Pyridonemorphinan analogs and biological activity on opioid receptors

Patent metadata

Field	Value
Publication number	US-9403824-B2
Application number	US-201514607805-A
Country	US
Kind code	B2
Filing date	Jan 28, 2015
Priority date	Dec 14, 2012
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The application is directed to compounds of Formula I-A

and pharmaceutically acceptable salts and solvates thereof, wherein , R 1a -R 3a , R 4 , Y and Z a 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.

First claim

What is claimed is:

1. A compound of Formula I-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1a 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 R 8a 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;
R 2a 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 R 8a groups;
R 3a 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 R 8a groups;
is a single bond or a double bond;
R 4 is absent, hydrogen or alkyl;
Y is C(═O) or COR 4a ; wherein
R 4a is hydrogen or alkyl; provided that
1) when R 4 is hydrogen or alkyl, then is a single bond and Y is C(═O); and
2) when R 4 is absent, then is a double bond and Y is COR 4a ;
Z a is —C(═O)R 5a , wherein
R 5a is selected from the group consisting of
(a) OH;
(b) optionally substituted alkoxy;
(c) —NR 6a R 7a ;
(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
R 6a is hydrogen or alkyl;
R 7a 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 R 8a groups; or
R 6a and R 7a together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; and
each R 8a is independently selected from the group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl.

2. The compound of claim 1 , having the Formula II-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a , R 2a , R 3a , R 4 , and Z a are as defined in claim 1 and
R 5a is —NR 6a R 7a , wherein R 6a is hydrogen or alkyl; and R 7a is selected from the group consisting of 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 portions are optionally substituted with 1, 2, or 3 independently selected R 8a groups; or
R 5a is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclo, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkenyl)alkyl, and optionally substituted (heterocyclo)alkyl, wherein two adjacent carbon atoms of said cycloalkyl or cycloalkenyl rings are optionally fused to a phenyl ring.

3. The compound of claim 2 , having the Formula III-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a , R 2a , R 3a , R 4 , and Z a are as defined in claim 2 .

4. The compound of claim 1 , having the Formula V-A:

or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a , R 2a , R 3a , R 4 , and Z a are as defined in claim 1 and
R 5a is —NR 6a R 7a , wherein R 6a is hydrogen or alkyl; and R 7a is selected from the group consisting of 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 portions are optionally substituted with 1, 2, or 3 independently selected R 8a groups; or
R 5a is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclo, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkenyl)alkyl, and optionally substituted (heterocyclo)alkyl, wherein two adjacent carbon atoms of said cycloalkyl or cycloalkenyl rings are optionally fused to a phenyl ring.

5. The compound of claim 1 , having the Formula VIII-A:

or a pharmaceutically acceptable salt or solvate thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1a is hydroxy or unsubstituted C 1-6 alkoxy;
R 2a is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, h

Assignees

• Purdue Pharma Lp

Inventors

• Lockman Jeffrey
• Tafesse Laykea
• Youngman Mark A

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title