Neuroactive steroids, compositions, and uses thereof

Patent metadata

Field	Value
Publication number	US-11780875-B2
Application number	US-202117472744-A
Country	US
Kind code	B2
Filing date	Sep 13, 2021
Priority date	Jun 18, 2014
Publication date	Oct 10, 2023
Grant date	Oct 10, 2023

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

We claim:

1. A method for treating a disorder selected from the group consisting of epilepsy and status epilepticus (SE) 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:

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; and
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 1 -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 1 , wherein R 4 is hydrogen, C 1 -C 6 alkyl, or —OH.

6. 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.

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

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

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

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; and
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.

10. The method of claim 9 , wherein R 1 is methyl.

11. The method of claim 9 , wherein R 3 is C 1 -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 .

12. The method of claim 9 , wherein R 4 is hydrogen or —OH.

13. The method of claim 9 , wherein both R 2a and R 2b are hydrogen and both R 5a and R 5b are hydrogen.

14. The method of claim 9 , wherein the compound of Formula (I) is the compound of Formula (Ia), and the compound of Formula (Ia) is selected from a group consisting of:

15. The method of claim 9 , wherein the compound of Formula (I) is the compound of Formula (Ib), and the compound of Formula (Ib) is selected from a group consisting of:

16. The method of claim 1 , wherein the disorder is epilepsy.

17. The method of claim 1 , wherein the disorder is status epilepticus (SE).

18. The method of claim 17 , wherein the status epilepticus is convulsive status epilepticus or non-convulsive status epilepticus.

19. The method of claim 18 , wherein the convulsive status epilepticus is early status epilepticus, established status epilepticus, refractory status epilepticus, or super-refractory status epilepticus and wherein the non-convulsive status epilepticus is generalized status epilepticus, or complex partial status epilepticus.

20. The method of claim 1 , wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• C07J41/005 Primary

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

• C07J5/0015

  not substituted in position 16 · CPC title

• C07J7/002

  not substituted in position 16 · CPC title

• C07J7/009

  by only one oxygen atom doubly bound · 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