Neuroactive steroids and their methods of use
Provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , R 20b , X, A, Z, q, u, r, s, t, m, and n are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) and methods of using the compounds, e.g., in the treatment of CNS-related disorders.
1 . A compound of Formula (VI-H):
or a pharmaceutically acceptable salt thereof;
wherein:
m is 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
X is
R 3 is hydrogen or substituted or unsubstituted alkyl;
R 5 is hydrogen or methyl;
R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 19 is hydrogen or substituted or unsubstituted alkyl; and
each of R 20a , R 20b , R 23a , and R 23b is independently selected from the group consisting of hydrogen, an unsubstituted alkyl group, a halogenated alkyl group, an unsubstituted alkoxy group, and a halogenated alkoxy group.
2 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 3 is substituted or unsubstituted alkyl.
3 . The compound or pharmaceutically acceptable salt of claim 2 , wherein R 3 is methyl.
4 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 5 is hydrogen.
5 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 18 is substituted or unsubstituted C 1-6 alkyl.
6 . The compound or pharmaceutically acceptable salt of claim 5 , wherein R 18 is unsubstituted C 1-6 alkyl.
7 . The compound or pharmaceutically acceptable salt of claim 6 , wherein R 18 is methyl or ethyl.
8 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 19 is unsubstituted C 1-6 alkyl.
9 . The compound or pharmaceutically acceptable salt of claim 8 , wherein R 19 is unsubstituted C 1-3 alkyl.
10 . The compound or pharmaceutically acceptable salt of claim 9 , wherein R 19 is methyl.
11 . The compound or pharmaceutically acceptable salt of claim 1 , wherein R 19 is hydrogen.
12 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each of R 20a and R 20b is independently hydrogen or an unsubstituted C 1-6 alkyl group.
13 . The compound or pharmaceutically acceptable salt of claim 12 , wherein one of R 20a and R 20b is methyl and the other is hydrogen.
14 . The compound or pharmaceutically acceptable salt of claim 12 , wherein R 20a and R 20b are both hydrogen.
15 . The compound or pharmaceutically acceptable salt of claim 1 , wherein each of R 23a and R 23b is independently hydrogen or unsubstituted C 1-3 alkyl.
16 . The compound or pharmaceutically acceptable salt of claim 15 , wherein one of R 23a and R 23b is hydrogen and the other is unsubstituted C 1-3 alkyl.
17 . The compound or pharmaceutically acceptable salt of claim 16 , wherein one of R 23a and R 23b is hydrogen and the other is methyl or ethyl.
18 . The compound or pharmaceutically acceptable salt of claim 15 , wherein both of R 23a and R 23b are hydrogen.
19 . The compound or pharmaceutically acceptable salt of claim 15 , wherein both of R 23a and R 23b are unsubstituted C 1-3 alkyl.
20 . The compound or pharmaceutically acceptable salt of claim 19 , wherein each of R 23a and R 23b is independently selected from methyl or ethyl.
21 . The compound or pharmaceutically acceptable salt of claim 20 , wherein both of R 23a and R 23b are methyl.
22 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (VI-H) is a compound of Formula (VI-IA):
or a pharmaceutically acceptable salt thereof.
23 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (VI-H) is a compound of Formula (VI-IB):
or a pharmaceutically acceptable salt thereof.
24 . The compound or pharmaceutically acceptable salt of claim 23 , wherein R 3 is substituted or unsubstituted alkyl.
25 . The compound or pharmaceutically acceptable salt of claim 24 , wherein R 3 is methyl.
26 . The compound or pharmaceutically acceptable salt of claim 23 , wherein R 5 is hydrogen.
27 . The compound or pharmaceutically acceptable salt of claim 23 , wherein R 18 is substituted or unsubstituted C 1-6 alkyl.
28 . The compound or pharmaceutically acceptable salt of claim 27 , wherein R 18 is unsubstituted C 1-6 alkyl.
29 . The compound or pharmaceutically acceptable salt of claim 28 , wherein R 18 is methyl or ethyl.
30 . The compound or pharmaceutically acceptable salt of claim 23 , wherein R 19 is unsubstituted C 1-6 alkyl.
31 . The compound or pharmaceutically acceptable salt of claim 30 , wherein R 19 is unsubstituted C 1-3 alkyl.
32 . The compound or pharmaceutically acceptable salt of claim 31 , wherein R 19 is methyl.
33 . The compound or pharmaceutically acceptable salt of claim 23 , wherein R 19 is hydrogen.
34 . The compound or pharmaceutically acceptable salt of claim 23 , wherein each of R 20a and R 20b is independently hydrogen or an unsubstituted C 1-6 alkyl group.
35 . The compound or pharmaceutically acceptable salt of claim 34 , wherein one of R 20a and R 20b is methyl and the other is hydrogen.
36 . The compound or pharmaceutically acceptable salt of claim 34 , wherein R 20a and R 20b are both hydrogen.
37 . The compound or pharmaceutically acceptable salt of claim 23 , wherein each of R 23a and R 23b is independently hydrogen or unsubstituted C 1-3 alkyl.
38 . The compound or pharmaceutically acceptable salt of claim 37 , wherein one of R 23a and R 23b is hydrogen and the other is unsubstituted C 1-3 alkyl.
39 . The compound or pharmaceutically acceptable salt of claim 38 , wherein one of R 23a and R 23b is hydrogen and the other is methyl or ethyl.
40 . The compound or pharmaceutically acceptable salt of claim 37 , wherein both of R 23a and R 23b are hydrogen.
41 . The compound or pharmaceutically acceptable salt of claim 37 , wherein both of R 23a and R 23b are unsubstituted C 1-3 alkyl.
42 . The compound or pharmaceutically acceptable salt of claim 37 , wherein each of R 23a and R 23b is independently selected from methyl or ethyl.
43 . The compound or pharmaceutically acceptable salt of claim 41 , wherein both of R 23a and R 23b are methyl.
44 . The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (VI-H) is selected from
or a pharmaceutically acceptable salt thereof.
45 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable excipient.
46 . A method of treating a CNS-related disorder related to GABA function in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 , wherein the CNS-related disorder is depression.
47 . The method of claim 46 , wherein the depression is postpartum depression or a major depressive disorder.
48 . The method of claim 47 , wherein the major depressive disorder is a moderate major depressive disorder or a severe major depressive disorder.
49 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
50 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
51 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
52 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
53 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
54 . The compound or pharmaceutically acceptable salt of claim 44 , wherein the compound of Formula (VI-H) is
or a pharmaceutically acceptable salt thereof.
55 . A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 44 , and a pharmaceutically acceptable excipient.
56 . A method of treating a CNS-related disorder related to GABA function in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 44 , wherein the CNS-related disorder is depression.
57 . The method of claim 56 , wherein the depression is postpartum depression or a major depressive disorder.
58 . The method of claim 57 , wherein the major depressive disorder is a moderate major depressive disorder or a severe major depressive disorder.