FXR receptor modulator, and preparation method and application thereof

A receptor modulator and solvate technology, applied in the field of FXR receptor modulator and its preparation, can solve the problem of not activating human or mouse receptors

Active Publication Date: 2017-07-14
GUANGZHOU HENOVCOM BIOSCI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Farnesoid and its derivatives, together known as farnesoids, were originally described as activating the murine ortholog at high concentrations, but they did not activate human or murine receptors

Method used

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  • FXR receptor modulator, and preparation method and application thereof
  • FXR receptor modulator, and preparation method and application thereof
  • FXR receptor modulator, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0137] 3-{2-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}-7-azaspiro[3.5]nonane-7 - Preparation of carbonyl}benzoic acid.

[0138]

[0139] Prepare according to the following lines:

[0140]

[0141] (1) Preparation of 2,6-dichlorobenzaldehyde oxime.

[0142] Dissolve 2,6-dichlorobenzaldehyde (5.0g, 28.6mmol) in absolute ethanol (45mL), stir at room temperature, and add NH 2 OH·HCl (2.3 g, 33.1 mmol), NaOH (1.3 g, 32.5 mmol) and water (20 mL), refluxed overnight in an oil bath at 90°C. After the reaction solution was cooled to room temperature, the solvent was spin-dried, water (100 mL) was added, extracted with ethyl acetate (2×100 mL), the combined organic layers were washed with saturated brine (2×100 mL), anhydrous Na 2 SO 4 Dry, filter, spin dry, add petroleum ether (100 mL), stir well, filter, and dry to obtain 3.5 g of white solid 2,6-dichlorobenzaldehyde oxime, yield: 64%.

[0143] (2) Preparation of chlorinated 2,6-dichlorobenzaldehyde oxime....

Embodiment 2

[0174] 2-{2-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}-7-azaspiro[3.5]nonane-7 Preparation of -yl}benzo[d]thiazole-6-carboxylic acid.

[0175]

[0176] (1) Preparation of ethyl 2-aminobenzo[d]thiazole-6-carboxylate.

[0177] Dissolve ethyl 4-aminobenzoate (4.9g, 30.0mmol), potassium thiocyanate (11.6g, 120.0mmol) in acetic acid (180mL), add bromine (1.5mL, 30.0mmol) dropwise at 19°C Acetic acid (20 mL) solution was added over 20 minutes, and then raised to room temperature to react overnight. Pour the reaction solution into water (100mL), stir for 10 minutes, add ammonia water dropwise to adjust the pH to about 8, filter, wash the filter cake with water and petroleum ether successively, and dry in vacuo to obtain 6.7g of a yellow solid, which is 2- Ethyl aminobenzo[d]thiazole-6-carboxylate, yield: 100%.

[0178] The characterization data is: 1 H NMR (400MHz, DMSO) δ: 8.28(d, J=1.6Hz, 1H), 7.88(s, 2H), 7.82(dd, J=1.6Hz, 8.4Hz, 1H), 7.37(d, J=8.4 Hz, 1H...

Embodiment 3

[0189] 3-{6-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol4-yl]methoxy}2-azaspiro[3.3]heptane-2-carbonyl } Preparation of benzoic acid.

[0190]

[0191] (1) Preparation of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate.

[0192] The method for preparing 2-hydroxyl-7-aza[3.5]nonane-7-carboxylate tert-butyl with reference to Example 1 prepares 6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl, Only tert-butyl 4-oxopiperidine-1-carboxylate was replaced by tert-butyl 3-oxazetidine-1-carboxylate.

[0193] Product characterization data are: 1 H NMR (400MHz, CDCl 3 )δ:4.20(m,1H),3.90(s,2H),3.89(s,2H),2.55(m,2H),2.09(m,2H),1.95(m,1H),1.44(s,9H ).

[0194] (2) 3-{6-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol4-yl]methoxy}2-azaspiro[3.3]heptane- Preparation of 2-carbonyl}benzoic acid.

[0195] Preparation of 3-{2-{[5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol4-yl]methoxy}-7-azaspiro[3.5] with reference to Example 1 Preparation of 3-{6-{[5-cyclopropyl-3-(...

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Abstract

The invention discloses an FXR receptor modulator, and a preparation method and an application thereof, belonging to the field of medicinal chemistry. The FXR receptor modulator with a structure characteristic as shown in a formula I in the specification or pharmaceutically-acceptable salts or stereoisomers or solvates or prodrugs thereof can bind with an FXR (i.e., NR1H4) receptor and is used as an agonist or a partial agonist of the FXR receptor, thereby being able to be applied to prevention and treatment of FXR mediated diseases, such as chronic intrahepatic or extrahepatic cholestasis, hepatic fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, or chronic hepatitis B, or gallstone, or liver cancer, or colon cancer, or inflammatory bowel diseases, etc., wherein a part of compounds specifically can reach an FXR-excited EC<50> of 100 nM or below, show good FXR agonist activity, have excellent application prospects, and provide a new medicine choice for clinical treatment of the FXR mediated diseases.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a FXR receptor modulator and its preparation method and application. Background technique [0002] Multicellular organisms rely on advanced information transmission mechanisms between cells and body compartments. The information transmitted can be highly complex and can lead to changes involving genetic programs of cell differentiation, proliferation, or regeneration. The signals (or hormones) used for transmission are usually low-molecular-weight molecules, such as peptides, fatty acids, or cholesterol derivatives. [0003] Many of these signals exert their effects by ultimately altering the transcription of specific genes. A well-studied group of proteins that regulate cellular responses to various signals is the family of transcription factors known as nuclear receptors, often referred to hereinafter as "NR". Members of this "NR" group include: steroid hormones, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D417/14C07D471/08C07D413/14A61P1/16A61P31/20A61P35/00A61P29/00
CPCC07D413/12C07D413/14C07D417/14C07D471/08A61P1/00A61P1/16A61P29/00A61P35/00Y02P20/55
Inventor 张健存邹晴安陈延维刘劲松
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
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