Sulfonamide peri-substituted bicyclics for occlusive artery disease

Abstract

Acyl sulfonamide, peri-substituted, fused bicyclic ring compounds useful for the treatment or prophylaxis of a prostaglandin-mediated disease or condition are disclosed. The compounds are of the general formula A representative example is:

1 . A compound of formula: 
     
       
         
         
             
             
         
       
     
     wherein
 A and B represent a pair of fused 5-, 6- or 7-membered rings, said fused A/B ring system containing from zero to four heteroatoms chosen from nitrogen, oxygen and sulfur and said rings additionally substituted with from zero to four substituents chosen independently from halogen, —OH, loweralkyl, —O-loweralkyl, fluoroloweralkyl, —O-lowerfluoroalkyl, methylenedioxy, ethylenedioxy, alkoxy-loweralkyl, hydroxyloweralkyl, oxo, oxide, —CN, nitro, —S-loweralkyl, amino, loweralkylamino, diloweralkylamino, diloweralkylaminoalkyl, carboxy, carboalkoxy, orthoester, acyl, acylalkyl, carboxamido, loweralkylsulfoxide, loweralkylsulfone, acylamino, phenyl, benzyl, spirothiazolidinyl, phenoxy and benzyloxy; 
 a and b represent points of attachment of residues Y and W respectively and a and b are in a peri relationship to one another on said fused A/B ring system; 
 d and e represent points of fusion between ring A and ring B in said fused A/B ring system; 
 W and Y are linkers comprising from zero to 8 atoms in a chain; 
 M is chosen from aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, C 6  to C 20  alkyl and substituted C 6  to C 20  alkyl; 
 Q is chosen from —N(SO 2 R 1 )—, —N(COR 1 )—, —N(CO 2 R 1 )—, —N[PO(O-alkyl) 2 ]-, —NHNR 10 (SO 2 R 1 ), and, when W is —CF 2 — or —CH 2 CF 2 —, Q may additionally be —NH—; 
 R 1  is chosen from aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 3 -C 20  alkyl and fluoroalkyl; and 
 R 10  is chosen from alkyl, aryl and heteroaryl. 
 
   
   
       2 . A compound according to  claim 1  wherein W and Y are independently chosen from C 1  to C 8  alkyl in which one or two —CH 2 — may be replaced by —O—, —C(═O)—, —CH═CH—, —CF 2 —, —S—, —SO—, —SO 2 —, —NH— or —N(alkyl)-. 
   
   
       3 . A compound according to  claim 1  wherein W and Y are linkers comprising one atom or two atoms in a chain. 
   
   
       4 . A compound according to  claim 3  wherein
 W is chosen from —CH 2 CH 2 —, —OCH 2 —, —C(═O)—, —CH 2 O—, —OCF 2 —, —OC(CH 3 ) 2 —, —OCH(CH 3 )—CH═CH—, —NHC(═O)— and —NHCH 2 —;   Y is chosen from —CH 2 —, —O—, —OCH 2 —, ═N—, —NH—, ═NSO 2 —, —NHSO 2 , —NHC(═O)—, —S—, —SO— and —SO 2 —; and the left-hand bond indicates the point of attachment to ring A or B.   
   
   
       5 . A compound according to  claim 1  wherein Q is —N[PO(O-alkyl) 2 ]-. 
   
   
       6 . A compound according to  claim 1  wherein Q is —N(COR 1 )—, —N(CO 2 R 1 )—. 
   
   
       7 . A compound according to  claim 6  wherein R 1  is chosen from phenyl, substituted phenyl, 5-membered ring heteroaryl, substituted 5-membered ring heteroaryl, CF 2 CF 3  and CF 3 . 
   
   
       8 . A compound according to  claim 1  wherein Q is —N(SO 2 R 1 )—. 
   
   
       9 . A compound according to  claim 8  wherein R 1  is chosen from phenyl, substituted phenyl, 5-membered ring heteroaryl, substituted 5-membered ring heteroaryl and CF 3 . 
   
   
       10 . A compound according to  claim 9  wherein R 1  is fluorophenyl. 
   
   
       11 . A compound according to  claim 1  wherein M is chosen from aryl, substituted aryl, heterocyclyl and substituted heteroaryl. 
   
   
       12 . A compound according to  claim 11  wherein M is chosen from phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl and substituted heteroaryl. 
   
   
       13 . A compound according to  claim 12  wherein M is fluorophenyl. 
   
   
       14 . A compound according to  claim 1  wherein the A/B ring system is a pair of fused 5-membered rings: 
     
       
         
         
             
             
         
       
     
   
   
       15 . A compound according to  claim 14  wherein the A/B ring system is chosen from 
     
       
         
         
             
             
         
       
     
   
   
       16 . A compound according to  claim 1  wherein the A/B ring system is a pair of fused 6-membered rings: 
     
       
         
         
             
             
         
       
     
   
   
       17 . A compound according to  claim 16  wherein the A/B ring system is chosen from: 
     
       
         
         
             
             
         
       
     
   
   
       18 . A compound according to  claim 1  wherein the A/B ring system is a fused 5- and 6-membered ring pair: 
     
       
         
         
             
             
         
       
     
   
   
       19 . A compound according to  claim 18  wherein the A/B ring system is chosen from an indole, an indoline, an indo lone, a tetrahydro indo lone, perhydroindolone, an isatin, a benzimidazole, a benzoxazolinone, a benzofuran and an indazole. 
   
