Derivatives Of Hydroxamic Acid As Metalloproteinase Inhibitors

Abstract

A compound of formula (I), or an enantiomer or diastereoisomer thereof, or a salt, hydrate or solvate thereof: for the treatment or prophylaxis of arthritis in mammals.

1 . A compound of formula (I), or an enantiomer or diastereoisomer thereof, or a salt, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein Ar represents an optionally substituted aryl, heteroaryl, C 3 -C 8  cycloalkyl or heterocycloakyl group; 
         R represents hydrogen or C 1 -C 6  alkyl, or C 3 -C 6  cycloalkyl; 
         Alk represents a divalent C 1 -C 5  alkylene or C 2 -C 5  alkenylene radical; and 
         R 1  and R 2  taken together with the nitrogen atom to which they are attached form a first heterocycloalkyl ring which is optionally fused to a second C 3 -C 8  cycloalkyl or heterocycloalkyl ring, the said first and second rings being optionally substituted by at least one group of formula (II): 
       
       
         
           
           
               
               
           
         
         wherein m, p and n are independently 0 or 1; 
         Z represents, hydrogen, or an optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms which is optionally fused to another optionally substituted carbocyclic or heterocyclic ring of from 5 to 7 ring atoms; 
         Alk 1  and Alk 2  independently represent optionally substituted divalent C 1 -C 3  alkylene radicals; 
         X represents —O—, —S—, —S(O)—, —S(O 2 )—, —C(═O)—, —NH—, —NR 3 —, —S(O 2 )NH—, —S(O 2 )NR 3 —, —NHS(O 2 )—, or —NR 3 S(O 2 )—, where R 3  is C 1 -C 3  alkyl; 
         wherein when Ar is phenyl, NR 1 R 2  do not form a piperazine ring. 
       
     
     
         2 . A compound as claimed in  claim 1  wherein R is hydrogen. 
     
     
         3 . A compound as claimed in  claim 1  wherein R is methyl. 
     
     
         4 . A compound as claimed in  claim 1  wherein R is ethyl, n-propyl, isopropyl, n-, sec- or tert-butyl, cyclopropyl, or cyclopentyl. 
     
     
         5 . A compound as claimed in  claim 1  wherein Ar is a 5- or 6-membered monocyclic aryl or heteroaryl ring, which is optionally substituted by at least one substituent selected from (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, hydroxy, hydroxy(C 1 -C 3 )alkyl, mercapto, mercapto(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio, halo, trifluoromethyl, trifluoromethoxy, nitro, nitrile (—CN), —COON, —COOR A , —COR A , —SO 2 R A , —CONH 2 , —SO 2 NH 2 , —CONHR A , —SO 2 NHR A , —CONR A R B , —SO 2 NR A R B , —NH 2 , —NHR A , —NR A R B , —OCONH 2 , —OCONHR A , —OCONR A R B , —NHCOR A , —NHCOOR A , —NR B COOR A , —NHSO 20 R A , —NR B SO 2 OR A , —NHCONH 2 , —NR A CONH 2 , —NHCONHR B , —NR A CONHR B , NHCONR A R B , or —NR A CONR A R B  wherein R A  and R B  are independently C 1 -C 3  alkyl, phenyl or a 5- or 6-membered monocyclic aryl or heteroaryl ring. 
     
     
         6 . A compound as claimed in  claim 5  wherein an optional substituent is in the 4-position in the case of a 6-membered ring, or in the 2- and/or 3-position in the case of a 5-membered ring. 
     
     
         7 . A compound as claimed in  claim 1  wherein Ar is optionally substituted phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, or 3-furanyl. 
     
     
         8 . A compound as claimed in  claim 1  wherein optional substituents in Ar are selected from methoxy, ethoxy, trifluoromethoxy, methyl, ethyl, trifluoromethyl, hydroxyl, mercapto, fluoro, chloro, and bromo. 
     
     
         9 . A compound as claimed in  claim 5  wherein Ar is 4-(C 1 C 3 alkoxy)phenyl. 
     
     
         10 . A compound as claimed in  claim 5  wherein Ar is 4-ethoxyphenyl. 
     
     
         11 . A compound as claimed in  claim 1  wherein Alk is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH═CH—, —CH 2 CH═CH—, —CH 2 CH═CHCH 2 —, or —CH═CHCH═CH—. 
     
     
         12 . A compound as claimed in  claim 1  wherein —NR 1 R 2  forms a pyrrolidinyl, morpholyl, or thiomorpholyl ring. 
     
     
         13 . A compound as claimed in  claim 1  wherein —NR 1 R 2  forms a piperidinyl, or piperazinyl ring. 
     
     
         14 . A compound as claimed in  claim 1  wherein in the group (II), when present, p is 0, Z is hydrogen and at least one of n and m is 1. 
     
     
         15 . A compound as claimed in  claim 1  wherein in the group (II), when present, m, n and p are all 0 and Z is a carbocyclic or heterocyclic ring directly linked to a ring carbon or ring nitrogen of the —NR 1 R 2  group. 
     
     
         16 . A compound as claimed in  claim 1  wherein in the group (II), when present, p is 0, at least one of m and n is 1, and Z is a carbocyclic or heterocyclic ring linked to a ring carbon or ring nitrogen of the —NR 1 R 2  group via a C 1 -C 6  alkylene linker between Z and the —NR 1 R 2  ring. 
     
     
         17 . A compound as claimed in  claim 1  wherein in the group (II), when present, p is 1. 
     
