Neuroactive steroids, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-10745436-B2
Application number	US-201916269779-A
Country	US
Kind code	B2
Filing date	Feb 7, 2019
Priority date	Jun 18, 2014
Publication date	Aug 18, 2020
Grant date	Aug 18, 2020

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 method for treating postpartum depression or seizure in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of a) a compound of Formula (I) or a pharmaceutically acceptable salt thereof or b) a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein:

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 6b 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 method of claim 1 , wherein R 1 is methyl.

3. The method of claim 1 , wherein both R 2a and R 2b are hydrogen.

4. The method of claim 1 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, C(O)R A , —C(O)OR A , or —C(O)NR B R C .

5. The method of claim 4 , wherein R 3 is —C(O)NR B R C .

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

7. The method of claim 6 , wherein R 4 is hydrogen.

8. The method 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.

9. The method of claim 1 , wherein Z is —CH 2 —.

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

11. The method of claim 1 , wherein the compound of Formula (I) is 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 ;
each of R 5a and R 5b is independently 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.

12. The method of claim 11 , wherein R 1 is methyl.

13. The method of claim 11 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C .

14. The method of claim 11 , wherein R 3 is C 1 -C 6 alkyl.

15. The method of claim 11 , wherein R 4 is hydrogen.

16. The method of claim 11 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.

17. The method of claim 11 , wherein the compound of Formula (Ia) is selected from a group consisting of:

18. The method of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ib):

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 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.

19. The method of claim 18 , wherein R 1 is methyl.

20. The method of claim 18 , wherein R 3 is C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carbocyclyl, heterocyclyl, —C(O)R A , —C(O)OR A , or —C(O)NR B R C .

21. The method of claim 18 , wherein R 3 is C 1 -C 6 alkyl.

22. The method of claim 20 , wherein R 3 is —C(O)NR B R C .

23. The method of claim 18 , wherein R 4 is —OH.

24. The method of claim 18 , wherein R 4 is hydrogen.

25. The method of claim 18 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.

26. The method of claim 18 , wherein the compound of Formula (Ib) is selected from a group consisting of:

27. The method of claim 1 , wherein the method is for treating postpartum depression.

28. The method of claim 27 , wherein the compound is administered orally.

29. The method of claim 1 , wherein the method is for treating seizure.

30. The method of claim 29 , wherein the compound is administered orally.

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• C07J21/006

  at position 3 · CPC title

• C07J41/005 Primary

  the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives · CPC title

• C07J13/007

  with double bond in position 17 (20) · 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

• C07J7/0085

  by an halogen atom · CPC title