Neuroactive steroids, compositions, and uses thereof
Described herein are steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein R 1 , R 2a , R 2b , R 3 , R 4 , R 5a , R 5b , R 6 and Z are as defined herein. Such compounds are contemplated useful for the prevention and treatment of a variety of CNS-related conditions, for example, treatment of sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, disorders of memory and/or cognition, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes, and tinnitus.
1. A method for treating a CNS-related disorder selected from the group consisting of tremor, a bipolar disorder, a major depressive disorder (MDD), or an anxiety 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 orb) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient,
wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C ,
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or —OR A ;
represents a single or double bond, wherein when one is a double bond, the other is a single bond;
wherein when the between —CR 6 and —CR 5a R 5b is a double bond, then one of R 5a or R 5b is absent; and
when one of the is a double bond, R 6 is absent;
each of R 5a and R 5b is independently absent, hydrogen, C 1 -C 6 alkyl, or halo;
R 6 is absent or hydrogen;
Z is —CR 7a R 7b —, wherein each of R 7a and R 7b is independently hydrogen or C 1 -C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring.
2. The method of claim 1 , wherein R 1 is methyl.
3. The method of claim 1 , wherein both R 2a and R 2b are hydrogen.
4. The method of claim 1 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, C(O)R A , —C(O)OR A , or —C(O)NR B R C .
5. The method of claim 4 , wherein R 3 is —C(O)NR B R C .
6. The method of claim 1 , wherein R 4 is hydrogen, C 1 -C 6 alkyl, or —OH.
7. The method of claim 6 , wherein R 4 is hydrogen.
8. The method of claim 1 , wherein both R 2a and R 2b are hydrogen, the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.
9. The method of claim 1 , wherein Z is —CH 2 —.
10. The method of claim 1 , wherein R 7a is hydrogen and R 7b is C 1 -C 6 alkyl.
11. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or OR A ;
each of R 5a and R 5b is independently hydrogen, C 1 -C 6 alkyl, or halo;
Z is —CR 7a R 7b —, wherein each of R 7a and R 7b is independently hydrogen or C 1 -C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring.
12. The method of claim 11 , wherein R 1 is methyl.
13. The method of claim 11 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C .
14. The method of claim 11 , wherein R 3 is C 1 -C 6 alkyl.
15. The method of claim 11 , wherein R 4 is hydrogen.
16. The method of claim 11 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.
17. The method of claim 11 , wherein the compound of Formula (Ia) is selected from a group consisting of:
18. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl;
each of R 2a and R 2b is independently hydrogen, C 1 -C 6 alkyl, halo, cyano, —OR A , or —NR B R C , or
R 2a and R 2b together with the carbon atom to which they are attached form a ring;
R 3 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C ;
R 4 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or OR A ;
each of R 5a and R 5b is independently hydrogen, C 1 -C 6 alkyl, or halo;
Z is —CR 7a R 7b —, wherein each of R 1 and R 7b is independently hydrogen or C 1 -C 6 alkyl, or R 7a and R 7b , together with the carbon atom to which they are attached, form a ring;
R A is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
each of R B and R C is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or taken together with the atom to which they are attached form a ring.
19. The method of claim 18 , wherein R 1 is methyl.
20. The method of claim 18 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C .
21. The method of claim 18 , wherein R 3 is C 1 -C 6 alkyl.
22. The method of claim 20 , wherein R 3 is —C(O)NR B R C .
23. The method of claim 18 , wherein R 4 is —OH.
24. The method of claim 18 , wherein R 4 is hydrogen.
25. The method of claim 18 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.
26. The method of claim 18 , wherein the compound of Formula (Ib) is selected from a group consisting of:
27. The method of claim 1 , wherein the CNS-related disorder is a major depressive disorder.
28. The method of claim 1 , wherein the CNS-related disorder is tremor.
29. The method of claim 28 , wherein the tremor is essential tremor.
30. The method of claim 1 , wherein the CNS-related disorder is a bipolar disorder.
31. The method of claim 1 , wherein the CNS-related disorder is an anxiety disorder.
32. The method of claim 31 , wherein the anxiety disorder is a generalized anxiety disorder (GAD).
33. The method of claim 31 , wherein the anxiety disorder is a social anxiety disorder.