Neuroactive 19-alkoxy-17(20)-Z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same

Patent metadata

Field	Value
Publication number	US-10053487-B2
Application number	US-201715671574-A
Country	US
Kind code	B2
Filing date	Aug 8, 2017
Priority date	Oct 8, 2012
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The present disclosure is generally directed to neuroactive 19-alkoxy-17(20)-Z-vinylcyano-substituted steroids as referenced herein, and pharmaceutically acceptable salts thereof, for use as, for example, an anesthetic, and/or in the treatment of disorders relating to GABA function and activity. The present disclosure is further directed to pharmaceutical compositions comprising such compounds.

First claim

What is claimed is:

1. A method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), wherein Formula (I) is:

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H;
R 2 is ═O, H, or OR a , where R a is selected from H, optionally substituted C 1 -C 4 alkyl, or optionally substituted aryl, with the proviso that when R 2 is ═O, R 8 is not present;
R 3 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, or optionally substituted aryl;
R 4 is independently selected from H and unsubstituted C 1 -C 4 alkyl;
R 5 is substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 6 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 alkoxy;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, or an optionally substituted morpholinyl ring;
R 8 , when present, is H or optionally substituted C 1 -C 4 alkyl; and,
- - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5 or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present.

2. The method according to claim 1 , wherein one or both of R 6 or R 7 , when present and other than H, are in the beta configuration.

3. The method according to claim 1 , wherein the R 3 group is selected from the group consisting of H, methyl, and trifluoromethyl.

4. The method according to claim 1 , wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring.

5. The method according to claim 1 , wherein R 5 is substituted methyl.

6. The method according to claim 1 , wherein R 6 is H.

7. The method according to claim 1 , wherein R 2 is ═O, methoxy or H.

8. The method according to claim 1 , wherein R 4 is methyl.

9. The method according to claim 1 , having Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

10. The method according to claim 1 , having Formula (I-j):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

11. The method according to claim 1 , having Formula (I-k):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

12. The method according to claim 1 , having a formula selected from the group consisting: of:

and pharmaceutically acceptable salts thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

13. The method according to claim 1 , having the structure:

or a pharmaceutically acceptable salt thereof.

14. A method of inducing anesthesia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), wherein Formula (II) is

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H;
R 2 is ═O, H, or OR a , where R a is selected from H, optionally substituted C 1 -C 4 alkyl, or optionally substituted aryl, with the proviso that when R 2 is ═O, R 8 is not present;
R x is ═O or OR d , where R d is H or C(O)R e , where R e is optionally substituted C 1 -C 22 alkyl or optionally substituted C 2 -C 22 alkenyl, with the proviso that when R x is OH, it is in the beta configuration (and when R x is R d , with R d being C(O)R e , then it is preferably in the beta configuration);
R 4 is independently selected from H and unsubstituted C 1 -C 4 alkyl;
R 5 is substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 6 is H, optionally substituted C 1 -C 4 alkyl, or optionally substituted C 1 -C 4 alkoxy;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, or an optionally substituted morpholinyl ring;
R 8 , when present, is H or optionally substituted C 1 -C 4 alkyl; and,
- - - denotes an optional, additional C—C bond, resulting in either a C═C bond between C 4 -C 5 or C 5 -C 6 , with the proviso that when present, the C 5 —H substituent is not present.

15. The method according to claim 14 , wherein R x is OH in the beta configuration.

16. The method according to claim 14 , wherein R x is ═O.

17. The method according to claim 14 , wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring.

18. The method according to claim 14 , wherein R 5 is substituted methyl.

19. The method according to claim 14 , wherein R 6 is H.

20. The method according to claim 14 , wherein R 2 is ═O, methoxy or H.

21. The method according to claim 14 , wherein R 4 is methyl.

22. The method according to claim 14 , having Formula (II-a):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

23. The method according to claim 14 , having Formula (II-j):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

24. The method according to claim 14 , having Formula (II-k):

or a pharmaceutically acceptable salt thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

25. The method according to claim 14 , having a formula selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein R b is optionally substituted C 1 -C 4 alkyl.

Assignees

• Univ Washington

Inventors

• Covey Douglas F

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07J1/0011

  substituted in position 17 by a keto group · CPC title

• C07J21/008

  at position 17 · CPC title

• C07J41/0094 Primary

  containing nitrile radicals, including thiocyanide radicals · CPC title