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1,3-substituted-5-acetaminoindolone compounds and application thereof to anti-tumor drugs

A technology of acetamido indole ketone and acetamido indole dione is applied in the field of pharmaceutical application and achieves the effects of short synthesis route, low cost and simple operation process

Active Publication Date: 2014-02-05
无锡珉琰管理咨询服务有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the 1,3-substituted derivative synthesis based on 5-acetylaminoindoledione has not been reported, and people's attention and research are urgently needed.

Method used

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  • 1,3-substituted-5-acetaminoindolone compounds and application thereof to anti-tumor drugs
  • 1,3-substituted-5-acetaminoindolone compounds and application thereof to anti-tumor drugs
  • 1,3-substituted-5-acetaminoindolone compounds and application thereof to anti-tumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] R 1 Is methyl, R 2 It is the oxime group, namely the synthesis of 1-methyl-3-oxime-5-acetamidoindolinone, the specific steps are as follows:

[0053] (1) Synthesis of intermediate 5-nitroindole dione

[0054] Weigh 5.00g (33.98mmol) of isatin and 3.44g (33.98mmol) of potassium nitrate, and slowly dissolve them in 20mL and 15mL of concentrated sulfuric acid under stirring. Then, at 0~-4℃, The concentrated sulfuric acid solution was slowly dropped into the concentrated sulfuric acid solution of potassium nitrate. After the addition, the stirring was continued for 30 minutes, and then stirred at room temperature for 10 minutes. TLC detected that the reaction was complete. Pour it into the ice-water mixture, stirred for 30 minutes, and suction filtered to obtain a yellow solid. After drying in a vacuum drying oven, 5.72 g of the target product 5-nitroindoledione was obtained with a yield of 87.6%.

[0055] 1 HNMR(DMSO400MHz): δ / ppm7.09(d,1H,J=8.8,ArH), 8.21(s,1H,ArH), 8.44(d,1H,J...

Embodiment 2

[0075] R 1 Is 4-bromobenzyl, R 2 It is the oxime group, namely the synthesis of 1-(4-bromobenzyl)-3-oxime-5-acetamidoindolinone, the specific steps are as follows:

[0076] (1) Synthesis of intermediate 1-(4-bromobenzyl)-5-acetamidoindoledione

[0077] Weigh 0.20g (0.98mmol) of 5-acetylaminoindolinone into a 25mL round bottom flask, add 3mL N,N-dimethylformamide, and then slowly add 0.41g anhydrous potassium carbonate while stirring in an ice bath (2.94 mmol), and finally add 0.27 g (1.08 mmol) of 4-bromobenzyl bromide, stir at room temperature for 5 min, and heat to reflux at 65° C. for 2 h. TLC detects that the reaction is complete, add 15 mL of water for quenching, extract three times with ethyl acetate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, spin off the solvent under reduced pressure, petroleum ether: ethyl acetate = 2:1, 200 mesh Purified by silica gel column chromatography. 0.31 g of 1-(4-bromobenzyl)-5-acetylaminoindoledione was o...

Embodiment 3

[0083] R 1 Is 4-methylbenzyl, R 2 It is an oxime group, namely the synthesis of 1-(4-methylbenzyl)-3-oxime-5-acetamidoindolinone, the specific steps are as follows:

[0084] (1) Synthesis of intermediate 1-(4-methylbenzyl)-5-acetylaminoindolinone

[0085] Weigh 0.20g (0.98mmol) of 5-acetylaminoindolinone into a 25mL round bottom flask, add 3mL N,N-dimethylformamide, and then slowly add 0.41g anhydrous potassium carbonate while stirring in an ice bath (2.94mmol), finally add 0.15g (1.08mmol) of 4-methylbenzyl chloride, stir at room temperature for 5min, and heat to reflux at 65°C for 2h. TLC detects that the reaction is complete, add 15 mL of water for quenching, extract three times with ethyl acetate, combine the organic phases, dry the organic phases with anhydrous sodium sulfate, spin off the solvent under reduced pressure, petroleum ether: ethyl acetate = 2:1, 200 mesh Purified by silica gel column chromatography. 0.26 g of 1-(4-methylbenzyl)-5-acetylaminoindoledione was obtai...

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Abstract

The invention relates to 1,3-substituted-5-acetaminoindolone compounds and an application thereof to anti-tumor drugs. The compounds are 1-methyl-5-acetamino-2-indolinone, 1-(4-bromobenzyl)-5-acetamino-2-indolinone, 1-(4-methylbenzyl)-3-oxime-5-acetaminoindolone, 1-(4-methoxybenzyl)-3-oxime-5-acetaminoindolone and the like. The in-vitro tumor cell inhibitory activities of the 1,3-substituted-5-acetaminoindolone compounds synthesized in the invention are tested and the results show that such kind of compounds have certain inhibiting effects (IC50(100mu M)) on human leukemia cells (K562), human colon cancer cells (HT-29) and human liver cancer cells (HepG2), have anti-tumor activities and can be used for preparing anti-tumor drugs.

Description

Technical field [0001] The invention belongs to the field of drug application, and specifically relates to a class of 1,3-substituted-5-acetamidoindolinone compounds and their application in antitumor drugs. technical background [0002] Indolinone is an important natural product. It is an endogenous active substance that exists in mammalian tissues and body fluids. Indolinone derivatives have a variety of biological activities, such as anti-cancer, anti-spasm, anti-tuberculosis, antibacterial, Anti-virus etc. Various types of chemical reactions can occur on the pyrrole ring and benzene ring of indolinone, which provides a broad space for the study of its derivatives. Therefore, indolinone-based organic synthesis and the synthesis of its derivatives and biological Active research is very active. [0003] Substitution and derivatization of different substituents at different positions of indolinone will make it have different physical and chemical properties and biological activit...

Claims

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Application Information

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IPC IPC(8): C07D209/38C07D209/40A61K31/404A61P35/00A61P35/02
CPCC07D209/38C07D209/40
Inventor 郁彭刘丰喜孙华滕玉鸥郭茜楠韩开林李欢欢杨尧宋彬彬
Owner 无锡珉琰管理咨询服务有限公司
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