Neuroactive 13, 17-substituted steroids as modulators for GABA type-A receptors
The present disclosure is generally directed to neuroactive 13,17-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 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):
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 2 is H, optionally substituted C 1 -C 4 alkoxy, aryloxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, or —O—C(O)—R x , where R x is optionally substituted C 1 -C 20 alkyl;
R 3 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted alkynyl, cyclopropyl, or C(O)R y , where R y is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;
R 4 is optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted cyclopropyl, or C(O)R z , where R z is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl;
R 5 is H, ═O, or OR v , where R v 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 6 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, aryloxy, morpholinyl, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, or —O—C(O)—R w , where R w , is optionally substituted C 1 -C 20 alkyl;
R 8 is, when present, H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl;
R 9 is H or C(O)R u , where R u is optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, or optionally substituted C 2 -C 20 alkynyl;
wherein the C 5 —H is in the alpha configuration; 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 of claim 1 , wherein R 9 is H.
3. The method of claim 1 , wherein R 2 is H or —OCH 3 .
4. The method of claim 1 , wherein R 5 is H or —OCH 3 .
5. The method of claim 1 , wherein R 6 is methyl or —CH 2 OCH 3 .
6. The method of claim 1 , wherein R 7 is H or —OCH 3 .
7. The method of claim 1 , wherein R 4 is —CH═CH 2 or —C(O)CH 3 .
8. The method of claim 1 , wherein R 3 is selected from the group consisting of —CH═CH 2 , ethyl, —C(O)CH 3 , hydroxy alkyl, and haloalkyl.
9. The method of claim 8 , wherein R 3 is hydroxy alkyl.
10. The method of claim 8 , wherein R 3 is —CH 2 Cl.
11. The method of claim 8 , wherein R 3 is selected from the group consisting —C(OH)CH 3 and —CH 2 (OH).
12. The method of claim 1 , wherein R 1 is H.
13. The method of claim 1 , wherein the compound is of the structure:
wherein R 3 is H, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted alkynyl, cyclopropyl, or C(O)R y , where R y is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl; and,
R 4 is optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted cyclopropyl, or C(O)R z , where R z is C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl.
14. The method of claim 1 , wherein the compound is of the structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutically acceptable salt of a compound of the method of claim 1 .
16. A pharmaceutical composition comprising a compound of the method of claim 1 , a pharmaceutically acceptable salt thereof, or a combination of two or more thereof, and a pharmaceutically acceptable carrier.