Indole and indoline-type piperidine compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-9963458-B2
Application number	US-201314654727-A
Country	US
Kind code	B2
Filing date	Dec 23, 2013
Priority date	Dec 27, 2012
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

The disclosure relates to indole-type piperidine compounds, indoline-type piperidine compounds and related piperidine-type bicyclic compounds containing a five-membered nitrogen-containing ring (e.g., pyrrole or dihydropyrrole) fused to a heteroaryl ring, compositions comprising an effective amount of such compounds, and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of an indole-type piperidine compound, indoline-type piperidine compound or related piperidine-type bicyclic compound containing a five-membered nitrogen-containing ring (e.g., pyrrole or dihydropyrrole) fused to a heteroaryl ring.

First claim

What claimed is:

1. A compound of the structure:

or a pharmaceutically acceptable salt or solvate thereof,
wherein M 1 is selected from the group consisting of:

and
M 2 is selected from the group consisting of:

R 3 is:
(a) —X, —(C 1 -C 6 )alkyl-X, -(5- or 6-membered)heterocycle-X, or -(5- or 6-membered)heterocycle-(C 1 -C 6 )alkyl-X; or
(b) —(CH 2 ) d —C(═Y)CN, —(CH 2 ) d —C(═Y)X, —(CH 2 ) d —C(═Y)T 3 , —(CH 2 ) d —C(═Y)YX, —(CH 2 ) d —C(═Y)C(═Y)YX, —(CH 2 ) d —C(═Y)YT 3 , —(CH 2 ) d —C(═Y)N(T 1 )(T 2 ), —(CH 2 ) d —C(═Y)N(R 9 )CN, —(CH 2 ) d —C(═Y)N(R 9 )X, —(CH 2 ) d —C(═Y)N(R 9 )YH, —(CH 2 ) d —C(═Y)N(R 9 )YX, —(CH 2 ) d —C(═Y)N(R 9 )YCH 2 X, —(CH 2 ) d —C(═Y)N(R 9 )YCH 2 CH 2 X, or —(CH 2 ) d —C(═Y)N(R 9 )S(═O) 2 T 3 ;

X is selected from:
(a) —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 7 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, -(5- or 6-membered)heterocycle, and -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 8 groups; and
(b) -phenyl, -naphthalenyl, —(C 14 )aryl, and -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups;

each Y is independently O or S;
each R 7 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)N(T 1 )(T 2 ), —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)N(T 1 )(T 2 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(T 1 )(T 2 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 8 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -(5- or 6-membered)heteroaryl, —(C 1 -C 6 )alkyl-C(═O)OR 9 , —N(R 9 )(C 1 -C 6 )alkyl-C(═O)OR 9 , —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, ═O, ═S, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)N(T 1 )(T 2 ), —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)N(T 1 )(T 2 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(T 1 )(T 2 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 9 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);
each R 12 is independently —H or —(C 1 -C 4 )alkyl;
each T 1 and T 2 is independently —H or —(C 1 -C 10 )alkyl;
each T 3 is independently —H or —(C 1 -C 10 )alkyl; and
each d is, independently, an integer selected from 0, 1, 2, and 3.

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

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

4. The compound of claim 1 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt or solvate thereof.

5. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from the group consisting of —H, —C(═O)C(═O)OH, —C(═O)C(═O)NH 2 , —CH 2 C(═O)OH, —CH 2 C(═O)NH 2 , —CF 2 C(═O)OH, and —CF 2 C(═O)NH 2 .

6. A compound selected from:

or a pharmaceutically acceptable salt or solvate thereof.

7. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

8. A method for modulating ORL-1 receptor function in a cell, comprising contacting a cell capable of expressing the ORL-1 receptor with an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

9. The method of claim 8 , wherein the composition or the compound or the pharmaceutically acceptable salt or solvate of the compound acts as an agonist at the ORL-1 receptor.

10. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof.

11. The compound of claim 1 or a pharmaceutically acceptable salt or solvate-thereof, wherein R 3 is selected from the group consisting of —H, —(CH 2 ) d —C(═Y)T 3 , —(CH 2 ) d —C(═Y)YX, —(CH 2 ) d —C(═Y)C(═Y)YX, and —(CH 2 ) d —C(═Y)YT 3 .

12. The compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof, R 3 is selected from the group consisting of —H, —C(═O)C(═O)OH, —C(═O)C(═O)NH 2 , —CH 2 C(═O)OH, and —CH 2 C(═O)NH 2 .

13. A pharmaceutical composition comprising an effective amount of the compound of claim 6 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier or excipient.

Assignees

• Tafesse Laykea
• Purdue Pharma Lp

Inventors

• Tafesse Laykea

Classifications

• C07D487/08 Primary

  Bridged systems · CPC title

• C07D471/08

  Bridged systems · CPC title

• A61P25/04

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