A kind of 4,6-pyrimidinediamine compound and its preparation method and application

A pyrimidinediamine and compound technology, which is applied in the field of 4,6-pyrimidinediamine compounds and their preparation, can solve the problems of unclear structure-activity relationship of EGFR inhibitors, inability to effectively inhibit EGFR kinase, and different effects, etc. Achieving excellent inhibitory effect, beneficial to industrial production, and simple synthesis process

Active Publication Date: 2018-08-31
WENZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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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  • A kind of 4,6-pyrimidinediamine compound and its preparation method and application
  • A kind of 4,6-pyrimidinediamine compound and its preparation method and application
  • A kind of 4,6-pyrimidinediamine compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0035]

[0036] Take 1g of 4,6-dichloropyrimidine and put it into a reaction bottle, add 30mL of ethanol, appropriate amount of KI, dissolve it by ultrasonic, stir with magnetic force, heat to reflux at 80°C, take 1.275g of 2,5-dimethoxyaniline and put it in another circle Bottom flask, and add 10mL ethanol to dissolve. Add 5 drops every 5 minutes to the 4,6-dichloropyrimidine solution, continue to reflux for 1-2 hours after the drop, filter with suction, and recrystallize to obtain 6-chloro-N-(2,5-dimethoxybenzene base)-pyrimidin-4-amine. Calculated yield 78-82%.

[0037] Put 100 mg of 6-chloro-N-(2,5-dimethoxyphenyl)-pyrimidin-4-amine into a flask, add 120 mg of 3-methoxyaniline and 30 mg of p-toluenesulfonic acid to dissolve in In 30 mL of ethanol, stir, heat and reflux at 80°C for 6 hours, take the reaction solution for TLC running, and observe the completion of the reac...

Embodiment 2

[0039] Embodiment 2 prepares N 4 , N 6 -(2,5-Dimethoxyphenyl)-pyrimidinediamine

[0040]

[0041] Take 1g of 4,6-dichloropyrimidine and put it into a reaction bottle, add 30mL of ethanol and 0.5mol p-toluenesulfonic acid, dissolve it by ultrasonic, put it into a magnet, stir, heat and reflux at 80°C, and take 2mol of 2,5-dimethyl The oxyaniline was dissolved, stirred by magnetic force, and heated to reflux at 80°C for 6 hours. The reaction solution was taken for TLC running, and the complete reaction was observed under ultraviolet fluorescence. Suction filtration, recrystallization to get N 4 , N 6 -(2,5-Dimethoxyphenyl)-pyrimidinediamine crude. Add saturated NaHCO 3 , stirred for 1 hour, filtered with suction, and passed through a chromatographic column to obtain a refined product. The calculated yield was 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...

Embodiment 3

[0043] Embodiment 3 The compounds of the present invention are tested for the inhibitory activity of 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 stop solution (100mM HEPES, pH7.5; 0.015% Brij-35; 0.2% Coating Reagent#3; 50mM EDTA); 10 times) add 10 μl of 2.5x substrate peptide solution (add kinase in 1x kinase reaction buffer), incubate at room temperature for 10 min, then add 10 μl of 2.5x substrate peptide solution (add FAM-labeled peptide in 1x kinase reaction buffer and ATP), add 25 μl kinase reaction stop solution after reacting at 28°C for a specific time. Test and collect data on Caliper, inhibition rate of kinase activity=[(max-conversion) / (max-min)]×100. "ma...

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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 and frequently-occurring disease that seriously threatens human health. It is characterized by abnormal proliferation of cells or mutant cells. At present, the death caused by malignant tumors accounts for the second place in the death rate of all diseases, second only to cardiovascular and cerebrovascular diseases. Due to the shortcomings of existing anti-tumor drugs such as high toxicity and easy drug resistance, the development of targeted anti-tumor drugs has always been an area of ​​focus and development for global pharmaceutical companies and governments. [0003] Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that activates and induces signaling pathways for cancer cell proliferation, sur...

Claims

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Application Information

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Patent Type & Authority Patents(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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