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Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof

A 6-d, tumor technology, applied in the direction of antineoplastic drugs, organic active ingredients, medical preparations containing active ingredients, etc., can solve the problems of EGFR inhibitory effects vary greatly, and the structure-activity relationship of EGFR inhibitors is unclear.

Active Publication Date: 2016-05-11
药谷(温州)科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, the structure-activity relationship of EGFR inhibitors is not clear, and some compounds with small structural differences have very different inhibitory effects on EGFR

Method used

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  • Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof
  • Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof
  • Parazole [5,6-d]pyrimidine type EGFR inhibitor and anti-tumor activity thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] The activity and selectivity of the compounds of Example 1 inhibiting EGFR in vitro

[0021] EGFR kinase in vitro activity screening: The method used in the experiment is CaliperMobilityShiftAssay, which is a detection platform based on the mobility detection technology of microfluidic chip technology. Experimental steps: configure 1.25x kinase reaction buffer (62.5mmol / LHEPES, pH7.5; 0.001875% Brij-35; 12.5mmol / LMgCl2; 2.5mMDTT) and kinase reaction termination solution (100mmol / LHEPES, pH7.5; 0.015% Brij-35; 0.2% CoatingReagent#3); Add 10 μl of 2.5x FGFR1 Kinase Solution (Kinase in 1.25x Kinase Reaction Buffer) ), incubate at room temperature for 10 min, then add 10 μl of 2.5x substrate peptide solution (add FAM-labeled peptide and ATP to 1.25x kinase reaction buffer), and add 25 μl of 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. "max" is ...

Embodiment 2

[0024] Antitumor activity verification of compound on the cell level in Example 2

[0025] The anti-tumor activity of compound WZ00411 at the cell level by MTT method was selected to contain EGFR T790M Highly expressed human NSCLC cell line (H1975), EGFR WT Seven kinds of cells, including the highly expressed human large cell lung cancer cell line (A549) and the human lung cancer cell line with primary dislocation mutation of EGFR (HCC827), were tested for their proliferation inhibitory activity. During the determination, PBS was used as the blank control, EGF was used as the negative control, (EGF+WZ4002) was used as the positive control, (EGF+sample to be tested) was used as the experimental group, 6 concentration gradients were set for each sample, and the IC was calculated. 50 value.

[0026] The effect of active compounds on intracellular EGFR pro-proliferation signaling pathway: the compound WZ00411 was selected, and EGF combined with different concentrations of WZ0041...

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Abstract

The invention provides a parazole [5,6-d]pyrimidine type EGFR inhibitor which comprises a parazole [5,6-d]pyrimidine type compound with an anti-tumor function. In addition, the invention further provides a medicinal compound containing the compound, anti-tumor application and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular, the invention relates to a pyrazol[5,6-d]pyrimidine compound with good antitumor activity. In addition, the present invention also relates to a pharmaceutical composition containing the compound and its use in the preparation of antitumor drugs and the like. Background technique [0002] Lung cancer is one of the malignant tumors with the highest morbidity and mortality. Worldwide, lung cancer causes more than 1 million deaths per year. In my country, the morbidity and mortality of lung cancer rank first among malignant tumors, among which non Small cell lung cancer (NSCLC) is the most common, accounting for more than 85% of the total number of cases. At present, classic surgical resection or radiotherapy and chemotherapy often have many defects such as high postoperative recurrence rate, high toxicity and side effects, metastasis and drug resistance. In view of the important ro...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P35/02
Inventor 张颖张乔乔叶清清何帆潘恺凌刘志国梁广李校堃
Owner 药谷(温州)科技发展有限公司
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