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

Patent metadata

Field	Value
Publication number	US-9765110-B2
Application number	US-201314434057-A
Country	US
Kind code	B2
Filing date	Oct 4, 2013
Priority date	Oct 8, 2012
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

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 compound of Formula (I):

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 compound of 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 compound of claim 1 , wherein the R 3 group is selected from the group consisting of H, methyl, and trifluoromethyl.

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

5. The compound of claim 1 , wherein R 5 is substituted methyl.

6. The compound of claim 1 , wherein R 6 is H.

7. The compound of claim 1 , wherein R 2 is ═O, methoxy or H.

8. The compound of claim 1 , wherein R 4 is methyl.

9. A compound of Formula (II):

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, 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.

10. The compound of claim 9 , wherein R x is OH in the beta configuration.

11. The compound of claim 9 , wherein R x is ═O.

12. The compound of claim 9 , wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally substituted morpholinyl ring.

13. The compound of claim 9 , wherein R 5 is substituted methyl.

14. The compound of claim 9 , wherein R 6 is H.

15. The compound of claim 9 , wherein R 2 is ═O, methoxy or H.

16. The compound of claim 9 , wherein R 4 is methyl.

17. The compound of claim 9 , wherein a carbon-carbon double bond is present between the C 4 and C 5 carbon atoms.

18. The compound of claim 9 , wherein a carbon-carbon double bond is present between the C 5 and C 6 carbon atoms.

19. A method for treating disorders related to GABA function in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of Formula (I) and Formula (II), 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;

and 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, 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.

20. The method of claim 19 , wherein the disorder is selected from the group consisting of insomnia, mood disorders, convulsive disorders, anxiety, and symptoms of ethanol withdrawal.

Assignees

• Univ Washington

Inventors

• Covey Douglas F

Classifications

• 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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title