Neuroactive steroids, compositions, and uses thereof
Described herein are neuroactive steroids of the Formula (I): or a pharmaceutically acceptable salt thereof; wherein R 1 , R 2 , R a , 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. A compound of the 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;
n is 0, 1, 2, 3, or 4; and
the compound is not selected from a compound selected from:
2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.
3. The compound of claim 2 , wherein R 1 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
4. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
5. The compound of claim 4 , wherein R 2 is —CH 3 .
6. The compound of claim 1 , wherein each of R 3a and R 3b is independently H or D.
7. The compound of claim 1 , wherein each of R 3a and R 3b is independently H.
8. The compound of claim 1 , wherein one of R 3a and R 3b is H, D, or C 1 -C 6 alkyl, and the other of R 3a and R 3b is H.
9. The compound of claim 1 , wherein the compound Formula (I) is a compound of Formula (I-a) or (I-b):
10. The compound of claim 9 , wherein X is N, and Y and Z are CH.
11. The compound of claim 9 , wherein X and Z are N, and Y is CH.
12. The compound of claim 9 , wherein X, Y, and Z are N.
13. The compound of claim 9 , wherein R 1 is C 1 -C 6 alkyl.
14. The compound of claim 9 , wherein R 2 is C 1 -C 6 alkyl.
15. The compound of claim 9 , wherein each of R 3a and R 3b is independently H or D.
16. The compound of claim 9 , wherein one of R 3a and R 3b is H, D, or C 1 -C 6 alkyl, and the other of R 3a and R 3b is H.
17. The compound of claim 9 , 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.
18. The compound of claim 9 , wherein n is 1.
19. The compound of claim 9 , wherein R a is C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
20. The compound of claim 9 , wherein R a is S(O) m R b , NR c R d , C(O)R e , or C(O)OR f .
21. The compound of claim 9 , wherein R a is halogen.
22. The compound of claim 9 , wherein n is 1 or 2, and R a is cyano, halogen, nitro, or C 1 -C 6 alkoxy.
23. The compound of claim 1 , wherein the compound is selected from:
and a pharmaceutically acceptable salt thereof.
24. A compound selected from:
and a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.