NEUROACTIVE SUBSTITUTED CYCLOPENTA[b]PHENANTHRENES AS MODULATORS FOR GABA TYPE-A RECEPTORS

Abstract

The present disclosure is generally directed to neuroactive substituted cyclopenta[b]phenanthrenes 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 - 20 . (canceled) 
     
     
         21 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; 
       wherein:
 R 1  is H, ═O, ═CHCN, ═CHCO 2 R z , where R z  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-CN, α-OH, α-OR y , where R y  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-NO 2 , spiroepoxy, or C(O)R x , where R x  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 2  is H, ═O, ═CHCN, ═CHCO 2 R w , where R w  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-CN, α-OH, α-OR v , where R v  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-NO 2 , spiroepoxy, or C(O)R u , where R u  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 3  is H, ═O, ═CHCN, ═CHCO 2 R t , where R t  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-CN, α-OH, α-OR s , where R s  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-NO 2 , spiroepoxy, or C(O)R r , where R r  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 4  is H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 5  is H, CO 2 R q , where R q  is 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, CH 2 OR p , where R p  is 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, C(O)R o , where R o  is 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, C(O)NHR n , where R n  is 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, CH 2 NHR m , where R m  is 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, CH 2 N(CH 3 ) 2 , or CH 2 N(CH 2 CH 3 ) 2 , 
 R 6  is H; 
 R 7  is H, ═O, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , OR j , where R j  is 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, or NR i , where R i  is 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 9  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 10  is H, optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; 
 R 11  is H or C(O)R g , where R g  is optionally substituted C 1 -C 20  alkyl, optionally substituted C 2 -C 20  alkenyl, or optionally substituted C 2 -C 20  alkynyl; 
 R 12  is H, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , optionally substituted morpholinyl, or OR h , where R h  is 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; and, 
 - - - denotes an optional, additional C—C bond, resulting in either a C═C bond between, C 1 -C 2 , C 4 -C 4a , C 4a -C 5 , C 8 -C 9 , or C 9 -C 10 , with the provisos that when present between: (i) C 4 -C 4a , the C 4a —H substituent is not present; (ii) C 4a -C 5 , the C 4a —H substituent is not present and R 7  is other than ═O; (iii) C 9 -C 10 , R 1  is other than ═O, ═CHCN or ═CHCO 2 R z , and R 2  is other than ═O, ═CHCN or ═CHCO 2 R w ; and, (iv) C 8 -C 9 , R 2  is other than ═O, ═CHCN or ═CHCO 2 R w , and R 3  is other than ═O, ═CHCN or ═CHCO 2 R t . 
 
     
     
         22 . The compound of  claim 21 , wherein R 11  is H. 
     
     
         23 . The compound of  claim 21 , wherein R 3  is ═O. 
     
     
         24 . The compound of  claim 21 , wherein R 3  is α-CN. 
     
     
         25 . The compound of  claim 21 , wherein R 3  is C(O)CH 3 . 
     
     
         26 . The compound of  claim 21 , wherein R 3  is spiroepoxy. 
     
     
         27 . The compound of  claim 21 , wherein R 2  is ═O. 
     
     
         28 . The compound of  claim 21 , wherein R 9  is H. 
     
     
         29 . The compound of  claim 21 , wherein R 12  is H. 
     
     
         30 . The compound of  claim 21 , wherein R 1  is H. 
     
     
         31 . The compound of  claim 21 , wherein R 2  is H. 
     
     
         32 . The compound of  claim 21 , wherein R 3  is H. 
     
     
         33 . The compound of  claim 21 , wherein R 4  is methyl. 
     
     
         34 . The compound of  claim 21 , wherein R 5  is H. 
     
     
         35 . The compound of  claim 21 , wherein R 7  is H. 
     
     
         36 . The compound of  claim 21 , wherein R 10  is H. 
     
     
         37 . The compound of  claim 21 , wherein the C 4a —H is in the alpha configuration. 
     
     
         38 . The compound of  claim 21 , of structure (II-a): 
       
         
           
           
               
               
           
         
         wherein R 2  is H, ═O, ═CHCN, ═CHCO 2 R w , where R w  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-CN, α-OH, α-OR v , where R v  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-NO 2 , spiroepoxy, or C(O)R u , where R u  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl; and, 
         R 3  is H, ═O, ═CHCN, ═CHCO 2 R t , where R t  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-CN, α-OH, α-OR s , where R s  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl, α-NO 2 , spiroepoxy, or C(O)R r , where R r  is optionally substituted C 1 -C 4  alkyl, optionally substituted C 2 -C 4  alkenyl, or optionally substituted C 2 -C 4  alkynyl. 
       
     
     
         39 . The compound of  claim 21  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         40 . A pharmaceutical composition comprising the compound of  claim 21 , a pharmaceutically acceptable salt thereof, or a combination of two or more thereof, and a pharmaceutically acceptable carrier.