19-nor neuroactive steroids and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10377790-B2
Application number	US-201615143312-A
Country	US
Kind code	B2
Filing date	Apr 29, 2016
Priority date	Apr 17, 2013
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

Provided herein are 3,3-disubstituted 19-nor-steroidal compounds according to Formula (I): and pharmaceutical compositions thereof. 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, 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, tinnitus, and status epilepticus.

First claim

The invention claimed is:

1. A method for positively modulating a GABA A receptor in a human subject in need thereof, comprising administering to the human subject an effective amount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
represents a single or double bond as valency permits;
A is of Formula (A-1) or Formula (A-2):

wherein the point of attachment is at G 1 or G 2 in Formula (A-1) and the point of attachment is at G 2 or G 3 in Formula (A-2);
G 1 is N, NR N1 , O, S, C, or C—R G1 as valency permits;
G 2 is N, NR N2 , O, S, C, —C═N—, or C—R G2 as valency permits;
G 3 is N, NR N3 , O, S, C, or C—R G3 as valency permits;
G 4 is N, NR N4 , C—R G4 , or C—(R G4 ) 2 as valency permits;
G 5 is N, NR N5 , C—R G5 , or C—(R G5 ) 2 as valency permits;
G 6 is N, NR N6 , C—R G6 , or C—(R G6 ) 2 as valency permits; and
G 7 is N, NR N7 , C—R G7 , or C—(R G7 ) 2 as valency permits;
each instance of R G1 , R G2 , R G3 , R G4 , R G5 , R G6 , and R G7 is, independently, hydrogen, halogen, —NO 2 , —CN, —OR GA , —N(R GA ) 2 , —C(═O)R GA , —C(═O)OR GA , —OC(═O)R GA , —OC(═O)OR GA , —C(═O)N(R GA ) 2 , —N(R GA )C(═O)R GA , —OC(═O)N(R GA ) 2 , —N(R GA )C(═O)OR GA , —S(═O) 2 R GA , —S(═O) 2 OR GA , —OS(═O) 2 R GA , —S(═O) 2 N(R GA ) 2 , —N(R GA )S(═O) 2 R GA , —S(═O)R GA , —S(═O)OR GA , —OS(═O)R GA , —S(═O)N(R GA ) 2 , —N(R GA )S(═O)R GA , substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R N1 , R N2 , R N3 , R N4 , R N5 , R N6 , and R N7 is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R GA is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocylyl, substituted or unsubstituted 3- to 6-membered heterocylyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted carbocyclic or heterocyclic ring;
R 1 is substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocylyl;
R 2 is hydrogen, halogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, substituted or unsubstituted C 3-6 carbocylyl, or —OR A2 , wherein R A2 is hydrogen or substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocylyl;
R 3a is hydrogen or —OR A3 , wherein R A3 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 alkynyl, or substituted or unsubstituted C 3-6 carbocylyl, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;
each of R 4a or R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or halogen;
provided if bond p is a double bond, then bond q is a single bond, provided if bond q is a double bond, then bond p is a single bond and R 4b is absent; and provided if both bonds p and q are single bonds, then the hydrogen at C5 is in the alpha or beta configuration, or a pharmaceutically acceptable salt thereof.

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

3. The method of claim 1 , wherein the compound is administered chronically.

4. The method of claim 2 , wherein the compound is administered orally.

5. The method of claim 1 , wherein the subject has a CNS-related disorder.

6. The method of claim 2 , wherein the compound is administered intravenously.

7. The method of claim 5 , 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, tinnitus, or status epilepticus.

8. The method of claim 5 , wherein the CNS-related disorder is a mood disorder.

9. The method of claim 8 , wherein the mood disorder is depression.

10. The method of claim 7 , wherein the CNS-related disorder is a sleep disorder.

11. The method of claim 10 , wherein the sleep disorder is insomnia.

12. The method of claim 1 , wherein the compound is of Formula (II):

or a pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is of Formula (II-a):

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 , wherein the compound is of one of the following formulae:

or a pharmaceutically acceptable salt thereof.

16. The method of claim 1 , wherein the compound is of Formula (II-b):

or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 , wherein the compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

18. The method of claim 1 , wherein the compound is one of the following formulae:

or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 , wherein th

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P27/16

  Otologicals · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title