Neuroactive 17(20)-Z-vinylcyano-substituted steroids, prodrugs thereof, and methods of treatment using same
The present disclosure is generally directed to neuroactive 17(20)-Z-vinylcyano-substituted compound of Formula (I) and (II), 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 alkene, optionally substituted C 2 -C 4 alkyne, or optionally substituted aryl;
R 4 and R 5 are each independently selected from H and unsubstituted C 1 -C 4 alkyl;
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 further with the provisos:
(1) that when the C═C bond is not resent between C 4 -C 5 or C 5 -C 6 and R 3 is H, R 2 is ═O, or OR a , where R a is selected from H, optionally substituted C 1 -C 4 alkyl, or optionally substituted aryl; or,
(2) that when the C═C bond is not resent between C 4 -C 5 or C 5 -C 6 and R 3 is H, R 2 is H, R 8 is H and R 7 is optionally substituted C 1 -C 4 alkoxy or an optionally substituted morpholinyl ring;
wherein the C 3 —OH group is in the alpha configuration and the C 3 -R 3 group is in the beta configuration with the proviso that the compounds
are excluded.
2. The compound of claim 1 , wherein the R 3 group is selected from the group consisting of H, methyl, and trifluoromethyl.
3. The compound of claim 1 , wherein R 7 is selected from the group consisting of H, methoxy, ethoxy, and an optionally morpholinyl ring.
4. The compound of claim 1 , wherein R 5 is methyl.
5. The compound of claim 1 , wherein R 2 is ═O, methoxy or H.
6. The compound of claim 1 of Formula (I-a):
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 of Formula (I-j):
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 of Formula (I-k):
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.