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 method for therapeutically treating a CNS-related disorder in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of (a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof or (b) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, 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; and
the compound is not selected from a compound selected from:
and
wherein the CNS-related disorder is selected from depression, essential tremor, epilepsy, and status epilepticus.
2. The method of claim 1 , wherein R 1 is C 1 -C 6 alkyl.
3. The method of claim 2 , wherein R 1 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .
4. The method of claim 1 , wherein R 2 is C 1 -C 6 alkyl.
5. The method of claim 4 , wherein R 2 is —CH 3 .
6. The method of claim 1 , wherein each of R 3a and R 3b is independently H or D.
7. The method of claim 1 , wherein each of R 3a and R 3b is independently H.
8. The method 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 method of claim 1 , wherein the compound Formula (I) is a compound of Formula (I-a):
10. The method of claim 9 , wherein X is N, and Y and Z are CH.
11. The method of claim 9 , wherein X and Z are N, and Y is CH.
12. The method of claim 9 , wherein X, Y, and Z are N.
13. The method of claim 9 , wherein R 1 is C 1 -C 6 alkyl.
14. The method of claim 9 , wherein R 2 is C 1 -C 6 alkyl.
15. The method of claim 9 , wherein each of R 3a and R 3b is independently H or D.
16. The method 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 method 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 method of claim 9 , wherein n is 1.
19. The method of claim 9 , wherein R a is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
20. The method 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 method of claim 9 , wherein R a is halogen.
22. The method of claim 9 , wherein n is 1 or 2, and R a is cyano, halogen, nitro, or C 1 -C 6 alkoxy.
23. The method of claim 1 , wherein the compound is selected from:
and a pharmaceutically acceptable salt thereof.
24. The method of claim 1 , wherein the CNS-related disorder is depression.
25. The method of claim 24 , wherein the depression is postnatal depression.
26. The method of claim 1 , wherein the CNS-related disorder is epilepsy or status epilepticus.
27. The method of claim 1 , wherein the CNS-related disorder is essential tremor.
28. The method of claim 1 , wherein the compound Formula (I) is a compound of Formula (I-b):
29. The method of claim 1 , wherein the CNS-related disorder is epilepsy.
30. A method for positively modulating a GABAA receptor in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, 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; and
the compound is not selected from a compound selected from:
31. The method of claim 30 , wherein the pharmaceutical composition is administered orally, subcutaneously, intravenously, or intramuscularly.
32. The method of claim 30 , wherein the pharmaceutical composition is administered chronically.
33. The method of claim 30 , wherein the subject has a CNS-related disorder selected from depression, essential tremor, epilepsy, and status epilepticus.
34. The method of claim 31 , wherein the pharmaceutical composition is administered orally.
35. The method of claim 31 , wherein the pharmaceutical composition is administered intravenously.