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 . 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): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof;
 wherein: 
 R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O); 
 R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present; 
 R3 is H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, or optionally substituted aryl; 
 R4 is independently selected from H and unsubstituted C1-C4 alkyl; 
 R5 is substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl; 
 R6 is H, optionally substituted C1-C4 alkyl, or optionally substituted C1-C4 alkoxy; 
 R7 is H, optionally substituted C1-C4 alkoxy, or an optionally substituted morpholinyl ring; 
 R8, when present, is H or optionally substituted C1-C4 alkyl; 
 - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C4-C5 or C5-C6, with the proviso that when present, the C5-H substituent is not present; and, 
 - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O. 
 
     
     
         2 . The method of  claim 1 , wherein the R3 group is selected from the group consisting of H, methyl, and trifluoromethyl. 
     
     
         3 . The method of  claim 1 , wherein R7 is H. 
     
     
         4 . The method of  claim 1 , wherein R5 is substituted methyl. 
     
     
         5 . The method of  claim 1 , wherein the C5-H is in the alpha position. 
     
     
         6 . The method of  claim 1 , wherein the C5-H is in the beta configuration and R5 group is in the beta configuration. 
     
     
         7 . The method of  claim 1 , wherein R6 is H. 
     
     
         8 . The method of  claim 1 , wherein R2 is ═O, methoxy or H. 
     
     
         9 . The method of  claim 1 , wherein R4 is methyl. 
     
     
         10 . The method of  claim 1 , wherein Formula (I) has the structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein Rb is optionally substituted C1-C4 alkyl. 
     
     
         11 . The method of  claim 10 , wherein Rb is methyl. 
     
     
         12 . The method of  claim 10 , wherein R1 is beta-methoxy. 
     
     
         13 . The method of  claim 10 , wherein R1 is beta-cyano. 
     
     
         14 . The method of  claim 10 , wherein R1 is ═O. 
     
     
         15 . The method of  claim 10 , wherein R1 is beta-CH3C(O)—. 
     
     
         16 . The method of  claim 10 , wherein R1 is beta-HOCH2C(O)—. 
     
     
         17 . The method of  claim 1 , wherein Formula (I) has the structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein Rb is optionally substituted C1-C4 alkyl. 
     
     
         18 . The method of  claim 17 , wherein Rb is methyl. 
     
     
         19 . The method of  claim 1 , having the structure Formula (I-g): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 R1 is selected from (C1-C4 alkyl)-O, spirooxirane, cyano, ═O, nitro, (C1-C4 alkyl)C(O), and HO(C1-C4 alkyl)C(O); 
 R2 is ═O, H, or ORa, where Ra is selected from H, optionally substituted C1-C4 alkyl, or optionally substituted aryl, with the proviso that when R2 is ═O, R8 is not present; 
 R3 is H, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, or optionally substituted aryl; 
 Rb is methyl; 
 R8, when present, is H or optionally substituted C1-C4 alkyl; 
 - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C16-C17, with the proviso that when present, the R1 is not ═O or spirooxirane. 
 
     
     
         20 . The method of  claim 1 , wherein the disorder is selected from the group consisting of insomnia, mood disorders, convulsive disorders, anxiety, or symptoms of ethanol withdrawal.