Histone deacetylase inhibitor, and preparation method and application thereof

A compound and sulfonyl technology, applied in the field of preparation of histone deacetylase inhibitor drugs, can solve the problems of large differences in drug exposure, cardiotoxicity, poor tolerance and the like

Inactive Publication Date: 2016-10-26
GUANGDONG ZHONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical data have shown that SAHA can lead to thrombosis and neurotoxicity, while the incidence of adverse reactions of grade 3 or higher related to FK228 is as high as 66%, and there is cardiotoxicity
In addition, SAHA and FK228, two drugs directly associated with clinically effective absorption peak concentrations, are significantly higher than the concentration required to inhibit the growth of normal or tumor cells in vitro, thereby producing direct cytotoxic effects on normal cells and increasing the toxicity of the drug. Side effects seriously limit their application in tumor therapy combined

Method used

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  • Histone deacetylase inhibitor, and preparation method and application thereof
  • Histone deacetylase inhibitor, and preparation method and application thereof
  • Histone deacetylase inhibitor, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0333] Synthesis of Compound 1-(Methoxymethoxy)-4-nitrobenzene (F1)

[0334]

[0335] Add 100mmol of p-nitrophenol to 300ml of dichloromethane, ice-water bath, and stir. Then DIPEA120mmol and MOMC1200mmol were added dropwise, and stirred at room temperature after completion. After reacting for 3 hours, the reaction solution was washed with saturated brine, water, 1N hydrochloric acid and saturated brine in sequence, and the organic layer was spin-dried under reduced pressure to obtain the dark red oily target product.

Embodiment 2

[0337] Synthesis of Compound 4-(Methoxymethoxy)aniline (F2)

[0338]

[0339] Add compound F1100mmol, 10% Pd / C5mmol to 250ml methanol, pass through hydrogen, react overnight at room temperature, after the reaction is complete, filter with diatomaceous earth, wash with ethyl acetate, combine organic layers, anhydrous NaSO 4 Drying and spin-drying under reduced pressure gave the dark red oily target product.

Embodiment 3

[0341] Synthesis of Compound 4-(Methoxymethoxy)-N-Methylaniline (F3)

[0342]

[0343] 100mmol Na was added to 200ml methanol several times in batches, and after the reaction was complete, 20mmol compound F2 and 28mmol paraformaldehyde were added into the reaction flask, and reacted overnight at room temperature. Then add 20mmol NaBH4 in batches, and heat to reflux for 2h. The reaction solution was concentrated under reduced pressure, the residue was added to 2N NaOH solution, extracted with tert-butyl methyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the target product in the form of dark red oil.

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Abstract

The invention provides a compound as shown in a formula I which is described in the specification and a pharmaceutically acceptable salt thereof and specifically relates to a novel 4-arylaminoquinazoline hydroxamic acid compound with histone deacetylase inhibitory activity, a preparation method for the compound, a pharmaceutical composition including the compound, and application of the compound and the pharmaceutical composition in preparation of histone deacetylase inhibitor drugs. The objective of the invention is to acquire a series of selective histone deacetylase inhibitors with subtype selectivity and good pharmacokinetic characteristics through optimization of enzyme surface recognition regions and joining regions of 4-arylaminoquinazoline via drug design and synthesis means so as to improve antineoplastic activity and reduce influence on normal tissue or cells.

Description

[0001] Cross References to Related Applications [0002] This application claims the rights and interests of the Chinese patent application No. 201510119932.2 submitted on March 18, 2015, the entire content of which is hereby incorporated by reference. technical field [0003] The invention belongs to the field of medicine, in particular, the invention relates to a novel compound of 4-arylaminoquinazoline hydroxamic acid with histone deacetylase inhibitory activity, a preparation method of the compound, and a method comprising the compound The pharmaceutical composition and the application of the compound and the pharmaceutical composition in the preparation of histone deacetylase inhibitor drugs. Background technique [0004] Tumor is a major disease that threatens human health, and the treatment of tumor has been paid close attention to all over the world. Traditional chemotherapy drugs non-specifically block cell division and cause cell death. While killing tumor cells,...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D401/12C07D403/12A61K31/517A61P35/00A61P35/02
CPCC07D239/94C07D401/12C07D403/12
Inventor 陈俐娟龙超峰陈小新刘卓伟叶昊宇谢称石
Owner GUANGDONG ZHONGSHENG PHARMA
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