Quinazolinyl-aryl urea derivatives with antitumor function and application thereof

A technology of aryl urea derivatives and quinazoline, which is applied in the field of medicine, can solve the problems of tumor cell line induction of apoptosis, influence of intracellular active oxygen levels, and insufficient research

Active Publication Date: 2015-01-21
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, it is unclear whether it can be used as a multi-target anti-tumor drug, and its effect on the treatment of advanced renal cancer, non-small cell lung cancer, gastric cancer and other malignant tumors has not been reported. Supported by basic experimental data such as induction of apoptosis by tumor cell lines, cycle arrest, and effects on intracellular reactive oxygen species levels

Method used

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  • Quinazolinyl-aryl urea derivatives with antitumor function and application thereof
  • Quinazolinyl-aryl urea derivatives with antitumor function and application thereof
  • Quinazolinyl-aryl urea derivatives with antitumor function and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0139] Preparation of isocyanate series compounds

[0140] For different isocyanates, it is advisable to use one of the following two methods to synthesize them: if the boiling point of the isocyanate is low, it can be prepared by general method one; and for the higher boiling point, it can be obtained by general method two. The prepared isocyanate is easy to absorb moisture in the air and hydrolyzes, so it is not suitable for further purification, and can be stored dry or used directly in the reaction.

[0141] General method 1: Add triphosgene (BTC, 18mmol, 0.5eqv.) and solvent dichloroethane (DCE, 20mL) to a 250mL flask in an ice bath and stir. After dissolving, slowly add Aniline or its derivatives (36 mmol) in DCE solution (10 mL), keep the temperature of the reaction system at 0-5°C. The dropwise addition time is about 1 hour. At this time, the reaction system becomes turbid. After the dropwise addition, it rises to room temperature and reacts for 1 hour, and then heats...

Embodiment 2-39

[0180] The structure of each compound in the quinazoline-aryl urea derivatives is shown in Table 1, including two series of products in Table 1, series I: N-substituted phenyl-N'-{3-[(6,7 -Dimethoxy-4-aminoquinazoline)benzyl]}urea, including compound I-1~compound I-19; series II: N-substituted phenyl-N'-{3-[(4-amino Quinazoline) benzyl]} urea, including compound II-1 to compound II-19.

[0181] The two series of product structural formulas that embodiment 2-39 obtains are as follows:

[0182]

[0183] Table 1

[0184]

[0185]

Embodiment 2

[0188] N-(2-methoxyphenyl)-N'-{3-[(6,7-dimethoxyquinazoline-4-amino)methyl]phenyl}urea (Compound I-1)

[0189] Step A: Preparation of 6,7-dimethoxyquinazolin-4-one

[0190] Add 2-amino-6,7-dimethoxybenzoic acid methyl ester (20g, 94.7mmol), formamide (160mL), formic acid (4mL) to a 250mL round bottom flask successively, reflux at 160°C for 10h, TLC ( V 乙酸乙酯 :V 石油醚 =1:1) to monitor the completion of the reaction, quickly pour the resulting mixture into ice water, stir, and let it stand for a while, the solid precipitates, is filtered by suction, washed with distilled water (3×15mL), ethyl acetate (3×15mL) ), dried, recrystallized from ethyl acetate, and dried to obtain off-white granular crystals, namely the product (16.44g, 84.22%). m.p.282.1~288.4℃. 1 H NMR (500MHz, DMSO-d 6 )δ(ppm):7.99(s,1H),7.45(s,1H),7.14(s,1H),3.91(s,3H),3.87(s,3H).ESI-HRMS(m / z): calcd.for C 10 h 10 N 2 o 3 [(M+H) + ], 207.07250; found, 207.07244.

[0191] Step B: Preparation of 4-chloro-6,7-...

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Abstract

The invention relates to quinazolinyl-aryl urea derivatives with antitumor function disclosed as general formula (II) and application thereof. The substituent group in the general formula (II) is defined in the specification. By using sorafenib and gefitinib as lead compounds, the pharmacophore-uramido group of the sorafenib is retained; and meanwhile, the quinazoline rings in the gefitinib and other EGFR-TKIs are retained to synthesize a series of quinazolinyl-aryl urea derivatives. The in-vitro activity test proves that parts of the compounds have excellent antitumor activity, and the compounds have higher research and practical values. (II).

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a class of quinazoline-aryl urea derivatives with antitumor effect and their application. Background technique [0002] Cancer generally refers to all malignant tumors. It is a series of diseases characterized by the uncontrolled proliferation and spread of abnormal cells. It is a major disease that seriously threatens human life and health. With the in-depth study of the mechanism of tumorigenesis, it is found that the signal transduction of solid tumors is a complex, multi-factor protein network system, and the inhibition of a single signal transduction is often not enough to curb the development of tumors. So far, many anti-tumor targets have been discovered, such as tumor neovascularization, cell signal transduction, cyclooxygenase-2 (COX-2) and so on. Among them, the Ras / Raf / MAPK / ERK signaling pathway regulates the functions of cell proliferation, differentiation, survival, and migrat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94A61K31/517A61P35/00
CPCC07D239/94
Inventor 陈家念王先富张广吉傅晓波沈星灿吴德文李亭蒋邦平纪仕辰覃江克黄春秋
Owner GUANGXI NORMAL UNIV
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