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Indolone derivative as well as preparation method and application thereof

A technology of compounds and metabolites, applied in the field of medicine, can solve the problem of no BRD4 inhibitor on the market yet

Active Publication Date: 2019-06-25
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Currently, several BRD4 inhibitors are in the clinical research stage, and the indications are mainly tumors, but no BRD4 inhibitor has been marketed yet

Method used

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  • Indolone derivative as well as preparation method and application thereof
  • Indolone derivative as well as preparation method and application thereof
  • Indolone derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0225] Example 1: 5-(3,5-dimethylisoxazol-4-yl)-3'-H-spiro[indole-3,1'-isobenzofuran]-2-one (compound 30 ) preparation

[0226]

[0227] The first step: preparation of compound 30b

[0228] Compound 30a (1.0g, 5.4mmol) was dissolved in 20mL MeOH, and NaBH was added under ice-cooling 4 (1.0 g, 5.6 mmol), reacted at room temperature for 2 h, the reaction solution was extracted with EA, concentrated, and purified by silica gel column chromatography to obtain compound 30b (1 g).

[0229] The second step: the preparation of compound 30e

[0230] Compound 30d (9.04g, 40mmol) was dissolved in 90mL DMF, NaH (2.4g, 60mmol) was added in batches at 0°C, stirred at room temperature for 30min, compound 30c was added dropwise, reacted at room temperature for 2h, and purified by silica gel column chromatography to obtain the compound 30e (7.2g).

[0231] The third step: the preparation of compound 30f

[0232] Compound 30b (0.54g, 2.9mmol) was dissolved in 10mL THF, n-BuLi (2.3mL, 5....

Embodiment 2

[0239] Example 2: Preparation of 5-(3,5-dimethylisoxazol-4-yl)spiro[indole-3,1'-isochroman]-2-one (compound 31)

[0240]

[0241] The first step: preparation of compound 31c

[0242] Compound 31b (1.28g, 6.36mmol) was dissolved in 10mL THF, n-BuLi (5.1mL, 12.7mmol) was added dropwise at -78°C, stirred at -78°C for 30min, and compound 31a (2.0g, 5.78 mmol) THF solution was added dropwise to the reaction system, reacted at -78°C for 30 min, then naturally raised to room temperature for 1 h, and was separated and purified by silica gel column chromatography to obtain compound 31c (1.5 g).

[0243] The second step: the preparation of compound 31d

[0244] Compound 31c, PPh 3 (1.26g, 4.81mmol) dissolved in 10mLTHF, N 2 Protected, DEAD (0.838g, 4.81mmol) was added dropwise at -10°C, reacted at room temperature for 1h, separated and purified by silica gel column chromatography to obtain compound 31d (1.3g).

[0245] The third step: the preparation of compound 31f

[0246] Com...

Embodiment 3

[0249] Example 3: 5'-(3,5-Dimethylisoxazol-4-yl)-2,2-dimethylspiro[[d][1,3]benzodioxin-4,3 Preparation of '-indoline]-2'-one (compound 32)

[0250]

[0251] The first step: preparation of compound 32c

[0252] Compound 32b (5.51 g, 32 mmol) was dissolved in 30 mL THF, N 2 protection, at -75°C, add n-BuLi dropwise to the system, after 1h, dissolve 32a (6.0g, 26mmol) in 50mL THF and add dropwise to the reaction system, naturally rise to room temperature and react overnight, pass through a silica gel column Chromatography afforded compound 32c (1.72).

[0253] The second step: the preparation of compound 32e

[0254] Compound 32c (1.72g, 5.41mmol), 32d (1.45g, 6.49mmol), K 2 CO 3 (1.86g, 13.52mmol) and Pd(dppf)Cl 2 (396mg, 0.54mmol) dissolved in 40mL dioxane and 8mL water, N 2 protected, reacted overnight at 100°C, and obtained compound 32e (500 mg) by silica gel column chromatography.

[0255] The third step: the preparation of compound 32

[0256] Compound 32e (172m...

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PUM

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Abstract

The invention relates to a compound represented by formula (A) or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorphic substance, a solvate, a metabolite or a prodrug thereof,and also relates to a pharmaceutical composition containing the compound. The compound can be used for treating cancer or immune system diseases.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to an indolinone derivative, a preparation method and application thereof, and a pharmaceutical composition containing the indolinone derivative. The indolinone derivatives can be used for treating cancer or immune system diseases. Background technique [0002] Cancer is a major disease that seriously endangers the quality of life and health of human beings. Tumor immunotherapy has become a promising new therapy for tumor treatment because of its effectiveness, safety, and low adverse reactions. It obtains anti-tumor effects by mobilizing or restoring the host's natural defense mechanisms. [0003] BET (Bromodomains and extra-terminal) proteins belong to the BRD (Bromodomain) family and are key protein molecules that recognize and bind acetylated lysine. The BET protein family mainly includes BRD2, BRD3, BRD4 and BRDT. BET protein contains two tandem conserved bromodomains (Bromodomain) BD1...

Claims

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Application Information

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IPC IPC(8): C07D491/107C07D471/10C07D513/10C07D487/10C07D413/04C07D413/14C07D498/10C07D491/113A61K31/496A61K31/4747A61K31/429A61K31/527A61K31/5377A61K31/422A61K31/549A61K31/537A61K31/427A61K31/4155A61P35/00A61P35/02A61P37/02
Inventor 朱加望蔡家强李桂英游泽金吴勇勇韩润丰葛勇王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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