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1,3-Substituted-5-Acetamidolindolinone Compounds and Their Application in Antineoplastic Drugs

A technology of acetaminoindolinone and acetamidoindoledione, which is applied in the field of pharmaceutical applications, and achieves the effects of simple operation process, short synthetic route and low cost

Active Publication Date: 2016-05-04
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-Acetamidolindolinone Compounds and Their Application in Antineoplastic Drugs
  • 1,3-Substituted-5-Acetamidolindolinone Compounds and Their Application in Antineoplastic Drugs
  • 1,3-Substituted-5-Acetamidolindolinone Compounds and Their Application in Antineoplastic Drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] R 1 is methyl, R 2 For the synthesis of oxime group, i.e. 1-methyl-3-oxime-5-acetylaminoindolinone, the specific steps are as follows:

[0053] (1) Synthetic intermediate 5-nitroindoledione

[0054] Weigh 5.00g (33.98mmol) of isatin and 3.44g (33.98mmol) of potassium nitrate, dissolve them slowly in 20mL and 15mL of concentrated sulfuric acid respectively under stirring, and then dissolve isatin at 0~-4℃ Slowly drop the concentrated sulfuric acid solution into the concentrated sulfuric acid solution of potassium nitrate, continue to stir for 30 minutes after the dropwise addition, then stir at room temperature for 10 minutes, TLC detects that the reaction is complete, pour it into the ice-water mixture, stir for 30 minutes, and suction filter to obtain a yellow solid. After drying in a vacuum 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=8.8,A...

Embodiment 2

[0075] R 1 is 4-bromobenzyl, R 2 For the synthesis of oxime group, i.e. 1-(4-bromobenzyl)-3-oxime-5-acetamidolindolinone, the specific steps are as follows:

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

[0077] Weigh 0.20 g (0.98 mmol) of 5-acetylaminoindolinone into a 25 mL round-bottomed flask, add 3 mL of N,N-dimethylformamide, and then slowly add 0.41 g of anhydrous potassium carbonate while stirring in an ice bath (2.94mmol), and finally added 0.27g (1.08mmol) of 4-bromobenzyl bromide, stirred at room temperature for 5min, and heated to reflux at 65°C for 2h. TLC detected that the reaction was complete, quenched by adding 15 mL of water, extracted three times with ethyl acetate, combined the organic phases, dried the organic phases with anhydrous sodium sulfate, and spun off the solvent under reduced pressure, petroleum ether: ethyl acetate = 2:1, 200 mesh Silica gel column chromatography purification. 0.31 g of 1-(4-bromobenzyl)-5...

Embodiment 3

[0083] R 1 is 4-methylbenzyl, R 2For the synthesis of oxime group, i.e. 1-(4-methylbenzyl)-3-oxime-5-acetamidolindolinone, 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 of anhydrous potassium carbonate while stirring in an ice bath (2.94mmol), and finally added 0.15g (1.08mmol) of 4-methylbenzyl chloride, stirred at room temperature for 5min, and heated to reflux at 65°C for 2h. TLC detected that the reaction was complete, quenched by adding 15 mL of water, extracted three times with ethyl acetate, combined the organic phases, dried the organic phases with anhydrous sodium sulfate, and spun off the solvent under reduced pressure, petroleum ether: ethyl acetate = 2:1, 200 mesh Silica gel column chromatography purification. 0.26 g of 1-(4-methylbenzyl)-5-acety...

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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, in particular to a class of 1,3-substituted-5-acetylaminoindolinone compounds and their application in antitumor drugs. technical background [0002] Indolinone is an important class of natural products, which are endogenous active substances present in mammalian tissues and body fluids. Indolinone derivatives have a variety of biological activities, such as anticancer, antispasmodic, antituberculosis, 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 research of its derivatives. Therefore, the organic synthesis based on indolinone 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 physicochemical properties and biologi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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