Oxa-and thiadiazoles and their use as metalloproteinase inhibitors

Abstract

Compounds formula (IA) or (IB), wherein W represents HO(C═O)—, HONH(C═O)— or H(C═O)N(OH)—; X represents —O— or —S—; and R 1 , R 2 , and R 3 are as defined in the description and claims, are inhibitors of matrix metal oproteinases, in particular MMP9 and/or MMP12.

1 . A method of treatment or prophylaxis of diseases mediated by MMPs in mammals comprising administering to the mammal an effective amount of a compound having formula (IA) or (IB) 
     
       
         
         
             
             
         
       
     
     wherein
 w represents HO(C═O)—, HONH(C═O)— or H(C═O)N(OH)—; 
 X represents —O— or —S—; 
 R 1  represents
 hydrogen; 
 —OH or —SH; 
 fluoro or chloro; 
 —CF 3 ; 
 (C 1 -C 6 )alkyl; 
 (C 1 -C 6 )alkoxy; 
 (C 2 -C 6 )alkenyl; phenyl or substituted phenyl; 
 phenyl (C 1 -C 6 )alkyl or substituted phenyl(C 1 -C 6 )alkyl; 
 phenyl (C 2 -C 6 )alkenyl or substituted phenyl(C 2 -C 6 )alkenyl heterocyclyl or substituted heterocyclyl; 
 heterocyclyl(C 1 -C 6 )alkyl or substituted heterocyclyl(C 1 -C 6 )alkyl; 
 
 a group BSO n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C 1 -C 6 ) alkyl, phenyl, substituted phenyl, heterocyclyl, substituted heterocyclyl, (C 1 -C 6 )acyl, phenacyl or substituted phenacyl group, and A represents (C 1 -C 6 )alkylene; 
 —NH 2 , (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino; 
 amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or carboxy(C 1 -C 6 ) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated; or 
 a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, halo, cyano (—CN), —CO 2 H, —CO 2 R, —CONH 2 , —CONHR, —CON(R) 2 , —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO 2 R wherein R is C 1 -C 6  alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring; 
 R 2  represents a group R 10 —(X 1 ) p -(ALK) m — wherein 
 R 10  represents hydrogen, or a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C 1 -C 12 )alkyl, (C 1 -C 12 )alkoxy, hydroxy, mercapto, (C 1 -C 12 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH 2 , COOR A , —NHCOR A , CONHR A , —NHR A , —NR A R B , or —CONR A R B  wherein R A  and R B  are independently a (C 1 -C 12 )alkyl group and 
 ALK represents a straight or branched divalent C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S-linkages, 
 X 1  represents —NH—, —O— or —S—, —NR c  or —NCOR c  wherein R c  is a (C 1 -C 12 )alkyl group, and 
 m and p are independently 0 or 1; 
 R 3  is C 1 -C 6  alkyl, phenyl, 2,3-, or 4-pyridyl, 2- or 3-thienyl, 2,-3-, or 4-hydroxyphenyl, 2,-3-, or 4-methoxyphenyl, 2,3-, or 4-pyridylmethyl, benzyl, 2,3-, or 4-hydroxybenzyl, 2,-3-, or 4-benzyloxybenzyl, 2,-3-, or 4-C 1 -C 6  alkoxybenzyl, or benzyloxy(C 1 -C 6  alkyl)-; or 
 the characterizing group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or 
 a group -[Alk] n R 6  where Alk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R 7 ) groups [where R 7  is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1, and R 6  is an optionally substituted cycloalkyl or cycloalkenyl group; or 
 a benzyl group substituted in the phenyl ring by a group of formula —OCH 2 COR 8  where R 8  is hydroxyl, amino, (C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, phenyl(C 1 -C 6 )alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; or 
 a heterocyclic(C 1 -C 6 )alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoromethyl (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylphenylmethyl; or 
 a group —CR a R b R c  in which: 
 each of R a , R b  and R c  is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl; or 
 R c  is hydrogen and R a  and R b  are independently phenyl or heteroaryl such as pyridyl; or 
 R c  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a  and R b  together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; 
 or R a , R b  and R c  together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or 
 R a  and R b  are each independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or a group as defined for R b  below other than hydrogen, or R a  and R c  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R b  is hydrogen, —OH, —SH, halogen, —CN, —CO 2 H, (C 1 -C 4 )perfluoroalkyl, —CH 2 OH, —CO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 2 -C 6 )alkenyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 ) alkyl, —S(C 2 -C 6 )alkenyl, —SO(C 2 -C 6 )alkenyl, —SO 2 (C 2 -C 6 )alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO 2 — and W represents a phenyl, phenylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylalkyl, (C 4 -C 8 )cycloalkenyl, (C 4 -C 8 )cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO 2 H, —CO 2 (C 1 -C 6 )alkyl, —CONH 2 , —CONH(C 1 -C 6 )alkyl, —CONH(C 1 -C 6  alkyl) 2 , —CHO, —CH 2 OH, (C 1 -C 4 )perfluoroalkyl, —O(C 1 -C 6 )alkyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NHCO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, phenyl or benzyl; 
 R 4  represents optionally substituted
 C 1 -C 6  alkyl, 
 C 2 -C 6  alkenyl, 
 C 2 -C 6  alkynyl, 
 C 1 -C 3  perfluoroalkyl, 
 cycloalkyl, 
 cycloalkyl(C 1 -C 6  alkyl), 
 cycloalkenyl, 
 cycloalkenyl(C 1 -C 6  alkyl)-, 
 phenyl, 
 phenyl(C 1 -C 6  alkyl)-, 
 naphthyl, 
 non-aryl heterocyclyl, 
 non-aryl heterocyclyl (C 1 -C 6 )alkyl-, 
 heteroaryl; or 
 heteroaryl(C 1 -C 6  alkyl)-; 
 
