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Farnesoid X receptor (FXR) stimulant

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

Active Publication Date: 2019-02-12
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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  • Farnesoid X receptor (FXR) stimulant
  • Farnesoid X receptor (FXR) stimulant
  • Farnesoid X receptor (FXR) stimulant

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0151] 1. Preparation of Intermediate 1

[0152] Dissolve starting material 1 (self-made or purchased) in an organic solvent (such as tetrahydrofuran, etc.), add starting material 2 (made or purchased), alkaline solution (such as potassium tert-butoxide, etc.) and 18-crown-6, React at 20°C-40°C. After the reaction was completed, the solvent was removed from the reaction liquid under reduced pressure, and purified by silica gel column chromatography to obtain intermediate 1.

[0153] 2. Preparation of Intermediate 2

[0154] Dissolve the intermediate 1 in an organic solvent (such as dichloromethane, etc.), add an acidic solution (such as trifluoroacetic acid, etc.), after the addition, stir the reaction at room temperature, after the reaction is complete, concentrate to obtain a crude product, or add the concentrated solution to the alkali neutral solution (such as saturated sodium bicarbonate solution, etc.), extracted with an organic solvent (such as ethyl acetate, etc.), t...

experiment example 1

[0170] Experimental Example 1: The effect of the compounds of the present invention on the relative expression of BSEP mRNA in HepG2 cells

[0171] Test substance: the compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

[0172] Reagents: PBS: Phosphate buffer saline.

[0173] experimental method:

[0174] 1. Plating cells, adding compounds and collecting cells

[0175] 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.

[0176] Dilute the compound to 3,0.3mM with DMSO; take 5ul of the stock solution diluted in the previous step and add it to 5ml of the culture medium. The concentrations of the obtained working solutions were 3 an...

experiment example 2

[0202] Experimental example 2: The metabolic stability experiment of liver microsomes of the compound of the present invention in different species

[0203] Test product: Compound 1 and Compound 3 of the present invention are self-made, and their chemical names and preparation methods are shown in the preparation examples of each compound.

[0204] Reference substance: compound 30-70, PX-104, prepared according to the method of the prior art, see the background art for its structure.

[0205] Experimental Materials:

[0206] The mixed liver microsomes of SD rats were purchased from XenoTech, the batch number is: 1410271, and the protein concentration of liver microsomal was 20 mg·mL -1 .

[0207] The mixed liver microsomes of Cyno monkeys were purchased from Reid Liver Disease Research Center (Shanghai Co., Ltd.), the batch number is: NMZC, and the concentration of liver microsomal protein is 20 mg·mL -1 .

[0208]Human mixed liver microsomes were purchased from XenoTech...

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PUM

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a compound as shown in the formula (I), and pharmaceutically acceptable salt and ester or a stereisomer thereof.R1, R2, R3, M1, M2, m, n, Q, L, ring A, ring B and ring C are as defined in the specification. The invention further relates to a preparation method of the compounds, and application in preparing medicines for treating and / or preventing related diseases such as non-alcoholic fatty liver disease, primary biliary cirrhosis, lipid metabolism disorders, diabetic complication and malignant tumors mediated by an FXR. The formula (I) is shown in the description.

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 in the preparation of drugs for the treatment and / or prevention of related diseases such as 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] 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-termin...

Claims

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Application Information

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IPC IPC(8): C07D471/08A61K31/439A61P1/16A61P9/10A61P7/02A61P3/10A61P1/00A61P35/00A61P3/06A61P25/00A61P27/02A61P13/12
CPCC07D471/08
Inventor 史澂空
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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