PROPELLANE-BASED COMPOUNDS AND THE USE THEREOF

摘要

The application is directed to compounds of Formula I;;and pharmaceutically acceptable salts and solvates thereof, wherein R1-R5 are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I, and the pharmaceutically acceptable salts and solvates thereof, to treat disorders responsive to the modulation of one or more opioid receptors, or as synthetic intermediates. Certain compounds of the present invention are especially useful for treating pain.

主权项

1. A compound of Formula I:or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 is hydrogen, hydroxy, halo, cyano, carboxy, or aminocarbonyl; or alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy or alkynyloxy, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3 independently selected R6 groups; or —O-PG, wherein PG is a hydroxyl protecting group; R2 is (a) hydrogen or carboxamido; or (b) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl, alkylcarbonyl, alkoxycarbonyl, (arylalkoxy)carbonyl, or (heteroarylalkoxy)carbonyl, any of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, alkyl, halo, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl, wherein said aryl, heteroaryl, heterocyclo, cycloalkyl, and cycloalkenyl are optionally substituted with 1, 2, or 3 independently selected R6 groups; R3 is hydrogen, and R4 and R5 together form a spirocyclic ringwherein
R7 and R8 are each independently selected from the group consisting of hydrogen; cycloalkyl; cycloalkenyl; heterocyclo; aryl; heteroaryl; alkyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, halo, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, alkoxycarbonyl, carboxamido, cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl; and an amine protecting group; wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl are optionally substituted with 1, 2, or 3 independently selected R6 groups; Y is C═O or CH2; Z is C═O or CHR9; wherein R9 is hydrogen, C1-6 alkyl, or phenyl optionally substituted with 1, 2, or 3 independently selected R6 groups; or R3 and R4 together form a fused ring and R5 is absentwherein
is a single bond or a double bond; R10 is absent, hydrogen or alkyl; T is C(═O) or COR10a; wherein R10a is hydrogen or alkyl; provided that 1) when R10 is hydrogen or alkyl, then is a single bond and T is C(═O); and 2) when R10 is absent, then is a double bond and T is COR10a; G is —C(═O)R11, wherein R11 is selected from the group consisting of (a) OH; (b) optionally substituted alkoxy; (c) NR12R13; (d) optionally substituted aryl; (e) optionally substituted heteroaryl; optionally substituted cycloalkyl; (g) optionally substituted cycloalkenyl (h) optionally substituted heterocyclo; (i) optionally substituted arylalkyl; (j) optionally substituted heteroarylalkyl; (k) optionally substituted (cycloalkyl)alkyl; (l) optionally substituted (cycloalkenyl)alkyl; and (m) optionally substituted (heterocyclo)alkyl; wherein two adjacent carbon atoms of said optionally substituted cycloalkyl and optionally substituted cycloalkenyl rings are optionally fused to a phenyl ring; and wherein R12 is hydrogen or alkyl; R13 is selected from the group consisting of hydrogen, optionally substituted carboxyalkyl, optionally substituted (alkoxycarbonyl)alkyl, optionally substituted (carboxamido)alkyl, hydroxyalkyl, alkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, and heteroarylalkyl, wherein two adjacent carbon atoms of said cycloalkyl and cycloalkenyl rings are optionally fused to a phenyl ring; and wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl and heteroaryl, and said cycloalkyl, cycloalkenyl, heterocyclo, aryl and heteroaryl portions are optionally substituted with 1, 2, or 3 independently selected R6 groups; or R12 and R together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; and each R6 is independently selected from the group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl.