Neuroactive steroids, compositions, and uses thereof

Abstract

Described herein are neuroactive steroids of the Formula (I):or a pharmaceutically acceptable salt thereof; wherein R1, R2, Ra G, X, Y, Z, and n are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. Also provided are pharmaceutical compositions comprising a compound described herein and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

1 - 66 . (canceled) 
     
     
         67 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 each X, Y, and Z is independently CH or N; 
 G is —C(R 3a )(R 3b )(OR 1 ); 
 R 1  is C 1 -C 6  alkyl, C 1 -C 6  alkenyl, C 1 -C 6  alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; 
 R 2  is C 1 -C 6  alkyl or C 1 -C 6  alkoxy; 
 each of R 3a  and R 3b  is independently H, D, or C 1 -C 6  alkyl; 
 R a  is cyano, halogen, nitro, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, S(O) m R b , NR c R d , C(O)R e , or C(O)OR f ; 
 R b  is C 1 -C 6  alkyl, NR c R d , or OR f ; 
 each of R c  and R d  is independently H, C 1 -C 6  alkyl, C(O)R e , or C(O)OR f ; 
 R e  is C 1 -C 6  alkyl or NR g R h ; 
 R f  is H or C 1 -C 6  alkyl; 
 each of R g  and R h  is independently H or C 1 -C 6  alkyl; 
 m is 0, 1, or 2; and 
 n is 0, 1, 2, 3, or 4; 
 
         with the proviso that at least one of R 3a  and R 3b  is D or C 1 -C 6  alkyl. 
       
     
     
         68 . The compound or pharmaceutically acceptable salt of  claim 67 , wherein R 1  is C 1 -C 6  alkyl. 
     
     
         69 . The compound or pharmaceutically acceptable salt of  claim 68 , wherein R 1  is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 . 
     
     
         70 . The compound or pharmaceutically acceptable salt of  claim 67 , wherein R 2  is C 1 -C 6  alkyl. 
     
     
         71 . The compound or pharmaceutically acceptable salt of  claim 67 , wherein one of R 3a  and R 3b  is D or C 1 -C 6  alkyl, and the other of R 3a  and R 3b  is H. 
     
     
         72 . A compound selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof. 
     
     
         73 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of  claim 67 , and a pharmaceutically acceptable excipient. 
     
     
         74 . A method of treating a CNS-related disorder related to GABA function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of  claim 67 . 
     
     
         75 . The method of  claim 74 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus; or wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome. 
     
     
         76 . The method of  claim 74 , wherein the CNS-related disorder is epilepsy or status epilepticus. 
     
     
         77 . The method of  claim 76 , wherein the CNS-related disorder is status epilepticus, and the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus. 
     
     
         78 . The method of  claim 74 , wherein the CNS-related disorder is seizure. 
     
     
         79 . The method of  claim 74 , wherein the CNS-related disorder is tremor. 
     
     
         80 . The method of  claim 79 , wherein the tremor is essential tremor. 
     
     
         81 . The method of  claim 74 , wherein the CNS-related disorder is a mood disorder or an anxiety disorder. 
     
     
         82 . The method of  claim 74 , wherein the CNS-related disorder is depression. 
     
     
         83 . The method of  claim 78 , wherein the depression is a major depressive disorder. 
     
     
         84 . The method of  claim 74 , wherein the compound or pharmaceutically acceptable salt is administered orally, intravenously, or intramuscularly. 
     
     
         85 . The method of  claim 74 , wherein the compound or pharmaceutically acceptable salt is administered chronically. 
     
     
         86 . The method of  claim 74 , wherein the compound or pharmaceutically acceptable salt is administered in combination with another therapeutic agent. 
     
     
         87 . A method of inducing sedation and/or anesthesia in a subject in need thereof, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of  claim 67  to the subject.