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