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Pyrrole BET inhibitor and preparation method and application thereof

A technology of pyrrole and compound, which is applied in the field of medicinal chemistry, can solve problems such as single structure, compound PK properties and in vitro properties, etc., and achieve the effect of easy-to-obtain raw materials, excellent drug-making properties, and excellent anti-tumor cell proliferation activity

Active Publication Date: 2021-08-17
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above types of inhibitors are relatively simple in structure, and the PK properties and in vitro properties of the compounds are not very ideal

Method used

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  • Pyrrole BET inhibitor and preparation method and application thereof
  • Pyrrole BET inhibitor and preparation method and application thereof
  • Pyrrole BET inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] 1-{2-Methyl-5-[5-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-b]pyridin-2-yl]-4-phenyl-1H -Pyrrol-3-yl}ethan-1-one (I-1)

[0085]

[0086] Step 1, 1-(2-methyl-4-phenyl-1H-pyrrol-3-yl)ethan-1-one (I-1a)

[0087] At room temperature, dissolve 1.0g (7.40mmol) of 2-amino-1-phenylethan-1-one, 3.64g (44.39mmol) of sodium acetate and 0.87g (8.73mmol) of acetylacetone in 10mL of 50% ethanol aqueous solution middle. After adding, heat up to 85°C, N 2 Reaction under protection for 3h. After the reaction, the reaction solution was cooled to room temperature, 100 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, suction filtered, and evaporated to dryness. The crude product was purified by column chromatography to obtain 1.04 g of light yellow solid with a yield of 70.6%. ESI-MS m / z:200.3[M+H] + .

[0088] Step 2, 4-acetyl-5-methy...

Embodiment 2

[0097] 1-{2-Methyl-5-[2-(4-methylpiperazin-1-yl)-7H-purin-8-yl]-4-phenyl-1H-pyrrol-3-yl}Eth- 1-keto (I-2)

[0098]

[0099] Step 1, 2-(4-methylpiperazin-1-yl)-5-nitropyrimidin-4-amine (I-2a)

[0100] Under the condition of ice bath, dissolve 1g (5.16mmol) of 2,4-dichloro-5-nitropyrimidine in 5mL of dichloromethane, control the temperature (-5)°C-0°C, and slowly add 0.88g of 30% ammonia water dropwise (15.47 mmol). After dropping, react at room temperature for 2h. After the reaction was completed, 10 mL of water was added to the reaction solution, the aqueous phase was extracted with dichloromethane (1 mL×3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered with suction, evaporated to dryness, and the crude product was purified by column chromatography. 0.73 g of a light yellow solid was obtained with a yield of 81.1%. ESI-MS m / z:175.5[M+H] + .

[0101] At room temperature, 0.7 g (4.01 mmol) of the above light yellow so...

Embodiment 3

[0107] 1-[5-(1H-imidazo[4,5-c]pyridin-2-yl)-2-methyl-4-phenyl-1H-pyrrol-3-yl]ethan-1-one (I- 3)

[0108]

[0109] Step 1, 1-[5-(1H-imidazo[4,5-c]pyridin-2-yl)-2-methyl-4-phenyl-1H-pyrrol-3-yl]ethan-1-one (I-3)

[0110] At room temperature, 0.2 g (1.83 mmol) of pyridine-3,4-diamine, 0.46 g (2.02 mmol) of I-1b and 0.031 g (0.183 mmol) of sodium metabisulfite were dissolved in 5 mL of absolute ethanol. After the addition was completed, the temperature was raised to 80°C for 20 hours. After the reaction, the reaction solution was cooled to room temperature, 20 mL of water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, filtered with suction, and evaporated to dryness. The crude product was purified by column chromatography to obtain 0.21 g of a light yellow solid with a yield of 35.5%. ESI-MS m / z:317.4[M+H] + . 1 H NMR (500MHz, Chloro...

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Abstract

The invention discloses a pyrrole BET inhibitor and a preparation method and application thereof. The compound is a structure as shown in a general formula (I) or one or a mixture of more of a tautomer, a meso-mer, a raceme, an enantiomer and a diastereoisomer of the compound, or a pharmaceutically acceptable salt of the compound. According to the compound or the mixture thereof or the pharmaceutically acceptable salt thereof, ethyl acetoacetate derivatives and amino aryl ethyl ketone serve as starting raw materials, the compound of the general formula (I) is obtained through a continuous reaction, the preparation method is simple and convenient, the raw materials are easy to obtain, and the preparation method has good applicability, and the medicine taking the derivative as an active ingredient can be used in medicines for effectively preventing and / or treating BET protein related diseases.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the pyrrole BET inhibitor and its preparation method and application, especially the use as a BET protein inhibitor. Background technique [0002] In recent years, tumors have become one of the main causes of human death worldwide. Tumors generally have the characteristics of low overall cure rate and high recurrence rate. Therefore, prevention, treatment and suppression of tumor recurrence have important scientific research value. It is quite urgent and challenging to realize the prevention and cure of tumors. [0003] Bromodomains (BRDs) are conserved protein domains that can specifically recognize acetylated lysine residues in histones. BRDs exist in different proteins and play key regulatory roles in chromatin assembly and gene transcription. Small molecule inhibitors of BRDs can interfere with the specific binding of BRDs domains to acetylated lysine, thereby blocking or...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D473/32C07D487/04C07D403/04A61K31/496A61K31/52A61K31/4985A61K31/5377A61K31/4184A61P19/02A61P19/06A61P35/00A61P35/02
CPCC07D471/04C07D473/32C07D487/04C07D403/04A61P19/02A61P19/06A61P35/00A61P35/02
Inventor 陈亚东陆涛孔博洪谦谦朱照宏唐伟方
Owner CHINA PHARM UNIV
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