Histone deacetylase inhibitor, and preparation method and application thereof

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,...

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 with other drugs with different mechanisms of action for comprehensive tumor therapy

The preclinical animal experiments based on benzamide HDAC inhibitors developed by Entinostat (MS-275) developed by Bayer in Germany and Syndax in the United States have shown that the compound has obvious anticancer activity against blood cancer, lung cancer, rectal cancer, etc., and is selective HDAC inhibitors, but due to their human elimination half-life of close to 100 hours, the drug exposure varies greatly, and it has shown extremely poor tolerance in human clinical trials, and the dosage cannot be increased

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