Hydroxamic acid derivatives as proteinase inhibitors

Abstract

Compounds of formula (I) are matrix metalloproteinase inhibitors wherein X represents a carboxylic acid group —COOH, or a hydroxamic acid group —CONHOH;R 2 represents a radical of formula (II): R 3 —(ALK) m —(Q) p —(ALK) n —, and W represents a cyclic amino radical of formula (IIIA) or (IIIB):

1 . A compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein 
 X represents a carboxylic acid group —COOH, or a hydroxamic acid group—CONHOH;  
 R 2  represents a radical of formula (ii) 
 R 3 —(ALK) m —(Q) p —(ALK) n —  (II) 
  wherein 
 R 3  represents hydrogen or an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, or optionally substituted heterocyclic ring having 5 or 6 ring members,  
 each ALK independently represents an optionally substituted divalent C 1 -C 3  alkylene radical,  
 Q represents —O—, —S—, —S(O)—, —S(O 2 )—, —C(O)O—, —OC(O)— or —N(R 9 )— wherein R 9  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy, and  
 m, n and p are independently 0 or 1;  
 
 R 1  represents a radical of formula (II) as defined for R 2 , except that R 1  is not hydrogen;  
 W represents a cyclic amino radical of formula (IIIA) or (IIIB):  
                     
  wherein 
 Y represents —O—, —S—, —S(O)—, —S(O 2 )—, —N(R 8 )—, —(CH(R 8 ))—, or —(C=N−R 8 )— wherein R 8  is a radical of formula (II) as defined in relation to R 2 ; and  
 (i) R 4 , R 5  R 6  and R 7  each independently represents a radical of formula (II) as defined in relation to R 2 , and R 4a  and R 7a  each independently represent hydrogen or C 1 -C 3  alkyl, or  
 (ii) R 4 , R 4a  and R 5  taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R 7a  represents hydrogen or C 1 -C 3  alkyl, and R 6  and R 7  each independently represents a radical of formula (II) as defined in relation to R 2 , or  
 (iii) R 4 , R 4a  and R 5  taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R 6 , R 7  and R 7a  taken together with the carbon atoms to which they are attached also form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, or  
 (iv) when W is a cyclic amino radical of formula (IIIA) wherein Y is —(CH(R 8 )—, then R 4  R 4a  and R 8  taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, R 7a  represents hydrogen or C 1 -C 3  alkyl, and R 5 , R 6  and R 7  each independently represents a radical of formula (II) as defined in relation to R 1  and R 2 , or  
 (v) when W is a cyclic amino radical of formula (IIIB) then R 4 , R 4a , R 7  and R 7a taken together with the carbon atoms to which they are attached form an optionally substituted benzene or pyridine ring fused to the cyclic amine ring, and R 5  and R 6  each independently represents a radical of formula (II) as defined in relation to R 1  and R 2 ,  
 
 or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
 
     
     
         2 . A compound as claimed in  claim 1  wherein R 1  is an optionally substituted C 1 -C 6 alkyl, phenyl, or phenyl(C 1 -C 6 alkyl)-group.  
     
     
         3 . A compound as claimed in  claim 3  wherein R 1  is n-propyl, iso-propyl n-butyl, iso-butyl, benzyl, phenylethyl, 4-fluorobenzyl, or 4-fluorophenylethyl.  
     
     
         4 . A compound as claimed in any preceding claim wherein R 2  is hydrogen, or an optionally substituted C 1 -C 6 alkyl, phenyl(C 1 -C 6 alkyl)-group, or an optionally substituted heterocyclic group.  
     
     
         5 . A compound as claimed in  claim 4  wherein R 2  is hydrogen, n-propyl, n-butyl, iso-butyl, benzyl, phenylethyl, tetrahydropyranyl, 1-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)propyl, or 1-(phthalimido)-propyl;  
     
     
         6 . A compound as claimed in any preceding claim wherein W is a radical of formula (IIIC), (IIID) or (IIIE)  
       
         
           
           
               
               
           
         
       
       wherein R 10  is as defined for R 2  in  claim 1 .  
     
     
         7 . A compound as claimed in  claim 6  wherein R 10  is an optionally substituted phenyl, biphenyl, phenyl(C 1 -C 6 alkyl)-, phenoxy, phenoxy(C 1 -C 3 )alkyl, or heterocyclic group.  
     
     
         8 . A compound as claimed in  claim 6  wherein R 10  is n-propyl, n-butyl or iso-butyl; or a phenyl, phenoxy, benzyl, phenylethyl, phenylpropyl, phenoxy, or phenoxymethyl group, any of which may be substituted in the phenyl ring, for example in the 4-position, by chloro, fluoro, methoxy or cyano; pyridinyl or pyridinyloxy either of which may be substituted by chloro, fluoro, methoxy or cyano; or biphenyl or 4-pyridinylphenyl, either of which may be substituted in either ring by chloro, fluoro, methoxy or cyano.  
     
     
         9 . A compound as claimed in  claim 6  wherein W is 4-phenylmethylpiperidinyl, 4 methylpiperidinyl, 4-(4-methylphenyl)piperidinyl, 4-(4-chlorophenoxy)piperidinyl, 4-phenylpiperidinyl, 4(4-fluorophenyl)piperidinyl, 4-(4-fluorophenoxy)piperidinyl, 4-(4-pyridinyloxy)-piperidinyl, 4-(4-cyanophenyloxy)piperidinyl, 4-(4-cyanophenoxyimino)-piperdinyl, 4-(4′-chloro-biphenyl-4-yl)-piperdinyl, 4-(2-chloro-biphenyl-4-yl) piperdinyl, 4-(4-fluorophenylmethyl)piperidinyl, 4-(4-fluorophenoxymethyl)-piperidinyl, 4-phenylpiperazinyl, 4-(4-fluorophenyl)piperazinyl, 4-(4-pyridinyl-methyl)piperazinyl, 4-(4-chlororophenyl)piperazinyl, 4-pyridin-4-ylpiperazinyl, 4-phenylmethylpiperazinyl, or 4-(4-fluorophenylmethyl)piperazinyl.  
     
     
         10 . 3-[4-(4-Fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-N-hydroxy-4-phenyl-butyramide or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
     
     
         11 . 3-(4-Benzyl-piperidine-1-sulfonyl)-N-hydroxy-4-phenyl-butyramide or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
     
     
         12 . A compound as claimed in  claim 1  which is specifically named and characterised in any of Examples 1, 3-5, or 7-18 herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.  
     
     
         13 . A pharmaceutical composition comprising a compound as claimed in any of the preceding claims, together with a pharmaceutically acceptable carrier.  
     
     
         14 . A method of treatment of diseases in mammals, in particular in humans, resulting from over production of, or over responsiveness to, MMPs, which method comprises administering to the mammal an effective amount of a compound as claimed in any of  claims 1  to  12   
     
     
         15 . A compound as claimed in any of  claims 1  to  12  or use in human or veterinary medicine treatment of conditions resulting from over production of, or over responsiveness to, MMPs.  
     
     
         16 . The use of a compound as claimed in any of  claims 1  to  12  in the preparation of an agent for treatment of conditions in mammals, in particular in humans, resulting from over production of, or over responsiveness to, MMPs.  
     
     
         17 . A method as claimed in  claim 14 , or the use as claimed in  claim 16  wherein the disease or condition is rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, gingivitis, corneal epidermal venous, diabetic or gastric ulceration, ulcerative colitis, Crohn's disease, pressure sores, tumour metastasis, invasion or growth, neuroinflammatory disorder, multiple sclerosis, psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas, hemangiomas, cardiac or cerebral infarction, or wound healing.