NEUROACTIVE ENANTIOMERIC 15-, 16- AND 17-SUBSTITUTED STEROIDS AS MODULATORS FOR GABA TYPE-A RECEPTORS

摘要

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.

主权项

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1 is H or —C(O)—Rz, where Rz is optionally substituted C1-C20 alkyl; 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, 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)—Rs, where Rs is optionally substituted C1-C20 alkyl; 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; with the proviso that when R5 and R6 are taken together, R5 and R6 combine to form ═O or ═CRq, (where Rq is CN, CH2NH2, C(O)—O—Rp (where Rp is H, optionally substituted C1-C10 or optionally substituted phenyl), or CH2ORo (where Ro is H, optionally substituted C1-C10, optionally substituted phenyl, or optionally substituted napthyl)); 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:when R5 is benzyloxy in the alpha configuration and R6 is H, R9 is other than ═O or spiroepoxide;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; or,when a double bond is present between C5-C6, R1 is other than H or R9 is other than ═O.