Benzomorphan analogs and the use thereof

Patent metadata

Field	Value
Publication number	US-10138207-B2
Application number	US-201314075176-A
Country	US
Kind code	B2
Filing date	Nov 8, 2013
Priority date	Nov 9, 2012
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The present invention is directed to Benzomorphan Analog compounds of the Formula I″, Formula IA″, Formula IB″, Formula IC″, or Formula ID″ as shown below; and related Formula I′, Formula IA′, Formula IB′, Formula IC′, or Formula ID′; Formula I, Formula IA, Formula IB, Formula IC, or Formula ID; wherein R 1 , R 2a , R 2b , R 3 and R 4 are as defined herein.

Compounds of the Invention are useful for treating pain, constipation, and other conditions modulated by activity of opioid and ORL-1 receptors.

First claim

What is claimed is:

1. A compound of Formula I′:

wherein
R 1 is selected from the group consisting of —(C 1 -C 10 )alkyl, (C 3 -C 12 )cycloalkyl-(C 1 -C 6 )alkyl-, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, diphenyl(C 1 -C 6 )alkyl-, each of which is optionally substituted by 1, 2 or 3 independently selected R 9 groups;
R 2a is absent, H or OH;
R 2b is —Z-G-R 10 ;
Z is absent;
G is selected from the group consisting of:
═CH, NR 8 , ═N—O, and ═N—NH; provided that when R 2a is absent, G is not NR 8 ;

R 10 is selected from the group consisting of —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —C(═O), —C(═O)—(C 1 -C 6 )alkyl, —C(═O)—(C 2 -C 6 )alkenyl, —C(═O)-(6- to 14-membered)aryl, —C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, —NH 2 , —NH(C 1 -C 6 )alkyl, CN, NR 5 R 6 , —(C 1 -C 6 )alkyl-NR 5 R 6 , —CONR 5 R 6 , —(C 1 -C 6 )alkyl-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —CO—(CH 2 ) n —COOR 7 , —CO—(CH 2 ) n —CO—NR 5 R 6 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, —(C 4 -C 12 )cycloalkenyl, ((C 4 -C 12 )cycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 6 -C 14 )bicycloalkyl, ((C 6 -C 14 )bicycloalkyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkyl, ((C 8 -C 20 )tricycloalkyl)-(C 1 -C 6 )alkyl-, —(C 7 -C 14 )bicycloalkenyl, ((C 7 -C 14 )bicycloalkenyl)-(C 1 -C 6 )alkyl-, —(C 8 -C 20 )tricycloalkenyl, ((C 8 -C 20 )tricycloalkenyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic ring system, ((7- to 12-membered)bicyclic ring system)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicyclic aryl, ((7- to 12-membered)bicyclic aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-, phenyl, benzyl and naphthyl; each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of —OH, (═O), halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, hydroxy(C 1 -C 6 )alkyl-, dihydroxy(C 1 -C 6 )alkyl-, —(C 1 -C 6 )alkoxy, ((C 1 -C 6 )alkoxy)CO(C 1 -C 6 )alkoxy-, phenyl, benzyl, —NH 2 , —NH(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-NH(C 1 -C 6 )alkyl-R 14 , —CN, —SH, —OR 11 , —CONR 5 R 6 , —(C 1 -C 6 alkyl)-CO—NR 5 R 6 , —COOR 7 , —(C 1 -C 6 )alkyl-CO—OR 7 , —(C 1 -C 6 )alkoxy-COOR 7 , —(OCH 2 CH 2 ) s —O(C 1 -C 6 )alkyl, —(CH 2 CH 2 O) s —(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl)sulfonyl, ((C 1 -C 6 )alkyl)sulfonyl(C 1 -C 6 )alkyl-, —NH—SO 2 (C 1 -C 6 )alkyl, NH 2 —SO 2 (C 1 -C 6 )alkyl-, —N(SO 2 (C 1 -C 6 )alkyl) 2 , —C(═NH)NH 2 , —NH—CO—(C 1 -C 6 )alkyl, —NH—CO—NH 2 , —NH—C(═O)—NH—(C 1 -C 6 )alkyl, —NH—C(═O)-(6- to 14-membered)aryl, —NH—C(═O)—(C 1 -C 6 )alkyl-(6- to 14-membered)aryl, —NH—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—(C 1 -C 6 )alkyl-CO—OR 7 , —NH—C(═O)—CH(NH 2 )—(C 1 -C 6 )alkyl-CO—OR 7 , —(C 3 -C 12 )cycloalkyl, ((C 3 -C 12 )cycloalkyl)-(C 1 -C 6 )alkyl-, -(6- to 14-membered)aryl, -(6- to 14-membered)aryloxy, —(C 1 -C 6 )alkoxy-C(O)NR 5 R 6 , —NH—(C 1 -C 6 )alkyl-C(O)—NR 5 R 6 , —C(O)NH—(C 1 -C 6 )alkyl-COOR 7 , ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, -(5- to 12-membered)heteroaryl, ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, -(3- to 12-membered)heterocycle, ((3- to 12-membered)heterocycle)-(C 1 -C 6 )alkyl-, -(7- to 12-membered)bicycloheterocycle, and ((7- to 12-membered)bicycloheterocycle)-(C 1 -C 6 )alkyl-;
R 3 is —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, or —(C 2 -C 6 )alkynyl;
R 4 is —OH or —(C 1 -C 5 )alkoxy;
R 5 and R 6 are each independently
a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo);
b) —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —C(O)OH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , phenyl, or CONR 5 R 6 ;
c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , or (C 1 -C 6 )alkyl-CONH—;
d) ((6- to 14-membered)aryl) optionally substituted with 1, 2, or 3 independently selected R 30 groups; or
e) R 5 and R 6 together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30 groups;

