C17, C20, and C21 substituted neuroactive steroids and their methods of use
Described herein are neuroactive steroids or a pharmaceutically acceptable salt thereof. 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 as for inducing sedation and/or anesthesia.
1. A compound of Formula (1-A):
or a pharmaceutically acceptable salt thereof, wherein:
a) the compound of Formula (1-A) is a compound of Formula (1-A-1)
wherein each instance of R Y4 is independently alkyl, cyano, or halo; and e is 0, 1, 2, 3, 4, or 5; or
b) the compound of Formula (1-A) is a compound of Formula (1-A-3)
wherein R Y1 is hydrogen, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or cycloalkyl; R Y2 is alkyl, cycloalkyl, heterocycyl, aryl, or heteroaryl; and b is 0, 1, 2, or 3; or
c) the compound of Formula (1-A) is a compound of Formula (1-A-5)
wherein each occurrence of R Y3 is aryl or heteroaryl; two R Y3 groups are joined together to form a 6-10 membered ring; c is 0, 1, 2, or 3; and d is 0, 1, 2, or 3,
and wherein
R 3 is —CH 3 , —CF 3 , —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 ;
each of R X and R Y is independently hydrogen, aryl, or alkyl; or R X and R Y are joined together to form a 3-10 membered heterocyclic ring;
R 19 is hydrogen or alkyl;
R 5 is absent or hydrogen;
a is 0; and
represents a single or double bond, wherein when one is a double bond, the other is a single bond and R 5 is absent.
2. The compound of claim 1 , wherein the compound is a compound of Formula (1-A-2)
3. The compound of claim 2 , wherein each instance of R Y4 is independently —CH 3 , —CN, or —F.
4. The compound of claim 2 , wherein R X is hydrogen.
5. The compound of claim 1 , wherein the compound is a compound of Formula (1-A-4)
6. The compound of claim 5 , wherein R Y2 is heterocyclyl, aryl, or heteroaryl.
7. A compound selected from the group consisting of:
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
9. A method for reducing the severity or retarding or slowing the progression of a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , wherein the CNS-related disorder is sleep disorder, mood disorder, anxiety disorder, epilepsy, essential tremor, tremor, status epilepticus, fragile X syndrome, pain, alcohol dependence, traumatic brain injury, bipolar disorder, morphine withdrawal, major depressive disorder, tinnitus, postnatal depression, schizophrenia, or autism.
10. A kit comprising a solid composition comprising a compound of claim 1 and a sterile diluent.
11. The method of claim 9 , wherein the CNS-related disorder is a bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder, depression, postnatal depression, or major depressive disorder.
12. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable excipient.
13. A method for reducing the severity or retarding or slowing the progression of a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 7 , wherein the CNS-related disorder is sleep disorder, mood disorder, anxiety disorder, essential tremor, tremor, epilepsy, status epilepticus, fragile X syndrome, pain, alcohol dependence, traumatic brain injury, bipolar disorder, morphine withdrawal, major depressive disorder, tinnitus, postnatal depression, schizophrenia, or autism.
14. The method of claim 13 , wherein the CNS-related disorder is a bipolar I disorder, bipolar II disorder, generalized anxiety disorder, social anxiety disorder, depression, postnatal depression, or major depressive disorder.
15. A kit comprising a solid composition comprising a compound of claim 7 and a sterile diluent.