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fxr receptor agonist

A technology selected from compounds, applied in anti-inflammatory agents, non-central analgesics, metabolic diseases, etc., can solve problems such as low bioavailability and instability to light

Active Publication Date: 2021-11-16
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to natural compounds, the FXR agonists currently developed internationally can be mainly divided into two categories, one is steroids, represented by Obeticholic acid (OCA) from Intercept, which targets non-alcoholic fat Liver indications, which are in clinical phase III; the other type is new molecular entities, such as GW4604 (WO2000 / 037077), which have been developed in the early stage. Although they have strong agonistic activity, they are unstable to light and have low bioavailability. In addition, PX-104 (WO2011020615A1) developed by Phenex has been transferred to Gilead and is currently in phase II clinical research

Method used

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Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0340] Preparation Example 1: Preparation of (E)-2,6-dichlorobenzaldehyde oxime

[0341]

[0342] Dissolve 2,6-dichlorobenzaldehyde (25g, 0.14mol) in ethanol (200mL), slowly add hydroxylamine hydrochloride (11g, 0.16mol) in batches, after the addition is complete, add NaOH solution (6.4g, 0.16mol, in 100mL water), heated to 90°C for 24 hours. After the reaction was completed, the solvent was removed from the reaction solution under reduced pressure, and the solid was washed with water (200 mL) and dried to obtain 25.9 g of the title compound with a yield of 97%.

preparation example 2

[0343] Preparation Example 2: Preparation of (Z)-2,6-dichloro-N-hydroxyiminobenzyl chloride

[0344]

[0345] Dissolve (E)-2,6-dichlorobenzaldehyde oxime (25.9g, 0.136mol) into DMF (300mL), and slowly add N-chlorosuccinimide (18.2g, 0.136mol) in batches, After the addition, the mixture was stirred at 25°C for one hour, and the reaction solution was poured into water (500 mL). Extracted with ethyl acetate (500 mL), washed the organic phase with water (200 mL) and saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, and removed the solvent to obtain 28 g of the title compound. The crude product was carried on to the next step without purification.

preparation example 3

[0346] Preparation Example 3: Preparation of ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4-carboxylate

[0347]

[0348] Dissolve (Z)-2,6-dichloro-N-hydroxyiminobenzyl chloride (28g, 0.125mol) in triethylamine (100mL), add ethyl 3-cyclopropyl-3-oxopropionate (19.5g, 0.125mol), react at 25°C for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure and separated by column chromatography (PE:EA=10:1) to obtain 24.4 g of the title compound, with a two-step yield of 55.1%.

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Abstract

The present invention provides the compound represented by the following general formula (1), its pharmaceutically acceptable salt, its ester or its stereoisomer, the present invention also provides the preparation method of the above-mentioned compound and the Use in drugs for treating non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetic complications and malignant tumors. Among them, R 1 , R 2 , R 3 , R 4 , m, n, W, A, Z, E, F, X, Y are as 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 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): C07D413/12C07D261/08A61K31/422A61K31/4725A61K31/42A61P1/16A61P29/00A61P1/00A61P9/10A61P3/06A61P7/02A61P3/10
CPCA61K31/42A61K31/422A61K31/4725C07D261/08C07D413/12
Inventor 吴永谦
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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