Phenylalanine derivatives

Abstract

Phenylalanine derivatives of formula (1) are described: wherein R is a carboxylic acid or a derivative thereof; L 1 is a linker atom or group; Ar is an optionally substituted aromatic group; and the salts, solvates, hydrates and N-oxides thereof. The compounds are able to inhibit the binding of alpha4 integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.

1 . A compound of formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R is a carboxylic acid or a derivative thereof;  
 R 1  is a hydrogen atom or a hydroxyl, straight or branched alkoxy or optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;  
 Alk 1  is an optionally substituted aliphatic or heteroaliphatic chain;  
 L 1  is a linker atom or group;  
 r and s, which may be the same or different, is each zero or an integer 1 provided that when r is zero R 1  is an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;  
 R a  and R b , which may be the same or different is each an atom or group —L 2 (CH 2 ) p L 3 (R c ) q  in which L 2  and L 3  is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and R c  is a hydrogen or halogen atom or a group selected from straight or branched alkyl, —OR d  [where R d  is a hydrogen atom or an optionally substituted straight or branched alkyl group], —SR d , —NR d R e , [where R e  is as just defined for R d  and may be the same or different], —NO 2 , —CN, —CO 2 R d , —SO 3 H, —SO 2 R d , —OCO 2 R , —CONR d R e , —OCONR d R e , —CSNR d R e , —COR d , N(R d )COR e , N(R d )CSR e , —SO 2 N(R d )(R e ), —N(R d )SO 2 R e , —N(R d )CONR e R f  [where R f  is a hydrogen atom or an optionally substituted straight or branched alkyl group], —N(R d )CSNR e R f  or —N(R d )SO 2 NR e R f ;  
 Alk 2  is a straight or branched alkylene chain;  
 m is zero or an integer 1;  
 R 2  is a hydrogen atom or a methyl group;  
 R 3  is a hydrogen atom or a straight or branched alkyl group;  
 Ar is an optionally substituted aromatic group;  
 and the salts, solvates, hydrates and N-oxides thereof for use in modulating cell adhesion.  
 
     
     
         2 . A compound of formula (1a):  
       
         
           
           
               
               
           
         
       
       wherein 
 R is a carboxylic acid or a derivatives thereof;  
 R 1  is an optionally substituted cycloaliphatic, polycycloaliphatic, heterocycloaliphatic, polyheterocyclialiphatic, aromatic or heteroaromatic group;  
 Alk 1  is an optionally substituted aliphatic or heteroaliphatic chain;  
 L 1  is a linker atom or group;  
 r and s, which may be the same or different, is each zero or an integer 1;  
 R a  and R b , which may be the same or different is each an atom or group —L 2 (CH 2 ) p L 3 (R c ) q  in which L 2  and L 3  is each a covalent bond or a linker atom or group, p is zero or the integer 1, q is an integer 1, 2 or 3 and R c  is a hydrogen or halogen atom or a group selected from straight or branched alkyl, —OR d  [where R d  is a hydrogen atom or an optionally substituted straight or branched alkyl group], —SR d , —NR d R e , [where R e  is as just defined for R d  and may be the same or different], —NO 2 , —CN, —CO 2 R , —SO 3 H, —SO 2 R , —OCO 2 R d , CONR d R e , —OCONR d R e , —CSNR d R e , —COR d , —N(R d )COR e , N(R d )CSR e , —SO 2 N(R d )(R e ), —N(R d )SO 2 R e , —N(R d )CONR e R f  [where R f  is a hydrogen atom or an optionally substituted straight or branched alkyl group], —N(R d )CSNR e R f  or —N(R d)SO 2 NR e R f ;  
 Alk 2  is a straight or branched alkylene chain;  
 m is zero or an integer 1;  
 R 2  is a hydrogen atom or a methyl group;  
 R 3  is a hydrogen atom or a straight or branched alkyl group;  
 Ar is an optionally substituted aromatic group;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
     
     
         3 . A compound according to  claim 2  wherein Ar is an optionally substituted phenyl group.  
     
     
         4 . A compound according to  claim 2  wherein R is a —CO 2 H group.  
     
     
         5 . A compound according to  claim 2  wherein Alk 2  is a —CH 2 - chain and m is an integer 1.  
     
     
         6 . A compound according to  claim 2  wherein each of R 2  and R 3  is a hydrogen atom.  
     
     
         7 . A compound according to  claim 2  wherein R 1  is an optionally substituted aromatic or heteroaromatic group.  
     
     
         8 . A compound according to  claim 7  wherein R 1  is an optionally substituted phenyl, pyridyl or pyrimidinyl group.  
     
     
         9 . A compound according to  claim 2  wherein —(Alk 1 ) r (L 1 ) s  is a —CH 2 O—, —SO 2 NH—, —C(O)O— or —CON(R 4 )— group.  
     
     
         10 . A compound according to  claim 9  wherein —(Alk 1 ) r (L 1 ) s  is a —CONH— group.  
     
     
         11 . A compound according to  claim 2  which has the formula (1b):  
       
         
           
           
               
               
           
         
       
       wherein —W═is —CH═ or —N═, R 9  and R 10  which may be the same or different is each a —L 1 (CH 2 ) p L 3 (R c ) q  atom or group, and the salts, solvates, hydrates and N-oxides thereof.  
     
     
         12 . A compound according to  claim 11  wherein Ar is an optionally substituted phenyl group.  
     
     
         13 . A compound which is: 
 (N-2,6-Dimethoxybenzoyl)-[O-3,5-dichloro-4-pyridinyl)methyl]-L-tyrosine;    2-Carboxybenzoyl-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    (N-2,6-Dimethoxybenzoyl)-N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    (N-3-Carboxybenzoyl)-(N′-3,5-dichloroisonicotoninoyl)-L-4-aminophenylalanine;    (N-4-Carboxybenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenyalanine;    (N-2-t-Butoxycarbonylbenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenyalanine;    (N-3-Cyanobenzoyl)-(N′-3,5 -dichloroisonicotinoyl)-L-4-aminophenyalanine;    [N-3-(1 -H-Tetrazol-5-yl)]-(N′3,5-dichloroisonicotinoyl)-L-4-aminophenyalanine;    [N-(3-Methoxycarbonylbenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenyalanine;    and the salts, solvates, hydrates and N-oxides thereof.    
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  together with one or more pharmaceutically acceptable carriers, excipients or diluents.  
     
     
         15 . A method for the prophylaxis or treatment of a disease or disorder in a mammal in which the extravasation of leukocytes plays a role, comprising administering to a mammal suffering from such a disease or disorder a therapeutically effective amount of a compound according to  claim 1 .  
     
     
         16 . A method according to  claim 15  wherein said disease or disorder is selected from the group consisting of inflammatory arthritis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses, asthma and inflammatory bowel disease.  
     
     
         17 . A method according to  claim 16  wherein said inflammatory arthritis is selected from the group consisting of rheumatoid arthritis vasculitis and polydermatomyositis.  
     
     
         18 . A method according to  claim 16  wherein said inflammatory dermatoses are selected from the group consisting of psoriasis and dermatitis.  
     
     
         19 . A method for inhibiting, in a mammal, the binding of α 4  integrins to the ligands thereof, comprising administering to the mammal an effective amount of a compound according to  claim 1 .  
     
     
         20 . A method according to  claim 19  wherein said α 4  integrins are selected from the group consisting of α 4 β 1  and α 4 β 7  integrins.