Neuroactive steroids, compositions, and uses thereof

Abstract

Described herein are neuroactive steroids of the Formula (I): (Formula (I)) or a pharmaceutically acceptable salt thereof; wherein R 1a and R 1b are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.

What is claimed is: 
     
         1 . A compound of the Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1a  is hydrogen, halo, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R b )(R c ), —OC(O)N(R b )(R c ), —OC(O)OR a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         R 1b  is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R d )(R e ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         wherein one of R 1a  and R 1b  is hydrogen; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring; and 
         each R d  and R e  is hydrogen, substituted methyl or C 2 -C 6  alkyl, or 
         R d  and R e , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is a compound of the Formula (Ib): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1a  is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R b )(R c ), —OC(O)N(R b )(R c ), —OC(O)OR a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         R 1b  is hydrogen, halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R d )(R e ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         wherein one of R 1a  and R 1b  is hydrogen; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring; and 
         each R d  and R e  is hydrogen, substituted methyl or C 2 -C 6  alkyl, or 
         R d  and R e , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring. 
       
     
     
         3 . The compound of  claim 1 , wherein one of R 1a  or R 1b  is hydroxy, alkyl, or alkoxy. 
     
     
         4 . The compound of  claim 3 , wherein one of R 1a  or R 1b  is hydroxy. 
     
     
         5 . The compound of  claim 3 , wherein one of R 1a  or R 1b  is alkoxy. 
     
     
         6 . The compound of  claim 5 , wherein R 1a  is methoxy. 
     
     
         7 . The compound of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . A compound of the Formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 2a  is hydrogen, chloro, fluoro, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6  alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         R 2b  is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6  alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         wherein one of R 2a  and R 2b  is hydrogen; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring; and 
         each R f  and R g  is independently hydrogen or C 1 -C 6  alkyl, or 
         R f  and R g , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur. 
       
     
     
         9 . The compound of  claim 8 , wherein the compound is a compound of the Formula (IIb): 
       
         
           
           
               
               
           
         
         wherein: 
         R 2a  is hydrogen, chloro, fluoro, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6  alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         R 2b  is hydrogen, halo, hydroxy, alkyl, methoxy, substituted ethoxy, C 3 -C 6  alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ); 
         wherein one of R 2a  and R 2b  is hydrogen; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring; and 
         each R f  and R g  is independently hydrogen or C 1 -C 6  alkyl, or 
         R f  and R g , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur. 
       
     
     
         10 . The compound of  claim 8 , wherein R 2a  or R 2b  is alkyl, methoxy, substituted ethoxy, or C 3 -C 6  alkoxy. 
     
     
         11 . The compound of  claim 10 , wherein R 2a  is alkyl, methoxy, substituted ethoxy, or C 3 -C 6  alkoxy. 
     
     
         12 . The compound of  claim 9 , wherein R 2b  is hydrogen. 
     
     
         13 . The compound of  claim 8 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . A compound of Formula (III): 
       
         
           
           
               
               
           
         
         wherein: 
         one of R 1a  and R 1b  is halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R h )(R i ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ) and the other one is hydrogen; or 
         R 1a  and R 1b  are taken together with the carbon to which they are attached to form C(═O); 
         one of R 2a  and R 2b  is chloro, fluoro, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen; 
         R 3  is hydrogen or C 1 -C 6  alkyl; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring; 
         each R f  and R g  is independently hydrogen or C 1 -C 6  alkyl, or 
         R f  and R g , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur; and 
         each R h  is unsubstituted C 1 -C 4  alkyl; 
         each R i  is hydrogen, substituted methyl or C 2 -C 6  alkyl, or 
         R h  and R i , taken together with the nitrogen atom to which they are attached, form a 3-7-membered heterocyclic ring. 
       
     
     
         15 . The compound of  claim 14 , wherein the compound is a compound of Formula (IIIb): 
       
         
           
           
               
               
           
         
         wherein: 
         one of R 1a  and R 1b  is halo, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R h )(R i ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen; or 
         R 1a  and R 1b  are taken together with the carbon to which they are attached to form C(═O); 
         one of R 2a  and R 2b  is chloro, fluoro, hydroxy, alkyl, alkoxy, —C(O)R a , —C(O)N(R b )(R c ), —C(O)OR a , —N(R f )(R g ), —OC(O)N(R b )(R c ), —OC(O)OR a , —OC(O)R a , —S(O) 0-2 R a , —S(O) 0-2 OR a , or —S(O) 0-2 N(R b )(R c ), and the other one is hydrogen; 
         each R a  is hydrogen or C 1 -C 6  alkyl; 
         each R b  and R c  is independently hydrogen or C 1 -C 6  alkyl, or 
         R b  and R c , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring; 
         each R f  and R g  is independently hydrogen or C 1 -C 6  alkyl, or 
         R f  and R g , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring optionally comprising one additional heteroatom selected from nitrogen and sulfur; and 
         each R h  is unsubstituted C 1 -C 4  alkyl; 
         each R i  is hydrogen, substituted methyl or C 2 -C 6  alkyl, or 
         R h  and R i , taken together with the nitrogen atom to which they are attached to form a 3-7-membered heterocyclic ring. 
       
     
     
         16 . The compound of  claim 14 , wherein R 1a  and R 1b  are taken together with the carbon to which they are attached to form C(═O). 
     
     
         17 . The compound of  claim 14 , wherein R 2a  or R 2b  is hydroxy, alkyl, or alkoxy. 
     
     
         18 . (canceled) 
     
     
         19 . The compound of  claim 14 , wherein R 1a  or R 1b  is hydroxy, alkyl, or alkoxy. 
     
     
         20 - 24 . (canceled) 
     
     
         25 . The compound of  claim 14 , wherein R 3  is alkyl. 
     
     
         26 . The compound of  claim 14 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 - 39 . (canceled) 
     
     
         40 . A pharmaceutical composition comprising a compound of Formula (I), (Ib), (II), (IIb), (III), or (IIIb), and a pharmaceutically acceptable excipient. 
     
     
         41 - 52 . (canceled)