 
     or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
   
   
       2 . A method for the preparation of a medicament for the treatment or prophylaxis of diseases mediated by MMPs comprising adding to a medicament formulation a compound having formula (IA) or (IB) 
     
       
         
         
             
             
         
       
     
     wherein
 W represents HO(C═O)—, HONH(C═O)— or H(C═O)N(OH)—; 
 X represents —O— or —S—; 
 R 1 , represents
 hydrogen; 
 —OH or —SH; 
 fluoro or chloro; 
 —CF 3 ; 
 (C 1 -C 6 )alkyl; 
 (C 1 -C 6 )alkoxy; 
 (C 2 -C 6 )alkenyl; phenyl or substituted phenyl; 
 phenyl (C 1 -C 6 )alkyl or substituted phenyl(C 1 -C 6 )alkyl; 
 phenyl (C 2 -C 6 )alkenyl or substituted phenyl(C 2 -C 6 )alkenyl heterocyclyl or substituted heterocyclyl; 
 heterocyclyl(C 1 -C 6 )alkyl or substituted heterocyclyl(C 1 -C 6 )alkyl; 
 
 a group BSO n A- wherein n is 0, 1 or 2 and B is hydrogen or a (C 1 -C 6 ) alkyl, phenyl, substituted phenyl, heterocyclyl, substituted heterocyclyl, (C 1 -C 6 )acyl, phenacyl or substituted phenacyl group, and A represents (C 1 -C 6 )alkylene; 
 —NH 2 , (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino; 
 amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or carboxy(C 1 -C 6 ) alkyl wherein the amino-, hydroxy-, mercapto- or carboxyl-group are optionally protected or the carboxyl-group amidated; or 
 a cycloalkyl, cycloalkenyl or non-aromatic heterocyclic ring containing up to 3 heteroatoms, any of which may be (i) substituted by one or more substituents selected from C 1 -C 6  alkyl, C 2 -C 6  alkenyl, halo, cyano (—CN), —CO 2 H, —CO 2 R, —CONH 2 , —CONHR, —CON(R) 2 , —OH, —OR, oxo-, —SH, —SR, —NHCOR, and —NHCO 2 R wherein R is C 1 -C 6  alkyl or benzyl and/or (ii) fused to a cycloalkyl or heterocyclic ring; 
 R 2  represents a group R 10 —(X 1 ) p -(ALK) m — wherein 
 R 10  represents hydrogen, or a C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, cycloalkyl, aryl, or heterocyclyl group, any of which may be unsubstituted or substituted by (C 1 -C 12 )alkyl, (C 1 -C 12 )alkoxy, hydroxy, mercapto, (C 1 -C 12 )alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, oxo, —COOH, —CONH 2 , COOR A , —NHCOR A , —CONHR A , —NHR A , —NR A R B , or —CONR A R B  wherein R A  and R B  are independently a (C 1 -C 12 )alkyl group and 
 ALK represents a straight or branched divalent C 1 -C 6  alkylene, C 2 -C 6  alkenylene, or C 2 -C 6  alkynylene radical, and may be interrupted by one or more non-adjacent —NH—, —O— or —S-linkages, 
 X 1  represents —NH—, —O— or —S—, —NR c  or —NCOR c  wherein R c  is a (C 1 -C 12 )alkyl group, and 
 m and p are independently 0 or 1; 
 R 3  is C 1 -C 6  alkyl, phenyl, 2,3-, or 4-pyridyl, 2- or 3-thienyl, 2,-3-, or 4-hydroxyphenyl, 2,-3-, or 4-methoxyphenyl, 2,3-, or 4-pyridylmethyl, benzyl, 2,3-, or 4-hydroxybenzyl, 2,-3-, or 4-benzyloxybenzyl, 2,-3-, or 4-C 1 -C 6  alkoxybenzyl, or benzyloxy(C 1 -C 6  alkyl)-; or 
 the characterizing group of a natural α-amino acid, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or 
