Batrachotoxin analogues, compositions, uses, and preparation thereof

摘要

Compounds relating to batrachotoxin are provided, in particular analogs that modulate the activity of sodium channels. Also provided are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier, including vehicles that modulate transdermal permeation of the compound. The subject compounds are useful in treatments, including treatments to reduce neuronal activity or to bring about muscular relaxation. The compounds also find use in the treatment of subjects suffering from a voltage-gated sodium channel-enhanced ailment or from pain. Further methods are provided for the preparation of the batrachotoxin-related compounds.

主权项

1. A compound represented by structural formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or —C(O)R, and is optionally substituted with 1 to 3 A groups; R2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or —C(O)R, and is optionally substituted with 1 to 3 A groups; R3 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, or —C(O)R, and is optionally substituted with 1 to 3 A groups; X is O, S, or R4, R5, R6, and R7 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkamino, silyl, sulfonyl, hydroxyl, mercapto, amino, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, guanidinyl, ureido, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamindo, or azido, and are optionally substituted with 1 to 3 A groups; R8 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, and is optionally substituted with 1 to 3 A groups; each R is independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, or heterocyclylalkamino, and is optionally substituted with 1 to 3 A groups; and each A is independently alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkylamino, aryl, aryloxy, arylamino, aralkyl, aralkoxy, aralkanoyl, aralkamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroaralkyl, heteroaralkoxy, heteroaralkanoyl, heteroaralkamino, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkoxy, cycloalkanoyl, cycloalkamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylalkyl, heterocyclylalkoxy, heterocyclylalkanoyl, heterocyclylalkamino, hydroxyl, mercapto, amino, alkanoylamino, aroylamino, aralkanoylamino, alkylcarboxy, alkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, guanidinyl, ureido, halo, trihalomethyl, cyano, nitro, phosphoryl, sulfonyl, sulfonamido, or azido; wherein each heteroaryl group is independently a 5-6 membered aromatic ring or a 9-12 membered bicyclic ring system wherein at least one ring is an aromatic ring, each aromatic ring having 1-3 heteroatoms selected from O, N, and S; each heterocyclyl group is independently a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic ring having 1-3 heteroatoms selected from O, N, and S; and each cycloalkyl and cycloalkenyl group is independently a 3-10 membered non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.