   
       20 . A compound according to  claim 4  wherein the A/B ring system is an indole or indolone. 
   
   
       21 . A compound according to  claim 20  wherein the A/B ring system is an indole. 
   
   
       22 . A compound according to  claim 21  wherein Q is —N(SO 2 R 1 )— and R 1  is chosen from phenyl, substituted phenyl, 5-membered ring heteroaryl, substituted 5-membered ring heteroaryl, fluorophenyl and CF 3 . 
   
   
       23 . A compound according to  claim 22  wherein M is chosen from substituted phenyl, naphthyl and bicyclic nitrogen heteroaryl. 
   
   
       24 . A compound according to  claim 23  wherein at least one of R 1  and M is fluorophenyl. 
   
   
       25 . A compound according to  claim 23  wherein Y is —CH 2 — and W is —CH═CH—. 
   
   
       26 . A compound according to  claim 25  wherein the A/B ring system is a disubstituted indole of formula 
     
       
         
         
             
             
         
       
     
   
   
       27 . A compound according to  claim 26  wherein M is 2,4-dichlorophenyl and R 1  is 4,5-dichlorothien-2-yl. 
   
   
       28 . A compound of formula 
     
       
         
         
             
             
         
       
     
     wherein
 U is chosen from —O— and —NH—; and 
 R 20 -R 25  are chosen independently from hydrogen, halogen and methyl. 
 
   
   
       29 . A method for the treatment or prophylaxis of a prostaglandin-mediated disease or condition comprising administering to a mammal a therapeutically effective amount of a compound or a salt, hydrate or ester thereof according to  claim 1 . 
   
   
       30 . A method according to  claim 29  wherein said disease or condition is chosen from pain, fever or inflammation associated with rheumatic fever, influenza or other viral infections, common cold, low back and neck pain, skeletal pain, post-partum pain, dysmenorrhea, headache, migraine, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns including radiation and corrosive chemical injuries, sunburns, pain following surgical and dental procedures, immune and autoimmune diseases;
 cellular neoplastic transformations or metastatic tumor growth;   diabetic retinopathy, tumor angiogenesis;   prostanoid-induced smooth muscle contraction associated with dysmenorrhea, premature labor, asthma or eosinophil related disorders;   Alzheimer's disease;   glaucoma;   bone loss;   osteoporosis;   Paget's disease;   peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or other gastrointestinal lesions; G1 bleeding;   coagulation disorders selected from hypoprothrombinemia, hemophilia and other bleeding problems;   kidney disease;   thrombosis, myocardial infarction, stroke; and   occlusive vascular disease.   
   
   
       31 . A method according to  claim 29  wherein said disease is occlusive vascular disease. 
   
   
       32 . A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a compound according to  claim 1  or an ester, a pharmaceutically acceptable salt or a hydrate of the compound. 
   
   
       33 . A pharmaceutical formulation according to  claim 32  comprising an additional therapeutic agent chosen from a platelet aggregation inhibitor, an HMG-CoA reductase inhibitor, an antihyperlipidemic agent and a cyclooxygenase inhibitor. 
   
   
       34 . A pharmaceutical formulation according to  claim 33  wherein said platelet aggregation inhibitor is chosen from tirofiban, dipyridamole, clopidogrel and ticlopidine. 
   
   
       35 . A pharmaceutical formulation according to  claim 33  wherein said HMG-CoA reductase inhibitor is chosen from lovastatin, simvastatin, pravastatin, rosuvastatin, mevastatin, atorvastatin, cerivastatin, pitavastatin and fluvastatin. 
   
   
       36 . A pharmaceutical formulation according to  claim 33  wherein said cyclooxygenase inhibitor is chosen from rofecoxib, meloxicam, celecoxib, etoricoxib, lumiracoxib, valdecoxib, parecoxib, cimicoxib, diclofenac, sulindac, etodolac, ketoralac, ketoprofen, piroxicam and LAS-34475. 
   
   
       37 . A method for in vitro screening for selective prostanoid receptor ligands comprising bringing a labeled compound according to  claim 1  into contact with a prostanoid receptor and measuring its displacement by a test compound. 
   
   
       38 . A method according to  claim 37  for in vitro screening for selective EP3 ligands comprising bringing said labeled compound into contact with a cloned human EP3 receptor and measuring its displacement by a test compound. 
   
   
       39 . A method for reducing plaque in the treatment of atherosclerosis comprising administering to a mammal a therapeutically effective amount of a compound or a salt, hydrate or ester thereof according to  claim 1 . 
   
   
       40 . A method for the promotion of bone formation or for cytoprotection comprising administering to a mammal a therapeutically effective amount of a compound or a salt, hydrate or ester thereof according to  claim 1 . 
   
   
       41 . A method for the treatment or prophylaxis of pain, inflammation, atherosclerosis, myocardial infarction, stroke or vascular occlusive disorder comprising administering to a mammal a therapeutically effective amount of a cyclooxygenase inhibitor and a compound or a salt, hydrate or ester thereof according to  claim 1 .