Back to results
US 10,202,413 B2Granted
Neuroactive enantiomeric 15-, 16- and 17-substituted steroids as modulators for GABA type-A receptors
AssigneeWashington University
InventorDouglas Covey
Life of this patent
Estimating the term…
Abstract
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.
Claims16
A compound of Formula (I):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- R1 is H;
- R2 is H, optionally substituted C1-C4 alkoxy, aryloxy, morpholinyl, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, or —O—C(O)—Rx, where Rx is optionally substituted C1-C20 alkyl;
- R3 is H, OH, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—Ru, where Ru is optionally substituted C1-C20 alkyl;
- R4 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or —O—C(O)—Rt, where Rt is optionally substituted C1-C20 alkyl;
- with the proviso that when R3 and R4 are taken together, R3 and R4 combine to form ═O or ═CRy, (where Ry is CN, CH2NH2, C(O)—O—Rw (where Rw is H, optionally substituted C1-C10 or optionally substituted phenyl), or CH2ORv (where Rv is H, optionally substituted C1-C10, optionally substituted phenyl, or optionally substituted napthyl));
- R5 is H;
- R6 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or —O—C(O)—Rr, where Rr is optionally substituted C1-C20 alkyl;
- R7 is H, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substituted COCH3;
- R8 is H, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH3;
- R9 is H, optionally substituted C1-C4 alkoxy, spiroepoxide or ═O;
- R10 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- R11 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- R12 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C4-C5, C5-C6, C6-C7, C7-C8, C15-C16, and/or C16-C17;
- and,
- with the provisos that:
- at least one of R7, R8 and R9 is not hydrogen;
- when R1-R8 and R12 are H, R10 and R11 are CH3, R9 is other than ═O or spiroepoxide;
- when R1-R8 and R11-R12 are H, R10 is CH3, and the C5—H is in the alpha position, R9 is other than ═O.
18 more elements
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:
- R1 is H;
- R2 is H, optionally substituted C1-C4 alkoxy, aryloxy, morpholinyl, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, or —O—C(O)—Rx, where Rx is optionally substituted C1-C20 alkyl;
- R3 is H, OH, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, aryloxy, acetyl, substituted acetyl, cyano, nitro, spiroepoxide or —O—C(O)—Ru, where Ru is optionally substituted C1-C20 alkyl;
- R4 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or —O—C(O)—Rt, where Rt is optionally substituted C1-C20 alkyl;
- with the proviso that when R3 and R4 are taken together, R3 and R4 combine to form ═O or ═CRy, (where Ry is CN, CH2NH2, C(O)—O—Rw (where Rw is H, optionally substituted C1-C10 or optionally substituted phenyl), or CH2ORv (where Rv is H, optionally substituted C1-C10, optionally substituted phenyl, or optionally substituted napthyl));
- R5 is H;
- R6 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or —O—C(O)—Rr, where Rr is optionally substituted C1-C20 alkyl;
- R7 is H, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, spirooxirane, cyano, ═O, nitro or optionally substituted COCH3;
- R8 is H, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkenoxy, optionally substituted C2-C4 alkynoxy, spirooxirane, cyano, ═O, ═CHCN, nitro or optionally substituted COCH3;
- R9 is H, optionally substituted C1-C4 alkoxy, spiroepoxide or ═O;
- R10 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- R11 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- R12 is H or optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, or optionally substituted C2-C4 alkynyl;
- - - - denotes an optional, additional C—C bond, resulting in a C═C bond between C4-C5, C5-C6, C6-C7, C15-C16, and/or C16-C17;
- and,
- with the provisos that:
- at least one of R7, R8 and R9 is not hydrogen;
- when R1-R8 and R12 are H, R10 and R11 are CH3, R9 is other than ═O or spiroepoxide;
- when R1-R8 and R11-R12 are H, R10 is CH3, and the C5—H is in the alpha position, R9 is other than ═O.
18 more elements
Dependencies are inferred from the claim text.