 . A compound represented by the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 0e  represents a hydrogen atom, a halogen atom, a nitro group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl, alkylsulfonylamino or arylsulfonylamino group; R 1e  represents an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl, alkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl group; R 2c  represents a hydrogen atom or a protecting group for carboxyl group; R 3e  and R 4e  may be the same or different represent a hydrogen atom, a halogen atom, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an 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 a salt thereof. 
       
     
     
         57 . The compound according to  claim 56 , wherein R 0e  is a hydrogen atom or a halogen atom; R 1e  is an unsubstituted or substituted alkyl group; R 3e  and R 4e  independently represent an unsubstituted or substituted alkoxy group; X 1e  is —C(O)—; and Z e  is a bonding unit. 
     
     
         58 . The benzene derivative according to  claim 56 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         59 . A composition comprising the compound of  claim 56  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         60 . A method for treating disease or disorder into which an excessive expression of AP-1 participates comprising administering an amount of the compound of  claim 56  sufficient to reduce the expression of AP-1 and ameliorate said disease. 
     
     
         61 . A compound represented by the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 1f  represents a halogen atom, an unprotected or protected hydroxyl group, an unprotected or protected amino group, a mercapto group or an unsubstituted or substituted alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, alkylamino, acylamino, alkylsulfonylamino, arylsulfonylamino or heterocyclic group; R 2f  represents a hydrogen atom or a protecting group for carboxyl group; R 3f  and R 4f  may be the same or different represent a hydrogen atom or an 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 a salt thereof. 
       
     
     
         62 . The compound according to  claim 61 , wherein R 1f  is an unsubstituted or substituted alkoxy group; R 3f  and R 4f  independently represent an unsubstituted or substituted alkyl group; X 1f  is —C(O)—; and Z f  is —CH 2 —. 
     
     
         63 . The benzene derivative according to  claim 61 , having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         64 . A composition comprising the compound of  claim 61  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
         65 . A method for treating disease or disorder into which an excessive expression of AP-1 participates comprising administering an amount of the compound of  claim 61  sufficient to reduce the expression of AP-1 and ameliorate said disease.