Benzomorphan analogs and the use thereof

Patent metadata

Field	Value
Publication number	US-10130615-B2
Application number	US-201515511360-A
Country	US
Kind code	B2
Filing date	Sep 17, 2015
Priority date	Sep 17, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

In one aspect, the invention provides compounds of Formula (I) or (II): (I) or (II) and pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2a , R 2b , R 3 , R 4 , Z and G are defined as set forth in the disclosure. The invention also provides compounds of Formulae A and B and pharmaceutically acceptable salts and solvates thereof. Other aspects of the invention include the use of compounds of Formulae I, II, A, and B, and pharmaceutically acceptable salts and solvates thereof for the treatment of disorders responsive to modulation of one or more opioid receptors. In certain embodiments, the Compounds of the Invention are useful for treating pain.

First claim

What is claimed is:

1. A compound of Formula II or a pharmaceutically acceptable salt or solvate thereof:

wherein
R 1 is—(C 1 -C 10 )alkyl optionally substituted by —(C 3 -C 12 )cycloalkyl;
R 2a and R 2b , are each independently, hydrogen or —(C 1 -C 5 )alkyl;
Z is—(CH 2 ) m — optionally substituted with 1 or 2 independently selected —(C 1 -C 6 )alkyl;
wherein
1) G is —N(R a )C(O)N(R a )—, wherein
each of R a independently is hydrogen or —(C 1 -C 5 )alkyl;
R 3 is selected from the group consisting of phenyl, —(C 1 -C 3 )alkyl-phenyl, and —S(O) 2 -phenyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, —COOR 6 , phenyl, and —OPh; and
R 6 is hydrogen or —(C 1 -C 3 )alkyl; or

2) G is —N(R d )—, wherein
R d is H or —(C 1 -C 3 )alkyl;
R 3 is selected from the group consisting of —(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 1 -C 6 )alkyl-(5- to 12-membered)heteroaryl, —S(O) 2 —(C 1 -C 6 )alkyl, —S(O) 2 -(C 3 -C 12 )cycloalkyl, and -(7- to 12-membered)bicycloheterocyclo; each of which is substituted with one or two substituents independently selected from the group consisting of halo, —COOR 6 , carboxamido, —NH 2 , (alkyl)amino, (dialkyl)amino, -(3- to 8- membered)heterocyclo, -(6- to 14-membered)aryl, —SO 2 NH 2 , and —(C 1 -C 6 )alkyl-(7- to 12-membered)bicycloheterocyclo optionally substituted by one or two same or different —(C 1 -C 3 )alkyl; or
R d and R 3 , together with the nitrogen atom to which they are attached, form

each of which is optionally substituted by one or two substituents independently selected from the group of (═O), —(C 1 -C 3 )alkyl-phenyl, —C(O)OH, —N(R a )SO 2 -phenyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and -(5- to 6-membered)heterocyclo, wherein each of the —(C 1 -C 3 )alkyl-phenyl, —N(R a )SO 2 -phenyl, and -(5- to 6-membered)heterocyclo is optionally substituted by one or two substituents independently selected from the group of halogen and phenyl optionally substituted by halogen; and wherein the -(5- to 6-membered)heterocyclo is further optionally fused together with a phenyl group; or

3) G is —C(O)N(R c )—, wherein
R c is H or —(C 1 -C 3 )alkyl;
R 3 is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, -(5- to 6-membered)heterocyclo, phenyl, and —(C 1 -C 3 )alkyl-phenyl; wherein each of the —(C 1 -C 6 )alkyl, -(5- to 6-membered)-heterocyclo, phenyl, and —(C 1 -C 3 )alkyl-phenyl is optionally substituted with one or two substituents independently selected from the group consisting of (═O), halo, —NHC(O)(C 1 -C 3 )alkyl, —C(O)R 5 , —COOR 6 , —NH 2 , and —SO 2 NH 2 ;
R 5 is —(C 1 -C 3 )alkyl; and
R 6 is H or —(C 1 -C 3 )alkyl; or

4) G is —N(R a )S(O) 2 N(R b )—, wherein
R a and R b , independently, are hydrogen or —(C 1 -C 3 )alkyl; and
R 3 is optionally-substituted —(C 1 -C 10 )alkyl; or

5) G is —C(O)—, wherein
R 3 is -(5- to 6-membered)heterocyclo substituted by —N(R a )SO 2 -phenyl, wherein the —N(R a )SO 2 -phenyl is further optionally substituted by —(C 1 -C 3 )alkyl or halogen; and R a is —(C 3 -C 6 )cycloalkyl;

