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4-substituted aniline quinazoline derivatives and their preparation method and use

A technology of aniline quinazolines and derivatives, which is applied in the field of drug synthesis, can solve problems such as easy drug resistance, and achieve strong anti-tumor cell proliferation activity and strong inhibitory activity

Active Publication Date: 2019-05-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although a single EGFR tyrosine kinase inhibitor has better antitumor activity, it is easy to produce drug resistance, such as the drug resistance phenomenon of Gefitinib (Kobayashi S etc. New England Journal of Medicine, 2005, 352 (8): 786-792.)

Method used

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  • 4-substituted aniline quinazoline derivatives and their preparation method and use
  • 4-substituted aniline quinazoline derivatives and their preparation method and use
  • 4-substituted aniline quinazoline derivatives and their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1 N-(4-nitrophenyl)benzamide

[0030] In an ice bath, under the protection of nitrogen, 4-nitroaniline (2.0mmol, 276mg), potassium carbonate (2.4mmol, 331mg) and anhydrous THF 10ml were added to a 50ml two-necked flask, and then benzoyl chloride (0.28ml , 2.4mmol), after the dropwise addition was completed, the reaction was carried out at room temperature for 2 hours. Add 10% dilute hydrochloric acid (10ml) to the reaction solution, stir, and a large amount of yellow solid precipitates out, let stand, filter with suction, add water to wash the filter cake, and dry to obtain 407 mg of yellow solid, which is N-(4-nitrophenyl)benzene Formamide, yield 84%.

[0031] Replace benzoyl chloride with the corresponding substituted benzoyl chloride, and use the same method to prepare: N-(4-nitrophenyl)-2-chlorobenzamide, yellow solid, yield 97.6%; N-(4-nitrophenyl) N-(4-nitrophenyl)-3-chlorobenzamide, yellow solid, yield 98%; N-(4-nitrophenyl)-4-chlorobenzamide, yellow so...

Embodiment 2

[0032] Example 2 N-(4-aminophenyl)benzamide

[0033] Add a mixed solvent of N-(4-nitrophenyl)benzamide (1.5mmol, 363mg), zinc powder (7.5mmol, 488mg) and 11ml of methanol / water (V / V=10 / 1) into a 50ml reaction flask In, and then slowly dropwise added glacial acetic acid (15mmol, 0.9ml), after the dropwise addition was completed, heated to reflux for 1 hour. After the reaction is complete, filter with suction, add a small amount of methanol to wash, and then concentrate the filtrate. The crude product was recrystallized from methanol water and dried to obtain 261 mg of a yellow solid, namely N-(4-aminophenyl)benzamide, with a yield of 72%.

[0034] With N-(4-nitrophenyl)-2-chlorobenzamide instead of N-(4-nitrophenyl)benzamide, the same method was used to prepare N-(4-aminophenyl)-2- Chlorobenzamide, yellow solid, yield 80%; replace N-(4-nitrophenyl)benzamide with N-(4-nitrophenyl)-3-chlorobenzamide, and use the same method Preparation of N-(4-aminophenyl)-3-chlorobenzamide, y...

Embodiment 3

[0035] Example 3 N-(4-nitrophenyl)phenylurea

[0036] Dissolve triphosgene (2.97g, 10mmol) in 20ml of dichloromethane, add dropwise a solution of 4-nitroaniline (1.38g, 10mmol) and triethylamine (2.8ml) in dichloromethane (10ml), and dropwise, Continue to stir for 30 minutes, then add aniline (0.93g, 10mmol), heat up to 40°C, stir and reflux for 30 minutes, spin dry dichloromethane, add acetone: water (2:1) 30ml, shake fully, there is solid precipitation, suction filtration, The filter cake was washed twice with 5 ml of acetone:water (1:1), and dried to obtain 1.58 g of a yellow solid, namely N-(4-nitrophenyl)phenylurea, with a yield of 61.7%.

[0037] Replace aniline with 4-chloroaniline, and use the same method to prepare N-(4-nitrophenyl)-4-chlorophenylurea, a yellow solid, with a yield of 58.6%; use 3-chloroaniline instead of aniline, and use the same method Preparation of N-(4-nitrophenyl)-3-chlorophenylurea, yellow solid, yield 62.1%; replace aniline with 2-methylanilin...

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Abstract

The invention discloses novel 4-substituted anilinoquinazoline derivatives or pharmaceutically acceptable salts thereof, or polymorphic substances, solvates or stereomers of the 4-substituted anilinoquinazoline derivatives, and a preparation method and application thereof. The 4-substituted anilinoquinazoline compounds have favorable inhibition activities for EGFR and VEGFR-2 in a biological test and have obvious effects in an in-vitro anti-human tumor cell proliferation activity test.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to 4-substituted aniline quinazoline derivatives and a preparation method thereof, and includes the application of these compounds in antitumor drugs. Background technique [0002] Malignant tumors are common and frequently-occurring diseases that seriously threaten human life. The essence of its carcinogenesis is that the abnormal expression of genes causes the disorder of cell signal transduction pathways, leading to the infinite proliferation of cells, in which tyrosine kinases (TKs) play a key role. [0003] Protein tyrosine kinases are a class of proteins with tyrosine kinase activity, and the signal transduction mediated by them is closely related to the occurrence and development of tumors. Protein tyrosine kinases can be divided into receptor tyrosine kinases and non-receptor tyrosine kinases according to their structure. Epidermal growth factor receptor (EGFR) is a typical r...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94A61K31/506A61K31/5377A61P35/00A61P3/10A61P37/02A61P25/28A61P27/02A61P9/10A61P29/00
CPCC07D239/94
Inventor 孙丽萍张海琪张驰龚飞虎徐云根
Owner CHINA PHARM UNIV
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