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Hypoxic selective antitumor prodrug benzpyrole [2,3-b] quinoxaline-11-oxygen derivative, medicine composition, preparation method and application

An oxygen-selective, anti-tumor technology, applied in the direction of anti-tumor drugs, drug combinations, pharmaceutical formulations, etc., can solve the problems of poor selectivity, toxic and side effects, etc., and achieve a good effect of hypoxic selective activity

Inactive Publication Date: 2015-10-21
HEBEI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In 1959, Goodwin and others isolated ellipticine for the first time from the elliptic rose tree of the Apocynaceae plant. It has good anti-tumor and anti-viral activities, but it also has the disadvantages of poor selectivity and easy to produce toxic side effects

Method used

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  • Hypoxic selective antitumor prodrug benzpyrole [2,3-b] quinoxaline-11-oxygen derivative, medicine composition, preparation method and application
  • Hypoxic selective antitumor prodrug benzpyrole [2,3-b] quinoxaline-11-oxygen derivative, medicine composition, preparation method and application
  • Hypoxic selective antitumor prodrug benzpyrole [2,3-b] quinoxaline-11-oxygen derivative, medicine composition, preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 compound Ⅰ-a

[0046] (1) Compound B 1 【C 16 h 12 N 3 OBr, the preparation of 6-(2-bromoethyl)-11-oxo-6H-indole[2,3-b]quinoxaline]:

[0047] In a reaction flask equipped with a reflux condenser, weigh 6-(2-bromoethyl)-6H-indole[2,3-b]quinoxaline (compound A 1 , 3.26g, 10mmol) and m-chloroperoxybenzoic acid (5.16g, 30mmol), add 150mL of dichloromethane, stir and heat to 50°C, reflux for 24h, cool to room temperature, and concentrate at -0.1MPa, 25°C Afterwards, it was separated by silica gel column chromatography, and then eluted with dichloromethane. After the obtained eluent was evaporated to remove the solvent and dried in vacuo, 2.72g of a yellow solid was obtained, which was Compound B 1 , yield 76%.

[0048] (2) Compound Ⅰ-a【C 19 h 14 N 6 o 3 , the preparation of 6-(2-(1-(2-nitro-1H-imidazole)) ethyl)-11-oxo-6H-indole [2,3-b] quinoxaline]:

[0049] In a reaction flask equipped with a reflux condenser, weigh 6-(2-bromoethyl...

Embodiment 2

[0058] The preparation of embodiment 2 compound Ⅰ-b

[0059] (1) Compound B 2 【C 18 h 16 N 3 OBr, the preparation of 6-(4-bromobutyl)-11-oxo-6H-indole[2,3-b]quinoxaline]:

[0060] In a reaction flask equipped with a reflux condenser, weigh 6-(4-bromobutyl)-6H-indole[2,3-b]quinoxaline (compound A 2 , 3.55g, 10mmol) and m-chloroperoxybenzoic acid (5.16g, 50mmol), add 150mL of dichloromethane, stir and heat to 50°C, reflux for 24h, cool to room temperature, and concentrate at -0.1MPa, 25°C Afterwards, it was separated by silica gel column chromatography, and then eluted with dichloromethane. After the obtained eluent was evaporated to remove the solvent and vacuum-dried, 2.37g of yellow solid was obtained, which was compound B 2 , yield 64%.

[0061] (2) Compound Ⅰ-b【C 21 h 18 N 6 o 3 , the preparation of 6-(4-(1-(2-nitro-1H-imidazole)) butyl)-11-oxo-6H-indole [2,3-b] quinoxaline]:

[0062] In a reaction flask equipped with a reflux condenser, weigh 6-(4-bromobutyl)-11...

Embodiment 3

[0071] The preparation of embodiment 3 compound I-c

[0072] (1) Compound B 3 【C 20 h 20N 3 OBr, the preparation of 6-(6-bromohexyl)-11-oxo-6H-indole[2,3-b]quinoxaline]:

[0073] In a reaction flask equipped with a reflux condenser, weigh 6-(6-bromohexyl)-6H-indole[2,3-b]quinoxaline (compound A 3 , 3.99g, 10mmol) and m-chloroperoxybenzoic acid (5.16g, 30mmol), add 150mL of dichloromethane, stir and heat to 50°C, reflux for 24h, cool to room temperature, and concentrate at -0.1MPa, 25°C Afterwards, it was separated by silica gel column chromatography, and then eluted with dichloromethane. After the obtained eluent was evaporated to remove the solvent and dried in vacuo, 2.25 g of a yellow solid was obtained, which was compound B 3 , yield 62%.

[0074] (2) Compound Ⅰ-c【C 23 h 22 N 6 o 3 , the preparation of 6-(6-(1-(2-nitro-1H-imidazolium) hexyl)-11-oxo-6H-indole[2,3-b]quinoxaline]:

[0075] In a reaction flask equipped with a reflux condenser, weigh 6-(6-bromohexyl)...

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Abstract

The invention discloses a hypoxic selective antitumor prodrug benzpyrole [2,3-b] quinoxaline-11-oxygen derivative which has a general structural formula shown in the formula (I), wherein a group R is H or F, and n is 2, 4 or 6. Additionally, the invention further discloses a preparation method of the derivative and an application to the preparation of antitumor prodrug. Hydroxyl radicals are generated by the benzpyrole [2,3-b] quinoxaline-11-oxygen derivative in the reducing environment of hypoxic cells, tumor cells are killed by the hydroxyl radicals by damaging DNA, 2-nitroimidazole side chains are reduced to form nitroso derivatives, hydroxylamine and amine in the reducing environment of the hypoxic cells, and reduction products can be coupled with the DNA; the benzpyrole [2,3-b] quinoxaline-11-oxygen derivative is not reduced in the normal oxygen environment, so that the benzpyrole [2,3-b] quinoxaline-11-oxygen derivative shows good hypoxic selective activity and can be used for preparing medicines for treating solid tumors.

Description

technical field [0001] The present invention relates to an anti-tumor prodrug compound, specifically a hypoxia-selective anti-tumor prodrug indole [2,3-b]quinoxaline-11-oxygen derivative, a pharmaceutical composition and a preparation method and apply. Background technique [0002] Malignant tumors, as one of the largest public health problems in the world, have greatly endangered human health and will become the number one killer of human beings in the new century. According to the statistics of the World Health Organization, there are 76 million cancer patients in the world, 7 million new cases are added every year, and 6 million deaths due to cancer account for 12% of the total death toll. It is estimated that there will be 15 million new cases by 2015 . my country is a country with a high incidence of malignant tumors. As a large developing country, due to the acceleration of industrialization, urbanization and population aging, the existence of unhealthy lifestyles a...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/4985A61P35/00
CPCC07D487/04
Inventor 张金超王晋杰王书香李胜辉周国强
Owner HEBEI UNIVERSITY