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A kind of bet/hdac dual-target inhibitor and its preparation method and application

An inhibitor and dual-target technology, applied in the field of medicine and chemical industry, can solve the problems of no BI-2536 derivative inhibitor report, etc., and achieve the effects of high yield, improved therapeutic effect and simple preparation method

Active Publication Date: 2018-08-21
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] There are no reports of BI-2536 derivative inhibitors with BET / HDAC dual targets

Method used

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  • A kind of bet/hdac dual-target inhibitor and its preparation method and application
  • A kind of bet/hdac dual-target inhibitor and its preparation method and application
  • A kind of bet/hdac dual-target inhibitor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] The following takes the synthesis of 15c (BI-C) as an example to further illustrate the present invention:

[0047] 1. To prepare compound 2, the reaction formula is as follows:

[0048]

[0049] Weigh compound 1 (1 g, 9.96 mmol) and dissolve it in 10 mL of methanol, slowly add thionyl chloride (1.48 ml, 20.36 mmol) in an ice-water bath at 0°C, reflux at 65°C for 1.5 hours, and distill under reduced pressure after the reaction. The remaining oily substance was mixed with 10 ml of methyl tert-butyl ether and stirred for 0.5 h, the colorless crystals obtained were filtered, washed with ether, and dried overnight in a vacuum to obtain colorless semi-solid crystals, namely target compound 2 (1.12 g, quant.).

[0050] Target product compound 2 1 The H NMR data are as follows:

[0051] 1H NMR (300MHz, CDCl 3 ) δ: 8.71 (s, 2H), 4.20-4.01 (m, 1H), 3.66 (s, 3H), 2.24-2.02 (m, 2H), 1.09 (t, J=7.0 Hz, 3H).

[0052] 2. To prepare compound 4, the reaction formula is as follows:

[0053]

[00...

example 5-1

[0071] Weigh compound 7 (280mg, 1mmol) and dissolve it in 5ml N,N-dimethylformamide solution, add methyl iodide (80μl, 1.3mmol), cool the reaction to -10°C, add 60% dispersed in mineral oil Sodium hydride (52mg, 1.3mmol) was reacted at 0°C for 30 minutes, and then heated to room temperature for 3 hours. The reaction was confirmed by tapping the plate, and crushed ice was added to terminate the reaction. It was extracted twice with ethyl acetate, washed with water, the organic phase was dried with anhydrous magnesium sulfate, filtered, distilled under reduced pressure, and column chromatography to obtain pale yellow compound 8 (294 mg, quant.)

[0072] Target product compound 8 1 The H NMR data are as follows:

[0073] 1 H NMR(300MHz, CDCl 3 )δ:

[0074] 7.67 (s, 1H), 4.38-4.30 (m, 1H), 4.24 (dd, J=7.47 Hz, 3.6 Hz, 1H), 3.33 (s, 3H), 2.08-2.02 (m, 1H).

example 5-2

[0076] Weigh compound 7 (280mg, 1mmol) and dissolve it in 5ml tetrahydrofuran solution, add methyl iodide (80μl, 1.3mmol), cool the reaction to -10°C, add 60% sodium hydride (52mg, 1.3mmol) dispersed in mineral oil React at 0°C for 30 minutes, warm to room temperature for 3 hours, click the plate to confirm that the reaction is over, add crushed ice to terminate the reaction. Extract twice with ethyl acetate, wash with water, dry the organic phase with anhydrous magnesium sulfate, filter, distill under reduced pressure, and column chromatography to obtain pale yellow compound 8 (235mg, yield 80%)

[0077] 6. The synthesis of compound 9, the reaction formula is as follows:

[0078]

[0079] Weigh compound 8 (235mg, 0.8mmol) and 4-amino-3-methoxybenzoic acid (208mg, 1.24mmol) into 0.6ml ethanol, 2.4ml water, 260μl concentrated hydrochloric acid mixed solvent, and the reaction mixture was refluxed at 95°C for 48h . Under reduced pressure distillation and column chromatography, compo...

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Abstract

The invention discloses a BET (bromodomain and extraterminal domain) / HDAC (histone deacetylase) double-target inhibitor, and a preparation method and application thereof. The structure of the double-target inhibitor is as shown in the specification, wherein n=2-6. Compared with the prior art, the double-target inhibitor has the advantage that pharmacophore of a BET inhibitor BI-2536 and pharmacophore of an HDAC inhibitor are spliced by a Linker to obtain a novel BET / HDAC inhibitor with BET / HDAC double-target inhibition effect. The preparation method is simple, mild in condition and easy to implement.

Description

Technical field [0001] The invention discloses a BET / HDAC dual target inhibitor and a preparation method and application thereof, belonging to the technical field of medicine and chemical industry. Background technique [0002] An important feature of many human diseases, especially tumors and autoimmune inflammation, is the abnormal acetylation level, which leads to abnormal transcription. The acetylation level of histone lysine is mainly controlled by histone acetyltransferases (HATs), histone deacetylases (HDACs) and bromodomain proteins (BRD). [0003] BRD is a type of protein domain that can specifically recognize histone acetylated lysine (KAc). The 61 types of BRD found in the human body exist in 46 types of proteins. According to their different functions, they are divided into 8 families. Among them, the bromodomain and extraterminal domain (BET) belong to the second part of the BRD family. Classes, including BRD2, BRD3, BRD4 and BRDT. BET protein regulates the expressi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04
Inventor 蔡进李丛丛吉民徐华刘文景
Owner SOUTHEAST UNIV
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