CRTH2 receptor ligands for medicinal uses

Abstract

Compounds of formula (I) are useful for the treatment of disease responsive to modulation of CRTH2 receptor activity, such as asthma, rhinitis, allergic airway syndrome, and allergic rhinobronchitis: wherein A represents a carboxyl group —COOH, or a carboxyl bioisostere; A 1 is hydrogen or methyl; ring Ar 1 is an optionally substituted phenyl ring or 5- or 6-membered monocyclic heteroaryl ring, in which AA 1 CHO— and L2 are linked to adjacent ring atoms; rings Ar 2 , Ar 3 each independently represent a phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5- or 6-membered carbocyclic or heterocyclic ring which is benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring or ring system being optionally substituted; t is 0 or 1; L2 and L3 are linker radicals as defined in the description.

1 . A method of treatment of disease responsive to modulation of CRTH2 receptor activity comprising administering to a subject suffering such disease a compound of formula (I) or a salt, hydrate or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein 
         A represents a carboxyl group —COOH, or a carboxyl bioisostere; 
         A 1  is hydrogen or methyl; 
         ring Ar 1  is an optionally substituted phenyl ring or 5- or 6-membered monocyclic heteroaryl ring, in which AA 1 CHO— and L2 are linked to adjacent ring atoms; 
         rings Ar 2 , Ar 3  each independently represent a phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5- or 6-membered carbocyclic or heterocyclic ring which is benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring or ring system being optionally substituted; 
         t is 0 or 1; 
         L2 and L3 each independently represent a divalent radical of formula —(Alk 1 ) m —(Z) n —(Alk 2 ) p  wherein
 m, n and p are independently 0 or 1, 
 Alk 1  and Alk 2  are independently optionally substituted straight or branched chain C 1 -C 3  alkylene or C 2 -C 3  alkenylene radicals which may contain a compatible —O—, —S— or —NR— link wherein R is hydrogen or C 1 -C 3  alkyl, and 
 Z is —O—; —S—; —C(═O)—; —SO 2 —; —SO—; —NR—, —NRSO 2 —, —SO 2 NR—, —C(═O)NR—, —NRC(═O)—, —NRCONH—, —NHCONR—, —NRC(═NR)NH—, —NHC(═NR)NR—, —C(R)═N—NR—, or —NR—N═C(R)— wherein R is hydrogen or C 1 -C 3  alkyl; or a divalent 5- or 6-membered monocyclic carbocyclic or heterocyclic radical, 
 
       
       PROVIDED THAT
 (A) the total length of L2 and L3 does not exceed that of an unbranched saturated chain of 10 carbon atoms; and 
 (B) L2 is not —C(═O)—, —C(═O)NR—, or —NRC(═O)— when Ar 2  is optionally substituted phenyl; and 
 (C) (a) L2 is not a bond and (b) p in L2 is not 0 when n is 1 and Z is aryl or heteroaryl, and 
 (D) (a) L2 is not —O—, —SO 2 —, —NR—, —CHR X R Y — or —CH(R X )(OR Y )—, wherein R x  and R Y  are independently hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 3 -C 7  cycloalkyl, or join to form a ring, and (b) when p is 1 and n is 1 and Z is aryl or heteroaryl then Alk 2  is not —CHR X R Y — or —CH(R X )(OR Y )—, wherein R X  and R Y  are independently hydrogen, halogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, or C 3 -C 7  cycloalkyl, or join to form a ring. 
 
     
     
         2 . A method as claimed in  claim 1 , wherein, in the compound (I), (i) the length of each of L2 and L3 does not exceed that of an unbranched saturated chain of 5 carbon atoms and (ii) the total length of L2 and L3 does not exceed that of an unbranched saturated chain of 7 carbon atoms, and (iii) neither of L2 and L3 includes more than two R substituents different from hydrogen, 
     
     
         3 . A method as claimed in  claim 1  wherein, in the compound (I), A l  is hydrogen and Z is —O—; —S—; —C(═O)—; —SO 2 —; —SO—; —NR—, —NRSO 2 — —C(═O)NR—, —NRCONH—, —NRC(═NR)NH—, or —C(R)═N—NR—, wherein R is hydrogen or C 1 -C 3  alkyl; or a divalent 5- or 6-membered monocyclic carbocyclic or heterocyclic radical. 
     
     
         4 . A method as claimed in  claim 1  wherein, in the compound (I), L2 is —N═CR—, —OCR 2 C(═O)NR—N═CR—, —C(═O)NR—, —N═CR—, —C(═O)—, —CH═CHC(═O)—, —(CH 2 ) 0-3 NRC(═O)—, —NRC(═O)(CH 2 ) 0-3 —, —O—N═CH—, —CH 2 NRCH 2 —, —NR(CH 2 ) 1-3 —, —(CH 2 ) 1-3 NR—, —S—, —CH 2 OCH 2 —, —O(CH 2 ) 1-3 —, —(CH 2 ) 1-3 O—, —CH 2 SCH 2 —, —S(CH 2 ) 0-3 —, —(CH 2 ) 0-3 S—, a divalent (C 2 -C 6 )alkylene radical, a divalent (C 2 -C 6 )alkenylene radical, or a divalent (C 2 -C 6 )alkynylene radical, wherein R is hydrogen or C 1 -C 3  alkyl. 
     
     
         5 . A method as claimed in  claim 1  wherein, in the compound (I), L2 is —NRN═CH—, —ON═CH—, or —N═CH—. 
     
     
         6 . A method as claimed in  claim 1  wherein, in the compound (I), L2 is —C(═O)—. 
     
     
         7 . A method as claimed in  claim 1  wherein, in the compound (I), L2 is —NHC(═O)— or —C(═O)NH—. 
     
