Use of KOR agonist in combination with MOR agonist in preparing drug for treating pain

Patent metadata

Field	Value
Publication number	US-11471503-B2
Application number	US-201816767523-A
Country	US
Kind code	B2
Filing date	Dec 5, 2018
Priority date	Dec 6, 2017
Publication date	Oct 18, 2022
Grant date	Oct 18, 2022

Abstract

Disclosed is the use of a KOR agonist in combination with a MOR agonist in preparing a drug for treating pain. The KOR agonist is selected from a compound as shown in the general formula (I), and the MOR agonist is selected from a compound as shown in the general formula (II), wherein the definitions of each substituent in the general formula (I) and (II) are the same as defined in the description.

First claim

What is claimed is:

1. A method of alleviating and/or treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a κ opioid receptor (KOR) agonist and μ opioid receptor (MOR) agonist, wherein the KOR agonist is a compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
G is selected from the group consisting of O, —NR 4 and —CR 5 R 6 ;
R 1 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —S(O) m R 7 and —NR 8 R 9 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 7 , —C(O)R 7 and —C(O)OR 7 , wherein the alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 3 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, —OR 7 , —C(O)R 7 and —C(O)OR 7 , wherein the alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 4 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, amino, alkoxycarbonyl, heterocyclyl, aryl, heteroaryl, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —S(O) m R 7 , —NR 8 R 9 and —NHC(O)NR 8 R 9 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —S(O) m R 7 , —NR 8 R 9 and —NHC(O)NR 8 R 9 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 7 is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 8 and R 9 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
m is 0, 1 or 2.

2. The method according to claim 1 , wherein the KOR agonist is a compound of formula (I-B):

or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 , wherein the KOR agonist is a compound of formula (I-C):

or diastereomer thereof, or a mixture thereof, or a pharmaceutically accepta 1e salt thereof.

4. The method according to claim 1 , wherein the KOR agonist is selected from the group consisting of:

or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 , wherein the MOR agonist is a compound of formula (II):

or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A is selected from the group consisting of cycloalkyl and heterocyclyl;
R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —S(O) m R 3 and —NR 4 R 5 ;
each R 1 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —S(O) m R 3 and —NR 4 R 5 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
each R 2 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 3 , —C(O)R 3 , —C(O)OR 3 , —S(O) m R 3 and —NR 4 R 5 , wherein the alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
or two R 2 are taken together to form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 3 is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, amino, alkoxy, hydroxyalkyl, cycl

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Huang Xiaoxing
• Cao Guoqing
• Yang Changyong
• Zhang Lianshan

Classifications

• C07K5/10

  Tetrapeptides · CPC title

• A61P25/04

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

• A61K38/07 Primary

  Tetrapeptides · CPC title

• A61K31/4433

  containing a six-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title