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EGFR inhibitor for targetedly treating cancer and preparation method and application thereof

A cancer and oxidant technology, applied in organic chemistry, drug combination, antineoplastic drugs, etc., to achieve the effect of small side effects

Active Publication Date: 2016-07-20
TSINGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the second-generation inhibitors have solved the problem of drug resistance to a certain extent, due to their high inhibition of wild-type EGFR, side effects such as diarrhea and rash

Method used

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  • EGFR inhibitor for targetedly treating cancer and preparation method and application thereof
  • EGFR inhibitor for targetedly treating cancer and preparation method and application thereof
  • EGFR inhibitor for targetedly treating cancer and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The preparation of the compound shown in embodiment 1, formula I

[0030] Add 81 mg of m-chloroperoxybenzoic acid to a solution of AZD9291 (formula II, 200 mg) in dichloromethane (25 mL) under stirring condition. Stir at 20 °C for 30 min. After the reaction was detected by TLC, the reaction solution was washed with saturated sodium bicarbonate solution (25 mL), extracted three times with dichloromethane (25 mL×3), and the obtained organic solvent layers were combined together, and the organic solvent was removed on a rotary evaporator. Purified by reverse HPLC (CH 3 OH / H 2 O10:1), to obtain the compound shown in formula I.

[0031] 1 H-NMR (400MHz, DMSO-d6) δ (ppm) 13.21 (s, 1H), 8.86 (s, 1H), 8.50 (s, 1H), 8.31 (d, J = 5.32Hz, 1H), 8.26 (d ,J=7.88Hz,1H),7.99-7.97(m,3H),7.50(J=8.40Hz,1H),7.26-7.14(m,4H),6.97(s,1H),6.20-6.15(m, 1H),5.62-5.59(m,1H),3.89(s,3H),3.86(s,3H),3.46-3.44(m,2H),3.33(s,3H),3.30(s,3H),3.25 -3.24(m,2H),2.74(s,3H);LRMS(ESI)calcdforC 16 h 18 C...

Embodiment 2

[0032] The inhibitory activity of the compound shown in embodiment 2, formula I to kinase

[0033] 1. Kinase test

[0034] The following methods are used to measure the effect of the compounds of the present invention on EGFR WT and EGFR T790M / L858R Inhibition of enzyme activity, the specific method is as follows:

[0035] The models of the kits are shown in Table 1.

[0036] Table 1 Kinase Model

[0037] Kinase

[0038] Invitrogen kits were used to detect the in vitro activity of EGFR inhibitors. According to the instructions of the kit, prepare the corresponding concentrations of enzyme buffer, enzyme / substrate peptide solution, ATP solution and fully phosphorylated substrate peptide in sequence, and mix gently; use distilled water to prepare a solution of the compound to be tested at a concentration of 4X ,well mixed.

[0039]Add 2.5 μL of the prepared enzyme / substrate peptide solution and fully phosphorylated substrate peptide into a 384-well plate, then ad...

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Abstract

The invention discloses an EGFR inhibitor for targetedly treating a cancer and a preparation method and application thereof.The structural formula of the EGFR inhibitor is shown in the formula I.The EGFR inhibitor can be used for preventing and / or treating the cancer such as a human skin caner or a lung cancer.The EGFR inhibitor can selectively inhibit cell lines of EGFR double mutation (EGFRT790M and L858R), and the inhibitory activity to EGFR wild type cells is weak; therefore, the EGFR inhibitor can be used for treating lung cancer patients with EGFRT790M and L858R mutation, and the side effects are fewer, wherein the side effects are caused by inhibiting wild type EGFR, for example, Afatinib.

Description

technical field [0001] The invention relates to an EGFR inhibitor for targeted treatment of cancer, 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 caused by abnormal proliferation of cells in the human body. Lung cancer, gastrointestinal cancer and liver cancer are the most common tumors in men, accounting for more than 70% of all cases (lung cancer 23%, gastric cancer 15.2%, liver cancer 13.57%, esophageal cancer 10.46%, colorectal cancer 9.39%), while breast cancer, Lung cancer, gastrointestinal cancer and liver cancer are the most common tumors in women, accounting for more than 60% of all cases (breast cancer 16.97%, lung cancer 14.85%, colorectal cancer 9.68%, gastric cancer 8.53%, liver cancer 6.17%). With the aging population in China, the prevalence of cancer is bound to increase. In addition, environmental pollution has also increa...

Claims

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Application Information

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IPC IPC(8): C07D403/04A61P35/00
CPCC07D403/04
Inventor 饶燏杨兴林
Owner TSINGHUA UNIV
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