Pyridonemorphinan analogs and biological activity on opioid receptors

摘要

The application is directed to compounds of Formula I-A;
and pharmaceutically acceptable salts and solvates thereof, wherein , R1a-R3a, R4, Y and Za are defined as set forth in the specification. The invention is also directed to use of compounds of Formula I-A 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-A:or a pharmaceutically acceptable salt or solvate thereof, wherein:
R1a 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 R8a groups; or —O-PG, wherein PG is a hydroxyl protecting group selected from the group consisting of alkyl, arylalkyl, heterocyclo, (heterocyclo)alkyl, acyl, silyl, and carbonate, any of which is optionally substituted; R2a 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 R8a groups; R3a is hydrogen, hydroxy, or halo; or alkoxy, alkylamino, or dialkylamino, 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 R8a groups; is a single bond or a double bond; R4 is absent, hydrogen or alkyl; Y is C(═O) or COR4a; wherein R4a is hydrogen or alkyl; provided that 1) when R4 is hydrogen or alkyl, then is a single bond and Y is C(═O); and 2) when R4 is absent, then is a double bond and Y is COR4a; Za is —C(═O)R5a, wherein R5a is selected from the group consisting of
(a) OH;(b) optionally substituted alkoxy;(c) —NR6aR7a;(d) optionally substituted aryl;(e) optionally substituted heteroaryl;(f) 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 R6a is hydrogen or alkyl; R7a 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 R8a groups; or R6a and R7a together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; and each R8a is independently selected from the group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl.