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Preparation method and purpose of pyrrolone BRD4 protein inhibitor

A technology of pyrrole and ethyl ketone, which can be used in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., and can solve many problems.

Active Publication Date: 2018-02-27
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although there are many research institutions and companies researching on BRD4 bromodomain and BRD4 bromodomain inhibitors, there are not many types of effective BRD4 bromodomain inhibitors entering clinical trials, and the development of novel BRD4 inhibitors is still an important challenge in modern drug development

Method used

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  • Preparation method and purpose of pyrrolone BRD4 protein inhibitor
  • Preparation method and purpose of pyrrolone BRD4 protein inhibitor
  • Preparation method and purpose of pyrrolone BRD4 protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] 3,5-Dimethyl-4-acetyl-1H-pyrrole-2-carboxylic acid ethyl ester (I-a)

[0183] Add 9.80 g (75.04 mmol) of ethyl acetoacetate and 20 mL of glacial acetic acid into a 250 mL eggplant-shaped bottle in sequence, and place in an ice bath

[0184] N-(2-(3,5-Dimethyl-4-acetyl-1H-pyrrol-2-yl)-1H-indol-3-yl)benzamide (II-7)

[0185] N-(2-(3,5-Dimethyl-4-acetyl-1H-pyrrol-2-yl)-IH-indol-3-yl)cyclohexanecarboxamide (II-8)

[0186] N-(2-(3,5-Dimethyl-4-acetyl-1H-pyrrol-2-yl)-1H-indol-3-yl)cyclopropanecarboxamide (II-9)

[0187] N-(2-(3,5-Dimethyl-4-acetyl-1H-pyrrol-2-yl)-1H-indol-3-yl)-2-methoxybenzamide (II-10)

[0188] 1-(1,2,4-Trimethyl-5-(1H-indol-2-yl)-1H-pyrrol-3-yl)ethanone (II-11)

[0189] 1-(2,4-Dimethyl-5-(5-morpholino-1H-indol-2-yl)-1H-pyrrol-3-yl)ethanone (II-12)

[0190] 1-(2,4-Dimethyl-5-(3-(pyridin-2-ylamino)-1H-indol-2-yl)-1H-pyrrol-3-yl)ethanone (II-13)

[0191] 1-(2,4-Dimethyl-5-(3-(phenylamino)-1H-indol-2-yl)-1H-pyrrol-3-yl)ethanone (II-14)

[0192] 1-(2,4-Di...

Embodiment 5

[0207] 1-(1,2,4-trimethyl-5-(1-methyl-1H-phenyl[d]imidazol-2-yl)-1H-pyrrol-3-yl)ethanone (I-33 )

[0208]Put 160mg (0.63mmol) of compound I-1 in a 50mL one-mouth bottle with anhydrous DMF solvent, stir in an ice bath and add 50mL NaHH (1.26mmol), add CH3I 0.051mL (0.82mmol) after 20mins, react at room temperature for 5h, TLC detects that the reaction is complete . The reaction solution was poured into 100 mL of water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and left to stand. After filtration, the solvent was distilled off under reduced pressure and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:9) to obtain 148 mg of solid with a yield of 83.44%. ESI-MS m / z: 304.3[M+Na] + . 1 H-NMR (300MHz, DMSO-d 6 )δ: 7.70-7.61 (m, 2H, ArH), 7.21-7.15 (m, 2H, ArH), 3.94 (s, 3H, -CH 3 ), 3.54(s, 3H, -CH 3 ), 2.48(s, 3H, O=C-CH 3 ), 2.43 (s, 3H,...

Embodiment 6

[0210] 2-(4-Acetyl-3,5-dimethyl-1H-pyrrol-2-yl)-1H-benzo[d]imidazole-6-carboxylic acid (I-d)

[0211] Add 165mg (1.00mmol) of compound (I-c), 152mg (1.00mmol) of 3,4-diaminobenzoic acid, 19mg (0.10mmol) of sodium metabisulfite, and 10mL of ethanol into a 50mL two-necked flask in turn, under nitrogen protection, and heat at 90°C After 5 h, TLC detected that the reaction was complete. After cooling, the reaction solution was poured into 100 mL of water, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and left to stand. After filtration, the solvent was distilled off under reduced pressure and separated by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 266 mg of an orange-yellow solid with a yield of 89.47%. ESI-MS m / z: 320.2[M+Na] + . 1 H-NMR (300MHz, DMSO-d 6 )δ: 12.38 (s, 1H, -COOH), 12.21 (s, 1H, -NH), 10.92 (s, 1H, -NH), 8.41 (s, 1H, ArH),...

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Abstract

The invention relates to the field of medicinal chemistry, in particular to pyrrolone derivatives, a preparation method of the pyrrolone derivatives, a pharmaceutical composition containing the compounds and medical purposes of the pharmaceutical composition, particularly an antitumor purpose of the pharmaceutical composition as a BRD4 protein inhibitor.

Description

technical field [0001] The present invention relates to pyrrolidone derivatives, a preparation method as a BRD4 protein inhibitor, a pharmaceutical composition containing these compounds and their medical application. Background technique [0002] Epigenetics refers to heritable changes in gene expression that do not change in DNA sequence. This change is a change in the heritable material other than genetic information in the cell, and this change can be stably transmitted during development and cell proliferation. Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes and contributes to the understanding of human disease. Epigenetics and epigenetic therapy have rapidly become one of the most promising fields in drug discovery. Epigenetic mechanisms include DNA methylation, non-coding RNA regulation, histone post-translational modifications (PTMs), and chromatin remodeling. Histone post-translational modif...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/14C07D413/04C07D417/04C07D403/14A61K31/4184A61K31/5377A61K31/454A61K31/496A61K31/428A61K31/423A61K31/4439A61K31/506A61K31/404A61K31/4155A61P35/00A61P35/02
CPCC07D401/14C07D403/04C07D403/14C07D413/04C07D417/04
Inventor 陈亚东姜飞马宇李慧丽崔勇陆涛唐伟方张德伟卞媛媛王志杰刘峰涛侯少华陈海芳
Owner CHINA PHARM UNIV
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