Neuroactive 19-alkoxy-17-substituted steroids, prodrugs thereof, and methods of treatment using same

Abstract

The present disclosure is generally directed to neuroactive 19-alkoxy-17-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

What is claimed is: 
     
         1 - 53 . (canceled) 
     
     
         54 . A compound of Formula (I-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is selected from (C 1 -C 4  spirooxirane, cyano, ═O, nitro, (C 1 -C 4  alkyl)C(O), and HO(C 1 -C 4  alkyl)C(O); 
 R 2  is ═O, H, or OR a , where R a  is selected from H, optionally substituted C 1 -C 4  alkyl, or optionally substituted aryl, with the proviso that when R 2  is ═O, R 8  is not present; 
 R 3  is H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, optionally substituted C 2 -C 4  alkynyl, or optionally substituted aryl; 
 R b  is optionally substituted C 1 -C 4  alkyl; 
 R 7  is H, optionally substituted C 1 -C 4  alkoxy, or an optionally substituted morpholinyl ring; 
 R 8 , when present, is H or optionally substituted C 1 -C 4  alkyl; 
 - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5  or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present; and, 
 - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 16 -C 17 , with the proviso that when present, the R 1  is not ═O. 
 
     
     
         55 . The compound of  claim 54 , wherein the R 3  group is selected from the group consisting of H, methyl, and trifluoromethyl. 
     
     
         56 . The compound of  claim 54 , wherein R 7  is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring. 
     
     
         57 . The compound of  claim 54 , wherein R 7  is H. 
     
     
         58 . The compound of  claim 54 , wherein each instance of - - - between C 5 -C 6  and C 6 -C 7  is absent and C 5 —H is in the alpha position. 
     
     
         59 . The compound of  claim 54 , wherein each instance of - - - between C 5 -C 6  and C 6 -C 7  is absent and C 5 —H is in the beta position. 
     
     
         60 . The compound of  claim 54 , wherein each instance of - - - between C 16 -C 17  is absent and R 1  is in the beta position. 
     
     
         61 . The compound of  claim 54 , wherein R 2  is ═O, methoxy or H. 
     
     
         62 . The compound of  claim 54 , wherein R b  is methyl. 
     
     
         63 . The compound of  claim 54 , wherein R 1  is beta-methoxy. 
     
     
         64 . The compound of  claim 54 , wherein R 1  is beta-spirooxirane. 
     
     
         65 . The compound of  claim 54 , wherein R 1  is beta-cyano. 
     
     
         66 . The compound of  claim 54 , wherein R 1  is ═O. 
     
     
         67 . The compound of  claim 54 , wherein R 1  is beta-nitro. 
     
     
         68 . The compound of  claim 54 , wherein R 1  is beta-CH 3 C(O)—. 
     
     
         69 . The compound of  claim 54 , wherein R 1  is beta-HOCH 2 C(O)—. 
     
     
         70 . The compound of  claim 54  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         71 . A method of inducing anesthesia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is selected from (C 1 -C 4  alkyl)-O, spirooxirane, cyano, ═O, nitro, (C 1 -C 4  alkyl)C(O), and HO(C 1 -C 4  alkyl)C(O); 
 R 2  is ═O, H, or OR a , where R a  is selected from H, optionally substituted C 1 -C 4  alkyl, or optionally substituted aryl, with the proviso that when R 2  is ═O, R 8  is not present; 
 R 3  is H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, optionally substituted C 2 -C 4  alkynyl, or optionally substituted aryl; 
 R b  is optionally substituted C 1 -C 4  alkyl; 
 R 7  is H, optionally substituted C 1 -C 4  alkoxy, or an optionally substituted morpholinyl ring; 
 R 8 , when present, is H or optionally substituted C 1 -C 4  alkyl; 
 - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5  or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present; and, 
 - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 16 -C 17 , with the proviso that when present, the R 1  is not ═O. 
 
     
     
         72 . A method for treating disorders related to GABA function in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I-a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is selected from (C 1 -C 4  alkyl)-O, spirooxirane, cyano, ═O, nitro, (C 1 -C 4  alkyl)C(O), and HO(C 1 -C 4  alkyl)C(O); 
 R 2  is ═O, H, or OR a , where R a  is selected from H, optionally substituted C 1 -C 4  alkyl, or optionally substituted aryl, with the proviso that when R 2  is ═O, R 8  is not present; 
 R 3  is H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, optionally substituted C 2 -C 4  alkynyl, or optionally substituted aryl; 
 R b  is optionally substituted C 1 -C 4  alkyl; 
 R 7  is H, optionally substituted C 1 -C 4  alkoxy, or an optionally substituted morpholinyl ring; 
 R 8 , when present, is H or optionally substituted C 1 -C 4  alkyl; 
 - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5  or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present; and, 
 - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 16 -C 17 , with the proviso that when present, the R 1  is not ═O. 
 
     
     
         73 . The method of  claim 72 , wherein the disorder is selected from the group consisting of insomnia, mood disorders, convulsive disorders, anxiety, or symptoms of ethanol withdrawal.