Quinazolinyl aryl urea derivatives and preparation method and application thereof

A kind of quinazoline aryl urea, quinazoline technology, applied in the field of drug synthesis, can solve the problem of aggravating side effects and the like

Active Publication Date: 2012-07-04
天津天诚新药评价有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the treatment of diseases caused by excessive cell proliferation, traditional quinazoline derivatives require a large dose to achieve effective treatment, which often aggravates side effects such as diarrhea and rashes. For this reason, further research is needed to find out Drugs that are effective and have low side effects

Method used

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  • Quinazolinyl aryl urea derivatives and preparation method and application thereof
  • Quinazolinyl aryl urea derivatives and preparation method and application thereof
  • Quinazolinyl aryl urea derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of 1-isocyanate-4-nitrobenzene

[0026] Add 5.92 g (20 mmol) of triphosgene and 20 mL of dichloromethane into a 250 mL three-necked flask, and stir at room temperature to dissolve it. 1.38g (10mmol) of p-nitroaniline was dissolved in 100mL of dichloromethane and dropped into the reaction solution. After the dropwise addition, slowly add triethylamine (10-15mL) solution diluted with 30mL of dichloromethane to the reaction solution until alkaline, continue the reaction for 1-1.5h after the dropwise addition, and proceed to the next reaction directly.

[0027] 2-Fluoro-1-isocyanate-4-nitrobenzene and 2-chloro-1-isocyanate-4-nitrobenzene were prepared using the same method.

Embodiment 2

[0028] Example 2 Preparation of 1-(3,4-difluorophenyl)-3-(4-nitrophenyl)urea

[0029] Add 1.29 g (10 mmol) of 3,4-difluoroaniline into a 500 mL three-necked flask, stir to dissolve in 20 mL of dichloromethane, and heat to reflux. Add the step reaction solution dropwise. After the dropwise addition, the reaction was continued for about 0.5h, and the reaction was stopped. After the reaction solution was evaporated to dryness, it was treated with 30 mL of acetone and 100 mL of water to obtain 1.7 g of a large amount of yellow solid, with a yield of 58.0%, m.p.78-79°C; 1 H NMR (400MHz, DMSO): δ7.15-7.17(m, 1H, ArH), 7.33-7.40(m, 1H, ArH), 7.63-7.73(m, 3H, ArH), 8.18-8.22(m, 2H , ArH), 9.11(s, 1H, NH), 9.48(s, 1H, NH), ESI-MS: m / z 294 [M+H] + .

[0030] Use the same method to prepare 1-(3-fluorophenyl)-3-(4-nitrophenyl)urea, 1-phenyl-3-(4-nitrophenyl)urea, 1-cyclopropyl- 3-(4-nitrophenyl)urea, 1-cyclohexyl-3-(4-nitrophenyl)urea, 1-(5-methyl-1,3,4-oxadiazol-2-yl )-3-(4-nitroph...

Embodiment 3

[0031] Example 3 Preparation of 1-(4-aminophenyl)-3-(3,4-difluorophenyl)urea (V-1)

[0032] Add 1-(3,4-difluorophenyl)-3-(4-nitrophenyl)urea 2.9g (10mmol), 150mL methanol and palladium carbon 0.4g (4mmol) into a 250mL round bottom flask, and continue to pass Enter H 2 React for 1-2 hours. After the reaction is complete, the palladium carbon is filtered out, and the mother liquor is evaporated to dryness to obtain the product, 2.5 g, with a yield of 86.2%. m.p.83-85℃; 1 H NMR (400MHz, DMSO): δ4.78(s, 2H, NH 2 ), 7.15-7.17(m, 1H, ArH), 7.33-7.40(m, 1H, ArH), 7.63-7.73(m, 3H, ArH), 8.18-8.22(m, 2H, ArH), 9.11(s, 1H, NH), 9.48 (s, 1H, NH), ESI-MS: m / z 264 [M+H] + .

[0033] Using the same method to prepare 1-(4-aminophenyl)-3-(3-fluorophenyl)urea (Ⅴ-2), 1-(4-aminophenyl)-3-phenylurea (Ⅴ -3), 1-(4-aminophenyl)-3-cyclopropylurea (Ⅴ-4), 1-(4-aminophenyl)-3-cyclohexylurea (Ⅴ-5), 1 -(4-aminophenyl)-3-(5-methyl-1,3,4-oxadiazol-2-yl)urea (Ⅴ-6), 1-(4-aminophenyl)- 3-(4-Chloro-3-(t...

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Abstract

The invention relates to quinazolinyl aryl urea derivatives with a general formula I and a preparation method and application thereof, wherein R1, R2 and R3 respectively have meanings limited in a specification. The invention further relates to the preparation method of the derivatives, and a physiologically-acceptable salt formed by the derivatives and an inorganic acid or an organic acid includes a medicinal combination of the derivatives. The compounds have a valuable pharmacologic property, particularly have an inhibition effect on the signal transduction caused by a tyrosine kinase, particularly have higher inhibition activity on mutant VEGFR-2 (Vascular Endothelial Growth Factor Receptor-2), and furthermore, have lower toxicity. The invention further relates to the application of the quinazolinyl aryl urea derivatives in the treatment of diseases, particularly tumor diseases, and the preparation method of the quinazolinyl aryl urea derivatives.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to quinazoline aryl urea derivatives and a preparation method thereof, pharmaceutical compositions containing these derivatives and their application in antitumor drugs. Background technique [0002] Tumor is a series of diseases characterized by the uncontrolled proliferation and spread of abnormal cells, and it is a major disease that seriously threatens human life and health. With the development of molecular biology, significant progress has been made in the molecular mechanism of tumorigenesis and development, making target-based therapy considered to be the development direction of future cancer treatment. Small molecule kinase inhibitors containing urea structures have been expected to treat cancer and inflammation since the early 1990s. Arylurea compounds were first reported in the 1996 patent, because of their unique kinase binding mode and kinase inhibitory conformation, a l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D413/14A61K31/517A61P35/00
Inventor 李祎亮蔡志强刘巍石玉邹美香汤立达张士俊商倩孟凡翠徐为人李洪明林木森刘金雷纪潇朗范宗兄
Owner 天津天诚新药评价有限公司
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