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 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 for use in modulating cell adhesion.  
 
     
     
         2 . A compound of formula (1a):  
       
         
           
           
               
               
           
         
       
       wherein 
 R is a carboxylic acid or a derivative 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 d , —SO 3 H, —SO 2 R d , —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  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 2 (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-aminophenyalanine;    (N-4-Carboxybenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    (N-2-t-Butoxycarbonylbenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    (N-3-Cyanobenzoyl)-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    [N-3-(1-H-Tetrazol-5-yl)]-(N′3,5-dichloroisonicotinoyl)-L-4-aminophenylalanine;    [N-(3-Methoxycarbonylbenzoyl)]-(N′-3,5-dichloroisonicotinoyl)-L-4-aminophenylalnine;    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.