19-nor C3, 3-disubstituted C21-C-bound heteroaryl steroids and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9725481-B2
Application number	US-201414785175-A
Country	US
Kind code	B2
Filing date	Apr 17, 2014
Priority date	Apr 17, 2013
Publication date	Aug 8, 2017
Grant date	Aug 8, 2017

Abstract

Provided herein are 19-nor C3,3-disubstituted steroids of Formula (I): and pharmaceutically acceptable salts thereof; wherein, , R 1 , R 2 , R 3a , R 3b , R 4a , and R 4b are as defined herein, and A is a carbon bound substituted or unsubstituted 5-to6-membered heteroaryl ring 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 steroid of Formula (I):

or a pharmaceutically acceptable salt thereof;
represents a single or double bond;
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 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, or substituted or unsubstituted C 3-6 carbocyclyl, 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 carbocyclyl;
R 3a is hydrogen or —OR A3 , wherein R A3 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, and R 3b is hydrogen; or R 3a and R 3b are joined to form an oxo (═O) group;
each instance of R 4a and R 4b is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, or halogen, provided if the between C5 and C6 is a single bond, then the hydrogen at C5 and R 4a are each independently provided in the alpha or beta configuration, and when is a double bond, then the hydrogen at C5 and R 4b are absent;
A is a carbon bound substituted or unsubstituted 5 or 6-membered heteroaryl, or 6-membered aryl of formula:

X is —O—, —S—, or —N(R N )—, wherein R N is independently hydrogen, substituted or unsubstituted C 1-6 alkyl, —C(═O)R GA , —C(═O)OR GA , —C(═O)N(R GA ) 2 , —S(═O) 2 R GA , —S(═O) 2 OR GA , —S(═O) 2 N(R GA ) 2 , or a nitrogen protecting group;
each instance of R 5 , R 6 , R 7 , R 8 , and R 9 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 , —N(R GA )C(═O)N(R GA ) 2 , —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 , 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 substituted or unsubstituted 3- to 6- membered heterocylyl; and
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, nitrogen protecting group when attached to nitrogen, or two R GA groups are taken with the intervening atoms to form a substituted or unsubstituted heterocylyl or heteroaryl ring.

2. The compound of claim 1 , wherein the compound is a compound of Formula (I-A):

3. The compound of claim 1 , wherein R 1 is —CH 3 , —CH 2 CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 OCH 3 , or substituted or unsubstituted cyclopropyl.

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

5. The compound of claim 1 , wherein R 2 is —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 CH 3 , —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , substituted or unsubstituted cyclopropyl, fluoro, or chloro.

6. The compound of claim 1 , wherein R 2 is hydrogen.

7. The compound of claim 1 , wherein R 3a and R 3b are both hydrogen.

8. The compound of claim 1 , wherein R 3a and R 3b are joined to form ═O (oxo).

9. The compound of claim 1 , wherein represents a double bond, and R 4a is hydrogen, fluoro, —CH 3 , or —CF 3 .

10. The compound of claim 1 , wherein represents a single bond, and both of R 4a and R 4b are hydrogen.

11. The compound of claim 1 , wherein represents a single bond, and both of R 4a and R 4b are —CH 3 or —CF 3 .

12. The compound of claim 1 , wherein represents a single bond, and both of R 4a and R 4b are fluoro.

13. The compound of claim 1 , wherein represents a single bond, and R 4a is substituted or unsubstituted C 1-6 alkyl, or halogen, and R 4b is hydrogen.

14. The compound of claim 13 , wherein R 4a is fluoro.

15. The compound of claim 1 , wherein at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is hydrogen.

16. The compound of claim 1 , wherein at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is substituted or unsubstituted C 1-2 alkyl, —CO 2 R GA , —C(═O)R GA , —CN, —NO 2 , or halogen, wherein R GA is substituted or unsubstituted C 1-2 alkyl.

17. The compound of claim 16 , wherein at least one of R 5 , R 6 , R 7 , R 8 , and R 9 is substituted or unsubstituted —CH 3 .

18. The compound of claim 1 , wherein R 5 , R 6 , R 7 , R 8 , and R 9 are hydrogen.

19. The compound of claim 1 , wherein the compound is a compound of Formula (I-A-i):

20. The compound of claim 1 , wherein A is:

21. The compound of claim 19 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable excipient.

23. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

24. The method of claim 23 , 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, or tinnitus.

25. The method of claim 23 , wherein the compound is administered orally, subcutaneously, intravenously, or intramuscularly.

26. The method of claim 23 , wherein the compound is administered chronically.

Assignees

• Sage Therapeutics Inc

Inventors

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

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07J43/003 Primary

  not condensed · CPC title