Squaric acid derivatives

Abstract

Squaric acid Derivatives of formula (1) are described: wherein R 1 is an integrin binding group; R 2 is a hydrogen atom or a C 1-6 alkyl group; L 1 is a covalent bond or a linker atom or group; n is zero or the integer 1; Alk 1 is an optionally substituted aliphatic chain; R 3 is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group: and the salts, solvates, hydrates and N-oxides thereof. The compounds are able to inhibit the binding of integrins to their ligands and are of use in the prophylaxis and treatment of immune of inflammatory disorders, or disorders involving the inappropriate growth or migration of cells.

1 . A compound of formula (1):  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is an integrin binding group;  
 R 2  is a hydrogen atom or a C 1-6 alkyl group;  
 L 1  is a covalent bond or a linker atom or group;  
 n is zero or the integer 1;  
 Alk 1  is an optionally substituted aliphatic chain;  
 R 3  is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group;  
 and the salts, solvates, hydrates and n-oxides thereof:  
 
     
     
         2 . A compound according to  claim 1  in which R 1  is an α 4 -integrin binding group.  
     
     
         3 . A compound according to  claim 1  in which R 1  is a group of formula Ar 1 L 2 Ar 2 Alk-, where Ar 1  is an optionally substituted aromatic or heteroaromatic group, L 2  is a linker atom or group, Ar 2  is an optionally substituted phenylene or nitrogen-containing six-membered heteroarylene group and Alk is a chain from: 
 —CH 2 —CH(R)—, —CH═C(R)—,  
                     
 where R is a carboxylic acid (—CO 2 H) or a derivative or biostere thereof.  
 
     
     
         4 . A compound according to  claim 3  in which Alk is a chain selected from 
 —CH 2 —CH(R)—, or  
                     
 
     
     
         5 . A compound according to  claim 4  in which R is a carboxylic acid (—CO 2 H) group.  
     
     
         6 . A compound according to  claim 3  in which Ar 2  is an optionally substituted 1,4-phenylene group.  
     
     
         7 . A compound according to  claim 3  in which Ar 1  is an optionally substituted phenyl, monocyclic heteroaromatic or bicycl1c heteroaromatic group.  
     
     
         8 . A compound according to  claim 7  in which Ar 1  is an optionally substituted pyridyl and pyrimidinyl group.  
     
     
         9  A compound according to  claim 8  in which L 2  is a —CON(R 8 )— group where R 8  is a hydrogen atom or an optionally substituted C 1-6 alkyl group.  
     
     
         10 . A compound according to  claim 9  in which R 8  is a hydrogen atom.  
     
     
         11 . A compound according to  claim 7  in which Ar 1  is an optionally substituted 2,6-naphthyridinyl and 4quinazolinyl groups.  
     
     
         12 . A compound according to  claim 11  in which L 2  is an —O— or —N(R 8 )— group where R 8  is a hydrogen atom or an optionally substituted C 1  6alkyl group.  
     
     
         13 . A compound according to  claim 12  in which R 8  is a hydrogen atom.  
     
     
         14 . A compound according to  claim 1  in which L 1  is a —N(R 8 )— group where R 8  is a hydrogen atom or an optionally substituted C 1-6 alkyl group.  
     
     
         15 . A compound according to  claim 14  in which R 8  is a hydrogen atom or methyl, ethyl or n-propyl group.  
     
     
         16 . A compound according to  claim 1  in which L 1  is a covalent bond.  
     
     
         17 . A compound according to any one of  claim 1  in which n is the integer 1 and Alk 1  is an optionally substituted straight or branched C 1-6 alkylene chain.  
     
     
         18 . A compound according to  claim 17  in which Alk 1  is a —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 — or —C(CH 3 ) 2 CH 2 — chain.  
     
     
         19 . A compound according to  claim 18  in which R 3  is a hydrogen atom.  
     
     
         20 . A compound according to  claim 3  of formula (2a):  
       
         
           
           
               
               
           
         
         wherein —W=is —CH= or —N═;  
         R 16  and R 17 , which may be the same or different is each a hydrogen atom or group -L 3 (Alk 2 ) t L 4 (R 4 ) u  in which: 
 L 3  is a covalent bond or a linker atom or group;  
 Alk 2  is an aliphatic or heteroaliphatic chain;  
 t is zero or the integer 1;  
 L 4  is a covalent bond or a linker atom or group;  
 R 4  is a hydrogen or halogen atom or a group selected from optionally substituted C 1-6 alkyl or C 3-8  cycloalkyl, —OR 5  (where R 5  is a hydrogen atom, an optionally substitued C 1-6 alkyl or C 3-8  cycloalkyl group], —SR 5 , —NR 5 R 6  [where R 6  is as just defined for R 5  and may be the same or different], —NO 2 , —CN, —CO 2 R 5 , —SO 3 H, —SOR 5 , —SO 2 R 5 , —SO 3 R 5 , —OCO 2 R 5 , —CONR 5 R 6 , —OCONR 5 R 6 , —CSNR 5 R 6 , —COR 5 , —OCOR 5 , —N(R 5 )COR 6 , —N(R 5 )CSR 6 , —SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 R 6 , N(R 5 )CON(R 6 )(R 7 ) [where R 7  is a hydrogen atom, an optionally substituted C 1-6 alkyl or C 3-8 cycloalkyl group], —N(R 5 )CSN(R 6 )(R 7 ) or —N(R 5 )SO 2 N(R 6 )(R 7 ), provided that when t is zero and each of L 3  and L 4  is a covalent bond then u is the integer 1 and R 4  is other than a hydrogen atom;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
       
