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Ketohexokinase (KHK) inhibitor and application thereof

A compound, selected technology, applied in anti-inflammatory agents, non-central analgesics, medical preparations containing active ingredients, etc., can solve problems such as unmet clinical needs

Inactive Publication Date: 2020-11-24
SHANDONG XUANZHU PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This condition has a high unmet clinical need

Method used

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  • Ketohexokinase (KHK) inhibitor and application thereof
  • Ketohexokinase (KHK) inhibitor and application thereof
  • Ketohexokinase (KHK) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] Example 1 2-((1R,5S,6s)-3-(2-(3-fluoro-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidine-4 Preparation of -yl)-3-azabicyclo[3.1.0]]hex-6-yl)acetic acid (compound 1)

[0134]

[0135] 1) 2-((1R,5S,6s)-3-(2-(3-fluoro-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidine-4- base)-3-azabicyclo[3.1.0]]hex-6-yl)methyl acetate

[0136]

[0137] 2-((1R,5S,6s)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl) Methyl acetate (50mg, 0.15mmol), 3-fluoro-2-methylazetidine hydrochloride (23mg, 0.18mmol), dissolved in acetonitrile (10mL), added N,N-diisopropyl Ethylamine (0.5 mL), heated to 65°C for 16 hours, spin-dried, and the residue was directly used in the next step.

[0138] 2) 2-((1R,5S,6s)-3-(2-(3-fluoro-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidine-4- base)-3-azabicyclo[3.1.0]]hex-6-yl)acetic acid

[0139]

[0140] 2-((1R,5S,6s)-3-(2-(3-fluoro-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidin-4-yl) -3-Azabicyclo[3.1.0]]hex-6...

Embodiment 2

[0143] Example 2 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazepin-1-yl)-6-(trifluoromethyl)pyrimidine-4 Preparation of -yl)-3-azabicyclo[3.1.0]hexane-6-yl)acetic acid (compound 2)

[0144]

[0145] 1) 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-methylazetidin-1-yl)-6-(trifluoromethyl)pyrimidine Preparation of -4-yl)-3-azabicyclo[3.1.0]hex-6-yl)methyl acetate

[0146]

[0147] 2-((1R,5S,6s)-3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hex-6-yl) Methyl acetate (60mg, 0.18mmol) was dissolved in acetonitrile (5mL), diisopropylaminoethylamine (0.16ml, 0.90mmol) and 3,3-difluoro-2-methylazetidine hydrochloride were added (39mg, 0.27mmol), reacted at 90°C for 6 hours, diluted with ethyl acetate (30mL), washed with saturated brine (10mL×3), dried the organic phase over anhydrous sodium sulfate, spin-dried, and column chromatography (25% ethyl acetate ester / petroleum ether) to obtain the product (50 mg, yield 67%).

[0148] 2) 2-((1R,5S,6s)-3-(2-(3,3-difluoro-2-met...

experiment example 1

[0155] Experimental example 1 In vitro KHK kinase inhibitory activity test of the compound provided by the embodiment of the present invention

[0156] Test product: the compound synthesized by the embodiment of the present invention, its structural formula is shown in Table 1.

[0157] Experimental reagents:

[0158]

[0159]

[0160] Experimental consumables:

[0161]

[0162] laboratory apparatus:

[0163]

[0164] experimental method:

[0165] 1. Compound dilution

[0166] 1) Use DMSO to prepare the compound of the present invention and the positive control drug to 10 mM as the test stock solution.

[0167] 2) Dilute the stock solution of the compound of the present invention 10 times to 1 mM, then dilute the compound of the present invention 3 times to 11 concentrations, the highest concentration is 1 mM, dilute the stock solution of the positive control drug 100 times to 0.1 mM, then, 3 times Gradually dilute the positive control drug to 11 concentration...

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Abstract

The invention relates to the technical field of medicine, in particular to a ketohexokinase (KHK) inhibitor compound, pharmaceutically acceptable salts of the compound, esters of the compound or stereoisomers of the compound, a pharmaceutical composition and preparation containing the compound, the pharmaceutically acceptable salts of the compound, the esters of the compound or the stereoisomers of the compound, and application of the compound, the pharmaceutically acceptable salts of the compound, the esters of the compound or the stereoisomers of the compound to preparation of drugs for treating and / or preventing KHK-mediated diseases and related diseases.

Description

technical field [0001] The present invention relates to the technical field of medicine, in particular to a ketohexokinase inhibitor compound, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, containing the compound, a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof. Pharmaceutical compositions and preparations of stereoisomers thereof, methods for preparing said compound, its pharmaceutically acceptable salt, its ester or its stereoisomer, and said compound, its pharmaceutically acceptable salt, its Use of the ester or its stereoisomer in the preparation of medicines for treating and / or preventing diseases mediated by KHK and related diseases. Background technique [0002] NAFLD / NASH is the hepatic manifestation of metabolic syndrome. Changes in diet and lifestyle have led to the prevalence of obesity and metabolic syndrome in Western countries and many Asian countries, resulting in a significant i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14A61K31/506A61P5/00A61P13/00A61P3/00A61P1/16A61P9/00A61P29/00A61P37/02A61P25/00A61P1/00A61P35/00
CPCC07D403/14A61P5/00A61P13/00A61P3/00A61P1/16A61P9/00A61P29/00A61P37/02A61P25/00A61P1/00A61P35/00
Inventor 刘斌
Owner SHANDONG XUANZHU PHARMA TECH CO LTD
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