An anti-tumor compound and its preparation method, application, and pharmaceutical compositions

An anti-tumor and compound technology, applied in the field of medicine, can solve problems such as low efficacy, cytotoxicity, and difficulty in reaching the level of cytotoxicity of drugs

Inactive Publication Date: 2013-02-13
ANHUI SIWEI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is also because of this hypoxic blood supply that it is difficult for drugs to reach cytotoxic levels
In these hypoxic are

Method used

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  • An anti-tumor compound and its preparation method, application, and pharmaceutical compositions
  • An anti-tumor compound and its preparation method, application, and pharmaceutical compositions
  • An anti-tumor compound and its preparation method, application, and pharmaceutical compositions

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preparation example Construction

[0034] see image 3 , which is a flowchart of the preparation method of the antitumor compound of the present invention. The preparation method of this antitumor compound comprises the following steps:

[0035] Phosphorus oxychloride (POCL 3 ) was dissolved in acetonitrile (MeCN), cooled to minus 30°C, and reacted with 4-nitro-substituted benzyl alcohol and triethylamine (TEA) to form a reaction mixture with structural formula II, which is:

[0036] ;

[0037]Structural formula is that the reaction mixture of II is dissolved in acetonitrile, adds 2-chloroethylamine hydrochloride (H 2 NCH 2 CH 2 CL) and triethylamine, stirred overnight at room temperature (RT);

[0038] Triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated, separated and purified by silica gel chromatography, suction filtered, and dried to form a solid antitumor compound with structural formula I.

[0039] The antitumor compound of the present invention can be applied...

Embodiment 1

[0046]

[0047] Preparation of 4-nitro-2-chlorobenzyl N,N'-bis(2-chloroethyl)phosphoramidate: Add 10 g (65 mmol) of phosphorus oxychloride to a 1-liter three-necked flask and 40 ml of acetonitrile, cooled to minus 30°C. In a 1-liter three-necked flask, add 13 g of 4-nitro-2-chlorobenzyl alcohol (65 mmol) and 9.1 mL of triethylamine (65 mmol), and 20 mL of acetonitrile as solvent. Into the cooled solution of phosphorus oxychloride, 4-nitro-2-chlorobenzyl alcohol / triethylamine solution, keeping the reaction temperature at -30°C for 15 minutes. Thereafter, to the above reaction mixture, 15.1 g of 2-chloroethylamine hydrochloride (130 mmol) was added, followed by 36.3 ml of triethylamine (262 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered to remove triethylamine hydrochloride, concentrated by rotary evaporation, and separated and purified by silica gel chromatography. The product is a white solid, ...

Embodiment 2

[0051]

[0052] Preparation of 4-nitro-2-methoxybenzyl N,N'-bis(2-chloroethyl)phosphoramidate: Add 10 g (65 mmol) of trichloride to a 1-liter three-necked flask Oxonphosphorus and 40 ml of acetonitrile were cooled to minus 30°C. In a 1-L three-necked flask, add 11.9 g of 4-nitro-2-methoxybenzyl alcohol (65 mmol) and 9.1 mL of triethylamine (65 mmol), and 20 mL of acetonitrile for solvent. Into the cooled solution of phosphorus oxychloride, 4-nitro-2-methoxybenzyl alcohol / triethylamine solution, keeping the reaction temperature at -30°C for 15 minutes. Thereafter, to the above reaction mixture, 15.1 g of 2-chloroethylamine hydrochloride (130 mmol) was added, followed by 36.3 ml of triethylamine (262 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was filtered to remove triethylamine hydrochloride, concentrated by rotary evaporation, and separated and purified by silica gel chromatography. The product is a wh...

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Abstract

The present invention discloses an anti-tumor compound and its preparation method,application, and pharmaceutical compositions. The anti-tumor compound is a 4 - nitro-substituted benzyl group ifosfamide ester prodrug thereof, or pharmaceuticallysalt, or solvate thereof of the structure of formula I. The structure of formula I. The present invention has the following advantage of being used for the treatment or prevention of mammalian tumor-related diseases, such as leukemia, hemangioma, glioma, Kaposi's sarcoma, ovarian cancer, breast cancer, lung cancer, pancreatic cancer, lymphoma, prostate, colon and skin tumors and their complications.

Description

technical field [0001] The present invention relates to the field of medicine, in particular to an antitumor compound, its preparation method, application and pharmaceutical composition. Background technique [0002] In rapidly growing tumors, the lack and lack of blood vessels in the tissue constitute areas of tumor hypoxia. It is also because of this hypoxic blood supply that it is difficult for drugs to reach cytotoxic levels. In these hypoxic areas, radiation therapy has little effect, and radiation cannot generate sufficient oxygen free radicals, resulting in cytotoxicity. In recent years, anaerobic bacteria with ultra-low oxygen characteristics have been used as transfer carriers for tumor gene therapy (scholars from the United Kingdom, the United States, etc.), and drugs are carried to hypoxic necrosis areas in solid tumors; The drug is highly selectively activated and decomposed in the anaerobic zone to release the anti-tumor medicinal ingredients (scholars from Ne...

Claims

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Application Information

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IPC IPC(8): C07F9/24A61K31/664A61P35/00A61P35/02
Inventor 林旭王世亮
Owner ANHUI SIWEI PHARMA
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