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SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof

A lysine methyl, inhibitor technology, applied in the field of preparation, SET8 lysine methyltransferase inhibitor and its intermediates

Active Publication Date: 2020-02-07
HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are few reports on the compounds targeting SET8 lysine methyltransferase. Therefore, the research of a new class of compounds targeting SET8 lysine methyltransferase is the difficulty and focus of current research.

Method used

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  • SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof
  • SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof
  • SET8 lysine methyltransferase inhibitor and intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Embodiment 1 prepares N-(2-(4-methoxyphenyl) thioacetyl) acetamide (formula II)

[0046]

[0047] Starting materials 2-(4-methoxyphenyl)thioacetamide (1.0 mmol, 181 mg), 4-dimethylaminopyridine (0.1 mmol, 12 mg), pyridine (0.15 mmol, 12 mg) were dissolved in 8 mL of dry acetonitrile , under nitrogen protection, under a water bath at room temperature, acetyl chloride (1.1 mmol, 86 mg) was added dropwise to the above system, and reacted at room temperature for 1 day. After the reaction solution was diluted with 50 mL of ethyl acetate, it was washed with 20 mL of water and saturated ammonium chloride solution successively, dried over anhydrous sodium sulfate, and after the reaction solution was concentrated, column chromatography separated [V (petroleum ether): V (ethyl acetate )=8:1-6:1] to obtain 38 mg of light yellow oil II, yield 17%.

Embodiment 2

[0048] Example 2 Preparation of 4-(3-(4-methoxybenzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-1-methylpiperidine (formula I)

[0049]

[0050] Formula II (0.16mmol, 36mg), 4-hydrazino-1-methylpiperidine (0.19mmol, 25mg), sodium acetate (0.2mmol, 16mg) were successively dissolved in 1mL acetic acid and 1mL 1,4-dioxane After being placed in the mixed solvent of the ring, it is sealed, and then reacted under heating at 80°C until the reaction of formula II is complete. After the reaction solution was diluted with 20 mL of ethyl acetate, it was washed successively with 20 mL of saturated sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after concentrating the reaction solution, column chromatography separated [V (ammonia in dichloromethane solution ): V (methanol)=25:1-20:1] to obtain 16 mg of light yellow oil I, yield 33%.

[0051] 1 H NMR (400MHz, CDCl 3 ):δ7.25(d,J=8.7Hz,2H),6.82(d,J=8.6Hz,2H),4.03–3.88(m,3H),3.77(s,3H),3...

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PUM

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Abstract

The invention provides an SET8 lysine methyltransferase inhibitor and an intermediate, a preparation method and application thereof. The structural general formula of the inhibitor is shown as follows. The inhibitor has a remarkable inhibition activity on SET8 lysine methyltransferase, meanwhile has a noticeable in-vitro anti-tumor activity and can be further developed into a targeted anti-tumor drug with SET8 being a target.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a SET8 lysine methyltransferase inhibitor and its intermediate, preparation method and application. Background technique [0002] Epigenetics is the change in gene expression that does not depend on changes in gene sequence, but on DNA methylation and chemical modification of histones. Genetic mutations, epigenetic mutations, lifestyle and environmental factors collectively affect human health and disease. The mutations of genes encoding epigenetic regulation are mainly reflected in four aspects: histone modification changes, DNA promoter hypermethylation, DNA extensive hypomethylation and abnormal chromatin structure during the development of tumors. Abnormal DNA methylation is likely to cause the inhibition of transcription of tumor suppressor genes, genome instability and abnormal activation of oncogenes. Mutations in histone-modifying enzymes in tumors, includi...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C327/52A61K31/4439A61P35/00
CPCA61P35/00C07C327/52C07D401/04
Inventor 苏学明李玮杨超
Owner HAINAN YILING MEDICAL INDUSTRY & DEVELOPMENT CO LTD
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