Neuroactive steroids, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-10246482-B2
Application number	US-201515319503-A
Country	US
Kind code	B2
Filing date	Jun 18, 2015
Priority date	Jun 18, 2014
Publication date	Apr 2, 2019
Grant date	Apr 2, 2019

Abstract

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.

First claim

The invention claimed is:

1. A compound of Formula (I):

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 ;
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;
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 compound of claim 1 , wherein R 1 is C 2- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, carbocyclyl, or heterocyclyl.

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

4. The compound of claim 3 , wherein R 1 is methyl.

5. The compound of claim 1 , wherein R 2a or R 2b is hydrogen.

6. The compound of claim 1 , wherein both R 2a and R 2b are hydrogen.

7. The compound of claim 1 , wherein R 1 is C 1- C 6 alkyl and both R 2a and R 2b are hydrogen.

8. The compound of claim 1 , wherein R 1 is methyl and R 2a or R 2b is hydrogen.

9. The compound of claim 7 , wherein R 1 is methyl and both R 2a and R 2b are hydrogen.

10. The compound of claim 1 , wherein R 3 is C 1- C 6 alkyl, carbocyclyl, heterocyclyl, or —C(O)NR B R C .

11. The compound of claim 10 , wherein R 3 is C 1- C 6 alkyl.

12. The compound of claim 1 , wherein R 1 is methyl and R 3 is C - C 6 alkyl.

13. The compound of claim 10 , wherein R 3 is heterocyclyl.

14. The compound of claim 1 , wherein R 1 is methyl and R 3 is heterocyclyl.

15. The compound of claim 10 , wherein R 3 is C(O)NR B R C .

16. The compound of claim 1 , wherein R 1 is methyl and R 3 is C(O)NR B R C .

17. The compound of claim 1 , wherein R 4 is C 1- C 6 alkyl, C 2- C 6 alkenyl, C 2- C 6 alkynyl, or carbocyclyl.

18. The compound of claim 1 , wherein R 4 is —OR A and R A is hydrogen or C 1- C 6 alkyl.

19. The compound of claim 1 , wherein R 4 is hydrogen, C 1- C 6 alkyl, or —OH.

20. The compound of claim 19 , wherein R 4 is —OH.

21. The compound of claim 19 , wherein R 4 is hydrogen.

22. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.

23. The compound of claim 1 , wherein R 1 is methyl, the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.

24. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.

25. The compound of claim 1 , wherein R 1 is methyl, the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.

26. The compound 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 R 5a or R 5b is hydrogen.

27. The compound 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.

28. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl or —OR A , the between —CR 6 and —CR 5a R 5b is a single bond, and R 5a or R 5b is hydrogen.

29. The compound of claim 1 , wherein R 4 is C 1 -C 6 alkyl or —OR A , the between —CR 6 and —CR 5a R 5b is a single bond, and both R 5a and R 5b are hydrogen.

30. The compound of claim 1 , wherein the between —CR 6 and —CR 5a R 5b is a double bond, one of R 5a or R 5b is hydrogen, and the other of R 5a or R 5b is absent.

31. The compound of claim 1 , wherein Z is —CH 2 —.

32. The compound of claim 1 , wherein R 7a is hydrogen and R 7b is C 1 -C 6 alkyl.

33. The compound 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 absent, 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;
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; or
R D is hydrogen, C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl.

34. The compound of claim 33 , wherein R 1 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, or heterocyclyl.

35. The compound of claim 33 , wherein R 1 is C 1 -C 6 alkyl.

36. The compound of claim 35 , wherein R 1 is methyl.

37. The compound of claim 33 , wherein R 2a or R 2b is hydrogen.

38. The compound of claim 33 , wherein both R 2a and R 2b are hydrogen.

39. The compound of claim 33 , wherein R 1 is C 1 -C 6 alkyl and both R 2a and R 2b are hydrogen.

40. The compound of claim 33 , wherein R 1 is methyl and R 2a or R 2b is hydrogen.

41. The compound of claim 33 , wherein R 1 is methyl and both R 2a and R 2b are hydrogen.

42. The compound of claim 33 , wherein R 3 is C 1 -C 6 alkyl, carbocyclyl, heterocyclyl, or —C(O)NR B R C .

43. The compound of claim 33 , wherein R 3 is C 1 -C 6 alkyl.

44. The compound of claim 33 , wherein

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• C07J13/007

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

• C07J7/007

  not substituted in position 17 alfa · CPC title

• C07J5/0015

  not substituted in position 16 · CPC title

• C07J21/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton · CPC title

• C07J17/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00) · CPC title