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; Het is an optionally substituted heteroaromatic 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, heterocyclo-aliphatic, 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;  
 Het is an optionally substituted heteroaromatic group;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein Het is an optionally substituted C 3-5  monocyclic heteroaromatic group containing one, two or three heteroatoms selected from oxygen, sulphur or nitrogen atoms.  
     
     
         3 . A compound according to  claim 2  wherein Het is an optionally substituted pyrrolyl or pyridyl group.  
     
     
         4 . A compound according to  claim 1  wherein R is a —CO 2 H group.  
     
     
         5 . A compound according to  claim 1  wherein Alk 2  is a —CH 2 — chain and is an integer 1.  
     
     
         6 . A compound according to  claim 1  wherein each of R 2  and R 3  is a hydrogen atom.  
     
     
         7 . A compound according to  claim 1  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 1  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 1  which has the formula (1a):  
       
         
           
           
               
               
           
         
       
       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 as generally and particularly defined above, and Alk 1 , r, L 1 , s, R a , R b , R and Het are as generally and particularly defined above, and the salts, solvates, hydrates and N-oxides thereof.  
     
     
         12 . A compound according to  claim 11  wherein Het is an optionally substituted pyrrolyl or pyridyl group.  
     
     
         13 . A compound according to  claim 1  which is: 
 2-Thio(S-2,5-dimethoxyphenyl)nicotinoyl-(N-2,6-dichlorobenzoyl)-L-4-aminophenylalanine;  
 2-Thio(S-2,5-dimethoxyphenyl)nicotinoyl-(N-2,6-dichlorobenzoyl)-L-4-aminophenylalanine;  
 N-(3,5-Dichloro-4-picolyl)-N′-(3,5-dichloro-4-picolyl)-L-4-aminophenylalanine;  
 N-(2-Chloronicotinoyl)-N′-(3,5-dichloro-4-picolyl)-L-4-amino-phenylalanine;  
 O-(2,6-dichlorobenzyl)-N-(4-acetyl-1,2,5-trimethyl-3-pyrroyl)-L-tyrosine;  
 (N′-3,5-Dichloroisonicotinoyl)-N-{([3-pyridinylmethyl]thio)isonicotinoyl}-L-4-aminophenylalanine;  
 N-(4-Acetyl-1,2,5-trimethyl-1H-pyrrole-3-carbonyl)-N′-(3,5-dichloro-4-picolyl)-L-4-aminophenylalanine; 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.