     
         18 . A compound as claimed in  claim 1  of formula (IB) or (IC) or an enantiomer or diastereoisomer thereof, or a salt, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
       
       wherein R is hydrogen or methoxy, R 3  is trifluoromethyl, trifluoromethoxy C 1 -C 3 alkoxy, hydroxy, or halo; R 4  is (i)-SO 2 R 5  or —COR 5  wherein R 5  is C 1 -C 6  alkyl or phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, optionally substituted by (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, hydroxy, hydroxy(C 1 -C 3 )alkyl, mercapto, mercapto(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio, halo, trifluoromethyl, trifluoromethoxy or (ii) phenyl or monocyclic heteroaryl having 5 or 6 ring atoms; optionally substituted by (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, hydroxy, hydroxy(C 1 -C 3 )alkyl, mercapto, mercapto(C 1 -C 3 )alkyl, (C 1 -C 3 )alkylthio, halo, trifluoromethyl, trifluoromethoxy. 
     
     
         19 . A compound as claimed in  claim 18  wherein a heteroaryl ring forming part of R 4  is pyridyl, pyrimidinyl, triazinyl, thienyl, or furanyl. 
     
     
         20 . A compound as claimed in  claim 1  having the stereochemical configuration shown in formula (IA): 
       
         
           
           
               
               
           
         
       
     
     
         21 . A compound as claimed in  claim 1 , which is selected from the group consisting of:
 6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)-hexanoic acid hydroxyamide;   3R-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-6-(4-ethoxyphenyl)-2S-hydroxy-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)-hexanoic acid hydroxyamide.   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2RS-methyl-morpholine-4-carbonyl)-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(2,6-RS-dimethyl-morpholine-4-carbonyl)-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(thiomorpholine-4-carbonyl)-hexanoic acid hydroxyamide;   3R-(4-benzyl-piperidine-1-carbonyl)-6-(4-ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide;   3R-[4-(acetyl-methyl-amino)-piperidine-1-carbonyl]-6-(4-ethoxy-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R—[4-(methyl-propyl-amino)-piperidine-1carbonyl]-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-benzyl-morpholine-4-carbonyl)-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-isobutyl-morpholine-4-carbonyl)-hexanoic acid hydroxyamide;   6-(4-ethoxy-phenyl)-2S-hydroxy-3R-(3S-phenyl-morpholine-4-carbonyl)-hexanoic acid hydroxyamide;   3R-benzyl-2S, N-dihydroxy-4-morpholin-4-yl-4-oxo-butyramide;   3R-(4-Benzyloxy-benzyl)-2S, N-dihydroxy-4-oxo-4-piperidin-1-yl-butyramide;   2S, N-dihydroxy-3R-(4-hydroxy-benzyl)-4-oxo-4-piperidin-1-yl-butyramide;   6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(morpholine-4-carbonyl)hexanoic acid hydroxyamide;   3R-(4-benzyl-piperidine-1-carbonyl)-6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-hexanoic acid hydroxyamide;   6-(3,5-bis-trifluoromethyl-phenyl)-3R-(6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-2S-hydroxy-hexanoic acid hydroxyamide; and   6-(3,5-bis-trifluoromethyl-phenyl)-2S-hydroxy-3R-(pyrrolidine-1-carbonyl)-hexanoic acid hydroxyamide.   
     
     
         22 . A pharmaceutical composition comprising a compound as claimed in  claim 1 , together with a pharmaceutically acceptable carrier. 
     
     
         23 . A compound as claimed in  claim 1  for use as a medicament. 
     
     
         24 . A method of treatment or prophylaxis of diseases or conditions responsive to inhibition of MMP-12 and/or MMP-9 in mammals, which method comprises administering to the mammal an effective amount of a compound as claimed in  claim 1 . 
     
     
         25 . (canceled) 
     
     
         26 . A method as claimed in  claim 24  wherein the disease or condition is bone resorption, tumour growth or invasion by secondary metastases; rheumatoid arthritis, septic arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, cardiac hypertrophy, acute respiratory distress syndrome, neuroinflammatory disorders, e.g. multiple sclerosis; restenosis; emphysemia; fibrotic disease e.g. fibrosis post radiotherapy, kerotid scarring, liver fibrosis and cystic fibrosis; chronic obstructive pulmonary disease; bronchitis; asthma; autoimmune disease; transplant rejection (e.g. graft versus host disease); cystic fibrosis; psoriasis; psoriatic arthritis; degenerative cartilage loss; inflammatory gastric conditions, e.g. Crohn's disease, inflammatory bowel disease, and ulcerative colitis; atopic dermatitis, epidermolysis bullosa; epidermic ulceration; a neuropathy or nephropathy e.g. interstitial nephritis, glomerulonephriris or renal failure; ocular inflammation; liver cirrhosis, Sjoegren's syndrome; or an inflammatory condition of the nervous system. 
     
     
         27 . A method as claimed in  claim 24  wherein the disease or condition is fibrotic disease, multiple sclerosis, emphysemia, bronchitis or asthma. 
     
     
         28 . A method of preparing metalloproteinase inhibitors of formula (IA) according to  claim 1  wherein R is hydrogen, comprising the deprotection and/or transformation step of: 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound of formula IIIB 
       
         
           
           
               
               
           
         
         wherein Ar, Alk, R 1  and R 2  are as defined in  claim 1 . 
       
     
     
         30 . A process for the preparation of a compound as claimed in  claim 29  comprising the step of reacting a compound of formula (III) 
       
         
           
           
               
               
           
         
       
       with a cyclic amine HNR 1 R 2 .