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

Patent metadata

Field	Value
Publication number	US-2017334944-A1
Application number	US-201715671574-A
Country	US
Kind code	A1
Filing date	Aug 8, 2017
Priority date	Oct 8, 2012
Publication date	Nov 23, 2017
Grant date	—

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:

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

• C07J21/008

  at position 17 · CPC title

• C07J1/0011

  substituted in position 17 by a keto group · CPC title

• C07J41/0094 Primary

  containing nitrile radicals, including thiocyanide radicals · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title