Neuroactive steroids and methods of use thereof

Abstract

(3alpha,3beta)-disubstituted 17beta steroidal compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided for the prevention and treatment of a variety of CNS-related conditions.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is substituted or unsubstituted aliphatic; 
 R 2  is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted cyclopropyl, or —OR A2 , wherein R A2  is hydrogen or substituted or unsubstituted alkyl; 
 R 3a  is hydrogen or —OR A3 , wherein R A3  is hydrogen or substituted or unsubstituted alkyl, and R 3b  is hydrogen; or R 3a  and R 3b  are joined to form an oxo (═O) group; 
 R 4  is hydrogen, substituted or unsubstituted alkyl, or halogen; 
 X is —C(R X ) 2 — or —O—, wherein R X  is hydrogen or fluorine, or one R X  group and R 5b  are joined to form a double bond; 
 each instance of R 5a  and R 5b  is independently hydrogen or fluorine; 
 R 6a  is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group, wherein the non-hydrogen group is optionally substituted with fluorine; and 
 R 6b  is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; 
    represents a single or double bond, provided if a single bond is present, then the hydrogen at C5 is in the alpha configuration; 
 
       and further provided that:
 (1) at least one of R X , R 5a , and R 5b  is fluorine; or 
 (2) at least one of R 6a  and R 6b  is a non-hydrogen group substituted with a fluorine; or 
 (3) R 6a  is a non-hydrogen group comprising between two and ten carbon atoms. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is unsubstituted C 1-3  alkyl. 
     
     
         3 . The compound of  claim 2 , wherein R 1  is —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 . 
     
     
         4 . The compound of  claim 1 , wherein R 2  is hydrogen. 
     
     
         5 . The compound of  claim 1 , wherein R 3a  and R 3b  are both hydrogen. 
     
     
         6 . The compound of  claim 1 , wherein R 4  is hydrogen. 
     
     
         7 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein R 5a  and R 5b  are both hydrogen. 
     
     
         13 . The compound of  claim 1 , wherein at least one of R 5a  and R 5b  is fluorine. 
     
     
         14 . (canceled) 
     
     
         15 . The compound of  claim 1 , wherein R 6a  is a non-hydrogen group substituted with fluorine. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein R 6a  is a non-hydrogen group substituted with one or more —OR A6  groups, wherein R A6  is hydrogen or substituted or unsubstituted alkyl. 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 1 , wherein R 6a  is a substituted or unsubstituted C 2-4  alkyl, substituted or unsubstituted C 2-3  alkenyl, substituted or unsubstituted C 2-3  alkynyl, or substituted or unsubstituted C 3  carbocyclyl. 
     
     
         20 . The compound of  claim 1  wherein R 6b  is hydrogen. 
     
     
         21 . The compound of  claim 1  wherein R 6b  is —CH 3  or —CF 3 . 
     
     
         22 . The compound of  claim 1 , wherein R 6a  is —CF 3  and R 6b  is hydrogen or C 1-4  alkyl. 
     
     
         23 . The compound of  claim 1 , wherein R 6a  is a non-hydrogen group substituted with fluorine, and R 6b  is —CH 3 . 
     
     
         24 . The compound of  claim 23 , wherein R 6a  is substituted with one or more —OR A6  groups, wherein R A6  is hydrogen or substituted or unsubstituted alkyl. 
     
     
         25 . The compound of  claim 1 , wherein R 6a  is a substituted or unsubstituted C 2-4  alkyl, substituted or unsubstituted C 2-3  alkenyl, substituted or unsubstituted C 2-3  alkynyl, or substituted or unsubstituted C 3  carbocyclyl, and R 6b  is —CH 3 . 
     
     
         26 - 27 . (canceled) 
     
     
         28 . The compound of  claim 1 , wherein R 1  is C 1-3  alkyl, R 6a  is a non-hydrogen group substituted with fluorine, and R 6b  is —CH 3 . 
     
     
         29 . The compound of  claim 1 , wherein R 1  is C 1-3  alkyl, R 6a  is a non-hydrogen group substituted with fluorine, and R 6b  is hydrogen. 
     
     
         30 . The compound of  claim 1 , wherein R 1  is C 1-3  alkyl, R 6a  is a non-hydrogen group selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, and R 6b  is —CH 3 . 
     
     
         31 - 33 . (canceled) 
     
     
         34 . The compound of  claim 1 , wherein R 1  is —CH 3  or —CH 2 CH 3  and at least one of R 5a  and R 5b  is fluorine or R 5a  and R 5b  are both hydrogen. 
     
     
         35 . The compound of  claim 1 , wherein R 1  is —CH 3  or —CH 2 CH 3  and R 6a  is a non-hydrogen group substituted with fluorine or one or more —OR A6  groups, wherein R A6  is hydrogen or substituted or unsubstituted alkyl. 
     
     
         36 - 37 . (canceled) 
     
     
         38 . The compound of  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         39 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         40 . A method for treating or preventing a CNS-related condition comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, of  claim 1 . 
     
     
         41 . (canceled)