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Quinazoline derivatives, preparation methods, intermediates, compositions and applications thereof

A technology of quinazoline and derivatives, which is applied in the field of quinazoline derivatives and can solve problems such as reversible inhibitor drug resistance

Active Publication Date: 2015-07-29
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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  • Quinazoline derivatives, preparation methods, intermediates, compositions and applications thereof
  • Quinazoline derivatives, preparation methods, intermediates, compositions and applications thereof
  • Quinazoline derivatives, preparation methods, intermediates, compositions and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0197] N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobut-2-enamide Preparation of (Compound 1)

[0198]

[0199] Step 1 Preparation of 4-(3-chloro-4-fluorophenylamino)-6-(2-fluoro-2-diethoxyphosphonoacetyl)amino-7-methoxyquinazoline

[0200] Raw material: 6-amino-4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazoline was prepared according to the method in J.Med.Chem.2009, 52, 6880-6888.

[0201]Raw material: 2-fluoro-2-diethoxyphosphoryl acetyl chloride was prepared according to the method in the literature Heterocycles, 2004, 63, 699-706.

[0202] 6-Amino-4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazoline (1 eq.) and triethylamine (1.5 eq.) were dissolved in DMF (10 ml), the The solution was stirred at 0 °C for 30 min. A solution of 2-fluoro-2-diethoxyphosphorylacetyl chloride (1.5eq.) in DMF (5ml) was slowly added dropwise to the above solution, and the reaction was stirred overnight at room temperature. After the reaction,...

Embodiment 2

[0211] (Z)-N-(4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobutyl- 2-enamide and (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl)-4-(dimethylamino)- Preparation of 2-fluorobut-2-enamide

[0212]

[0213] The mixture of cis and trans isomers obtained in Example 1 was separated by using Gilson 215 semi-preparative chromatograph (322 type pump, 156 type UV detector).

[0214] Chromatographic column: Phenomenon Gimini 30×250mm, 10μm

[0215] Detection wavelength: 254nm

[0216] Column temperature: room temperature

[0217] Sample processing method: the sample (mixture of cis and trans isomers) was dissolved in methanol and obtained by filtration. The concentration is 22mg / ml, and the injection volume of each needle is 800μL.

[0218] Mobile phase: water: acetonitrile (with 0.05% ammonia added) = 49:51

[0219]

[0220] The fraction with a retention time of 14.5 min was collected to obtain the (Z)-type isomer (comp...

Embodiment 3

[0227] According to the same method as in Example 1, using different raw materials, the following compounds were prepared, all of which were mixtures of cis and trans isomers.

[0228] Compound 3-1: N-(4-(3-chloro-4-fluorophenylamino)-7-(2-methoxy)ethoxyquinazolin-6-yl)-4-(dimethyl Amino)-2-fluorobut-2-enamide

[0229]

[0230] The raw material 6-amino-4-(3-chloro-4-fluorophenylamino)-7-(2-methoxy)ethoxyquinazoline was prepared according to the method of document WO2008 / 33747; other raw materials were prepared as in Example 1 .

[0231] MS (ESI + ): m / z=492, 493, 494 [M+H] +

[0232] Rf value: 0.38 (silica gel, ethyl acetate / methanol=9:1)

[0233] Compound 3-2: N-(4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)-2-fluorobutyl -2-enamide

[0234]

[0235] Raw material 6-amino-4-(3-chloro-4-fluorophenylamino)-7-ethoxyquinazoline according to 6-amino-4-(3-chloro-4-fluorophenyl in document WO2008 / 33747 Amino)-7-(2-methoxy)ethoxyquinazoline ...

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Abstract

Disclosed are as represented by Formula (I) a quinazoline derivative and a pharmaceutical acceptable salt thereof, or, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, or a prodrug of both. Also disclosed are a preparation method therefor, an intermediate, a pharmaceutical composition having the quinazoline derivative, and an application thereof. The quinazoline derivative of the present invention is provided with improved anti-tumor activity.

Description

technical field [0001] The present invention specifically relates to a quinazoline derivative, its preparation method, its intermediate, its pharmaceutical composition and its application. Background technique [0002] Protein kinases play an important role in cell signaling. It can transfer phosphate groups from ATP to specific amino acid residues in functional proteins, triggering a series of biochemical reactions. According to the type of amino acid used as a substrate in the phosphorylation process, protein kinases can be divided into serine-threonine kinases (STKs) and tyrosine kinases (PTKs). Among them, PTKs can be divided into three categories: ① receptor tyrosine kinases (receptor protein tyrosine kinases, RPTKs), which are single transmembrane proteins, and more than 50 species have been found in vertebrates; ② cytoplasmic tyrosine kinases, such as Src family, Tec family, JAK family, etc.; ③nuclear tyrosine kinases such as Abl and Wee. [0003] The extracellular...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94C07D405/12C07D403/12C07D401/12C07D413/12C07F9/6512C07F9/6558A61K31/517A61K31/5377A61P35/00
CPCC07D413/12C07D405/12C07D403/12C07D401/12C07D239/94A61P35/00A61P43/00
Inventor 夏广新沈竞康俞永平陈文腾张春春郝宇张晶李柏俊刘学军
Owner SHANGAI PHARMA GRP CO LTD
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