Substituted aryl oximes

Abstract

The present invention relates to substituted aryl oximes and methods of using them.

1 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof 
       wherein: 
       R 1  is a direct bond to A, C 1 -C 4  alkylene, or —O—C 1 -C 4  alkylene; 
       R 2  and R 3  are, independently hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 3  perfluoroalkyl, —O—C 1 -C 3  perfluoroalkyl, C 1 -C 3  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) p -aryl, —O(CH 2 ) p -heteroaryl, aryl, heteroaryl, —NH(CH 2 ) p -aryl, —NH(CH 2 ) p -heteroaryl, —NH(CO)-aryl, —NH(CO)-heteroaryl, —O(CO)-aryl, —O(CO)-heteroaryl, —NH(CO)—CH═CH-aryl, or —NH(CO)—CH═CH-heteroaryl; 
       p is an integer from 0-6; 
       R 4  is hydrogen, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl; 
       A is COOH or an acid mimic; 
       X is C 1 -C 8  alkylene, C 3 -C 6  cycloalkylene, —(CH 2 ) m O—, or —(CH 2 ) m NH—; 
       m is an integer from 1-6; 
       R 5  and R 6 , are, independently, hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  perfluoroalkyl, —O—C 1 -C 6  perfluoroalkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) n -aryl, —O(CH 2 ) n -heteroaryl, aryl, or heteroaryl; and 
       n is an integer from 0-6, 
       wherein C 1 -C 4  alkylene, —O—C 1 -C 4 alkylene, alkyl, aryl and heteroaryl are each optionally substituted by one or more substituents. 
     
   
   
       2 . A compound according to  claim 1  wherein R 1  is a direct bond, —CH 2 —, or —CH 2 —CH 2 —. 
   
   
       3 . A compound according to  claim 1  wherein the rings of the aryl and heteroaryl groups are optionally substituted with 1 to 3 groups selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  perfluoroalkyl, —O—C 1 -C 6  perfluoroalkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —CN, aryl, —O-aryl, —NH-aryl, —NH—CO-alkyl, or —NH—CO-aryl. 
   
   
       4 . A compound according to  claim 1  wherein the rings of the aryl or heteroaryl groups are optionally substituted by 1 to 3 groups selected from halogen, C 1 -C 4  alkyl, C 1 -C 3  perfluoroalkyl, —O—C 1 -C 3  perfluoroalkyl, C 1 -C 3  alkoxy, —OH, —NH 2 , —CN or —NO 2 . 
   
   
       5 . A compound according to  claim 1  wherein R 2  and R 3  are, independently, hydrogen, —OH, halogen, O(CO)-aryl [optionally substituted with CF 3 , phenyl, —OCH 3  or t-butyl], —O(CH 2 )-aryl [optionally substituted with CF 3 ], or —NH(CO)-aryl [optionally substituted with t-butyl, CF 3 , —OCF 3  or phenyl]. 
   
   
       6 . A compound according to  claim 1  wherein R 4  is hydrogen or C 1 -C 6  alkyl. 
   
   
       7 . A compound according to  claim 1  wherein R 5  is hydrogen, aryl, t-butyl, or CF 3 . 
   
   
       8 . A compound according to  claim 1  wherein R 6  is hydrogen, aryl, t-butyl, or CF 3 . 
   
   
       9 - 10 . (canceled) 
   
   
       11 . The compound of  claim 1  that is (4-{3-[1-(4-tert-butyl-phenyl)-ethylideneaminooxy]-propoxy}-phenyl)-acetic acid or a pharmaceutically acceptable salt or ester form thereof; {4-[1-(4-tert-butyl-phenyl)-ethylideneaminooxymethyl]-phenyl}-acetic acid or a pharmaceutically acceptable salt or ester form thereof or [4-(4-tert-butyl-benzylideneaminooxymethyl)-phenyl]-acetic acid or a pharmaceutically acceptable salt or ester form thereof. 
   
   
       12 - 18 . (canceled) 
   
   
       19 . A method of inhibiting PAI-1 activity in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
   
   
       20 . The method of  claim 19 , wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       21 . A method for treating a PAI-1 related disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 1 . 
   
