Neuroactive enantiomeric 15-, 16- and 17-substituted steroids as modulators for GABA type-A receptors
The present disclosure is generally directed to neuroactive enantiomeric 15-, 16- and 17-substituted steroids with additional optional substituents at carbons 3, 4, 6, 7, 10 and 13, and pharmaceutically acceptable salts thereof, for use as, for example, modulators for GABA type-A receptors. 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 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 x , where R x is optionally substituted C 1 -C 20 alkyl;
R 3 is H, OH, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R u , where R u is optionally substituted C 1 -C 20 alkyl;
R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or —O—C(O)—R t , where R t is optionally substituted C 1 -C 20 alkyl;
with the proviso that when R 3 and R 4 are taken together, R 3 and R 4 combine to form ═O or ═CR y , (where R y is CN, CH 2 NH 2 , C(O)—O—R w (where R w is H, optionally substituted C 1 -C 10 or optionally substituted phenyl), or CH 2 OR v (where R v is H, optionally substituted C 1 -C 10 , optionally substituted phenyl, or optionally substituted napthyl));
R 5 is H;
R 6 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or —O—C(O)—R r , where R r is optionally substituted C 1 -C 20 alkyl;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substituted COCH 3 ;
R 8 is H, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH 3 ;
R 9 is H, optionally substituted C 1 -C 4 alkoxy, spiroepoxide or ═O;
R 10 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 11 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 12 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
- - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 4 -C 5 , C 5 -C 6 , C 6 -C 7 , C 7 -C 8 , C 15 -C 16 , and/or C 16 -C 17 ; and,
with the provisos that:
at least one of R 7 , R 8 and R 9 is not hydrogen;
when R 1 -R 8 and R 12 are H, R 10 and R 11 are CH 3 , R 9 is other than ═O or spiroepoxide;
when R 1 -R 8 and R 11 -R 12 are H, R 10 is CH 3 , and the C 5 —H is in the alpha position, R 9 is other than ═O.
2. The compound of claim 1 , wherein R 2 , when not H and no double bond is present between C 4 -C 5 , is in the alpha configuration.
3. The compound of claim 1 , wherein R 8 , when not ═O, is in the alpha configuration.
4. The compound of claim 1 , wherein R 9 , when not ═O, is in the alpha configuration.
5. The compound of claim 1 , wherein R 2 is selected from the group consisting of H and methoxy.
6. The compound of claim 1 , wherein R 3 is H.
7. The compound of claim 1 , wherein R 4 is H.
8. The compound of claim 1 , wherein R 6 is H.
9. The compound of claim 1 , wherein R 7 is selected from the group consisting of H and —OCH 3 .
10. The compound of claim 1 , wherein R 8 is selected from the group consisting of ═O, —OCH 3 , COCH 3 , CN and ═CHCN.
11. The compound of claim 1 , wherein R 9 is ═O.
12. The compound of claim 1 , wherein R 10 is selected from the group consisting of H and methyl.
13. The compound of claim 1 , wherein R 11 is selected from the group consisting of H and methyl.
14. The compound of claim 1 , wherein R 12 is selected from the group consisting of H and methyl.
15. The compound of claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
16. A method of inducing anesthesia in a subject in need thereof, said 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;
R 2 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 x , where R x is optionally substituted C 1 -C 20 alkyl;
R 3 is H, OH, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—R u , where R u is optionally substituted C 1 -C 20 alkyl;
R 4 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or —O—C(O)—R t , where R t is optionally substituted C 1 -C 20 alkyl;
with the proviso that when R 3 and R 4 are taken together, R 3 and R 4 combine to form ═O or ═CR y , (where R y is CN, CH 2 NH 2 , C(O)—O—R w (where R w is H, optionally substituted C 1 -C 10 or optionally substituted phenyl), or CH 2 OR v (where R v is H, optionally substituted C 1 -C 10 , optionally substituted phenyl, or optionally substituted napthyl));
R 5 is H;
R 6 is H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl or —O—C(O)—R r , where R r is optionally substituted C 1 -C 20 alkyl;
R 7 is H, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substituted COCH 3 ;
R 8 is H, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 2 -C 4 alkenoxy, optionally substituted C 2 -C 4 alkynoxy, spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH 3 ;
R 9 is H, optionally substituted C 1 -C 4 alkoxy, spiroepoxide or ═O;
R 10 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 11 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
R 12 is H or optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, or optionally substituted C 2 -C 4 alkynyl;
- - - denotes an optional, additional C—C bond, resulting in a C═C bond between C 4 -C 5 , C 5 -C 6 , C 6 -C 7 , C 15 -C 16 , and/or C 16 -C 17 ; and,
with the provisos that:
at least one of R 7 , R 8 and R 9 is not hydrogen;
when R 1 -R 8 and R 12 are H, R 10 and R 11 are CH 3 , R 9 is other than ═O or spiroepoxide;
when R 1 -R 8 and R 11 -R 12 are H, R 10 is CH 3 , and the C 5 —H is in the alpha position, R 9 is other than ═O.