Opioid receptor modulating oxabicyclo[2.2.2]octane morphinans

Patent metadata

Field	Value
Publication number	US-9862726-B2
Application number	US-201415107023-A
Country	US
Kind code	B2
Filing date	Dec 23, 2014
Priority date	Dec 26, 2013
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The application is directed to compounds of Formula (I) and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2 , Y, Z, and G are defined as set forth in the specification. The invention is also directed to use of compounds of Formula (I), and 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.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 1 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 3 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 3 groups;
each R 3 is independently selected from the group consisting of hydroxy, halo, alkyl, haloalkyl, cyano, nitro, amino, alkylamino, dialkylamino, carboxy, alkoxy, and alkoxycarbonyl;
G is selected from the group consisting of G 1 and G 2 , wherein
G 1 is —N(R 4 )-Q-R 5 , wherein
R 4 and R 5 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocyclo)alkyl, arylalkyl, heteroarylalkyl, and an amine protecting group, wherein said cycloalkyl, cycloalkenyl, heterocyclo, aryl, and heteroaryl portions thereof are optionally substituted; and
Q is absent, C(═O), C(═O)NH, SO 2 , or SO 2 NH, wherein R 5 is attached to the nitrogen atom of C(═O)NH and SO 2 NH; or
R 4 and R 5 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring and Q is absent;
G 2 is —OR 6 , wherein
R 6 is hydrogen or alkyl;
Z is C(═O) or CHR 7 , wherein
R 7 is hydrogen or alkyl; and
Y is C(═O) or CHR 8 , wherein
R 8 is hydrogen, alkyl, or hydroxy.

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

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 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 3 groups.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is 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 3 groups.

6. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein G is G 1 .

7. The compound of claim 1 , or a pharmaceutically acceptable solvate thereof, wherein R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo(C 1-6 )alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, 5- or 6-membered heterocyclo, phenyl, 5- or 6-membered heteroaryl, (C 3-7 cycloalkyl)(C 1-6 )alkyl, (C 3-7 cycloalkenyl)(C 1-6 )alkyl, (5- or 6-membered heterocyclo)(C 1-6 )alkyl, phenyl(C 1-6 )alkyl, and (5- or 6-membered heteroaryl)(C 1-6 )alkyl, wherein said cycloalkyl, cycloalkenyl, heterocyclo, phenyl, and heteroaryl portions thereof are optionally substituted with 1, 2, or 3 independently selected R 3 groups.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Q is absent.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is C(═O).

10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is C(═O).

11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Z is CHR 7 , wherein R 7 is hydrogen or alkyl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein
R 1 is hydroxy or unsubstituted C 1-6 alkoxy;
R 2 is unsubstituted C 1-4 alkyl, or 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
Z is CH 2 or C(═O).

13. The compound of claim 1 , selected from the group consisting of
(4bR,6S,8aS,9R)-6-amino-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-15-one;
(4bR,6S,8aS,9R)-11-(cyclopropylmethyl)-6-hydroxy-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-15-one;
(4bR,6S,8aS,9R)—N,N-dibenzyl-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-6-amine;
(4bR,6S,8aS,9R)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-6-amine;
(4bR,6S,8aS,9R)-11-(cyclopropylmethyl)-3,6-dihydroxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-15-one;
(4bR,6S,8aS,9R)—N-benzyl-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-6-amine;
(4bR,6S,8aS,9R)—N-(cyclohexylmethyl)-11-(cyclopropylmethyl)-3-methoxy-5,6,7,8,9,10-hexahydro-9,4b-(epiminoethano)-8a,6-(epoxymethano)phenanthren-6-amine;
(4bR,6S,8aS,9R)-6-amino-11-(cyclopropylmethyl)-5,6,7,8

Assignees

• Purdue Pharma Lp

Inventors

• Youngman Mark

Classifications

• C07D491/08

  Bridged systems · CPC title

• C07D491/18 Primary

  Bridged systems · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• G01N2500/04

  Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A) · CPC title