   
       22 . The method of  claim 21 , wherein the therapeutically effective amount is from 25 mg/kg/day to 200 mg/kg/day. 
   
   
       23 . The method of  claim 21 , wherein the PAI-1 related disorder is impairment of the fibrinolytic system. 
   
   
       24 . The method of  claim 21 , wherein the PAI-1 related disorder is thrombosis, atrial fibrillation, pulmonary fibrosis, myocardial ischemia, thromboembolic complication of surgery, cardiovascular disease, stroke, atherosclerotic plaque formation, chronic obstructive pulmonary disease, renal fibrosis, polycystic ovary syndrome, diabetes, Alzheimer's disease, or cancer. 
   
   
       25 . The method of  claim 24 , wherein the thrombosis is selected from the group consisting of venous thrombosis, arterial thrombosis, cerebral thrombosis, and deep vein thrombosis. 
   
   
       26 . The method of  claim 24 , wherein the PAI-1 related disorder is cardiovascular disease caused by noninsulin dependent diabetes mellitus in a subject. 
   
   
       27 . A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt or ester form thereof, and a pharmaceutically acceptable excipient or carrier. 
   
   
       28 . 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 the compound of formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof 
       wherein: 
       R 1  is a direct bond to A, C 1 -C 4  alkylene, or —O—C 1 -C 4  alkylene; 
       R 2  and R 3  are, independently hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 3  perfluoroalkyl, —O—C 1 -C 3  perfluoroalkyl, C 1 -C 3  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) p -aryl, —O(CH 2 ) p -heteroaryl, aryl, heteroaryl, —NH(CH 2 ) p -aryl, —NH(CH 2 ) p -heteroaryl, —NH(CO)-aryl, —NH(CO)-heteroaryl, —O(CO)-aryl, —O(CO)-heteroaryl, —NH(CO)—CH═CH-aryl, or —NH(CO)—CH═CH-heteroaryl; 
       p is an integer from 0-6; 
       R 4  is hydrogen, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl; 
       A is COOH or an acid mimic; 
       X is C 1 -C 8 , alkylene, C 3 -C 6  cycloalkylene, —(CH 2 ) m O—, or —(CH 2 ) m NH—; 
       m is an integer from 1-6; 
       R 5  and R 6 , are, independently, hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  perfluoroalkyl, —O—C 1 -C 6  perfluoroalkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) n -aryl, —O(CH 2 ) n -heteroaryl, aryl, or heteroaryl; and 
       n is an integer from 0-6. 
     
   
   
       29 . A compound of the formula: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt or ester form thereof 
       wherein: 
       R 1  is a direct bond to A, C 1 -C 4  alkylene, or —O—C 1 -C 4  alkylene; 
       R 2  and R 3  are, independently hydrogen, halogen, C 1 -C 4  alkyl, C 1 -C 3  perfluoroalkyl, —O—C 1 -C 3  perfluoroalkyl, C 1 -C 3  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) p -aryl, —O(CH 2 ) p -heteroaryl, aryl, heteroaryl, —NH(CH 2 ) p -aryl, —NH(CH 2 ) p -heteroaryl, —NH(CO)-aryl, —NH(CO)-heteroaryl, —O(CO)-aryl, —O(CO)-heteroaryl, —NH(CO)—CH═CH-aryl, or —NH(CO)—CH═CH-heteroaryl; 
       p is an integer from 0-6; 
       R 4  is hydrogen, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl; 
       A is COOH or an acid mimic; 
       X is C 1 -C 8  alkylene, C 3 -C 6  cycloalkylene, —(CH 2 ) m O—, or —(CH 2 ) m NH—; 
       m is an integer from 1-6; 
       R 5  and R 6 , are, independently, hydrogen, halogen, C 1 -C 6  alkyl, C 1 -C 6  perfluoroalkyl, —O—C 1 -C 6  perfluoroalkyl, C 1 -C 6  alkoxy, —OH, —NH 2 , —NO 2 , —O(CH 2 ) n -aryl, —O(CH 2 ) n -heteroaryl, aryl, or heteroaryl; and 
       n is an integer from 0-6 
     
   
   
       30 . A method for treating a PAI-1 related disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 29 . 
   
   
       31 . A method of inhibiting PAI-1 activity in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of  claim 29 .