C7, C12, and C16 substituted neuroactive steroids and their methods of use
Described herein are neuroactive steroids of Formula (I), Formula (V), or Formula (IX) or a pharmaceutically acceptable salt thereof; wherein each instance of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11a , R 11b , R 12 , R 16 , R 17 , R 19 , and 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 as for inducing sedation and/or anesthesia.
1. A compound of Formula (IX):
or a pharmaceutically acceptable salt thereof, wherein represents a single or double bond as valency permits;
each of R 2 , R 4 , R 6 , R 11a and R 11b is independently hydrogen;
R 3 is C 1 -C 6 alkyl;
R 5 is absent or hydrogen; and represents a single or double bond, wherein when one of a double bond, the other is a single bond; when both of are single bonds, then R 5 is hydrogen; and when one of the is a double bond, R 5 is absent;
R 17 is alkoxy, cyano, nitro, aryl, heteroaryl, —C(O)R B1 , —C(O)CH 2 R B1 , or —C(O)CH 2 CH 2 R B1 , wherein R B1 is hydrogen, —OH, —N(R A1 ) 2 , alkoxy, aryl, or heteroaryl, and each R A1 is independently hydrogen, C 1 -C 6 alkyl, carbocyclyl, aryl, or heteroaryl;
R 19 is hydrogen or alkyl; and
R 16 or OR A1 .
2. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (IX) is a compound of Formula (IX-a) or (IX-b):
or a pharmaceutically acceptable salt thereof.
3. The compound or pharmaceutically acceptable salt of claim 2 , wherein the compound of Formula (IX) is a compound of Formula (X-c) or (X-d):
or a pharmaceutically acceptable salt thereof.
4. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 17 is —CH 3 .
5. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 17 is —OCH 3 , —CN, or —C(O)CH 3 .
6. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 17 is —C(O)CH 2 R B1 .
7. The compound or pharmaceutically acceptable salt of claim 3 , wherein R 17 is alkoxy, cyano, or —C(O)R B1 .
8. The compound or pharmaceutically acceptable salt of claim 3 , wherein R B1 is pyrazolyl.
9. The compound or pharmaceutically acceptable salt of claim 3 , wherein R B1 is tetrazolyl.
10. The compound or pharmaceutically acceptable salt of claim 3 , wherein R B1 is a bicyclic heteroaryl.
11. The compound or pharmaceutically acceptable salt of claim 3 , wherein R B1 is
12. The compound or pharmaceutically acceptable salt of claim 3 , wherein R B1 is
13. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 17 is C 1 -C 6 alkoxy, cyano, or nitro.
14. The compound or pharmaceutically acceptable salt of claim 1 , wherein R 19 is hydrogen or unsubstituted C 1 -C 6 alkyl.
15. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (IX) is a compound of Formula (X-a1) or (X-b1):
or a pharmaceutically acceptable salt thereof, wherein IV is hydrogen, methyl, or —OH.
16. The compound or pharmaceutically acceptable salt of claim 1 , wherein the compound of Formula (IX) is a compound of Formula (XI-a) or (XI-b):
or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2, n is 0, 1, or 2, each R b is hydrogen, halogen, A is a 5-10 membered heteroaryl ring, and each R c is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, cyano, or —OH.
17. A compound selected from the group consisting of:
18. A pharmaceutically acceptable salt of a compound selected from the group consisting of:
19. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of claim 1 , and a pharmaceutically acceptable excipient.
20. A kit comprising a solid composition comprising a compound or pharmaceutically acceptable salt of claim 1 and a sterile diluent.
21. A method of inducing sedation and/or anesthesia in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
22. The method of claim 21 , wherein the subject experiences sedation and/or anesthesia within two hours of administration.
23. The method of claim 21 , wherein the subject experiences sedation and/or anesthesia within one hour of administration.
24. The method of claim 21 , wherein the subject experiences sedation and/or anesthesia instantaneously.
25. The method of claim 21 , wherein the compound or pharmaceutically acceptable salt is administered by intravenous, oral, or intramuscular administration.
26. The method of claim 21 , wherein the compound or pharmaceutically acceptable salt is administered chronically.
27. The method of claim 21 , wherein the subject is a mammal.
28. The method of claim 21 , wherein the subject is a human.
29. The method of claim 21 , wherein the compound or pharmaceutically acceptable salt is administered in combination with another therapeutic agent.
30. A method of treating seizure in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
31. A method of treating epilepsy or status epilepticus in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
32. A method of treating a neuroendocrine disorder or dysfunction in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
33. A method of treating a neurodegenerative disease or disorder in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
34. A method of treating a movement disorder or tremor in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
35. A method of treating a mood disorder or anxiety disorder in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
36. A method of treating disorders related to GABA function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
37. A method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt of claim 1 .
38. The method of claim 37 , wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a disorder of memory and/or cognition, a movement disorder, a personality disorder, autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, or tinnitus.
39. The method of claim 37 , wherein the subject is a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome.