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 compound of Formula (I): 
       
         
           
           
               
               
           
         
         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 4  is independently selected from H and unsubstituted C 1 -C 4  alkyl; 
 R 5  is substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 6  is H, optionally substituted C 1 -C 4  alkyl, or optionally substituted C 1 -C 4  alkoxy; 
 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. 
 
       
     
     
         2 . The compound of  claim 1 , wherein one or both of R 6  or R 7 , when present and other than H, are in the beta configuration. 
     
     
         3 . The compound of  claim 1  or  2 , wherein the R 3  group is selected from the group consisting of H, methyl, and trifluoromethyl. 
     
     
         4 . The compound of one of the preceding claims, wherein R 7  is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring. 
     
     
         5 . The compound of one of the preceding claims, wherein R 7  is H. 
     
     
         6 . The compound of one of the preceding claims, wherein R 5  is substituted methyl. 
     
     
         7 . The compound of one of the preceding claims, wherein the C 5 —H is in the alpha position. 
     
     
         8 . The compound of one of preceding  claims 1 - 6 , wherein the C 5 —H is in the beta configuration and R 5  group is in the beta configuration. 
     
     
         9 . The compound of one of the preceding claims, wherein R 6  is H. 
     
     
         10 . The compound of one of the preceding claims, wherein R 2  is ═O, methoxy or H. 
     
     
         11 . The compound of one of the preceding claims, wherein R 4  is methyl. 
     
     
         12 . The compound of  claim 1  having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R b  is optionally substituted C 1 -C 4  alkyl. 
       
     
     
         13 . The compound of  claim 12  wherein R b  is methyl. 
     
     
         14 . The compound of  claim 12  or  13 , wherein R 1  is beta-methoxy. 
     
     
         15 . The compound of  claim 12  or  13 , wherein R 1  is beta-spirooxirane. 
     
     
         16 . The compound of  claim 12  or  13 , wherein R 1  is beta-cyano. 
     
     
         17 . The compound of  claim 12  or  13 , wherein R 1  is ═O. 
     
     
         18 . The compound of  claim 12  or  13 , wherein R 1  is beta-nitro. 
     
     
         19 . The compound of  claim 12  or  13 , wherein R 1  is beta-CH 3 C(O)—. 
     
     
         20 . The compound of  claim 12  or  13 , wherein R 1  is beta-HOCH 2 C(O)—. 
     
     
         21 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein R b  is optionally substituted C 1 -C 4  alkyl. 
       
     
     
         22 . The compound of  claim 21 , wherein R b  is methyl. 
     
     
         23 . A pharmaceutically acceptable salt of a compound of one of the preceding claims. 
     
     
         24 . A prodrug of a compound of one of the preceding claims. 
     
     
         25 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
         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 x  is ═O or OR d , where R d  is H or C(O)R e , where R e  is optionally substituted C 1 -C 22  alkyl or optionally substituted C 2 -C 22  alkenyl, with the proviso that when R x  is OH, it is in the beta configuration (and when R x  is R d , with R d  being C(O)R e , then it is preferably in the beta configuration); 
 R 4  is independently selected from H and unsubstituted C 1 -C 4  alkyl; 
 R 5  is substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 6  is H, optionally substituted C 1 -C 4  alkyl, or optionally substituted C 1 -C 4  alkoxy; 
 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, 
 provided that the compound does not have one of the following structures: 
 
       
       
         
           
           
               
               
           
         
         
           or alternatively provided that: (i) when R x  is ═O, a C═C bond is present between C 4 -C 5 , and R 5  is CH 2 OCH 3 , then R 1  is selected from methoxy, spirooxirane, cyano, nitro, and CH 3 C(O)—; and/or (ii) when R x  is beta-OH, a C═C bond is present between C 5 -C 6 , and R 5  is CH 2 OCH 3 , then R 1  is selected from methoxy, spirooxirane, cyano, nitro, and HOCH 2 C(O)—. 
         
       
     
     
         26 . The compound of  claim 25 , wherein R x  is OH in the beta configuration. 
     
     
         27 . The compound of  claim 25 , wherein R x  is ═O. 
     
     
         28 . The compound of one of preceding  claims 25 - 27 , wherein R 7  is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring. 
     
     
         29 . The compound of one of preceding  claims 25 - 28 , wherein R 7  is in the beta position. 
     
     
         30 . The compound of one of preceding  claims 25 - 29 , wherein R 5  is substituted methyl. 
     
     
         31 . The compound of one of preceding  claims 25 - 30 , wherein the C 5 —H is in the alpha configuration and R 5  is in the beta configuration. 
     
     
         32 . The compound of one of preceding  claims 25 - 30 , wherein the C 5 —H is in the beta configuration and R 5  is in the beta configuration. 
     
     
         33 . The compound of one of preceding  claims 25 - 32 , wherein R 6  is H. 
     
     
         34 . The compound of one of preceding  claims 25 - 33 , wherein R 2  is ═O, methoxy or H. 
     
     
         35 . The compound of one of preceding  claims 25 - 34 , wherein R 4  is methyl. 
     
     
         36 . The compound of  claim 25 , wherein a carbon-carbon double bond is present between the C 4  and C 5  carbon atoms. 
     
     
         37 . The compound of  claim 25 , wherein a carbon-carbon double bond is present between the C 5  and C 6  carbon atoms. 
     
     
         38 . The compound of  claim 25  having the structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R b  is optionally substituted C 1 -C 4  alkyl. 
       
     
     
         39 . The compound of  claim 38  wherein R b  is methyl. 
     
     
         40 . The compound of  claim 38  or  39 , wherein R 1  is beta-methoxy. 
     
     
         41 . The compound of  claim 38  or  39 , wherein R 1  is beta-spirooxirane. 
     
     
         42 . The compound of  claim 38  or  39 , wherein R 1  is beta-cyano. 
     
     
         43 . The compound of  claim 38  or  39 , wherein R 1  is ═O. 
     
     
         44 . The compound of  claim 38  or  39 , wherein R 1  is beta-nitro. 
     
     
         45 . The compound of  claim 38  or  39 , wherein R 1  is beta-CH 3 C(O)—. 
     
     
         46 . The compound of  claim 38  or  39 , wherein R 1  is beta-HOCH 2 C(O)—. 
     
     
         47 . The compound of  claim 25 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein R b  is optionally substituted C 1 -C 4  alkyl. 
       
     
     
         48 . The compound of  claim 47 , wherein R b  is methyl. 
     
     
         49 . A pharmaceutically acceptable salt of a compound of one of preceding  claims 25 - 48 . 
     
     
         50 . A pharmaceutical composition comprising a compound of one of  claims 1 - 48 , a pharmaceutically acceptable salt thereof, or a combination of two or more thereof, and a pharmaceutically acceptable carrier. 
     
     
         51 . 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 one of  claims 1 - 48 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of  claim 50 . 
     
     
         52 . 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 one of  claims 1 - 48 , a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of  claim 50 . 
     
     
         53 . The method of  claim 52 , wherein the disorder is selected from the group consisting of insomnia, mood disorders, convulsive disorders, anxiety, or symptoms of ethanol withdrawal.