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Coupling compound of NSAID anti-inflammatory pain killers and EGFR kinase inhibitor and synthetic method and application of coupling compound

A coupling compound, anti-inflammatory and analgesic technology, applied in the field of chemical medicine, can solve problems such as insensitivity and drug resistance of patients

Active Publication Date: 2014-01-01
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although EGFR inhibitors have achieved encouraging efficacy in the clinical treatment of tumors with their advantages of high selectivity and low toxicity, some patients are not sensitive to this type of treatment, and some patients eventually develop resistance to this type of drug

Method used

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  • Coupling compound of NSAID anti-inflammatory pain killers and EGFR kinase inhibitor and synthetic method and application of coupling compound
  • Coupling compound of NSAID anti-inflammatory pain killers and EGFR kinase inhibitor and synthetic method and application of coupling compound
  • Coupling compound of NSAID anti-inflammatory pain killers and EGFR kinase inhibitor and synthetic method and application of coupling compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 2-(4-(3-ethynylaniline)-7-(2-methoxyethoxy)quinazoline-6-oxyl)ethyl-2-(4-benzoylphenyl)propionic acid synthesis

[0031]

[0032] step 1

[0033] Synthesis of ethyl 3-hydroxy-4-(2-methoxyethoxy)benzoate

[0034]

[0035] Dissolve 10.9g of ethyl 3,4-dihydroxybenzoate in 40ml of dry DMF (dimethylformamide), slowly add 3.6g of NaH under ice-cooling, and slowly drop in 8.34g of 2-bromoethyl after 10min under the protection of argon A solution of methyl ether and 100 mg KI dissolved in 10 ml of dry DMF was added dropwise within 3 hours, during which the reaction temperature was maintained at 0°C. After the dropwise addition, the reaction temperature was naturally raised to room temperature, and the reaction was carried out overnight, followed by TLC until the end of the reaction. The reaction solution was diluted with water, extracted with ethyl acetate, washed successively with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The crude ...

Embodiment 2

[0077] 2-(4-(3-ethynylaniline)-7-(2-methoxyethoxy)quinazoline-6-oxyl)ethyl-2-(4-isobutylphenyl)propionic acid synthesis

[0078]

[0079] The synthesis method is as in Example 1.

[0080] 1 H NMR (400MHz, CDCl 3 )δ8.59(s,1H),7.83(s,1H),7.73(d,J=8.0Hz,1H),7.31-7.00(m,8H),4.52-4.46(m,1H),4.42-4.36 (m,1H),4.16-4.14(m,4H),3.73-3.68(m,3H),3.40(s,3H),3.06(s,1H),2.39(d,J=7.2Hz,2H), 1.81(m,1H),1.47(d,J=7.2Hz,3H),0.85(d,J=6.4Hz,6H); 13 C NMR (125MHz, CDCl 3 )δ174.5, 156.4, 154.1, 153.4, 148.6, 147.1, 140.5, 138.8, 137.3, 129.4, 129.2, 128.8, 127.6, 127.0, 125.1, 122.6, 122.4, 109.3, 106.5, 103.4, 77.3, 08, 83.3 ,69.2,66.5,62.3,59.2,44.9,29.6,22.3,18.5,13.9;

[0081] ESI + m / z568.3(M+H) + .

Embodiment 3

[0083] Synthesis of 2-(4-(3-ethynylaniline)-7-(2-methoxyethoxy)quinazoline-6-oxyl)ethyl-2-acetoxybenzoic acid

[0084]

[0085] The synthesis method is as in Example 1, wherein the acid chloride used in step 8 is a purchased product, not self-made.

[0086] 1 H NMR (400MHz, CDCl 3 )δ8.61(s,1H),8.08(br.,1H),7.96(d,J=8.0Hz,1H),7.83-7.80(m,1H),7.72(d,J=8.0Hz,1H) ,7.51(dt,J=1.6,8.0Hz,1H),7.29-7.16(m,5H),7.06(d,J=8.0Hz,1H),4.62(t,J=4.0Hz,2H),4.31( t,J=4.0Hz,2H),4.12(t,J=4.0Hz,2H),3.70(t,J=4.4Hz,2H),3.34(s,3H),3.09(s,1H),2.31( s,3H); 13 CNMR (125MHz, CDCl 3 )δ169.8, 164.0, 156.3, 153.9, 153.4, 150.6, 148.6, 133.9, 131.7, 129.9, 128.8, 127.5, 125.9, 123.6, 122.5, 122.3, 119.1, 117.4, 109.4, 107.7, 783.7, 103.3 ,76.7,70.6,68.9,66.5,62.8,20.8.

[0087] ESI + m / z542.0(M+H) + .

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Abstract

The invention discloses a coupling compound or salt or a stereoisomer or prodrug molecules, which are pharmaceutically acceptable. The coupling compound of the structure shown in the formula I or II or III is formed by connecting NSAID anti-inflammatory pain killers and an EGFR kinase inhibitor through ester bonds, wherein the R is the NSAID anti-inflammatory pain killers. The coupling compound obtained by coupling the NSAID anti-inflammatory pain killers and the EGFR kinase inhibitor has the good cancer treatment effect, and the new drug is provided for clinic treatment choices.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a coupling compound of a class of NSAID anti-inflammatory analgesic drugs and EGFR kinase inhibitors or pharmaceutically acceptable salts or stereoisomers thereof and prodrug molecules and their synthesis methods and Application in synthetic medicine. Background technique [0002] Tumor is a common disease with high mortality in modern society. The traditional method of treating tumors is mainly based on radical surgical resection, supplemented by preoperative and postoperative chemotherapy, but the curative effect is not satisfactory. Targeted drugs have attracted much attention due to their strong specificity and low toxicity. [0003] Studies in recent years have shown that the high expression of epidermal growth factor receptor (EGFR) in most tumors is closely related to the occurrence, development and prognosis of tumors. Therefore, targeted drugs targeting EGF...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D405/12C07D403/12C07D403/14A61K31/517A61P35/00
CPCC07D239/94C07D403/12C07D403/14C07D405/12
Inventor 张艳梅丁克廖进喜王贻灿陈盘余
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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