Benzomorphan analogs and use thereof

Patent metadata

Field	Value
Publication number	US-9975854-B2
Application number	US-201515308987-A
Country	US
Kind code	B2
Filing date	May 5, 2015
Priority date	May 6, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The invention provides compounds as represented by Formula I or I′ and pharmaceutically acceptable salts, solvates, and diastereomers thereof: Wherein R 1 , R 2 , R 2a , R 3 , and R 4 are defined in the disclosure. The invention also provides compounds of Formulae II, III, and A-H, and pharmaceutically acceptable salts, solvates, and diastereomers thereof. In certain embodiments, Compounds of the Invention are useful for treating pain, constipation, and other conditions as delineated in the disclosure. Without wishing to be bound by any theory, it is believed that Compounds of the Invention are effective in treating conditions that are modulated by activity of opioid and/or ORL-1 receptors.

First claim

What is claimed is:

1. A compound of Formula C, or a pharmaceutically acceptable salt thereof:

wherein
R 1 is (C 1 -C 10 )alkyl;
R 3 is —(C 1 -C 6 )alkyl;
R 4 is selected from —OH, —CN, —COOH, —CONH 2 , and —(C 1 -C 5 )alkoxy;
R 5 is selected from the group consisting of
i) —(C 1 -C 6 )alkyl optionally substituted by one, two, or three substituents independently selected from the group consisting of —OH; —CONR 8 R 9 ; —NR 8 R 9 , —OR 12 ; —(C 3 -C 12 )cycloalkyl; -(6- to 14-membered)aryl optionally substituted by —SO 2 —(C 1 -C 6 )alkyl; and hydroxy(C 3 -C 12 )cycloalkyl-;
ii) —C(═O)—(C 1 -C 6 )alkyl or —C(═O)—(C 1 -C 5 )alkyl-(6- to 14-membered)aryl, each optionally substituted by -(3- to 12-membered)heterocycle, —SO 2 —(C 1 -C 6 )alkyl, or —CONR 8 R 9 ;
iii) ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl- optionally substituted with 1 or 2 substituents independently selected from the group of halo, —C(halo) 3 , CN, and —SO 2 —(C 1 -C 6 )alkyl;
iv) ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl- optionally substituted with 1 or 2 substituents independently selected from the group of —C(═O)—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —CONR 8 R 9 , hydroxy(C 1 -C 6 )alkyl-, —SO 2 —(C 1 -C 6 )alkyl-phenyl, and —SO 2 —((C 3 -C 12 )cycloalkyl);
v) —CONR 8 R 9 ;
vi) —SO 2 —(C 1 -C 6 )alkyl optionally substituted by -(6- to 14-membered)aryl;
vii) —SO 2 -((6- to 14-membered)aryl); and
viii) —C(═O)—(C 2 -C 6 )alkenyl substituted by -(5- to 12-membered)heteroaryl;

R 6 is selected from the group consisting of H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-CO—OR 10 , —(C 1 -C 6 )alkyl-OR 10 , and —(C 1 -C 6 )alkyl-CONR 8 R 9 ;
R 8 and R 9 are each independently selected from the group consisting of hydrogen; —COOR 10 ; —(C 1 -C 6 )alkyl-COOR 10 ; —CONH 2 ; (C 1 -C 6 )alkyl-CONH—; ((6- to 14-membered)aryl) optionally substituted with 1, 2, or 3 independently selected R b groups; and -((5- to 12-membered)heteroaryl) optionally substituted with 1 or 2 independently selected R b groups;
each R 10 is independently hydrogen or —(C 1 -C 6 )alkyl
each R 12 is independently (6- to 14-membered)aryl, ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl-, (5- to 12-membered)heteroaryl, or ((5- to 12-membered)heteroaryl)-(C 1 -C 6 )alkyl-;
each R b is independently selected from the group consisting of —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), halo, —(C 1 -C 6 )alkyl, and CN;

Provided that
i) when R 1 is methyl, and R 5 is ((3- to 12 membered)-heterocycle)-(C 1 -C 6 )alkyl-, then
the ((3- to 12 membered)heterocycle) moiety in said ((3- to 12 membered)heterocycle)-(C 1 -C 6 )alkyl- of R 5 is further substituted by a substituent selected from the group consisting of —SO 2 —(C 1 -C 6 )alkyl, —CONR 8 R 9 , hydroxy(C 1 -C 6 )alkyl-, —C(═O)—(C 1 -C 6 )alkyl, and —SO 2 —((C 3 -C 12 )cycloalkyl);

ii) when both of R 1 and R 3 are methyl, and R 4 is methoxy, then
R 6 is —(C 1 -C 6 )alkyl, and R 5 is —C(═O)—(C 1 -C 6 )alkyl substituted by -(3- to 12-membered)heterocycle; and

iii) when R 1 is methyl, R 6 is H or —(C 1 -C 6 )alkyl, and R 5 is optionally-substituted —CONR 8 R 9 , then
R 3 is methyl, R 4 is —OH, and R 5 is selected from the group consisting of

