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Quinoline and quinazoline derivative, preparation method, intermediate, composition and application

A technology for quinazoline and derivatives, applied in quinoline and quinazoline derivatives, preparation, intermediates, compositions and applications, capable of solving problems such as reversible inhibitor drug resistance

Active Publication Date: 2014-08-06
SHANGAI PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, Gefitinib and Erlotinib, which are already on the market, are reversible inhibitors. With their clinical use, reversible inhibitors gradually show drug resistance problems

Method used

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  • Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
  • Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
  • Quinoline and quinazoline derivative, preparation method, intermediate, composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0367] N-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobutane Preparation of -2-enamide

[0368]

[0369] Step 1 4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(2-fluoro-2-diethoxyphosphoacetyl)amino-7-methoxyquinazoline Preparation

[0370] Raw material: 6-amino-4-((3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazoline according to the literature J.Med.Chem.2009,52,6880- Prepared by the 6888 method.

[0371] Raw material: 2-Fluoro-2-diethoxyphosphoryl acetyl chloride was prepared according to the method of Heterocycles, 2004, 63, 699-706.

[0372] Combine 6-amino-4-((3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazoline (1eq.) (876mg) and triethylamine (1.5eq. ) (423μL) was dissolved in DMF (10ml), and the solution was stirred at 0°C for 30min. Add 2-fluoro-2-diethoxyphosphorylacetyl chloride (1.5eq.) (640μL) in DMF (5ml) Slowly add dropwise to the above solution, then stir overnight at room temperature. Af...

Embodiment 2

[0383] (Z)-N-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)- 2-fluorobut-2-enamide and (E)-N-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazolin-6-yl )-4-(dimethylamino)-2-fluorobut-2-enamide and preparation

[0384]

[0385] The Thar SFC Pre80 supercritical preparative chromatograph was used to separate the mixture of cis and trans isomers obtained in Example 1.

[0386] Column: AD-H (20×250mm, 5μm, Tianjin Agela)

[0387] Monitoring wavelength: 254nm

[0388] Column temperature: 38 degrees

[0389] Sample dissolution: methanol dissolution, filtration

[0390] Mobile phase: ethanol (containing 0.1% DEA): carbon dioxide = 40:60

[0391] Collect the fraction with a retention time of 5.09 min to obtain the (Z)-isomer (compound 2-1); the fraction with a retention time of 8.61 min to obtain the (E)-isomer (compound 2-2).

[0392] (Z)-isomer

[0393] 1 H NMR(400MHz,DMSO)δ9.75(s,1H),9.69(s,1H),8.68(s,1H),8.53(s,1H),7.99(d,J=2.8Hz,1H),7....

Embodiment 3～11

[0397] According to the same method as in Example 1, using different raw materials, the following compounds were prepared, and the obtained products were all mixtures of cis and trans isomers.

[0398]

[0399]

[0400]

[0401]

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PUM

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Abstract

The invention discloses a quinoline and quinazoline derivative I, a preparation method, an intermediate C, composition and an application. The preparation method comprises two methods, wherein the first method comprises steps as follows: 1, a compound A and a compound B react in a solvent under the action of alkali 1 to obtain a compound C; and 2, the product C obtained in the step 1 reacts with a compound D under the action of alkali 2; and the second comprises step as follows: the compound A and a compound E react in the solvent under the action of the alkali 1. The invention further provides the application of the compound represented in formula I or medicine composition in preparation of an EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor, an A431 or H1975 cell proliferation inhibitor or medicine for preventing or treating tumor diseases. The provided compound has better antitumor activity.

Description

Technical field [0001] The present invention specifically relates to a quinoline and quinazoline derivatives, preparation methods, intermediates, compositions and applications. Background technique [0002] Protein kinases play an important role in cell signal transduction. It can transfer phosphate groups from ATP to specific amino acid residues of functional proteins, triggering a series of biochemical reactions. According to the types of amino acids used as substrates during phosphorylation, protein kinases can be divided into serine-threonine kinases (STKs) and tyrosine kinases (PTKs). Among them, PTKs can be divided into three categories: ①receptor protein tyrosine kinases (RPTKs), which are single transmembrane proteins, have been found in more than 50 species in vertebrates; ②cytoplasmic tyrosine kinases, such as Src Family, Tec family, JAK family, etc.; ③Nuclear tyrosine kinases such as Abl and Wee. [0003] The extracellular domain of RPTKs is a ligand binding domain. T...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D405/12C07D401/12C07D215/54A61K31/517A61K31/5377A61K31/4706A61K31/4709A61P35/00C07F9/6512
CPCC07D215/54C07D239/94C07D401/12C07D405/12C07F9/60C07F9/65128C07F9/65583C07F9/65586
Inventor 夏广新俞永平陈文腾张永沈竞康
Owner SHANGAI PHARMA GRP CO LTD
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