     
     
         21 . A compound according to  claim 3  of formula (2b)  
       
         
           
           
               
               
           
         
         wherein R 16  is a hydrogen atom or a group -L 3 (Alk 2 ) t L 4 (R 4 ) u  in which 
 L 3  is a covalent bond or a linker atom or group;  
 Alk 2  is an aliphatic or heteroaliphatic chain;  
 t is zero or the integer 1;  
 L 4  is a covalent bond or a linker atom or group;  
 R 4  is a hydrogen or halogen atom or a group selected from optionally substituted C 1-6 alkyl or C 3-8  cycloalkyl, —OR 5  [where R 5  is a hydrogen atom, an optionally substitued C 1-6 alkyl or C 3-8  cycloalkyl group], —SR 5 , —NR 5 R 6  [where R 6  is as just defined for R 5  and may be the same or different], —NO 2 , —CN, —CO 2 R 5 , —SO 3 H, —SOR 5 , —SO 2 R 5 , —SO 3 R 5 , —OCO 2 R 5 , —CONR 5 R 6 , —OCONR 5 R 6 , —CSNR 5 R 6 , —COR 5 , —OCOR 5 , —N(R 5 )COR 6 , —N(R 5 )CSR 6 , —SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 R 6 , N(R 5 )CON(R 6 )(R 7 ) [where R 7  is a hydrogen atom, an optionally substituted C 1-6 alkyl or C 3-9 cycloalkyl group], —N(R 5 )CSN(R 6 )(R 7 ) or —N(R 5 )SO 2 N(R 6 )(R 7 ), provided that when t is zero and each of L 3  and L 4  is a covalent bond then u is the integer 1 and R 4  is other than a hydrogen atom;  
 g is zero or the integer 1, 2, 3 or 4;  
 and the salts, solvates, hydrates and N-oxides thereof.  
 
       
     
     
         22 . A compound according to  claim 3  of formula (2c)  
       
         
           
           
               
               
           
         
         wherein R 16  is a hydrogen atom or a group in which L 3  is a covalent bond or a linker atom or group;  
         Alk 2  is an aliphatic or heteroaliphatic chain;  
         t is zero or the integer 1;  
         L 4  is a covalent bond or a linker atom or group;  
         R 4  is a hydrogen or halogen atom or a group selected from optionally substituted C 1-6 alkyl or C 3-8  cycloalkyl, —OR 5  [where R 5  is a hydrogen atom, an optionally substitued C 1-6 alkyl or C 3-8  cycloalkyl group], —SR 5 , —NR 5 RO [where R 6  is as just defined for R 5  and may be the same or different], —NO 2 , —CN, —CO 2 R 5 , —SO 3 H, —SOR 5 , —SO 2 R 5 , O 3 R 5 , —OCO 2 R 5 , —CONR 5 R 6 , —OCONR 5 R 6 , —CSNR 5 R 6 , —COR 5 , COR 5 -N(R 5 )COR 6 , —N(R 5 )CSR 5 , —SO 2 N(R 5 )(R 6 ), —N(R 5 )SO 2 R 6 , N(R 5 )CON(R 6 )(R 7 ) [where R 7  is a hydrogen atom, an optionally substituted C 1-6 alkyl or C 3-8 cycloalkyl group], —N(R 5 )CSN(R 6 )(R 7 ) or —N(R 5 )SO 2 N(R 6 )(R 7 ), provided that when t is zero and each of L 3  and L 4  is a covalent bond then u is the integer 1 and R 4  is other than a hydrogen atom;  
         g is zero or the integer 1, 2, 3 or 4;  
         and the salts, solvates, hydrates and N-oxides thereof.  
       
     
     
         23 . A compound which is: 
 (S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-2-(2-propylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-(3,5-Dichloro4-pyridylcarboxamido)phenyl]-242-t-butyl-3,4-dioxocyclobut-1 enyl)amino]propanoic acid;    (S)-3-{4[(6,7-Dimethoxy4qunazolinyl)amino]phenyl}2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([6,7-Dimethoxy-4qunazolinyl)oxy]phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([6,7-Methoxy4-qunazolinyl]amino)phenyl]-2[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-dipropylamino-3,4-dioxocyclobut-1enyl)amino]propanoic acid;    (S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-piperidin-1-yl-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (R)-3-{4-(3,5-Dichloro4-pyridylcarboxamido)phenyl)}3-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-dipropylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    (S)-3-[4([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N, -ethyl-N-isopropylamino3,4-dioxocyclobut-1-enyl)amino]propanoic acid;    and the salts, solvates, hydrates and N-oxides thereof.    
     
     
         24 . A pharmaceutical composition comprising a compound according to  Claim 1  together with one or more pharmaceutically acceptable carriers, excipients or diluents.