Each of R a independently is hydrogen, —(C 1 -C 5 )alkyl, or —(C 3 -C 12 )cycloalkyl;
R 4 is hydrogen, OH, halo, —(C 1 -C 5 )alkyl, —C(O)NH 2 , —(C 1 -C 5 )alkoxy, —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, or —(CH 2 ) n —O—(CH 2 ) n —CH 3 ;
R 5 is selected from the group consisting of hydrogen, —OH, —NH 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(C 1 -C 6 )alkoxy, and —(C 3 -C 8 )cycloalkyl, each of —NH 2 , —(C 1 -C 6 )alkyl, —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(C 1 -C 6 )alkoxy, and —(C 3 -C 8 )cycloalkyl is optionally substituted with 1, 2, or 3 independently selected R 6 groups;
R 6 is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 12 )cycloalkyl, —(C 4 -C 12 )cycloalkenyl, ((C 3 -C 12 )cycloalkyl)—(C 1 -C 6 )alkyl-, and ((C 4 -C 12 )cycloalkenyl)—(C 1 -C 6 )alkyl-;
m is 1, 2, 3, 4, 5 , or 6; and
n is 0, 1, 2, 3, 4, 5 , or 6;

provided that
i) when -G-R 3 is —C(O)NH 2 , then R 1 is —(C 1 -C 10 )alkyl that is either unsubstituted or substituted by cyclobutyl; and
ii) when R 1 is cyclopropylmethyl, R 4 is methoxy, Z is —(CH 2 ) 2 —, one of R 2a and R 2b is H, and the other is methyl, and G is —NHC(O)—, then
R 3 is —(C 1 -C 6 )alkyl, -(7- to 12-membered)bicycloheterocyclo, or —(C 1 -C 6 )alkyl-(6- to 14-membered)aryl; each of which is substituted with one, or two substituents independently selected from the group consisting of halo, —NH 2 , —COOR 6 , -(3- to 8-membered)-heterocyclo, -(6- to 14-membered)aryl, —SO 2 NH 2 , and —(C 1 -C 6 )alkyl-(7- to 12-membered)bicycloheterocyclo; wherein each of the -(6- to 14-membered)aryl, and —(C 1 -C 6 )alkyl-(7- to 12-membered)bicycloheterocyclo is further optionally substituted by one or two substituents independently selected —(C 1 -C 3 )alkyl;

iii) when R 1 is unsubstituted —(C 1 -C 10 )alkyl, then R 1 is a straight —(C 1 -C 10 )alkyl chain;
iv) when R 1 is cyclopropylmethyl, Z is —(CH 2 ) 2 —, and
R 3 is
a) —(C 1 -C 6 )alkyl substituted by —NH 2 or (dialkyl)amino; or
b) —C(═O)—(C 1 -C 6 )alkyl substituted by —NH 2 or (dialkyl)amino;

then R 4 is methoxy.

2. The compound of claim 1 , wherein said compound is a compound of Formula A:

or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 , wherein Z is optionally-substituted —(CH2) m —, and m is 1, 2, 3 , or 4.

4. The compound of claim 1 , wherein G is —N(R a )C(O)N(R a )—, and each of R a independently is hydrogen or —(C 1 -C 5 )alkyl.

5. The compound of claim 4 , wherein R 3 is selected from the group consisting of phenyl, —(C 1 -C 3 )alkyl-phenyl, and —S(O) 2 -phenyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, —COOR 6 , phenyl, and —OPh, and wherein R 6 is hydrogen or —(C 1 -C 3 )alkyl.

6. The compound of claim 1 , wherein G is —N(R d )—.

7. The compound of claim 6 , wherein R d is H or —(C 1 -C 3 )alkyl.

8. The compound of claim 6 , wherein R 3 is selected from the group consisting of —(C 1 -C 6 )alkyl, —C(═O)—(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 1 -C 6 )alkyl-(5- to 12-membered)heteroaryl, —S(O) 2 —(C 1 -C 6 )alkyl, —S(O) 2 —(C 3 -C 12 )cycloalkyl, and -(7- to 12-membered)bicycloheterocyclo; each of which is substituted with one or two substituents independently selected from the group consisting of halo, —COOR 6 , carboxamido, —NH 2 , (alkyl)amino, (dialkyl)amino, -(3- to 8-membered)heterocyclo, —(6- to 14-membered)aryl, —SO 2 NH 2 , and —(C 1 -C 6 )alkyl-(7- to 12-membered)bicycloheterocyclo optionally substituted by one or two same or different —(C 1 -C 3 )alkyl.

9. The compound of claim 6 , wherein R d and R 3 , together with the nitrogen atom to which they are attached, form

each of which is optionally substituted by one or two substituents independently selected from the group of (═O), —(C 1 -C 3 )alkyl-phenyl, —C(O)OH, —N(R a )SO 2 -phenyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and -(5- to 6-membered)heterocyclo, wherein each of the —(C 1 -C

Assignees

• Purdue Pharma Lp

Inventors

• Zhou Xiaoming
• Tafesse Laykea
• Engel John J

Classifications

• C07D221/26

  Benzomorphans · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• A61K31/435 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title