Histone deacetylase inhibitor and its preparation method and use

A compound and unsaturated technology, applied in drug combination, organic chemistry, pharmaceutical formulation, etc., can solve the problem of non-selectivity of HDACs and achieve good curative effect

Inactive Publication Date: 2008-03-26
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Most of the existing HDACs inhibitors

Method used

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  • Histone deacetylase inhibitor and its preparation method and use
  • Histone deacetylase inhibitor and its preparation method and use
  • Histone deacetylase inhibitor and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Preparation of 5-chloromethyl, ethyl 2-furoate

[0099]

[0100] Add 14.0 grams (0.1 mol) of ethyl 2-furoate into a three-necked flask, then add 100 milliliters of anhydrous chloroform to dissolve to obtain a clear solution, then add 3.0 grams (0.1 mol) of paraformaldehyde, 27.2 grams (0.2 mol) of chlorine zinc oxide. Pass dry hydrochloric acid gas into the reaction solution, heat to 35°C, stir the reaction until the reaction is complete, then stop the reaction. After the reaction, the reaction solution was divided into two layers. The reaction solution was poured into 50 ml of ice water, separated, and the chloroform layer was taken and dried over anhydrous sodium sulfate. Concentrated and distilled under reduced pressure to obtain the product, 12.7 g of oily substance, yield 65%.

Embodiment 2

[0102] (E)--5-styryl, the preparation of ethyl 2-furanoate

[0103]

[0104] Add 4.50 g (0.01 mol) of 5-chloromethyl, ethyl 2-furoate triphenylphosphine salt, 1.06 g (0.01 mol) of benzaldehyde, 5.6 ml (0.04 mol) of triethylamine and 50 ml Dichloromethane was heated to reflux for 4 hours. After the reaction solution was cooled, the reaction solution was poured into 100 milliliters of petroleum ether, a large amount of white precipitates were precipitated, suction filtered, the filter cake was washed with petroleum ether, the filtrates were combined, concentrated, and column chromatography gave 1.34 grams (52.6%) of the product . 1 H NMR (300MHz, DMSO-d 6 ): δppm: IR(KBr)cm -1 :

Embodiment 3

[0106] (E)--5-phenethyl, the preparation of ethyl 2-furanoate

[0107]

[0108] Add (E)--5-styryl, 1.15 g (0.005 mol) of ethyl 2-furancarboxylate into the reaction flask, add methanol to dissolve, add a catalytic amount of palladium carbon (10%), and catalytically hydrogenate at room temperature (5 bar) . The reaction stopped after 5 hours. The remaining palladium carbon was removed by suction filtration, the filtrate was concentrated and recrystallized to obtain 1.06 g of the product. Yield 92%.

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PUM

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Abstract

The present invention relates to medicinal chemistry, and is especially one kind of hydroxamic acids as histone deacetylse inhibitor, and discloses their preparation process and new intermediate for preparing these compounds. These compounds may be applied in treating diseases caused by disorder of histone deacetylse activity, such as solid tumor, leukemia and nerve degenerative diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of hydroxamic acid histone deacetylase inhibitors, a preparation method thereof, a pharmaceutical preparation containing the same and its medical application. Background technique [0002] The expression of eukaryotic genes is regulated by both genetic regulation and epigenetic regulation. Genetic regulation includes gene transcription, post-transcriptional processing, translation, and post-translational modification; epigenetic regulation refers to the structural adjustment of genes at the chromatin level before transcription1, which is a unique regulatory mechanism of eukaryotic genomes. Epigenetic regulation mainly includes three aspects: DNA methylation, RNA interference, and histone modification, which can cause heritable silencing of genes without changing the DNA coding sequence (Egger, Liang, Aparicio and Jones, Epigenetics in human disease and prospects for ep...

Claims

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Application Information

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IPC IPC(8): C07D307/68C07D307/54C07D407/06A61K31/341A61K31/36A61P35/00
Inventor 尤启冬苏红刘改刘宗亮卢塞尔.安徒生安吉拉.奈伯逊
Owner CHINA PHARM UNIV
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