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Dialkylaminoquinazoline compounds and their application in the preparation of antitumor drugs

A technology of dialkylaminoquinazoline and alkylaminoquinazoline, which is applied in the field of preparation of antitumor drugs and can solve problems such as serious side effects

Active Publication Date: 2021-05-07
SHAANXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the second-generation irreversible EGFR inhibitors, Afatinib (Dungo RT, Keating G M. Drug, 2013, 73 (13): 1503-1515.), Dacomitinib, Neratinib (Hwei-ruT, etal. Journal of Medicinal Chemistry, 2005, 48(4):1107-1131.), although they have a good curative effect in the treatment of non-small cell lung cancer with T790M mutation, but their dose-related side effects are relatively serious, such as diarrhea, rash, etc. (WenjunZ, DaliaE, Liang C, et al. Nature, 2009, 462(7276): 1070-1074.)

Method used

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  • Dialkylaminoquinazoline compounds and their application in the preparation of antitumor drugs
  • Dialkylaminoquinazoline compounds and their application in the preparation of antitumor drugs
  • Dialkylaminoquinazoline compounds and their application in the preparation of antitumor drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthetic compound 1: 4-[3-chloro-4-(3-fluorobenzyloxy)anilino]-6-[5-((N,N-diethylaminoethyl)aminomethyl)furan-2- base] quinazoline

[0025]

[0026] Add 0.09g (0.75mmol) of N,N-diethylaminoethylamine represented by formula II-1 and 5.0mL of methanol into a 50mL single-necked bottle, adjust the pH to 5-6 with formic acid, and then add 0.28g (2.00mmol ) anhydrous sodium sulfate, 0.06g (1.00mmol) sodium cyanoborohydride, under stirring, 4-[3-chloro-4-(3-fluorobenzyloxy) shown in 0.24g (0.50mmol) formula I-1 )anilino]-6-(5-formylfuran-2-yl)quinazoline and the mixture of 5mL tetrahydrofuran were dripped into the reaction system, after the dropwise addition, stirred at room temperature for 30 minutes, then added 0.06g (1.00 mmol) sodium cyanoborohydride, continue stirring for 90 minutes, adjust the pH to 9-10 with aqueous sodium hydroxide solution, filter with suction, evaporate the filtrate to remove the solvent, and separate the residue by silica gel column chromatogra...

Embodiment 2

[0028] Synthetic compound 2: 4-(3-ethynylanilino)-6-[5-((N,N-diethylaminoethyl)aminomethyl)furan-2-yl]quinazoline

[0029]

[0030] Add 0.09g (0.75mmol) of N,N-diethylaminoethylamine represented by formula II-1 and 5.0mL of methanol into a 50mL single-necked bottle, adjust the pH to 5-6 with formic acid, and then add 0.28g (2.00mmol ) anhydrous sodium sulfate, 0.06g (1.00mmol) sodium cyanoborohydride, under stirring, 4-(3-ethynylphenylamino)-6-(5- The mixture of formylfuran-2-yl)quinazoline and 5mL tetrahydrofuran was dropped into the reaction system, after the dropwise addition, the reaction was stirred at room temperature for 30 minutes, then 0.06g (1.00mmol) sodium cyanoborohydride was added, and the stirring was continued React for 90 minutes, adjust the pH to 9-10 with aqueous sodium hydroxide solution, filter with suction, evaporate the filtrate to remove the solvent, and separate the residue by silica gel column chromatography (methanol:chloroform=1:15, V / V) to obtai...

Embodiment 3

[0032] Synthetic compound 3: 4-[4-(E)-propenylanilino]-6-[5-((N,N-diethylaminoethyl)aminomethyl)furan-2-yl]quinazoline

[0033]

[0034] Add 0.09g (0.75mmol) of N,N-diethylaminoethylamine represented by formula II-1 and 5.0mL of methanol into a 50mL single-necked bottle, adjust the pH to 5-6 with formic acid, and then add 0.28g (2.00mmol ) anhydrous sodium sulfate, 0.06g (1.00mmol) sodium cyanoborohydride, under stirring, 4-[4-(E)-propenylanilino]-6 shown in 0.18g (0.50mmol) formula I-3 The mixture of -(5-formylfuran-2-yl)quinazoline and 5mL tetrahydrofuran was dropped into the reaction system. After the dropwise addition, the reaction was stirred at room temperature for 30 minutes, and then 0.06g (1.00mmol) cyanoborohydrogenation was added Na, continue to stir and react for 90 minutes, adjust the pH to 9-10 with aqueous sodium hydroxide solution, filter with suction, evaporate the filtrate to remove the solvent, and separate the residue by silica gel column chromatography ...

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Abstract

The invention discloses a class of dialkylaminoquinazoline compounds and their application in the preparation of antitumor drugs. The chemical structure of the compound is R in the formula 1 Represents hydrogen, halogen, ethynyl, propen-1-yl or halogenated benzyloxy; n is an integer of 1 to 3; m is an integer of 1 to 4; R 2 , R 3 Stand alone for C 1 ~C 4 alkyl. The compound of the invention has obvious proliferation inhibitory effect on human colon cancer cells, human non-small cell lung cancer cells, human skin squamous cancer cells and human lung cancer cells containing EGFR T790M / L858R double mutation, and can be used for preparing antitumor drugs.

Description

technical field [0001] The present invention relates to a class of novel quinazoline compounds; and relates to a preparation method of the compounds and their use in the preparation of antitumor drugs. Background technique [0002] Tumors are a great threat to human health, and the treatment of tumors is a major problem. The commonly used antineoplastic drugs in clinical practice are mainly cytotoxic drugs, which have unavoidable toxic and side effects. With the development of science and technology, targeted tumor therapy has brought good news to cancer patients in recent years. Targeted tumor therapy drugs enter the body and can specifically combine with cancer-causing targets to play a role, causing tumor cells to specifically die without harming surrounding normal cells. Studies have shown that a variety of tumors show the overexpression of epidermal growth factor receptor (EGFR) tyrosine kinase, and inhibiting the activity of EGFR has a positive effect on the treatmen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04A61K31/517A61P35/00
CPCC07D405/04
Inventor 李宝林高莉张娅玲陈丽李夏冰王伟
Owner SHAANXI NORMAL UNIV
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