Propanoic acid derivatives

Abstract

Propanoic acid derivatives of formula (1) are described: Ar—X 1 —Ar 1 —Z—R  (1) in which Ar is a nitrogen base containing group; X 1 is linker atom or group; Ar 1 is an optionally substituted 5- or 6-membered nitrogen-containing aromatic or non-aromatic monocycle; Z is a group —CH(R 13 )CH 2 — [in which R 13 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], —C(R 12a )(R 13 )—CH(R 12b )— [in which R 12a and R 12b together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl group] or C(R 13 )═CH—; R is a carboxylic acid (—CO 2 H) or a derivative or biostere thereof; and the salts, solvates, hydrates and N-oxides thereof. The compounds are able to inhibit the binding of α v integrins to their ligands and are of use in the prophylaxis and treatment of immune or inflammatory disorders.

1 . A compound of formula (1): 
       Ar—X 1 —Ar 1 —Z—R 
       wherein: 
 (1) Ar is a group R 1a N(R 2 )L 1 Ar 2 — in which: 
 R 1a N(R 2 ) is a nitrogen base;  
 L 1  is a —C(R 3 )(R 4 )— [where R 3  and R 4 , which may be the same or different, is each a hydrogen atom, a straight or branched alkyl group or a hydroxyl group], —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —P(O)—, —P(O)(OR a )— [where R a  is a hydrogen atom or a straight or branched C 1-6 alkyl group] or —P(O)(OR a )O— group; and  
 Ar 2  is an optionally substituted six-membered 1,4-arylene or 1,4-heteroarylene ring; or  
 
 (2) Ar is a group R 1b Ar 2  in which R 1b  is a cyclic or acyclic nitrogen base and Ar 2  is as just defined; or  
 (3) Ar is a bicyclic ring:  
                     
 in which R 1c  is a nitrogen base, L 1  and Ar 2  are as just defined and —L 1a — is a covalent bond a —(CH 2 ) 2 — or —(CH 2 ) 3 — group or a group L 1  as just defined; or  
 (4) Ar is a group R 1d L 1 Ar 2 — in which R 1d  is a nitrogen base and L 1  and Ar 2  as just defined; 
 X 1  is an —O— or —S— atom or a group selected from —C(O)—, —C(S)—, —S(O)—, —S(O) 2 —, —C(R 5 )(R 6 )— {where R 5  is a hydrogen atom or an optionally substituted straight or branched alkyl group and R 6  is a hydrogen or halogen atom or a straight or branched alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, aromatic, heteroaromatic, or —(Alk) m R 7  group [in which Alk 1  is a C 1-3 alkylene chain, m is zero or the integer 1 and R 7  is a —OH, —SH, —NO 2 , —CN, —CO 2 H, —CO 2 R 8  (where R 8  is an optionally substituted straight or branched C 1-6 alkyl group), —SO 3 H, —SOR 8 , —SO 2 R 8 , —OCO 2 R 8 , C(O)H, —C(O)R 8 , —OC(O)R 8 , —C(S)R 8 , —NR 9 R 10  (where R 9  and R 10 , which may be the same or different is each a hydrogen atom or a straight or branched alkyl group), —C(O)N(R 9 )(R 10 ), —OC(O)N(R 9 )(R 10 ), —N(R 9 )C(O)R 10 , —CSN(R 9 )(R 10 ), —N(R 9 )C(S)R 10 , —SO2N(R 9 )(R 10 ), —N(R 9 )SO 2 R 10 , —N(R 9 )C(O)N(R 10 )(R 11 ) [where R 11  is a hydrogen atom or a straight or branched alkyl group], —N(R 9 )C(S)N(R 10 )(R 11 ), —N(R 9 )SO 2 N(R 10 )(R 11 ), aromatic or heteroaromatic group or —N(R 5 )—;  
 Z is a group —CH(R 13 )CH 2 — [in which R 13  is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group], C(R 12a )(R 13 )—CH(R 12b )— [in which R 12a  and R 12b  together with the carbon atoms to which they are attached form a C 3-7 cycloalkyl group] or —C(R 13 )═CH—;  
 R is a carboxylic acid (—CO 2 H) or a derivative or biostere thereof;  
 Ar1 is an optionally substituted 5- or 6-membered nitrogen-containing aromatic or non-aromatic monocycle selected from:  
 (A)  
                     
 where one of X and Y is a nitrogen atom and the other is a nitrogen, oxygen or sulphur atom, Z 1  is a carbon, nitrogen, oxygen or sulphur atom and the broken line (--) represents saturation or unsaturation; or  
 (B)  
                     
 where X, Y and the broken line are as just defined and Z 2  and Z 3  is each a carbon, nitrogen, oxygen or sulphur atom;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
 
     
     
         2 . A compound according to  claim 1  in which R is a —CO 2 H group.  
     
