Substituted sulfonamide-indoles

Abstract

The present invention relates generally to substituted sulfonamide indoles such as substituted sulfonamide indoles, and methods of using them.

1 . A compound having the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof, 
       wherein:
 X is O or NH; 
 R 1  and R 2  are independently, hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, C 7 -C 11  bicycloalkyl, arylalkyl, carboxyalkyl, C 6 -C 10  aryl, or heterocycle; 
 R 3  is hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 3  perfluoroalkyl, C 1 -C 6  alkoxy, C 3 -C 8  cycloalkyl, or —C(═O)C 1 -C 3  alkyl; 
 A 1  is C 6 -C 10  aryl or heterocycle; and 
 A 2  is C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, C 7 -C 11  bicycloalkyl, C 6 -C 10  aryl, or heterocycle; 
 
       said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle groups or part of groups being optionally substituted. 
     
   
   
       2 . A compound of  claim 1 , having the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof, 
       wherein Aa is an amino acid. 
     
   
   
       3 . A compound of  claim 2  wherein Aa is L-Leu or L-Phe. 
   
   
       4 . A compound of  claim 1  having the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof. 
     
   
   
       5 . A compound of  claim 1  wherein R 1  is hydrogen, C 1 -C 6  alkyl, C 2 -C 7  alkenyl, C 2 -C 7  alkynyl, C 3 -C 8  cycloalkyl, C 7 -C 11  bicycloalkyl, carboxyalkyl, or C 6 -C 10  aryl. 
   
   
       6 . A compound of  claim 1  wherein R 1  is hydrogen, C 1 -C 6  alkyl, unsubstituted aralkyl, arylalkyl wherein the ring of the aryl group is substituted with aryl or the alkyl group of arylalkyl is substituted by aryl. 
   
   
       7 . A compound of  claim 6  wherein R 1  is hydrogen, unsubstituted benzyl, benzyl wherein the benzyl ring is substituted with phenyl, unsubstituted C 1 -C 6  alkyl or C 1 -C 6  alkyl substituted with benzhydryl. 
   
   
       8 . A compound of  claim 1  wherein A 2  is alkyl, quinoline, unsubstituted aryl or aryl substituted with OCF 3 , alkyl or aryl. 
   
   
       9 . A compound of  claim 1  wherein R 3  is hydrogen, C 1 -C 6  alkyl optionally substituted with halogen, —CN, or C 1 -C 3  alkoxy. 
   
   
       10 . A compound of  claim 1  that is N-{[1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indol-2-yl]carbonyl}-L-leucine or a pharmaceutically acceptable salt or ester form thereof; N-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl}carbonyl)-L-phenylalanine or a pharmaceutically acceptable salt or ester form thereof; N-({5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indol-2-yl}carbonyl)-L-leucine or a pharmaceutically acceptable salt or ester form thereof; N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-phenylalanine or a pharmaceutically acceptable salt or ester form thereof or N-[(5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indol-2-yl)carbonyl]-L-leucine or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       11 . A compound of  claim 1  that is 1-benzyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-3-phenyl-5-[(quinolin-8-ylsulfonyl)amino]-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof or 1-methyl-3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       12 . A compound of  claim 1  that is 5-{[(4-tert-butylphenyl)sulfonyl]amino}-1-methyl-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-1-methyl-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-(1,1′-biphenyl-4-ylmethyl)-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; or 1-benzhydryl-5-[(methylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       13 . A compound of  claim 1  that is 1-benzhydryl-3-phenyl-5-[(phenylsulfonyl)amino]-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-3-(4-tert-butylphenyl)-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 1-benzyl-5-[(phenylsulfonyl)amino]-1H, 1′H-3,5′-biindole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof; 3-phenyl-5-({[4-(trifluoromethoxy)phenyl]sulfonyl}amino)-1H-indole-2-carboxylic or a pharmaceutically acceptable salt or ester form thereof or 5-{[(4-tert-butylphenyl)sulfonyl]amino}-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       14 . A compound of  claim 1  that is 5-[(1,1′-biphenyl-4-ylsulfonyl)amino]-3-phenyl-1H-indole-2-carboxylic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       15 . A method of inhibiting PAI-1 activity comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
   
   
       16 . A method for treating a PAI-1 related disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 . 
   
   
       17 . The method of  claim 16 , wherein the PAI-1 related disorder is impairment of the fibrinolytic system. 
   
   
       18 . The method of  claim 16 , wherein the PAI-1 related disorder is thrombosis, atrial fibrillation, pulmonary fibrosis, myocardial ischemia, stroke, thromboembolic complication of surgery, cardiovascular disease, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer. 
   
   
       19 . The method of  claim 18  wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis. 
   
   
       20 . The method of  claim 16  wherein the PAI-1 related disorder is cardiovascular disease caused by noninsulin dependent diabetes mellitus in a subject. 
   
   
       21 . The method of  claim 16  wherein the PAI-1 related disorder is diabetes. 
   
   
       22 . The method of  claim 15  wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       23 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable excipient or carrier. 
   
   
       24 . A method for treating thrombosis, atrial fibrillation, pulmonary fibrosis, thromboembolic complication of surgery, stroke, myocardial ischemia, atherosclerotic plaque formation, chronic obstructive pulmonary disease, or renal fibrosis comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 .