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Quinazoline derivative as well as preparation method and use thereof

A quinazoline and derivative technology, applied in the field of drug synthesis, can solve the problems of increasing the difficulty of curing and the probability of recurrence, and achieve the effects of good inhibitory activity and selectivity

Inactive Publication Date: 2014-02-05
SHENYANG POLYTECHNIC UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If the receptors of cancer cells are overexpressed or overactivated, the cancer cells will grow in large numbers, thus increasing the difficulty of curing and the probability of recurrence

Method used

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  • Quinazoline derivative as well as preparation method and use thereof
  • Quinazoline derivative as well as preparation method and use thereof
  • Quinazoline derivative as well as preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] 1-(4-((4-((6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-yl)amino) Synthesis of phenoxy)methyl)piperidin-1-yl)ethanone (Ⅰ-1)

[0039]

[0040] Add 500 mL of ethanol and 5 mL of sulfuric acid into a 1000 mL four-necked reaction flask, then add 50 g of 1-(4-((4-nitrophenoxy)methyl)piperidin-1-yl)ethanone 1, and heat up to reflux. Add 60g of reduced iron powder several times in small amounts, and continue the reflux reaction for 3 hours after adding the iron powder. Cool to room temperature, add ammonia water dropwise, adjust pH=9 or so, filter, remove iron sludge, and wash with water. The filtrate was adjusted to pH=4 with hydrochloric acid, the product was precipitated, filtered, and the filter cake was dried to obtain 36.8 g of 1-(4-((4-aminophenoxy)methyl)piperidin-1-yl)ethanone 2. 1 H NMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH 2 ),2.00(m,1H,CH),2.36(s,3H,CH3 ),3.20-3.40(m,4H,CH 2 ),3.90(d,2H,CH 2 ),6.50-6.80(dd,4H,ArH);ESI-MS:m / z249[M+H] + . ...

Embodiment 2

[0045] Cyclopropyl 1-(4-((4-((6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-yl )amino)phenoxy)methyl)piperidin-1-yl)methanone (I-2) synthesis

[0046]

[0047] Prepared according to the same method as in Example 1, cyclopropyl (4-((4-nitrophenoxy) methyl) piperidin-1-yl) ketone is reduced by iron powder to obtain compound (4-(( 4-aminophenoxy)methyl)piperidin-1-yl)cyclopropylmethanone, reacted with 4-chloro-6-iodoquinazoline, and then reacted with 5-formyl-2-furylboronic acid, Finally react with 2-methanesulfonylethylamine to obtain the target compound I-2, 1 H NMR(400MHz,DMSO):δ0.72-0.93(m,4H,CH 2 ),1.15-1.17(m,1H,CH),1.34-1.59(m,4H,CH 2 ),2.00(m,1H,CH),2.83(s,3H,CH 3 ),3.11(m,2H,CH 2 ),3.20-3.40(m,4H,CH 2 ),3.53(m,2H,CH 2 ),3.67(s,2H,CH 2 ),3.90(d,2H,CH 2 ),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m ,2H,ArH),8.60(s,1H,ArH);ESI-MS:m / z604[M+H] + .

Embodiment 3

[0049] 6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)-N-(4-((1-(methylsulfonyl)piperidin-4-yl )methoxy)phenyl)quinazolin-4-amine (Ⅰ-3) synthesis

[0050]

[0051] Prepared according to the same method as in Example 1, 1-methylsulfonyl-(4-((4-nitrophenoxy)methyl)piperidine was reduced by iron powder to obtain compound (4-((1-methylsulfonyl) Acyl)piperidin-4-yl)methoxyaniline, then reacted with 4-chloro-6-iodoquinazoline, then with 5-formyl-2-furylboronic acid, and finally with 2-methanesulfonylethylamine The reaction gives the target compound I-3, 1 H NMR(400MHz,DMSO):δ1.34-1.59(m,4H,CH 2 ),2.00(m,1H,CH),2.83(s,3H,CH 3 ),2.96(s,3H,CH 3 ),3.11(m,2H,CH 2 ),3.20-3.40(m,4H,CH 2 ),3.53(m,2H,CH 2 ),3.67(s,2H,CH 2 ),3.90(d,2H,CH 2 ),6.39(d,1H,ArH),6.74(d,2H,ArH),7.35(d,1H,ArH),7.60(d,2H,ArH),7.93(d,1H,ArH),8.20(m ,2H,ArH),8.60(s,1H,ArH);ESI-MS:m / z614[M+H] + .

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Abstract

The invention belongs to the technical field of medicinal chemistry, and relates to a quinazoline derivative of a general formula (I) and a preparation method thereof, physiologically acceptable salts formed by inorganic or organic acid or alkaline thereof, pharmaceutical compositions containing the salts, and application thereof in preparing medicaments for treating diseases, especially medicaments for treating the diseases with the characteristic of abnormal erbB-family PTK (Protein Tyrosine Kinase) activity. The compound has valuable pharmacological properties, and has an inhibitory effect for signal transduction caused by tyrosine kinase.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a preparation method of quinazoline derivatives and their use as pharmaceutical preparations. Background technique [0002] Tyrosine Kinase Inhibitor (Tyrosine Kinase Inhibitor), mainly acts on epidermal growth factor receptor (Epidermal Growth Factor Receptor, EGFR). EGFR has an important influence and control correlation on the growth of cancer cells. If the receptors of cancer cells are overexpressed or overactivated, the cancer cells will grow in large numbers, thereby increasing the difficulty of curing and the probability of recurrence. EGFR receptors can be divided into four types of human epidermal growth factor receptors (Human Epidermal Receptor). The first type is usually called EGFR, the second type is called HER2, and the other types are third and fourth. Among these four types, the presence or absence of type II receptors is the most important, because the overexpre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14A61K31/517A61P35/00
CPCC07D405/14
Inventor 蔡志强李素君侯玲胡志泉孙洪涛李志利郭洪彬蔡奥飞
Owner SHENYANG POLYTECHNIC UNIV
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