     
         3 . A compound according to  claim 1  in which Ar 1  is an optionally substituted aromatic or non-aromatic monocycle selected from:  
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound according to  claim 3  in which AR 1  is an optionally substituted 2,4-pyrimidinyl group.  
     
     
         5 . A compound according to  claim 1  in which X 1  is a —O—, —S—, —NH— or —N(CH 3 )— group.  
     
     
         6 . A compound according to  claim 1  in which L 1  is a group —C(R 3 )(R 4 )— or —CO—.  
     
     
         7 . A compound according to  claim 6  in which L 1  is a group —CH 2 —.  
     
     
         8 . A compound according to  claim 1  in which Ar is a group R 1a N(R 2 )L 1 Ar 2  in which R 2  is a hydrogen atom.  
     
     
         9 . A compound according to  claim 8  in which R 1a  is a group H 2 NC(═NH)— imidazolinyl, benzimidazlyl or an optionally substituted pyridyl group.  
     
     
         10 . A compound according to  claim 1  in which Ar is a group R 1b Ar 2  in which R 1b  is an optionally substituted pyridyl or imidazolyl group.  
     
     
         11 . A compound according to  claim 1  in which Ar is a group R 1d L 1 Ar 2  in which R 1d  is a group H 2 NC(═NH)— or an optionally substituted imidazoyl, imidazolinyl, triazolyl or pyridyl group.  
     
     
         12 . A compound according to  claim 1  in which Z is a group —CH(R 13 )CH 2 — or —C(R 13 )═CH—.  
     
     
         13 . A compound according to  claim 12  in which R 13  is an optionally substituted aromatic or heteroaromatic group.  
     
     
         14 . A compound according to  claim 13  in which R 13  is an optionally substituted phenyl or five- or six-membered heteroaromatic group.  
     
     
         15 . A compound according to  claim 14  in which R 13  is an optionally substituted phenyl group.  
     
     
         16 . A compound which is: 
 3-(4-[2-Aminoethyl]benzamide)-3-(2-[4}(2-pyridinylamino)methyl}phenoxy]-4-pyrimidinyl)propanoic acid;    3-(2-{4-[(4,5-Dihydro-1H-imidazol-2-ylamino)methyl]phenoxy pyrimidinyl)-3(4-fluorophenyl)propanoic acid    3-(2-[4-({[Amino(imino)methyl]amino}methyl)phenoxy]pyrimidinyl) 3-(4-benzoic acid)propanoic acid;    3-[2-(4-[({Amino(imino)methyl}amino)methyl]—N-methylanilino)-4 pyrimidinyl]-3-(4-fluorophenol)propanoic acid;    3-(3-Methoxyphenyl)-3-(2-{4-{(2-pyridinylamino)methyl]phenoxy}-4-pyrimidinyl) propanoic acid;    3-[2-(4-{6-Amino-2-pyridinyl}phenoxy)4-pyrimidinyl]-3F4carboxy phenyl)propanoic acid;    3-[2-(4-[2-(N-methylamino)-6-pyridinyl}phenoxy)4-pyrimidinyl]-3-(4-carboxyphenyl)propanoic acid;    3-(2-[4{(1H-1,3-Benzimidazol-2-yl-amino)methyl}phenoxy]4-pyrimidinyl)-3-(4-fluorophenyl)propanoic acid;    3-(3-Benzenecarboxylic acid)-3-(2-(4-[(2pyridinylamino)methyl] phenoxy}4-pyrimidinyl)propanoic acid; and the salts, solvates, hydrates and N-oxides thereof.    
     
     
         17 . A pharmaceutical composition comprising a compound according to  claim 1  together with one or more pharmaceutically acceptable carriers, excipients or diluents.