wherein X 1 is H, halo, or CN;

iv) when R 1 is methyl, and R 5 is selected from the group consisting of a) —(C 1 -C 6 )alkyl substituted by -(6- to 14-membered)aryl; and b) ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl- optionally substituted by one or two halos, then
R 6 is a group other than H; and

v) when R 5 is —C(═O)—(C 2 -C 6 )alkenyl substituted by -(5- to 12-membered)heteroaryl, then
R 4 is —OH; and R 6 is H;

and further provided that
said compound is not selected from the group consisting of
N-((2R,6R,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methyl-2-(4-(methylsulfonyl)phenyl)acetamide;
(2R,6R,11S)-3,6-dimethyl-11-(methyl(phenethyl)amino)-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-8-ol;
N-((2R,6S,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methyl-2-phenylacetamide;
N-((2R,6S,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N-methyl-2-phenylacetamide;
tert-butyl (3-(((2R,6S,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)amino)propyl)carbamate;
N-((2R,6S,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-N,4-dimethylpentanamide;
tert-butyl (2-(((2R,6S,11S)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)amino)ethyl)carbamate;
3-(5-fluorobenzo[d]thiazol-2-yl)-1-((2R,6S,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)-1-methylurea; and
1-(5-fluorobenzo[d]thiazol-2-yl)-3-((2R,6S,11R)-8-hydroxy-3,6-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methanobenzo[d]azocin-11-yl)urea.

2. The compound of claim 1 , wherein R 5 is —(C 1 -C 6 )alkyl optionally substituted by one, two, or three substituents independently selected from the group consisting of —OH, —CONR 8 R 9 , —NR 8 R 9 , —OR 12 , —(C 3 -C 12 )cycloalkyl, -(6- to 14-membered)aryl, and hydroxy(C 3 -C 12 )cycloalkyl-.

3. The compound of claim 1 , wherein R 5 is —C(═O)—(C 1 -C 6 )alkyl optionally substituted by -(3- to 12-membered)heterocycle or —CONR 8 R 9 , wherein one of R 8 and R 9 is H, and the other is ((6- to 14-membered)aryl) optionally substituted with 1 or 2 independently selected R b groups, or -((5- to 12-membered)heteroaryl) optionally substituted with 1 or 2 independently selected R b groups, and wherein R b each independently is halo or —C(halo) 3 .

4. The compound of claim 1 , wherein R 5 is ((6- to 14-membered)aryl)-(C 1 -C 6 )alkyl- optionally substituted with 1 or 2 substituents independently selected from the group of halo, —C(halo) 3 , CN, and —SO 2 —(C 1 -C 6 )alkyl.

5. The compound of claim 1 , wherein R 5 is ((3- to 12 membered)-heterocycle)-(C 1 -C 6 )alkyl- optionally substituted with 1 or 2 substituents independently selected from the group of —C(═O)—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —CONR 8 R 9 , hydroxy(C 1 -C 6 )alkyl-, —SO 2 —(C 1 -C 6 )alkyl-phenyl, and —SO 2 —((C 3 -C 12 )cycloalkyl), wherein one of R 8 and R 9 is H, and the other is —(C 1 -C 6 )alkyl.

6. The compound of claim 1 , wherein R 5 is —CONR 8 R 9 , wherein one of said R 8 and said R 9 is H, and the other is phenyl or benzoin[d]thiazolyl, wherein each of said phenyl and said benzo[d]thiazolyl is optionally substituted with 1 or 2 R b groups independently selected from the group of CN, halo, and —C(halo) 3 .

7. The compound of claim 1 , wherein R 5 is —C(═O)—(C 2 -C 6 )alkenyl substituted by -(5- to 12-membered)heteroaryl.

8. The compound of claim 1 , wherein R 6 is H, —(C 1 -C 6 )alkyl, —CH 2 —COOH, —CH 2 CH 2 OH, or —CH 2 CONH 2 .

9. The compound of claim 1 , wherein R 1 is (C 1 -C 3 )alkyl.

10. The compound of claim 1 , wherein R 4 is OH or —(C 1 -C 3 )alkoxy.

11. A compound of Formula H, or a pharmaceutically acceptable salt thereof:

wherein
R 1 is (C 1 -C 6 )alkyl;
R 2 is —OH or (C 1 -C 6 )alkoxy;
R 2a is —OH or (C 1 -C 6 )alkoxy;
R 3 is —(C 1 -C 6 )alkyl; and
R 4 is —CN, —COOH, or —CONH 2 .

12. A compound selected from the group consisting of:
(2R,6S,11R)-3,6-dimethyl-11-((4-(methyls

Assignees

• Purdue Pharma Lp

Inventors

• Tafesse Laykea
• Yao Jiangchao
• Yu Jianming
• Goehring R Richard

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

• C07D221/26 Primary

  Benzomorphans · CPC title

• C07D403/12

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