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Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity

A deacetylase and benzamide technology, applied in organic chemistry, drug combination, anti-tumor drugs, etc., can solve problems such as nonconformity, rapid metabolism, increase production cost, etc., and achieve mild reaction conditions and simple purification methods. Effect

Inactive Publication Date: 2015-09-02
TAIZHOU EOC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

The above types of HDAC inhibitors currently have a variety of HDAC inhibitors that have entered the clinical trial stage. According to relevant studies and reports, they can inhibit the proliferation of various tumor cells and induce tumor cell differentiation and / or apoptosis (Wang Xin, Liu Dan, Lu Jinling, Yu Weishe, Xu Ye, Zhao Linxiang, WANG Xin, LIU Dan, L(U) Jin-ling, YU Wei-she, XU Ye, ZHAO Lin-xiang-《Chinese Journal of Medicinal Chemistry》2006-5 ), but some of the above-mentioned HADC inhibitors have some shortcomings in clinical application: short-chain fatty acid HDAC inhibitors such as butyric acid are rapidly metabolized in the body and have poor selectivity; hydroxamic acid HDAC inhibitors For example, trichostafin A (TSA) is unstable in vivo, which affects its activity in vivo; but the benzoyl HADC inhibitors that have been found, such as MS-275, are more selective than other HDAC inhibitors. Stronger, less toxic, better tolerated
At present, there are few reports on the synthesis method of benzamide HDAC inhibitor MS-275 in patents and literatures. US6794392 and EP0847992 disclose a kind of preparation method for preparing MS-275: in the preparation process of the crude product, it is necessary to pass through the process of column chromatography Method (eluent: dichloromethane / methanol=30 / 1) obtains target compound, because the method for column chromatography purification needs to consume a large amount of solvents (low-boiling solvents are not easy to recover and apply mechanically) and man-hours, increase production while reducing production capacity Cost, does not meet the requirements of industrialization in the future, this method should not be applied in industrialized production in the future; Literature Synthesis and Histone Deacetylase Inhibitory Activity of New Benzamide Derivatives (J.Med.Chem.1999,42,3001-3003) reported that MS- The related synthetic route and method of 275 uses the more harmful oxalyl chloride in its preparation method, because oxalyl chloride will have different degrees of influence on the relevant sites, equipment and operators during storage and use, which does not meet the requirements of future regulations. Industrialization Requirements

Method used

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  • Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity
  • Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity
  • Preparation of benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The synthesis of embodiment 1 compound VI

[0057]

[0058] Add N,N to the 500ml reaction bottle ， -Carbonyldiimidazole 75g (462.5mmol), tetrahydrofuran 100ml, stir well, at room temperature (10 ~ 20 ℃), add dropwise 50ml of tetrahydrofuran solution of 3-pyridinemethanol (25.2g, 231mmol) that has been prepared, after the dropwise addition React at room temperature (10-20°C) for 6h. Cool the system down to about 0°C, add 34.9g (231mmol) of 4-aminomethylbenzoic acid under temperature control at about 0°C, stir for 30min, then add 59.7 g of N,N-diisopropylethylamine dropwise at about 0°C g (462.5mmol), react at 0-10°C for 8h after the dropwise addition. After the reaction, control the temperature at 0-20°C and add concentrated hydrochloric acid dropwise to adjust the pH of the system to 4-5. After the adjustment, stir at 0-20°C for 4 hours. Filter, wash the filter cake twice with 500ml of purified water, and dry the wet product at 40-50°C for 8 hours. Obtained light...

Embodiment 2

[0061] Synthesis of Example 2 Compound VII

[0062]

[0063] Put 42g (146.7mmol) of compound VI and 100ml of dimethylformamide into a 500ml reaction flask, add 35.7g (220mmol) of N,N,-carbonyldiimidazole at room temperature (10-20°C), ~20°C) and stirred for 2h. Cool the system down to about 0°C, control the temperature at about 0°C, add dropwise 150ml of a dimethylformamide solution of o-phenylenediamine (47.6g, 440.1mmol) that has been prepared, and stir for 30min at about 0°C after the drop is complete. Control the temperature at about 0°C and add 28.2g (293.4mmol) of methanesulfonic acid dropwise, and react at 0-20°C for 8h after the drop is completed. After the reaction, the reaction liquid was poured into 2500ml of purified water, and was beaten at room temperature (10-20° C.) for 12 hours. After filtering, the filter cake was washed twice with 800ml of purified water, and after being sucked dry, the wet product was vacuum-dried at 40-50°C for 20 hours to obtain ligh...

Embodiment 3

[0068] The synthesis of embodiment 3 compound VI

[0069] Add 37.5g (231mmol) of N,N,-carbonyldiimidazole and 200ml of tetrahydrofuran into a 500ml reaction flask, stir evenly, and add 3-pyridinemethanol (25.2g, 231mmol) dropwise at room temperature (10-20°C) ) in 60ml of tetrahydrofuran solution, react at room temperature (10-20° C.) for 6 hours after the dropwise addition. Cool the system down to about 0°C, add 69.8g (462mmol) of 4-aminomethylbenzoic acid at about 0°C, stir for 30min, add 35.1g (346.5mmol) of triethylamine dropwise at about 0°C, drop After the addition, react at 0-10°C for 8h. After the reaction, control the temperature at 0-20°C and add concentrated hydrochloric acid dropwise to adjust the pH of the system to 4-5. After the adjustment, stir at 0-20°C for 4 hours. After filtering, the filter cake was washed twice with 500ml of purified water, and after being sucked dry, the wet product was air-dried at 40-50°C for 8 hours. The light yellow solid compound ...

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Abstract

The invention discloses a preparation method of a benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity. The structure of the benzamide histone deacetylase inhibitor is as shown in a general formula (I), wherein A, Z, Y, B, R1, R2, X1, X2, X3 and X4 are defined as the specification. The compound as a histone deacetylase inhibitor can be used for curing and differentiating the diseases, such as cancer and psoriasis which are related to proliferation.

Description

technical field [0001] The present invention relates to the synthesis of new small molecule compounds with therapeutic effects. Background technique [0002] Abnormal gene expression plays an important role in the pathogenesis of many diseases, including tumors, endocrine disorders, immune system diseases, genetic diseases and neurological diseases. The human genome exists as a chromatin structure packaged with DNA, histones and non-histones, and the chromatin structure plays an important role in determining whether a specific gene is expressed or not. Overall, condensed chromatin represses transcription, whereas transcriptionally active genes tend to be located in open chromatin. [0003] The basic repeating unit of chromatin, the nucleosome, consists of double strands of DNA surrounding a histone core containing four histones. This histone core contains one H3-H4 tetramer and two H2A-H2B dimers. Histone H1 attaches to the junction between nucleosomes and maintains the s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30A61P35/00
CPCC07D213/30
Inventor 李合亭常伟王元国张斌冀学芳邹晓明
Owner TAIZHOU EOC PHARMA CO LTD
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