Miazines compound, EGFR inhibitor and application thereof

A technology of compounds and pyrimidines, which is applied in the field of medicine, can solve the problems of severe side effects of skin rashes and poor curative effect of drug-resistant patients, and achieve the effects of low toxicity, reduced inhibitory activity, and reduced mutation selectivity

Active Publication Date: 2017-11-24
TETRANOV PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the second-generation inhibitors also have strong wild-type EGFR inhibitory activity, and the inhibitory activity to wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation. Some first-generation EGFR inhibitor-resistant patients respond to these drugs

Method used

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  • Miazines compound, EGFR inhibitor and application thereof
  • Miazines compound, EGFR inhibitor and application thereof
  • Miazines compound, EGFR inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0073] The preparation method of intermediate A is method A1, method A2 or method A3, specifically as follows.

[0074] Method A1: Add 7.8mmol of compound a1-1 into a 100mL single-necked bottle, add 3mL of diisopropylethylamine and 30mL of n-butanol to obtain a mixture; use a cold bath to cool the mixture to -20°C, and slowly Add compound a2 (13.8mmol) dropwise, react at low temperature for 1h after the addition, remove the cooling bath and warm up to room temperature, stir overnight, evaporate the solvent to dryness under reduced pressure, add the residue to 100mL of ethyl acetate (EA), and then add 50mL washed with water twice, the organic phase was evaporated to dryness, and the residue was separated by column chromatography (eluent: ethyl acetate:petroleum ether=1:30 (volume ratio)) to obtain intermediate A1.

[0075] The reaction formula that above-mentioned method A1 involves is as follows:

[0076]

[0077] Wherein, Ar is selected from phenyl or substituted phenyl, ...

Embodiment 1

[0118] The pyrimidine compound of the present embodiment has a structural formula as shown in formula I-1:

[0119]

[0120] The preparation method of the pyrimidine compound of the present embodiment is as follows: 50 mg (0.15 mmol) of intermediate B, 150 mg (0.5 mmol) of intermediate A and 35 mg (0.18 mmol) of p-toluenesulfonic acid monohydrate are dissolved in 5 mL of 2 -amyl alcohol, then warmed up to 50°C, stirred overnight under nitrogen protection, TLC showed that the raw material basically disappeared, spin-dried to volume, then added 20mL dichloromethane and 20mL saturated aqueous sodium carbonate solution, layered, and then washed with 20mL dichloromethane The aqueous phase was collected twice, and the organic phase was combined, dried and spin-dried, and separated by TLC to obtain 20 mg of the product, which was compound I-1. The analytical data of this compound are as follows: 1H-NMR (400MHz, CDCl 3 ): δ: 10.18 (br, 1H); 9.19 (br, 1H); 8.38 (s, 1H); 7.52 (dt, J...

Embodiment 42

[0139] The pyrimidine compound of the present embodiment is the mesylate of the pyrimidine compound (I-6) shown in Example 6, and its structural formula is as shown in formula I-42:

[0140]

[0141] The preparation method of the pyrimidine compound (methanesulfonate) in this example is: add 0.37g of compound I-6 into a 50mL single-necked bottle, add 10mL of acetone and 1mL of water, and slowly add After adding 64mg of methanesulfonic acid, react at 50°C for 3h, evaporate the reaction solution to dryness, add 6mL of acetonitrile and raise the temperature to 70°C, stir for 30min, cool slowly to precipitate the solid, filter the solid, wash with acetonitrile, After drying, 140 mg of a white solid was obtained, namely compound I-30. Its purity was 98.5% as detected by HPLC. The analytical data of gained compound 1-30 is: HNMR (400M, d 6 -DMSO): 9.35(s1H), 9.14(s,1H), 8.76(s,1H), 8.70(s,1H), 8.36(s,1H), 7.95(s,2H), 7.85(d,J= 8.10Hz, 1H), 7.41(m, 2H), 6.97(s, 1H), 6.60(m, 1H)...

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Abstract

The invention discloses a miazines compound, an EGFR inhibitor and application thereof. The miazines compound comprises a compound shown as formula I, or pharmaceutically acceptable salt, stereisomer, solvate or prodrug thereof; and the EGFR inhibitor contains the miazines compound. The miazines compound disclosed by the invention can inhibit the activation or resistant mutation of one or more EGFRs; the multiplication of EGFRT790M / L858R amphimutation enzyme can be inhibited under nanomole concentration, and the inhibition for wild type EGFR enzyme is relatively weak; the miazines compound can be used for the treatment of EGFR sensitive mutation cancers, and is also applicable for cases generating secondary drug resistance in current EGFR-TKI treatment; and moreover, the mutation selectivity greatly reduces toxic and side effects generated by the inhibition of the wild type EGFR, and the miazines compound is an ideal therapeutic drug for diseases caused by EGFR mutation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a pyrimidine compound, and also relates to an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, especially non-small cell lung cancer. Applications. Background technique [0002] Epidermal Growth Factor Receptor EGFR (Epidermal Growth Factor Receptor) is a transmembrane protein tyrosine kinase of the erbB receptor family. When it binds to a growth factor ligand such as epidermal growth factor (EGF), the receptor can homodimerize with an additional EGFR molecule, or with another family member such as erbB2 (HER2), erbB3 (HER3) , or erbB4 (HER4)) undergoes heterodimerization. Homodimerization and / or heterodimerization of the erbB receptor leads to phosphorylation of key tyrosine residues in the intracellular domain and to stimulation of many intracellular signaling pathways involved in cell proliferation...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48C07D403/12C07D401/12A61K31/506A61K31/5377A61K31/505A61P35/00A61P3/10A61P37/02A61P25/00A61P9/00
CPCC07D239/48C07D401/12C07D403/12A61K31/505A61K31/506A61K31/5377A61P3/10A61P9/00A61P25/00A61P35/00A61P37/00
Inventor 吴豫生牛成山耿阳梁阿鹏郭中伟刘建涛杨俊亮霍云峰韩兴旺孟庆国李敬亚郭瑞云邹大鹏
Owner TETRANOV PHARMA CO LTD
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