Neuroactive steroids, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-10329320-B2
Application number	US-201615552201-A
Country	US
Kind code	B2
Filing date	Feb 19, 2016
Priority date	Feb 20, 2015
Publication date	Jun 25, 2019
Grant date	Jun 25, 2019

Abstract

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.

First claim

What is claimed is:

1. A compound of the Formula (I):

or a pharmaceutically acceptable salt thereof, 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;
n is 0, 1, 2, 3, or 4; and
the compound is not selected from a compound selected from:

2. The compound of claim 1 , wherein R 1 is C 1 -C 6 alkyl.

3. The compound of claim 2 , wherein R 1 is —CH 3 , —CH 2 CH 3 , or —CH(CH 3 ) 2 .

4. The compound of claim 1 , wherein R 2 is C 1 -C 6 alkyl.

5. The compound of claim 4 , wherein R 2 is —CH 3 .

6. The compound of claim 1 , wherein each of R 3a and R 3b is independently H or D.

7. The compound of claim 1 , wherein each of R 3a and R 3b is independently H.

8. The compound 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 compound of claim 1 , wherein the compound Formula (I) is a compound of Formula (I-a) or (I-b):

10. The compound of claim 9 , wherein X is N, and Y and Z are CH.

11. The compound of claim 9 , wherein X and Z are N, and Y is CH.

12. The compound of claim 9 , wherein X, Y, and Z are N.

13. The compound of claim 9 , wherein R 1 is C 1 -C 6 alkyl.

14. The compound of claim 9 , wherein R 2 is C 1 -C 6 alkyl.

15. The compound of claim 9 , wherein each of R 3a and R 3b is independently H or D.

16. The compound 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 compound 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 compound of claim 9 , wherein n is 1.

19. The compound of claim 9 , wherein R a is C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.

20. The compound 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 compound of claim 9 , wherein R a is halogen.

22. The compound of claim 9 , wherein n is 1 or 2, and R a is cyano, halogen, nitro, or C 1 -C 6 alkoxy.

23. The compound of claim 1 , wherein the compound is selected from:

and a pharmaceutically acceptable salt thereof.

24. A compound selected from:

and a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Sage Therapeutics Inc

Inventors

• Robichaud Albert J
• Salituro Francesco G
• Harrison Boyd L
• Martinez Botella Gabriel

Classifications

• A61P25/20

  Hypnotics; Sedatives · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07J13/007

  with double bond in position 17 (20) · CPC title

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title