T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs

An anti-tumor drug and inhibitor technology, applied in the field of drugs for the treatment of tumors, can solve problems such as loss of inhibitor activity, wild-type cytotoxic side effects, and increased affinity between EGFR and ATP.

Active Publication Date: 2015-08-26
PHARMA SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Further studies have confirmed that due to the T790M mutation of the EGFR gene, that is, the encoded threonine is converted to methionine, resulting in steric hindrance that hinders the combination of the inhibitor with the ATP binding region and ultimately leads to the loss of inhibitor activity.
At present, studies have also shown that the mutation of the T790M site does not directly affect the affinity of the inhibitor to EGFR, but the mutation leads to a great increase in the affinity of EGFR and ATP, which greatly reduces the affinity of the inhibitor to EGFR ( Inhibitors compete with ATP for binding)
The second-generation inhibitors, such as afatinib and dacomitinib, are superior to the first-generation in that they have increased recognition of EGFR, which can distinguish tumor cells from normal cells, so...

Method used

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  • T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs
  • T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs
  • T790M mutant epidermal growth factor receptor (EGFR) inhibitor and application of same in preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1, (R)-N-(3-(1-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-tri Fluoromethylpyrimidin-4-yl)oxy)ethyl)propyl)acrylamide

[0091]

[0092] Synthetic steps:

[0093]

[0094] Step 1: Preparation of tert-butyl 3-acetylphenylcarbamate (compound 2)

[0095] To a solution of 1-(3-aminophenyl)ethanone (compound 1) (8.0 g, 59.3 mmol) in dioxane (100 mL) was added (Boc) 2 O (16.8 g, 77.1 mmol). The obtained reaction solution was reacted at 150° C. for 4 hours, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (PE:EA=8:1 to 4:1) to obtain the target product (12.4 g, 88.6% yield) as a white solid. 1 H NMR (400MHz, CDCl 3 )δ7.95(s,1H),7.66(d,J=7.6Hz,1H),7.60(d,J=7.8Hz,1H),7.37(t,J=7.9Hz,1H),6.88(s, 1H), 2.59(s, 3H), 1.52(s, 9H).

[0096] Step 2: Preparation of (R)-(3-(1-hydroxyethyl)phenyl)carbamate tert-butyl ester (Compound 3)

[0097] (+)-DIP-Cl (5.5 g, 17.0 mmol) was dissolved in anhydro...

Embodiment 2

[0104] Example 2, (S)-N-(3-(1-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-tri Fluoromethylpyrimidin-4-yl)oxy)ethyl)propyl)acrylamide

[0105]

[0106] The synthetic method is as embodiment 1,

[0107] 1 H NMR (400MHz, CDCl 3 )δ8.34(s,1H),7.86(m,2H),7.57(m,3H),7.30(t,J=7.8Hz,1H),7.16(d,J=7.4Hz,1H),6.64– 6.37(m,3H),6.28(m,2H),5.78(d,J=10.3Hz,1H),3.87(s,3H),3.80–3.70(m,2H),3.69–3.54(m,2H) ,3.22–2.98(m,4H),2.19(s,3H),1.66(d,J=6.6Hz,3H).LC-MS:m / z 585(M+H) + .

Embodiment 3

[0108] Example 3, N-(3-(1-((2-((4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl)amino)-5-trifluoromethylpyrimidine -4-yl)oxy)ethyl)propyl)acrylamide

[0109]

[0110] The synthetic method is as embodiment 1,

[0111] 1 H NMR (400MHz, CDCl 3 )δ8.34(s,1H),7.85(m,2H),7.48(m,3H),7.31(t,J=7.8Hz,1H),7.16(d,J=7.6Hz,1H),6.64– 6.37(m,3H),6.27(m,2H),5.79(d,J=10.2Hz,1H),3.86(s,3H),3.82–3.70(m,2H),3.68–3.58(m,2H) ,3.25–2.91(m,4H),2.06(s,3H),1.66(d,J=6.5Hz,3H).LC-MS:m / z 585(M+H) + .

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Abstract

The invention provides a T790M mutant EGFR inhibitor and an application of the same in preparation of antitumor drugs. The inhibitor is a pyrimidine compound with structural characteristics of a formula (I). The compound can inhibit various tumor cells and particularly can act on EGFR L858R/T790M and EGFR E 745_A750/T790M lung cancer cells selectively, and the IC 50 of the compound is 10 timers and even 100 times higher than that of wild cancer cells. The compound is the protease inhibitor which is capable of overcoming prior EGFR-TKI drug resistance and has selectivity and can be applied to preparation of antitumor drugs. (img file= 'DDAS0000708455660000011. TIF' wi= '716' he= '576'/).

Description

technical field [0001] The invention relates to a drug for treating tumors, in particular to an inhibitor of T790M mutant EGFR and its application in the preparation of anti-tumor drugs. Background technique [0002] In the past 30 years, the mortality rate of lung cancer has increased by 465%, and the incidence rate has increased by 26.9% every year. It has replaced liver cancer as the first cause of death from malignant tumors in my country. This disease with the highest mortality rate is a serious threat to human health. Among them, non-small cell lung cancer (NSCLC for short) accounts for more than 80% of all lung cancers, only one-third of NSCLC patients have the opportunity for surgical treatment, and about 70% of the patients are localized at the time of treatment. Late stage or distant metastasis, lost the chance of surgical treatment. In this case, drug treatment is particularly important. [0003] In the traditional cancer treatment process, chemotherapy is the ...

Claims

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Application Information

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IPC IPC(8): C07D239/47C07D487/10C07D403/12A61K31/5377A61K31/506A61P35/00A61P35/02
CPCC07D239/47C07D403/12C07D487/10
Inventor 周鼎崔大为蔡振伟陈平
Owner PHARMA SHANGHAI
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