FXR (farnesol X receptor) agonist

A stereoisomer, selected technology, applied in the field of FXR receptor agonists, can solve problems such as unknown structure

Active Publication Date: 2019-04-05
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In addition, GS-9674 developed by Gilead and LJN-452 developed by Novartis are both in phase II clinical trials. The indications are primary biliary cirrhosis, primary sclerosing cholangitis, and nonalcoholic steatohepatitis. The structure is unknown.

Method used

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  • FXR (farnesol X receptor) agonist
  • FXR (farnesol X receptor) agonist
  • FXR (farnesol X receptor) agonist

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0125] 1. Preparation of Intermediate 1

[0126] The starting material 1 (homemade or purchased), alkaline solution and phase transfer catalyst are dissolved in an organic solvent, and the starting material 2 (homemade or purchased) is added to react at 25°C-50°C. After the reaction is completed, the reaction solution is cooled, the solvent is removed from the reaction solution under reduced pressure, and the silica gel column chromatography is purified to obtain Intermediate 1. The alkaline solution is selected from sodium hydrogen, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium iodide, sodium iodide, etc., preferably potassium tert-butoxide, potassium iodide, iodine The organic solvent is selected from tetrahydrofuran, DMF, toluene, acetonitrile, etc., preferably tetrahydrofuran; the phase transfer catalyst is selected from 18-crown-6, tetrabutylammonium iodide, etc., preferably 18-crown-6.

[01...

experiment example 1

[0144] Experimental Example 1: The effect of the compound of the present invention on the relative expression of BSEP mRNA in HepG2 cells

[0145] Test product: The compound of the present invention, for its chemical name and preparation method, see the preparation examples of each compound.

[0146] Reference substance: compound PX-104, prepared according to the prior art method, and its structure is shown in the background art.

[0147] Reagents: PBS: phosphate buffered saline.

[0148] experimental method:

[0149] 1. Pour cells, add compound and collect cells

[0150] Use trypsin to digest and collect the cells, and determine the cell concentration; according to the counting results, resuspend the cells to a density of 7.5e5cell / mL; 6-well cell culture plate, inoculate 2mL cells per well; put the culture plate in the incubator at 37℃, 5% CO 2 Conditioned for 24 hours.

[0151] Use DMSO to dilute the compound to 3,0.3mM; take 5ul of the stock solution diluted in the previous step and ...

experiment example 2

[0180] Experimental Example 2: Metabolic stability test of liver microsomes of the present invention in different species

[0181] Test product: The compound of the present invention, self-made, its chemical name and preparation method are shown in the preparation examples of each compound.

[0182] Reference substance: compound 30-70, prepared according to the prior art method, and its structure is shown in the background art.

[0183] Experimental Materials:

[0184] Mixed liver microsomes of SD rats, Beagle dogs, and CD-1 mice were purchased from XenoTech. The batch numbers are: 1410271 (SD rats), 1310086 (Beagle dogs), 1510043 (CD-1 mice), liver microsomes Protein concentration is 20mg·mL -1 .

[0185] Cyno monkey mixed liver microsomes were purchased from Reid Liver Disease Research Center (Shanghai Co., Ltd.), the batch number is NMZC, and the liver microsomal protein concentration is 20 mg·mL -1 .

[0186] Human mixed liver microsomes were purchased from Corning, the product nu...

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Abstract

The invention belongs to the technical field of medicine and particularly relates to a compound shown as formula (I) that is shown in the description, and its pharmaceutically acceptable salts, estersor stereoisomers, with R1, R2, R3, M1, M2, Q, L, ring A, ring B and m defined as in the description and the claims. The invention also relates to a preparation method these compounds, pharmaceuticalpreparations and their application in the preparation of drugs for the treatment and / or prevention of FXR-mediated non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications, malignant tumors and related diseases.

Description

Technical field [0001] The present invention relates to FXR receptor agonists, their pharmaceutically acceptable salts, their esters, and their stereoisomers, pharmaceutical preparations containing these compounds, and the compounds, their pharmaceutically acceptable salts, their esters, and their The stereoisomers are used in the preparation of drugs for the treatment and / or prevention of non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications and malignant tumors mediated by FXR receptors the use of. Background technique [0002] FXR receptor (farnesol X receptor) is a member of the nuclear receptor family of ligand-activated transcription factors and has a typical nuclear receptor structure, namely the highly conserved DNA binding domain (DBD) at the amino terminal and the ligand binding domain at the carboxyl terminal (LBD), amino-terminal ligand-independent transcriptional activation functional area (AF1), carboxy-terminal li...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/427A61K31/438A61K31/4709A61K31/435A61P9/10A61P1/16A61P7/02A61P3/10A61P29/00A61P1/00A61P15/00A61P3/06A61P13/12A61P25/00A61P27/02A61P35/00
CPCC07D417/14
Inventor 方文奎
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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