     
         8 . A method as claimed in  claim 1  wherein, in the compound (I), L2 is a divalent radical selected from one of the following formulae, wherein either (i) the bond marked * is attached to Ar 2  while the bond marked ** is attached to Ar 1 , or (ii) the bond marked * is attached to Ar 1  while the bond marked ** is attached to Ar 2 : 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R is hydrogen or C 1 -C 3  alkyl. 
       
     
     
         9 . A method as claimed in  claim 8  wherein, in the compound (I), A1 is hydrogen and L2 has one of the following formulae wherein the bond marked * is attached to Ar 2  while the bond marked ** is attached to Ar 1 : 
       
         
           
           
               
               
           
         
         wherein R is hydrogen or C 1 -C 3  alkyl. 
       
     
     
         10 . A method as claimed in  claim 1  wherein the disease is one associated with elevated levels of prostaglandin D2 (PGD2) or one or more active metabolites thereof. 
     
     
         11 . A method as claimed in  claim 1  wherein the disease is an inflammatory, autoimmune, respiratory or allergy disease. 
     
     
         12 . A method as claimed in  claim 1  wherein the disease is selected from asthma, rhinitis, allergic airway syndrome, allergic rhinobronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer's lung, fibroid lung, cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Huntington's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, Guillain-Barre syndrome, chronic demyelinating polyradiculoneurophathy, multifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and encephalomyelitis, CNS trauma, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Behçet's Disease, bursitis, carpal tunnel syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, dermatomyositis, Ehlers-Danlos Syndrome (EDS), fibromyalgia, myofascial pain, osteoarthritis (OA), osteonecrosis, psoriatic arthritis, Reiter's syndrome (reactive arthritis), sarcoidosis, scleroderma, Sjogren's Syndrome, soft tissue disease, Still's Disease, tendinitis, polyarteritis Nodossa, Wegener's Granulomatosis, myositis (polymyositis dermatomyositis), gout, atherosclerosis, lupus erythematosus, systemic lupus erythematosus (SLE), type I diabetes, nephritic syndrome, glomerulonephritis, acute and chronic renal failure, eosinophilia fascitis, hyper IgE syndrome, sepsis, septic shock, ischemic reperfusion injury in the heart, allograft rejection after transplantations, and graft versus host disease. 
     
     
         13 . A method as claimed in  claim 1  wherein the disease is selected from asthma, rhinitis, allergic airway syndrome, and allergic rhinobronchitis, 
     
     
         14 . A method as claimed in  claim 1  wherein, in the compound (I), ring Ar 2  is (i) an optionally substituted phenyl or naphthyl ring; (ii) a phenyl ring fused to a 5- or 6-membered nitrogen-containing heterocyclic ring, either or both of such rings being optionally substituted; (iii) an optionally substituted nitrogen-containing 5- or 6-membered heteroaryl ring; or (iv) a nitrogen-containing 5- or 6-membered heterocyclic ring fused to a phenyl ring, either of which rings being optionally substituted. 
     
     
         15 . A method as claimed in  claim 14  wherein, in the compound (I), ring Ar 2  is optionally substituted phenyl, pyridyl, pyrimidyl, diazolyl, thiazolyl, oxazolyl, triazinyl, quinolinyl, pyrrollyl, furanyl, thiazolyl. 
     
     
         16 . A method as claimed in  claim 15  wherein, in the compound (I), optional substituents in Ar 2  are selected from fluoro, chloro, bromo, (C 1 -C 3 )alkyl, trifluoromethyl, (C 1 -C 3 )alkoxy, trifluoromethoxy, trifluoromethylthio, dimethylamino, cyano, (C 1 -C 3 alkyl)SO 2 —, NH 2 SO 2 —, (C 1 -C3alkyl)NHSO 2 —, (C 1 -C 3 alkyl) 2 NSO 2 —, and nitro. 
     
     
         17 . A method as claimed in  claim 1  wherein, in the compound (I), Ar 1  is a 5- or 6-membered nitrogen-containing heteroaryl ring, optionally substituted. 
     
     
         18 . A method as claimed in  claim 1  wherein in the compound (I), Ar 1  is a phenyl ring and L3 is linked to the 4-position thereof relative to the ACHA 1 O— radical. 
     
     
         19 . A method as claimed in  claim 1  wherein in compound (I), t is 1 and Ar 3  is a 5- or 6-membered heteroaryl ring, optionally substituted. 
     
     
         20 . A method as claimed in  claim 1  wherein in compound (I), t is 1 and Ar 3  is a phenyl ring, optionally substituted. 
     
     
         21 . A method as claimed in  claim 1  wherein in compound (I), any optional substituents in ring Ar 1  or Ar 3  are selected from fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, (C 1 -C 3 alkyl)SO 2 —, NH 2 SO 2 —, (C 1 -C 3 alkyl)NHSO 2 —, (C 1 -C 3 alkyl) 2 NSO 2 —, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, cycloalkyl, aryl, aryloxy, aryl(C 1 -C 6)—  or aryl(C 1 -C 6  alkoxy)-. 
     
     
         22 . A method as claimed in  claim 1  wherein in compound (I), t is 0 and L3 is a bond. 
     
     
         23 . A method as claimed in  claim 1  wherein, in the compound (I), A is —COOH. 
     
     
         24 . A method as claimed in  claim 1  wherein, in the compound (I), A is a carboxyl bioisostere selected from —SO 2 NHR and —P(═O)(OH)(OR) wherein R is hydrogen methyl or ethyl, —SO 2 OH, —P(═O)(OH)(NH 2 ), —C(═O)NHCN and groups of formulae: 
       
         
           
           
               
               
           
         
       
     
     
         25 . A method as claimed in  claim 1  wherein, in the compound (I), A 1  is hydrogen.