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Use of a kind of kappa opioid receptor agonist in preparation of medicine for treating pruritus caused by farnesoid x receptor agonist

A receptor agonist, kappa opioid technology, applied in the field of itching drugs, can solve the problems of undisclosed itching, undisclosed kappa opioid receptor agonists combined use, etc.

Active Publication Date: 2021-10-08
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, none of the above-mentioned documents discloses the combined use of κ opioid receptor agonists and farnesoid X receptor agonists, let alone the use for alleviating pruritus caused by farnesoid X receptor agonists

Method used

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  • Use of a kind of kappa opioid receptor agonist in preparation of medicine for treating pruritus caused by farnesoid x receptor agonist
  • Use of a kind of kappa opioid receptor agonist in preparation of medicine for treating pruritus caused by farnesoid x receptor agonist
  • Use of a kind of kappa opioid receptor agonist in preparation of medicine for treating pruritus caused by farnesoid x receptor agonist

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the preparation of formula (II) and formula (III) compound

[0049] The monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), and the system of developing agent used in the reaction has: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.

[0050] Formula (II) compound: the following formula 1, (R)-N-((R)-6-amino-1-(4-(3-methylureido)piperidin-1-yl)-1-oxygen Hexan-2-yl)-2-((R)-2-((R)-2-amino-3-phenylpropanylamino)-3-phenylpropanylamino)-4-methylpentane Amide

[0051]

[0052]

[0053] first step

[0054] tert-butyl 4-((phenoxycarbonyl)amino)piperidine-1-carboxylate 1b

[0055] 4-Aminopiperidine-1-carboxylic acid tert-butyl ester 1a (0.5g, 2.5mmol), pyridine (0.22g, 2.75mmol) was dissolved in 15mL tetrahydrofuran, and phenyl chloroformate (0...

Embodiment 2

[0106] Example 2: Study on the therapeutic effect of κ opioid receptor agonists on obeticholic acid-induced pruritus

[0107] laboratory apparatus:

[0108] Table 1. Main instrument information

[0109]

[0110] Preparation of the test solution:

[0111] (1) 20mM acetic acid solution: Take 1.13mL of glacial acetic acid in a suitable container, add pure water to dilute to 1000mL.

[0112](2) 20mM sodium acetate buffer solution: Weigh 1.64g of sodium acetate into a suitable container, add 1000mL of pure water, stir until completely dissolved, adjust the pH to 4.5-4.6 with 20mM acetic acid solution, and stir evenly.

[0113] (3) Obeticholic acid solution: Weigh an appropriate amount of obeticholic acid and grind it, dissolve it in ultrapure water to prepare an administration solution with a concentration of 1.0 mg / mL.

[0114] (4) Compound solution of formula (III): Weigh an appropriate amount of compound of formula (III), and prepare administration solutions with concentra...

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Abstract

The invention relates to the use of a κ opioid receptor agonist in the preparation of a medicine for treating pruritus caused by the farnesoid X receptor agonist. The present invention also relates to a combination of farnesoid X receptor agonist and kappa opioid receptor agonist in the preparation of treatment of portal hypertension, cholestatic liver disease, primary biliary cirrhosis, bile acid diarrhea or non-alcoholic fatty liver Uses in medicine.

Description

technical field [0001] The invention relates to the use of a κ opioid receptor agonist in the preparation of medicine for treating pruritus caused by the farnesoid X receptor agonist. Background technique [0002] Obeticholic acid (Obeticholic acid, OCA, INT-747) is a farnesoid X receptor agonist developed by Intercept Pharmaceuticals under the license of the University of Perugia, Italy. It is in the 7α configuration and is used for the treatment of portal vein Hypertension, primary biliary cirrhosis, bile acid diarrhea, non-alcoholic fatty liver disease, and non-alcoholic fatty liver disease completed phase 3 clinical trials in the United States in January 2014. On May 27, the U.S. Food and Drug Administration granted accelerated approval to Ocaliva (obeticholic acid) in combination with ursodeoxycholic acid (UDCA) for the treatment of primary biliary cholangitis (PBC) in adults with an inadequate response to UDCA, or as a monotherapy. Drug therapy is used in adult patien...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/06A61K31/575A61K31/485A61K38/07A61P17/04A61P9/12A61P1/16
CPCA61K31/485A61K31/575A61K38/07A61K45/06A61P1/16A61P9/12A61P17/04
Inventor 孙飘扬桂雨舟杨昌永张连山黄晓星
Owner JIANGSU HENGRUI MEDICINE CO LTD