 a group -[Alk] n R 6  where Alk is a (C 1 -C 6 )alkyl or (C 2 -C 6 )alkenyl group optionally interrupted by one or more —O—, or —S— atoms or —N(R 7 ) groups [where R 7  is a hydrogen atom or a (C 1 -C 6 )alkyl group], n is 0 or 1, and R 6  is an optionally substituted cycloalkyl or cycloalkenyl group; or 
 a benzyl group substituted in the phenyl ring by a group of formula —OCH 2 COR 5  where R 8  is hydroxyl, amino, (C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, phenyl(C 1 -C 6 )alkylamino, the residue of an amino acid or acid halide, ester or amide derivative thereof, said residue being linked via an amide bond, said amino acid being selected from glycine, α or β alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid; or 
 a heterocyclic(C 1 -C 6 )alkyl group, either being unsubstituted or mono- or di-substituted in the heterocyclic ring with halo, nitro, carboxy, (C 1 -C 6 )alkoxy, cyano, (C 1 -C 6 )alkanoyl, trifluoromethyl (C 1 -C 6 )alkyl, hydroxy, formyl, amino, (C 1 -C 6 )alkylamino, di-(C 1 -C 6 )alkylamino, mercapto, (C 1 -C 6 )alkylthio, hydroxy(C 1 -C 6 )alkyl, mercapto(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylphenylmethyl; or 
 a group —CR a R b R c  in which: 
 each of R a , R b  and R c  is independently hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl; or 
 R c  is hydrogen and R a  and R b  are independently phenyl or heteroaryl such as pyridyl; or 
 R c  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl, and R a  and R b  together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; 
 or R a , R b  and R c  together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or 
 R a  and R b  are each independently (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl(C 1 -C 6 )alkyl, or a group as defined for R c  below other than hydrogen, or R a  and R b  together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R c  is hydrogen, —OH, —SH, halogen, —CN, —CO 2 H, (C 1 -C 4 )perfluoroalkyl, —CH 2 OH, —CO 2 (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —O(C 2 -C 6 )alkenyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 ) alkyl, —S(C 2 -C 6 )alkenyl, —SO(C 2 -C 6 )alkenyl, —SO 2 (C 2 -C 6 )alkenyl or a group -Q-W wherein Q represents a bond or —O—, —S—, —SO— or —SO 2 — and W represents a phenyl, phenylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkylalkyl, (C 4 -C 8 )cycloalkenyl, (C 4 -C 8 )cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, —CN, —CO 2 H, —CO 2 (C 1 -C 6 )alkyl, —CONH 2 , —CONH(C 1 -C 6 )alkyl, —CONH(C 1 -C 6  alkyl) 2 , —CHO, —CH 2 OH, (C 1 -C 4 )perfluoroalkyl, —O(C 1 -C 6 )alkyl, —S(C 1 -C 6 )alkyl, —SO(C 1 -C 6 )alkyl, —SO 2 (C 1 -C 6 )alkyl, 
 —NO 2 , —NH 2 , —NH(C 1 -C 6 )alkyl, —N((C 1 -C 6 )alkyl) 2 , —NHCO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, phenyl or benzyl; 
 R 4  represents optionally substituted
 C 1 -C 6  alkyl, 
 C 2 -C 6  alkenyl, 
 C 2 -C 6  alkynyl, 
 C 1 -C 3  perfluoroalkyl, 
 cycloalkyl, 
 cycloalkyl(C 1 -C 6  alkyl), 
 cycloalkenyl, 
 cycloalkenyl(C 1 -C 6  alkyl)-, 
 phenyl, 
 phenyl(C 1 -C 6  alkyl)-, 
 naphthyl, 
 non-aryl heterocyclyl, 
 non-aryl heterocyclyl (C 1 -C 6 )alkyl-, 
 heteroaryl; or 
 heteroaryl(C 1 -C 6  alkyl)-; 
 