R 5a and R 6a are each independently selected from the group consisting of:
a) hydrogen, —OH, halo, —C(halo) 3 , —CH(halo) 2 , and —CH 2 (halo);
b) —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and —(C 1 -C 6 )alkoxy, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from —OH, halo, —(C 1 -C 10 )alkyl, —(C 2 -C 12 )alkenyl, —(C 2 -C 12 )alkynyl, —(C 1 -C 10 )alkoxy, —(C 3 -C 12 )cycloalkyl, —CHO, —COOH, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —(CH 2 ) n —O—(CH 2 ) n —CH 3 , and phenyl;
c) —(C 3 -C 8 )cycloalkyl, ((C 3 -C 8 )cycloalkyl)-(C 1 -C 6 )alkyl-, —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —CONH 2 , and (C 1 -C 6 )alkyl-CONH—;
d) -(6- to 14-membered)aryl optionally substituted with 1, 2, or 3 independently selected R 30 groups; or
e) R 5a and R 6a together with the nitrogen atom to which they are attached form a (4- to 8-membered)heterocycle optionally substituted with 1, 2, or 3 independently selected R 30 groups;

each R 7 is independently 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-;
each R 8 is methyl or ethyl;
each R 9 is independently phenyl, or CONR 5a R 6a ;
each R 11 is independently selected from —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —(C 2 -C 5 )alkenyl, —(C 2 -C 5 )alkynyl, —(CH 2 ) n —O—(CH 2 ) n —CH 3 , (6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, and ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-;
each R 14 is independently selected from —COOR 7 , —(C 1 -C 6 )alkyl-COOR 7 , —C(═O)—(C 1 -C 6 )alkyl-COOR 7 , —(C 1 -C 6 )alkyl-C(═O)—(C 1 -C 6 )alkyl-COOR 7 , CONH 2 , or —(C 1 -C 6 )alkyl-CONH;
each R 30 is independently selected from COOR 7 , CONR 5a R 6a , —C(═O), CN, -(3- to 12-membered)heteroaryl, ((3- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-, NH 2 , halo, and ((6- to 14-membered)aryl)-(C 1 -C 6 )alkoxy-;
m is an integer 1, 2, 3, 4, 5, or 6;
n is an integer 0, 1, 2, 3, 4, 5, or 6;
s in an integer 1, 2, 3, 4, 5, or 6;
provided that when R 4 is —(C 1 -C 5 )alkoxy then:
R 2a and R 2b cannot be taken together to form ═O;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having Formula IA′:

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 having Formula IB′:

or a pharmac

Assignees

• Purdue Pharma Lp
• Purdue Pharma Lp

Inventors

• Lockman Jeffrey
• Tafesse Laykea
• Yao Jiangchao
• Yu Jianming

Classifications

• A61P25/04

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

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/12

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

• A61P1/10

  Laxatives · CPC title

• C07D409/12

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