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Benzamide histone deacetylase inhibitor and application thereof

A technology of phenyl and compound, which is applied in the field of benzamide histone deacetylase inhibitors and its application, and can solve the problems of high toxicity, few types of drugs, and inaccurate curative effect, etc.

Inactive Publication Date: 2011-08-31
苏州东南药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The purpose of the present invention is to provide a benzamide-based histone deacetylase inhibitor, which solves the problems in the prior art that the histone deacetylase inhibitors have fewer types of drugs, inaccurate curative effect and high toxicity.

Method used

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  • Benzamide histone deacetylase inhibitor and application thereof
  • Benzamide histone deacetylase inhibitor and application thereof
  • Benzamide histone deacetylase inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] The biological activity research of embodiment 1 compound of the present invention

[0075] Investigate the compound of the present invention that obtains in the embodiment 2~15 of different concentrations to human non-small cell lung adenocarcinoma cell line (A549) and human large cell lung cancer cell (NCI-H661) after acting 72h, WST-8 method detects that the drug has the effect on the cell. effects on proliferation.

[0076] Drugs: The positive drugs SAHA and MS-275 were synthesized by our laboratory.

[0077] Reagents and instruments: HyQR modified RPMI 1640 medium, DMEM medium, WST-8 (Sigma), electron coupling reagent 1-Methoxy PMS (Sigma), trypsin. CO 2 Incubator, sterile operating table, microplate reader, centrifuge, pipette gun, pipette, centrifuge tube and 96-well plate, etc.

[0078] method:

[0079] 1) Tumor cell line culture

[0080] Human large cell lung cancer cells (NCI-H661): use RPMI 1640 medium containing 10% fetal bovine serum at 37°C, 5% CO 2 ...

Embodiment 2

[0096] Example 2 Preparation of 3-phenyl-5-(chloromethyl)-1,2,4-oxadiazole

[0097]

[0098] Aniline oxime (13.6 g, 0.10 mol) was dissolved in acetone (300 mL), and anhydrous potassium carbonate (13.8 g, 0.10 mol) was added. A solution of chloroacetyl chloride (8.07 mL, 11.3 g, 0.10 mol) in acetone (10 mL) was added dropwise over 75 min at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was distilled off under reduced pressure to obtain a white solid. The solid was dissolved in ethyl acetate (400 mL), and the organic layer was successively washed with water (3×100 mL), washed with saturated brine (3×100 mL), and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 23.9 g of a white powdery solid O-acylated product (93%).

[0099] The O-acylated product (22.9 g, 0.089 mol) was suspended in 300 mL of xylene and refluxed for 3 h. The solvent was distilled off under...

Embodiment 3

[0101] Example 3 Preparation of methyl 4-{[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]aminomethyl}benzoate

[0102]

[0103] Dissolve 0.015mol of methyl p-aminomethylbenzoate in 50mL of DMF, add 0.025mol of anhydrous potassium carbonate, dropwise add 0.01mol of 3-phenyl-5-(chloromethyl)-1,2,4 - Oxadiazole, stirred at 40°C for 8h. Then it was poured into ice water, extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesium sulfate, and the product could be obtained by column chromatography with a yield of 55%.

[0104] Mp: 41-43°C. 1 H-NMR (500Hz, CDCl3): δ8.08-8.10(m, 2H), 8.01((d, J=8.2Hz, 2H), 7.47-7.51(m, 3H), 7.44((d, J=8.2 Hz, 2H), 4.11 (s, 2H), 3.98 (s, 2H), 3.90 (s, 3H), 2.10 (br s, 1H). 13 C-NMR (125Hz, CDCl3): δ178.03, 168.31, 166.84, 144.18, 131.22, 129.83, 129.30, 128.86, 128.83, 128.10, 127.47, 127.44, 126.62, 52.58, 51.99, 43.96. MS: (M+H)+324.1, (M+Na)+346.1.

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Abstract

The invention discloses a compound with the structure of the general formula (I) or pharmaceutically acceptable salt thereof. Ar is aryl or heterocyclic group and is substituted by optional one or more of the following groups: C1-8 alkyl, C1-8 alkoxy, halogen, nitryl, C1-8 aminoalkyl, C1-8 alkyl amino group, C1-8 thio-alkyl, C1-8 halogenated alkyl, C1-8 halogenated alkoxy, C1-8 ester group, phenyl or heterocyclic group. R1 is hydrogen or C1-8 alkyl. The drugs prepared by the compound can be used for treating solid tumors or leukemia correlating with cell differentiation or proliferation.

Description

technical field [0001] The invention relates to a gene therapy drug related to a benzamide histone deacetylase inhibitor and the application of the inhibitor in the treatment of tumors, inflammations, immune system diseases, neurodegenerative diseases and the like. Background technique [0002] The formation of many diseases, including tumors, is a rather complex process, involving how various genes respond to changes in the internal and external environment, thereby achieving the regulation of expression in time and space. A frontier field emerging in genetics in recent years - epigenetics (Epigenetics) provides new ideas for answering these questions. The molecular basis of epigenetics mainly involves two aspects: one is the methylation modification of DNA, and the other is the acetylation modification of chromatin histones. In addition to the DNA sequence as the genetic code, epigenetic mechanisms are the most fundamental regulators of gene expression and subsequent prot...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D271/06C07D413/04A61K31/4245A61K31/4439A61P35/00A61P35/02
Inventor 吉民魏红涛吴晓晴
Owner 苏州东南药业股份有限公司
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