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Novel pyrazine structure FXR agonist, preparation method and application

A compound, selected technology, applied in the direction of pharmaceutical formulations, medical preparations containing active ingredients, drug combinations, etc., can solve the problem of low activation activity

Pending Publication Date: 2022-06-24
JIANGSU TASLY DIYI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned compounds have relatively low activation activity at the farnesoid nuclear receptor FXR target

Method used

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  • Novel pyrazine structure FXR agonist, preparation method and application
  • Novel pyrazine structure FXR agonist, preparation method and application
  • Novel pyrazine structure FXR agonist, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Example 1: Synthetic route of compound TM-1

[0220]

[0221] experiment procedure:

[0222] 3-(3-Bromophenyl)cyclobutanone

[0223]

[0224] To a solution of N,N-dimethylformamide (2.1 g, 24.6 mmol) in 1,2-dichloroethane (40 mL) at -15°C, trifluoromethanesulfonic anhydride (11.6 mmol) was slowly added dropwise. g, 41.0 mmol) and stirred at -15°C for 30 minutes. Then 3-bromostyrene (3.0 g, 16.4 mmol) and 2,4,6-collidine (2.9 g, 24.6 mmol) were added and stirred at room temperature overnight. The reaction was quenched by adding water, stirred at room temperature overnight, dichloromethane was added to dilute and separate the organic phase, the organic phase was washed with water and saturated brine (200 ml) respectively, dried over anhydrous magnesium sulfate, filtered with suction, concentrated under reduced pressure, and subjected to a gradient of silica gel column chromatography. Elution separation and purification (PE:EA=15:1, v / v) gave 1.3 g of 3-(3-bromoph...

Embodiment 2

[0239] Example 2: Synthetic route of compound TM-2

[0240]

[0241] Synthesis steps:

[0242] Synthesis of methyl 3-(3-hydroxyazetidine-1-yl)benzoate 3b

[0243]

[0244] To methyl 3-iodobenzoate 3a (5.0 g, 19.1 mmol) in DMSO-D 6 (70 mL) solution was added 3-azetidin-3-ol hydrochloride (2.5 g. 22.9 mmol), Cs 2 CO 3 (15.5 g, 47.7 mmol), CuI (726 mg, 3.8 mmol) and L-proline (878 mg, 7.6 mmol), then the mixture was heated at 90 °C for 18 hours under an argon atmosphere. The solution was diluted with ethyl acetate and water, and then the organic layer was washed three times with brine, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (DCM / MeOH=10 / 1, v / v) to obtain the product 3b as a white solid ( 2.7g, 68%).

[0245] Synthesis of methyl 3-(3-oxoazetidin-1-yl)benzoate 3

[0246]

[0247]Dimethyl sulfoxide (1.6 g, 20.3 mmol) was dissolved in dichloromethane (30 mL), at -78 °C, oxalyl chloride (1.3 g, 10.1 mmol) was ...

Embodiment 3

[0256] Example 3: Synthetic route of compound TM-3

[0257] 3-(3-Bromophenyl)-1-(5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)pyrazine- 2-yl)cyclobutanol

[0258]

[0259] A 100 mL three-necked flask was protected with nitrogen, and 4-(5-bromopyrazine-2-methyleneoxy)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1.14 g, 2.3mmol) was dissolved in anhydrous tetrahydrofuran (5mL) and poured into a reaction flask, then ethanol and liquid nitrogen were added to a 500mL low-temperature Dewar flask to make the temperature drop to -78°C, and n-butyllithium (1.7ml, 2.7mmol) was slowly added dropwise. , after stirring for 10 min, slowly add 3-(3-oxocyclobutanone) methyl 3-(3-oxocyclobutanone) benzoate solution (0.56 g, 2.5 mmol) dissolved in tetrahydrofuran (10 mL) dropwise, react at -78 °C for 2 h and then warm to room temperature for reaction overnight. After the reaction was completed, the reaction solution was slowly poured into an ice-water mixture, extracte...

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PUM

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Abstract

The invention relates to a novel pyrazine structure FXR agonist as well as a preparation method and application thereof, in particular to a compound as shown in the following general formula, a hydrate, a solvate, a pharmaceutically acceptable salt or a split single isomer of the compound, and the compound has the effect of treating non-alcoholic fatty liver disease.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical compound, in particular to a novel pyrazine structure FXR agonist, a preparation method and an application. Background technique [0002] Since the discovery in 1999 that bile acids can activate FXR to produce a variety of physiological functions, selective and highly active FXR agonists have been discovered one after another. These FXR agonists can be divided into steroids and non-steroids according to their structures. The steroids are mainly chenodeoxycholine (chenodeoxycholic acid, CDCA, one of the bile acids) and its derivatives and the FXR agonist MFA-1 developed by Merck; non-steroids include isoxazoles GW4064 and its derivatives Analogs, Fexaramine compounds, azaindole compounds XL335 and its derivatives, benzimidazolyl amide compounds, pyrazole diketone compounds, etc. [0003] Non-alcoholic fatty liver disease (NAFLD) is a group of clinicopathological syndromes with no history...

Claims

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Application Information

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IPC IPC(8): C07D413/12A61K31/497A61P1/16
CPCC07D413/12A61P1/16A61K31/497C07D413/14A61K31/4965C07D261/02A61K31/42
Inventor 马维维王国成
Owner JIANGSU TASLY DIYI PHARMA CO LTD
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