7,8-cyclicmorphinan analogs

Patent metadata

Field	Value
Publication number	US-8957084-B2
Application number	US-201314138380-A
Country	US
Kind code	B2
Filing date	Dec 23, 2013
Priority date	Dec 28, 2012
Publication date	Feb 17, 2015
Grant date	Feb 17, 2015

Abstract

The application is directed to compounds of Formula I-A

and pharmaceutically acceptable salts and solvates thereof, wherein Cy, R 1a -R 3a , R 4a , and R 4b 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:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
Cy is a fused, saturated or partly unsaturated, 3- to 8-membered carbocyclic ring;
R 1 is hydrogen, OH, halo, cyano, carboxy, or —C(═O)NH 2 ; 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, 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 5 groups; or —O-PG, wherein PG is a hydroxyl protecting group;

R 2 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 5 groups;
R 3 is hydrogen, OH, 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 5 groups;
R 4a is hydrogen;
R 4b is OH; 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, and aminocarbonyl; or
R 4a and R 4b together form ═O or ═CHR 4c , wherein
R 4c is hydrogen or C 1-4 alkyl; and
each R 5 is independently selected from the group consisting of hydioxy, alkyl, haloalkyl, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl.

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

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

3. The compound of claim 1 , having the Formula III:

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

4. The compound of claim 1 , having the Formula IV:

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

5. The compound of claim 1 , having the Formula V:

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

6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the Formula VIII, Formula IX, or Formula X:

wherein is a single bond or a double bond.

7. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having the Formula XI

wherein is a single bond or a double bond.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is OH or unsubstituted C 1-6 alkoxy.

9. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is C 3-7 (cycloalkyl)(C 1-4 )alkyl or C 3-7 (cycloalkenyl)(C 1-4 )alkyl, optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is hydrogen.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is OH.

12. The compound of claim 1 , or a pharmaceutically salt or solvate thereof, wherein R 4a is hydrogen and R 4b is OH or —O—CH 2 —CH═CH 2 ; or R 4a and R 4b together form ═O or —CH 2 .

13. The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is OH or unsubstituted C 1-6 alkoxy;
R 2 is cyclopropyl(C 1-4 )alkyl, cyclobutyl(C 1-4 )alkyl, cyclopentyl(C 1-4 )alkyl, or cyclohexyl(C 1-4 )alkyl, optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, C 1-4 alkyl, halo, halo(C 1-4 )alkyl, amino, C 1-4 alkylamino, di(C 1-4 )alkylamino, carboxy, C 1-4 alkoxy, and C 1-4 alkoxycarbonyl; and
R 3 is hydrogen or OH.

14. The compound of claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is unsubstituted cyclopropyl(C 1-4 )alkyl.

15. The compound of claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt or solvate thereof.

16. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

17. A method of treating or preventing pain, constipation, diarrhea, pruritic, an addictive disorder, withdrawal from alcohol addiction or withdrawal from drug addiction in a patient, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, to the patient in need of such treatment or prevention.

18. The method of claim 17 , wherein the method is for treating pain.

19. The method of claim 18 , wherein said pain is acute pain, chronic pain or surgical pain.

20. A method of modulating one or more opioid receptors in a patient, comprising administering to the patient an effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt or solvate thereof.

21. The method of claim 20

Assignees

• Purdue Pharma Lp

Inventors

• Kyle Donald J
• Tafesse Laykea
• Zhou Xiaoming

Classifications

• A61P43/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P29/00

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

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title