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Histone deacetylase inhibitor as well as preparation and application thereof

A technology of solvate and general formula, applied in the field of histone deacetylase inhibitor and its preparation and application, can solve the problems of high toxicity and the like

Active Publication Date: 2021-04-27
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, they were found to be relatively toxic in vivo experiments. Therefore, in 2013, Wang Jingjing used the modification method of forming amides to introduce substituted benzoyl or β-elemene substituted piperazine amide derivatives were synthesized by substituting phenylacryloyl groups, and the synthesized compounds were tested in vitro for human cervical cancer cells, human liver cancer cells, human fibrosarcoma cells and other 10 kinds of tumor cells by MTT method. Antitumor activity. Preliminary in vitro experiments showed that the antitumor effects of β-elemene-substituted piperazine amide derivatives were mostly stronger than those of β-elemene, and the IC of the target compound on human melanoma cells A375-S2 50 Most of the values ​​are less than 10 μM, which indirectly proves that the introduction of amide bonds in β-elemene piperazine derivatives may enhance their specific selectivity for a certain type of tumor cells

Method used

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  • Histone deacetylase inhibitor as well as preparation and application thereof
  • Histone deacetylase inhibitor as well as preparation and application thereof
  • Histone deacetylase inhibitor as well as preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1 monochlorinated β-elemene intermediate preparation of

[0037] Add 5.0g of β-elemene (24.47mmol, 1eq.), 3.5mL of glacial acetic acid (61.17mmol, 2.50eq.) and 40mL of methylene chloride into a 100mL three-necked flask, cool to 5°C in an ice-water bath, and slowly Add 15mL (25.45mmol, 1.04eq.) of sodium hypochlorite solution dropwise, drop it in 15min, and continue the reaction for 4h. After the reaction, 30 mL of water was added, the aqueous layer was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, and the organic layer was retained, dried over anhydrous sodium sulfate, filtered, and concentrated by distillation under reduced pressure to obtain a crude product. Column chromatography gave 2.7 g of monochlorinated β-elemene oil, with a yield of 46.2%.

Embodiment 2

[0038] Embodiment 2β-elemene piperazine preparation of

[0039] Dissolve 2.0g (8.38mmol, 1eq.) of monochlorinated β-elemene mixture and 1.8g (20.94 mmol, 2.5eq.) of anhydrous piperazine in 40mL of absolute ethanol, and react at 20-80°C for 7h. After the reaction, distill under reduced pressure, add water to the residue and extract with dichloromethane, retain the organic layer, wash the organic layer three times with saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain 1.2 g light yellow Oil, yield 49.7%.

Embodiment 3

[0040] Embodiment 3 intermediate 6-aminocaproic acid methyl ester hydrochloride preparation of

[0041] Add 120mL of anhydrous methanol to a 250mL three-necked flask, under nitrogen protection, lower the temperature of the reaction system to -10°C, slowly add 10.9mL of thionyl chloride (152.47mmol, 5eq.) to the reaction solution dropwise , kept at -10°C for 10 min, then added 4 g (30.49 mmol, 1 eq.) of 6-aminocaproic acid to the reaction liquid, and finally moved the reaction liquid to room temperature for 24 h. After the reaction was finished, concentrate by distillation under reduced pressure, then add 25 mL of anhydrous methanol to the residue to dissolve, add 100 mL of anhydrous ether to precipitate the product, and then filter to obtain 3.2 g of 6-aminocaproic acid methyl ester hydrochloride A1, yield 57.8% , mp: 118-121°C. ESI-MS, m / z 146.3 [M+H-Cl] + .

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Abstract

The invention relates to a histone deacetylase inhibitor and preparation and an application thereof, in particular to a novel histone deacetylase inhibitor based on a beta-elemene structure and a preparation method thereof, and further relates to an intermediate for synthesizing the histone deacetylase inhibitor and a preparation method thereof. The invention also relates to an application of the histone deacetylase inhibitor in preparation of antitumor drugs, and belongs to the technical field of chemical synthesis of drugs. The zinc ion combined compound and the salt or solvate thereof are shown as a general formula (I) or (II), wherein R, X, n and i are described in the claims and the specification.

Description

Technical field: [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to histone deacetylase inhibitors and their preparation and application, in particular to novel histone deacetylase inhibitors based on the structure of β-elemene and their preparation methods, and also to the synthesis of all The invention relates to an intermediate of the histone deacetylase inhibitor and a preparation method thereof, and also relates to the application of the histone deacetylase inhibitor in the preparation of antitumor drugs. Background technique: [0002] Histone deacetylase inhibitors (HDACi) activate tumor suppressor genes and inhibit cancer genes by regulating the acetylation and deacetylation levels of histone N-terminal lysine residues, further inhibiting tumor cell growth and inducing Apoptosis of tumor cells (Armeanu S, Pathil A, Venturelli S, et al. Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/14C07C259/06C07C237/04C07D295/205C07D295/185C07D295/215C07C227/16C07C227/18C07C231/02C07C231/12A61K31/315A61P35/00A61P35/02
CPCC07C229/14C07C259/06C07C237/04C07D295/205C07D295/185C07D295/215C07C227/16C07C227/18C07C231/02C07C231/12A61P35/00A61P35/02C07C2601/14
Inventor 徐莉英吴斐斐景永奎张美慧王林包宇董金华
Owner SHENYANG PHARMA UNIVERSITY
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