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FXR receptor agonist

A technology of stereoisomers and alkyl groups, applied in the field of FXR receptor agonists, can solve problems such as unknown structures

Active Publication Date: 2019-01-25
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 receptor agonist
  • FXR receptor agonist
  • FXR receptor agonist

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0211] 1. Preparation of Intermediate 1

[0212] Intermediate 1 was purchased or prepared.

[0213] 2. Preparation of Intermediate 2

[0214] Intermediate 2 was purchased or prepared.

[0215] 3. Preparation of Intermediate 3

[0216] Dissolve intermediate 1 in an organic solvent containing a catalyst (such as tetrahydrofuran, etc.), add an alkaline reagent (such as potassium tert-butoxide) under ice-cooling, and maintain the reaction at 0°C, then add intermediate 2, and rise to 10-35°C React for 8-16 hours, remove the solvent, and purify (purification method is preferably: preparative high performance liquid chromatography, silica gel column chromatography, etc.) to obtain intermediate 3.

[0217] 4. Preparation of Intermediate 4

[0218] Dissolve intermediate 3 in an organic solvent (such as ethanol, etc.) at a low temperature (such as 0° C.), add an acidic solution (such as an ethanol solution containing HCl, etc.), and react for 5-30 hours. After the reaction is comple...

experiment example 1

[0233] Experimental Example 1: The effect of the compounds of the present invention on the relative expression of BSEP mRNA in HepG2 cells

[0234] (1) Test substance: the compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

[0235] PBS stands for phosphate buffered saline.

[0236] Control drug: PX-104, see background technology for specific structure.

[0237] (2) Experimental method:

[0238] ①Laying cells, adding compounds and collecting cells

[0239] Use trypsin to digest and collect the cells, and measure the cell concentration; according to the counting results, resuspend the cells to a density of 7.5e5cell / mL; inoculate 2 mL of cells in each well of a 6-well cell culture plate; place the culture plate in an incubator, at 37°C, 5%CO 2 Conditioned for 24 hours.

[0240] Dilute the compound to be tested to 0.3 and 3 mM with DMSO; take 5 μL of the stock solution diluted in the previous s...

experiment example 2

[0264] Experimental example 2: Experiment on the metabolic stability of liver microsomes of compounds of the present invention

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Abstract

The present invention discloses an FXR receptor agonist, belongs to the technical field of medicine, and particularly relates to a compound represented by a formula (I), a pharmaceutically acceptablesalt, an ester or a stereoisomer thereof, wherein R<1>, R<2>, R<3>, M, L, L1, W, A , B, Q, m and n are defined in the specification. The present invention further relates to a preparation method of the compound, a pharmaceutical preparation, and applications in preparation of drugs for treatment and / or prevention of nonalcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorder, diabetic complication, malignant tumors and other related diseases mediated by FXR receptors. The formula I is defined in the specification.

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 stereoisomers Use of the isomer in the preparation of medicines for treating and / or preventing non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorders, diabetic complications, malignant tumors and other related diseases mediated by FXR receptors . Background technique [0002] The FXR receptor (farnesoid X receptor) belongs to the nuclear receptor family of ligand-activated transcription factors and has a typical nuclear receptor structure, namely, a highly conserved DNA-binding domain (DBD) at the amino-terminus and a ligand-binding domain at the carboxyl-terminus. (LBD), amino-terminal ligand-independent transcriptional activation domain (AF1), carboxy-ter...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/08C07D471/08C07D513/08C07D495/08A61K31/5386A61K31/439A61K31/4995A61K31/547A61P9/10A61P1/16A61P3/10A61P35/00A61P1/00A61P13/12A61P25/00A61P27/02
CPCC07D471/08C07D495/08C07D498/08C07D513/08
Inventor 方文奎陈博
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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