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Farnesoid X receptor (FXR) stimulant

A technology of stereoisomers and alkyl groups, applied in anti-inflammatory agents, non-central analgesics, digestive system, etc., can solve problems such as unknown structures

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

[0007] 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
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Effect test

preparation example Construction

[0107] The present invention also provides the preparation method of the compound of formula (I), which includes but not limited to the following process route:

[0108] The definitions represented by each abbreviation are as follows:

[0109] THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; MeOH: methanol.

[0110]

[0111] R 1 , R 2 , R 3 , R 4 , W, A, Z, E, X, Y, n are as described above, and a' represents a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

[0112] The specific exemplary steps are as follows:

[0113] 1. Raw material 1: purchased or prepared.

[0114] 2. Raw material 2: purchased or prepared.

[0115] 3. Preparation of Intermediate 1

[0116] After acidifying raw material 2 with acid, it was dissolved in an organic solvent with raw material 1, reacted at 100°C for 12 hours, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to obtain intermediate 1. Wherein the acid i...

experiment example 1

[0130] Experimental example 1: Effects of the compounds of the present invention on the relative expression of BSEP mRNA in HepG2 cells and human hepatocytes

[0131] (1) Test substance: the compound of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound.

[0132] PBS: Phosphate buffered saline.

[0133] (2) Experimental method:

[0134] 1. Plating cells, adding compounds and collecting cells

[0135]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.

[0136] 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 s...

Embodiment 1

[0160] Example 1: 2-((2R,4r,6S)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)- 2,6-Dimethylpiperidin-1-yl)benzo[d]thiazole-6-carboxylic acid

[0161]

[0162] 1. Preparation of (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one

[0163]

[0164] 3-Carbonyl glutaric acid (40.0g, 0.28mol) and 40% acetaldehyde (60.5g, 1.37mol) were stirred at 25°C for 10min, then slowly added benzylamine (30mL, 0.28mol), and the reaction solution was Stir at ℃ for 78 h, adjust the pH to 2 with 1N hydrochloric acid, and then stir for 1 h, then adjust the pH to 7 with saturated sodium bicarbonate solution, extract with dichloromethane, dry over anhydrous sodium sulfate, concentrate, and perform silica gel column chromatography (petroleum ether: acetic acid Ethyl ester=9:1) to obtain the cis-title compound (2 g, yield: 3.4%).

[0165] 2. Preparation of (2R, 6S)-2,6-dimethylpiperidin-4-one

[0166]

[0167] Add (2R,6S)-1-benzyl-2,6-dimethylpiperidin-4-one (2g, 9.2mol) and 20% p...

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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, R4, W, A, Z, E, X, Y and n are as defined in the specification and the claims. The invention further relates to a preparation method of the compounds, pharmaceutical preparation 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 andmalignant tumors mediated by an FXR. The formula (I) is shown in the description.

Description

technical field [0001] The invention belongs to the field of medical technology, and in particular relates to FXR agonists, pharmaceutically acceptable salts and stereoisomers thereof, pharmaceutical preparations containing these compounds, and the compound, pharmaceutically acceptable salts and stereoisomers thereof Application of the body in the preparation of drugs for preventing and / or treating related diseases such as non-alcoholic fatty liver, primary biliary cirrhosis, lipid metabolism disorder, diabetes complications and malignant tumors mediated by FXR. Background technique [0002] FXR receptor (farnesoid X receptor) is a member of 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 terminal and a ligand binding domain at the carboxyl terminal. (LBD), the amino-terminal ligand-independent transcriptional activation domain (AF1), the carbo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/14A61K31/4523A61P9/10A61P1/16A61P1/00A61P3/10A61P13/12A61P25/00A61P29/00A61P27/02A61P35/00
CPCC07D417/14
Inventor 史澂空陈博
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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