 or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
 
   
   
       3 . The method according to  claim 1  wherein the disease is selected from the group consisting of bone resorption, tumour growth or invasion by secondary metastases, rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, neuroinflammatory disorders, restenosis, emphysemia, fibrotic diseases, chronic obstructive pulmonary disease, bronchitis, asthma, autoimmune disease, transplant rejection, cystic fibrosis, psoriasis, psodatic arthritis, degenerative cartilage loss, inflammatory gastric conditions, inflammatory bowel disease, and ulcerative colitis, atopic dermatitis, epidermolysis bullosa, epidermic ulceration, a neuropathy or nephropathy, lomerulonephriris and renal failure; ocular inflammation; liver cirrhosis, Sjoegren's syndrome; and an inflammatory condition of the nervous system. 
   
   
       4 . The method according to  claim 1  wherein the disease is selected from the group consisting of multiple sclerosis, emphysema, liver fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, Crohn's disease, inflammatory bowel disease, and liver sclerosis. 
   
   
       5 . The method according to  claim 1  wherein the disease is hepatitis. 
   
   
       6 . The method according to  claim 2 , wherein the disease is selected from the group consisting of bone resorption, tumour growth or invasion by secondary metastases, rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, neuroinflammatory disorders, restenosis, emphysemia, fibrotic disease, chronic obstructive pulmonary disease, bronchitis, asthma, autoimmune disease, transplant rejection, cystic fibrosis, psoriasis, psodatic arthritis, degenerative cartilage loss, inflammatory gastric conditions, inflammatory bowel disease, and ulcerative colitis, atopic dermatitis, epidermolysis bullosa, epidermic ulceration, a neuropathy or nephropathy, glomerulonephritis and renal failure, ocular inflammation, liver cirrhosis, Sjoegren's syndrome, and an inflammatory condition of the nervous system. 
   
   
       7 . The method according to  claim 2 , wherein the disease is selected from the group consisting of multiple sclerosis, emphysema, liver fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, Crohn's disease, inflammatory bowel disease, and liver sclerosis. 
   
   
       8 . The method according to  claim 2 , wherein the disease is hepatitis.