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Dual HDAC/BRD4 inhibitor and preparation method and application thereof

An inhibitor, dual technology, applied in the field of medicine and chemical industry, can solve the problems such as no dual HDAC/BET inhibitor reports, achieve high yield, improve therapeutic effect, and simple preparation method

Active Publication Date: 2016-08-10
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are currently no reports of dual HDAC / BET inhibitors

Method used

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  • Dual HDAC/BRD4 inhibitor and preparation method and application thereof
  • Dual HDAC/BRD4 inhibitor and preparation method and application thereof
  • Dual HDAC/BRD4 inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 Preparation of compound 3

[0067]

example 1-1

[0069] Weigh compound 1 (2.85g, 20mmol) and dissolve it in 20mL N,N-dimethylacetamide, add 10mL acetonitrile, 0.1g copper chloride, 3g potassium hydroxide in sequence, and react at room temperature (25°C) under an oxygen atmosphere 12h. After the reaction, 1 mol / L hydrochloric acid was slowly added dropwise to adjust the pH to 7, filtered through diatomaceous earth, the filtrate was washed three times with water, and then washed three times with saturated brine, and the organic layer was dried with anhydrous sodium sulfate and evaporated to dryness. Column chromatography gave a yellow solid, the target compound 3 (2.92 g, yield 82%).

[0070] The target product compound 3 1 The data of H NMR are as follows:

[0071] 1 H NMR (300MHz, DMSO-d6)δ:

[0072] 2.95(s, 2H), 7.58(d, J=8.30Hz, 2H), 7.80(t, J=8.52Hz, 2H)

example 1-2

[0074] Compound 1 (2.85 g, 20 mmol) was weighed and dissolved in 20 mL of tetrahydrofuran, 10 mL of acetonitrile, 0.1 g of copper chloride, and 3 g of potassium hydroxide were added in sequence, and reacted at room temperature under an oxygen atmosphere for 12 h. After the reaction, 1 mol / L hydrochloric acid was slowly added dropwise to adjust the pH to 7, filtered through diatomaceous earth, the filtrate was washed three times with water, and then washed three times with saturated brine, and the organic layer was dried with anhydrous sodium sulfate and evaporated to dryness. Column chromatography gave a yellow solid, the target compound 3 (2.5 g, yield 70%).

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Abstract

The invention discloses a dual HDAC / BRD4 inhibitor and a preparation method and application thereof .The structural formula of the dual HDAC / BRD4 inhibitor is shown in the formula 16 .The invention further discloses a preparation method of the dual HDAC / BRD4 inhibitor and application of the dual HDAC / BRD4 inhibitor in preparing medicine .A pharmacophore of an HDAC inhibitor and a pharmacophore of a BRD4 inhibitor are spliced through a linker, and therefore the novel dual HDAC / BRD4 inhibitor with a dual HDAC / BRD4 inhibiting effect is obtained .The preparation method is simple, mild in condition and easy to implement .

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a dual HDAC / BRD4 inhibitor and its preparation method and application. Background technique [0002] An important feature of many human diseases, especially tumors and autoimmune inflammation, is abnormal acetylation levels that lead to transcriptional abnormalities. The acetylation level of histone lysine is mainly controlled by histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomains (BETs). [0003] HDACs are catalytic subunits of multi-protein complexes, HDACs mediate changes in nucleosome structure, participate in the regulation of gene expression, and regulate cell cycle progression and differentiation. The occurrence and development of various diseases such as cancer, acute myeloid leukemia, infection, etc. are all related to HDAC. In general, the level of histone acetylation is positively correlated with gene transcriptio...

Claims

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Application Information

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IPC IPC(8): C07D495/14A61K31/551A61P35/00A61P35/02
CPCC07D495/14
Inventor 蔡进陈国庆吉民李丛丛郭明亮徐华刘文景
Owner SOUTHEAST UNIV
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