Quinazoline hydroxamic acid derivative and preparation method and application thereof

A technology of quinazoline hydroxamic acid and derivatives is applied in the field of medicine and achieves the effects of good application prospect, simple preparation method and good anti-cancer effect

Active Publication Date: 2021-03-12
SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Overexpression of G9a/GLP will methylate H3K9 and H3K2

Method used

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  • Quinazoline hydroxamic acid derivative and preparation method and application thereof
  • Quinazoline hydroxamic acid derivative and preparation method and application thereof
  • Quinazoline hydroxamic acid derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] The preparation of embodiment 1 compound D1

Embodiment 1A

[0055] Example 1A intermediate 2-chloro-6,7-dimethoxy-N-(1-methylpiperidin-4-yl)quinazolin-4-amine (compound shown in formula III)

[0056] With 2,4-dichloro-6,7-dimethoxyquinazoline (compound shown in formula II) (1eq) and corresponding carrying R 1 The amino derivative of the group (2eq) was added to a round bottom flask, dissolved in an organic solvent such as tetrahydrofuran, stirred at room temperature under nitrogen protection, and reacted overnight, and then extracted with dichloromethane to obtain a crude product, which was separated by column chromatography to obtain a pure product.

Embodiment 1B

[0057] Example 1B 6-(6,7-dimethoxy-4-((1-methylpiperidine) quinazoline-amino)) methyl hexanoate

[0058] (compound shown in formula IV, Y=2-aminocaproamide, R 1 =1-methylpiperidine)

[0059] This step reaction is completed by nucleophilic substitution reaction, and the general process is as follows: the compound (1eq) obtained in Example 1A is dissolved in an organic solution such as acetonitrile, and DIEA (2eq) and the corresponding fatty acid ester of terminal primary amine (6-amino Methyl hexanoate) (2eq), react under nitrogen protection at 80°C for 2 hours, and spot plate monitoring until the reaction of the compound of Example 1A is complete. Add water and dichloromethane for extraction, and the organic phase is separated by column chromatography to obtain the product.

[0060] Example 1C 6-((6,7-dimethoxy-4-((1-methylpiperidin-4-yl) amino) quinazoline-2-yl) amino)-N-hydroxyl caproamide ( D1)

[0061] (compound shown in formula I, Y=2-aminocaproamide, R 1 =1-methylpi...

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Abstract

The invention relates to a quinazoline hydroxamic acid derivative and a preparation method and application thereof. The structural formula of the quinazoline hydroxamic acid derivative is as shown informula I: Y is substituted or unsubstituted aliphatic hydrocarbon group or aromatic hydrocarbon group, R1 is a nitrogen-containing substituent group, and R2 and R3 are each independently hydrogen oran alkyl group. Researches show that the compound shown in the formula I has good inhibitory activity on histone methyltransferase and histone deacetylase, can effectively inhibit tumor cell proliferation, and can be used as a lead compound for research and development of antitumor drugs.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a quinazoline hydroxamic acid derivative with histone methyltransferase and histone deacetylase inhibitory activity, a preparation method and application thereof. Background technique [0002] Cancer is a common malignant disease that seriously threatens human health and affects people's quality of life. It is the second leading cause of death after cardiovascular disease. Its occurrence and development are not only related to gene mutations, but also closely related to epigenetic changes. Histone methyltransferases (Histone methyltransferases) and histone deacetylases (Histone deacetylases, HDACs) catalyze the methylation and deacetylation of histones, respectively, and are important regulatory methods of epigenetics. Among them, HDAC is a relatively mature and important target for the development of anti-tumor drugs. Currently, five HDAC inhibitors (Vorinostat, Romidepsin, ...

Claims

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Application Information

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IPC IPC(8): C07D401/12A61K31/506A61P35/00
CPCC07D401/12A61P35/00
Inventor 蒋宇扬戴求资袁梓高吴伟彬张存龙孙钦升陈妍李露露刘子健谭春燕
Owner SHENZHEN GRADUATE SCHOOL TSINGHUA UNIV
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