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4,6-pyrimidine diamine compound and preparing method and application thereof

A pyrimidinediamine and compound technology, applied in the field of 4,6-pyrimidinediamine compounds and their preparation, can solve the problems of unclear structure-activity relationship of EGFR inhibitors, different effects, inability to effectively inhibit EGFR kinase, and the like, To achieve the effect of excellent inhibitory effect, good inhibitory activity and simple synthesis process

Active Publication Date: 2015-08-19
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] One of the purposes of the present invention is to solve the unclear structure-activity relationship of EGFR inhibitors. Some compounds with little structural difference have very different effects on EGFR inhibition, and cannot effectively inhibit EGFR kinase and anti-EGFR. The problem of high expression of tumor cell activity

Method used

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  • 4,6-pyrimidine diamine compound and preparing method and application thereof
  • 4,6-pyrimidine diamine compound and preparing method and application thereof
  • 4,6-pyrimidine diamine compound and preparing method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Preparation of N 4 -(2,5-Dimethoxyphenyl)-N 6 -(3-Methoxyphenyl)-pyrimidinediamine

[0035]

[0036] Take 1g of 4,6-dichloropyrimidine into the reaction flask and add 30mL of ethanol, an appropriate amount of KI, dissolve by ultrasonic, magnetic stirring, heat to reflux at 80°C, take 1.275g of 2,5-dimethoxyaniline and place in another circle Add 10mL ethanol to the bottom flask to dissolve. Add 5 drops every 5 minutes to the 4,6-dichloropyrimidine solution, continue to reflux for 1-2 hours after dropping, filter with suction and recrystallize to obtain 6-chloro-N-(2,5-dimethoxybenzene) Yl)-pyrimidin-4-amine. The calculated yield is 78-82%.

[0037] Take 100mg of 6-chloro-N-(2,5-dimethoxyphenyl)-pyrimidin-4-amine into the flask, and add 120mg of 3-methoxyaniline and 30mg of p-toluenesulfonic acid to dissolve In 30 mL of ethanol, stir and heat to reflux at 80° C. for 6 hours, take the reaction solution for TLC run, and observe that the reaction is complete under u...

Embodiment 2

[0039] Example 2 Preparation of N 4 , N 6 -(2,5-Dimethoxyphenyl)-pyrimidinediamine

[0040]

[0041] Take 1g of 4,6-dichloropyrimidine into the reaction flask and add 30mL ethanol, 0.5mol p-toluenesulfonic acid, dissolve it ultrasonically, put it in a magnet, stir and heat to reflux at 80℃, take 2mol 2,5-dimethyl The oxyaniline was dissolved, stirred magnetically, and heated to reflux at 80°C for 6 hours. Take the reaction solution and run the TLC plate, and observe that the reaction is complete under ultraviolet fluorescence. Suction filtration, recrystallization to get N 4 , N 6 -(2,5-Dimethoxyphenyl)-pyrimidinediamine crude product. Add saturated NaHCO 3 , Stir for 1 hour, filter with suction, and pass through a chromatography column to obtain a refined product. The calculated yield is 75%-82%.

[0042] Melting point: 187°C. NMR data (d 6 -DMSO): 3.669(s,6H,5’-Ph-OCH 3 ×2),3.752(s,6H,2’-Ph-OCH 3 ×2), 6.257 (s, 1H, -NH), 6.551-6.597 (m, 2H, 5'-PhH), 6.931-6.946 (m, 2H, 3'-PhH...

Embodiment 3

[0043] Example 3 Test of the inhibitory activity of the compounds of the present invention on different EGFR kinases

[0044] The method used in the experiment is Caliper Mobility Shift Assay, which is a detection platform based on the migration detection technology of microfluidic chip technology. Experimental steps: configure 1x kinase reaction buffer (50mM HEPES, pH7.5; 0.0015% Brij-35; 10mM MgCl 2 , 10mM MnCl 2 2Mm DTT) and kinase reaction termination solution (100mM HEPES, pH7.5; 0.015% Brij-35; 0.2% Coating Reagent#3; 50mM EDTA); in 5μl of 5x concentration compound solution (use DMSO solution, diluted with water 10 times) add 10μl of 2.5x substrate peptide solution (add kinase in 1x kinase reaction buffer), incubate at room temperature for 10 minutes, then add 10μl of 2.5x substrate peptide solution (add FAM labeled peptide in 1x kinase reaction buffer And ATP), add 25μl of kinase stop solution after reacting at 28°C for a specific time. Test and collect data on Caliper, t...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a 4,6-pyrimidine diamine compound and a preparing method and an application thereof; the 4,6-pyrimidine diamine compound is an N4,N6-(2,5-dialkoxy phenyl)-pyrimidine diamine compound or an N4-(2,5-dialkoxy phenyl)-N6-(3-alkoxy phenyl)-pyrimidine diamine compound, and in particular, alkoxy can be C1-C4 alkane. The 4,6-pyrimidine diamine compound can be used for broad-spectrum inhibition of the activity of an EGFR kinase and resisting of EGFR expressed tumor cell activity. The EGFR kinase is a wild-type or drug-resistant mutant EGFR kinase, and provides a basis for new drug screening. And the synthesis method of the 4,6-pyrimidine diamine compound provided by the invention is simple in synthesis process and is in favor of industrialized production.

Description

Technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a 4,6-pyrimidinediamine compound and a preparation method and application thereof. Background technique [0002] Malignant tumor is a common disease and frequently-occurring disease that seriously threatens human health. It is characterized by abnormal proliferation of cells or mutant cells. At present, human deaths caused by malignant tumors account for the second place in all disease mortality, second only to cardiovascular and cerebrovascular diseases. Due to the shortcomings of existing anti-tumor drugs, such as high toxicity and resistance to drug resistance, the development of targeted anti-tumor drugs has always been the focus and development area of ​​global pharmaceutical companies and governments. [0003] Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that can activate and induce the signal pathways of cancer cell proliferation, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48A61K31/505A61P35/00
CPCC07D239/48
Inventor 叶发青王跃武俞淑芳王宇陈弟陈梁芳宋晓琴谢自新梁广李校堃刘志国林丹张金三
Owner WENZHOU MEDICAL UNIV
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