Compositions and methods for treating CNS disorders

Patent metadata

Field	Value
Publication number	US-10774108-B2
Application number	US-201515531313-A
Country	US
Kind code	B2
Filing date	Nov 27, 2015
Priority date	Nov 27, 2014
Publication date	Sep 15, 2020
Grant date	Sep 15, 2020

Abstract

Described herein are neuroactive steroids of the Formula (II): or a pharmaceutically acceptable salt thereof; wherein A, R 1 , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 and are as defined herein. Such compounds are envisioned, in certain embodiments, to behave as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention 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 (II):

or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom;
R 1 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 carbocyclyl;
each of R 2a and R 2b is independently selected from 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 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —N(R A )(R B ), or —OR A2 , wherein each of R A and R B 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R A and R B , together with the nitrogen atom to which they are attached form a ring or R 2a and R 2b , together with the carbon atom to which they are attached form a ring; 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, substituted or unsubstituted C 3-6 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3a is hydrogen, —N(R A )(R B ), 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 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and
R 3b is hydrogen or —N(R A )C(O)R A3 ; or
R 3a and R 3b are joined to form an oxo (═O) group;
each of R 4a and R 4b is independently selected from hydrogen or halogen;
R 5 is hydrogen, unsubstituted C 1-6 alkyl, or —CH 2 OR A5 , wherein R A5 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 carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R 6 is absent or hydrogen; and
represents a single or double bond, wherein
when one of is a double bond, the other is a single bond; and
when one of the is a double bond, R 6 is absent.

2. A compound of the Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
Ring A is substituted or unsubstituted aryl or heteroaryl, wherein A is linked through a carbon atom;
R 1 is hydrogen, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 2-6 alkenyl, or substituted or unsubstituted C 3-6 carbocyclyl;
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 carbocyclyl, —N(R A )(R B ), or —OR A2 , wherein each of R A and R B 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 carbocyclyl, or substituted or unsubstituted heterocyclyl, or R A and R B , together with the nitrogen atom to which they are attached form a ring; 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 carbocyclyl;
R 3a is hydrogen, —N(R A )(R B ), 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 carbocyclyl, and R 3b is hydrogen or —N(R A )C(O)R A3 ; or
R 3a and R 3b are joined to form an oxo (═O) group;
R 4 is hydrogen or halogen;
R 5 is hydrogen, unsubstituted C 1-6 alkyl, or —CH 2 OR A5 , wherein R A5 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 carbocyclyl;
R 6 is absent or hydrogen; and
represents a single or double bond, wherein
when one of is a double bond, the other is a single bond; and
when one of the is a double bond, R 6 is absent.

3. The compound of claim 2 , wherein the compound of Formula (I) is a compound of Formula (I-a):

wherein:
n is 0, 1, 2, 3, 4, 5, or 6; and
each R a is independently halogen, cyano, C 1-6 alkyl, —N(R A )(R B ), —N(R A )C(O)R AA , —N(R A )C(O)OR AA , —SR AA or —OR AA , wherein R AA is 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 carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or
two R a groups, together with the atoms with which they are attached form a ring.

4. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-b):

5. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-b-i) or (I-b-ii):

6. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-c):

7. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-c-i) or (I-c-ii):

8. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-f):

9. The compound of claim 3 , wherein the compound of Formula (I) is a compound of Formula (I) is a compound of Formula (I-d-i) or (I-d-ii):

10. The compound of claim 2 , wherein A is a 5-10-membered ring.

11. The compound of claim 10 , wherein A is phenyl, naphthyl, furan, thiophene, thiazole, pyrrole, imidazole, pyrazole, or triazole.

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

13. The compound of claim 12 , wherein R 1 is —CH 3 .

14. The compound of clai

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• C07J43/00

  Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton · CPC title

• C07J31/006

  not covered by C07J31/003 · CPC title

• A61K45/06

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

• C07J33/002

  not condensed · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title