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Epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, preparation method and application thereof

A technology of epidermal growth factor and tyrosine kinase, applied in the epidermal growth factor receptor tyrosine kinase inhibitor and its preparation, quinazoline compounds, the application field of the drug as an anti-tumor agent, can solve the treatment failure , There is no obvious prolongation of the patient's survival period, etc., and the effect of inhibiting proliferation and excellent anti-tumor activity is achieved

Active Publication Date: 2016-06-29
HARBIN MEDICAL UNIVERSITY
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AI Technical Summary

Problems solved by technology

At present, reversible and irreversible EGFRTKI have significant curative effect on mutated EGFR non-small cell lung cancer in a short period of time, but eventually all of them failed due to acquired drug resistance, and did not significantly prolong the survival of patients

Method used

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  • Epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, preparation method and application thereof
  • Epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, preparation method and application thereof
  • Epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of embodiment 1EGFRTKI-IRSF and EGFRTKI-IRSH

[0040] The molecular structural formula of EGFRTKI-IRSF is as shown in formula I, and the molecular structural formula of EGFRTKI-IRSH is as shown in formula II:

[0041]

[0042] The preparation flow chart is as figure 1 and figure 2 As shown, the specific preparation method is as follows:

[0043] 1) Dissolve 16.8g of methyl 3,4-dihydroxybenzoate, 3.3g of potassium iodide, and 15.2g of anhydrous potassium carbonate in 80ml of acetonitrile under nitrogen protection, heat up to 95°C, and start adding dropwise 20ml of Benzyl chloride containing 12.7g Acetonitrile solution (12.7g of benzyl chloride dissolved in 20ml of acetonitrile), add 1h, reflux at 95°C for 1-1.5h after addition, cool, filter with suction, wash the filter cake with dichloromethane, spin dry the mother liquor, Carry out column chromatography separation, using dichloromethane: ethyl acetate volume ratio = 100:1 and 6:1 mixed solution t...

Embodiment 2I

[0056] Example 2 Inhibitory Effect Test of IRSF and IRSH on Non-small Cell Lung Cancer Cell Line PC-9 with EGFR19 Exon Deletion Mutation

[0057] 1, test compound: IRSF and IRSH, prepared by the method of Example 1

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Abstract

The invention discloses epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, a preparation method and application thereof. By optimization and improvement of a gefitinib chemical structure, brand-new EGFR TKI (epidermal growth factor receptor tyrosin kinase inhibitors) named as IRSF (shown as formula I) and IRSH (shown as formula II) are obtained. According to researches, the IRSF and IRSH are higher in water solubility and fewer in toxic and side effects and have high inhibition activity on mutant EGFR non-small-cell lung cancer, and the IRSF and IRSH inhibit phosphorylation of cancer cell epidermal growth factor receptor tyrosin kinase to prevent downstream signal path activation so as to promote tumor cell apoptosis. In addition, the invention further discloses a method for preparing the epidermal growth factor receptor tyrosin kinase inhibitors with antitumor activity. The epidermal growth factor receptor tyrosin kinase inhibitors IRSF and IRSH with antitumor activity, the preparation method and application thereof provide effective technical means for tumor treatment, especially treatment of the non-small-cell lung cancer.

Description

technical field [0001] The invention relates to quinazoline compounds, in particular to an epidermal growth factor receptor tyrosine kinase inhibitor with antitumor activity and a preparation method thereof. The invention also relates to the application of the drug as an antitumor agent, belonging to the field of biomedicine. Background technique [0002] The currently discovered EGFR tyrosine kinase (EGFRTK) can catalyze the transfer of high-energy phosphate bonds of ATP to several tyrosine sites of EGFR to phosphorylate them, thereby activating downstream PI3K / Akt, Ras / MAPK and other signaling pathways, Promote cell growth, proliferation, metabolism, and inhibit cell apoptosis. When EGFR is overexpressed and mutated in cells, it will hinder the programmed death of cells, make the growth regulation of cells out of control, and obtain unlimited proliferation and invasion ability, that is, develop into malignant tumor cells. EGFRTKI competes with ATP for the binding site of ...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/5377A61P35/00
CPCC07D239/94
Inventor 申宝忠孙夕林杨丽丽王颖奕韩兆国桂媛郁冬青马鸿钊徐志红
Owner HARBIN MEDICAL UNIVERSITY
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