Unlock instant, AI-driven research and patent intelligence for your innovation.

Quinazoline compound serving as epidermal growth factor receptor (EGFR) triple mutation inhibitor and application of quinazoline compound

A technology of compounds and stereoisomers, applied in the fields of compounds of Group 5/15 elements of the periodic table, organic chemistry, drug combination, etc., can solve the problem that the third-generation inhibitors cannot covalently bind protein kinases, etc.

Active Publication Date: 2019-10-25
EAST CHINA UNIV OF SCI & TECH
View PDF13 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

After research, it was found that the occurrence of drug resistance was mainly due to the mutation of Cys797 residue to form Ser797 residue, resulting in the inability of the third-generation inhibitors to covalently bind to protein kinases

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Quinazoline compound serving as epidermal growth factor receptor (EGFR) triple mutation inhibitor and application of quinazoline compound
  • Quinazoline compound serving as epidermal growth factor receptor (EGFR) triple mutation inhibitor and application of quinazoline compound
  • Quinazoline compound serving as epidermal growth factor receptor (EGFR) triple mutation inhibitor and application of quinazoline compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0082] The preparation method of the compound of the present invention may be a conventional method in the art, or the synthetic route of the present invention may be adopted.

[0083]

[0084] Wherein, the reaction reagents and conditions of each step are as follows:

[0085] (a) tert-butyl 4-((toluenesulfonyloxy)methyl)piperidine-1-carboxylate, DMF, K 2 CO 3 ;120℃,5h;

[0086] (b) HCHO, HCOOH, 120°C, 8h;

[0087] (c) fuming nitric acid, DCM, 25°C, overnight;

[0088] (d) Pd / C, MeOH / DCM, H 2 ,25℃,4h;

[0089] (e) Formamidine acetate, CH 3 OCH 2 CH 2 OH, 120℃, 8h;

[0090] (f)SOCl 2 ,DMF,80℃,3h;

[0091] (g) THF, Et 3 N, 60℃, 5h;

[0092] (h)Pd / C,H 2 , MeOH / DCM, 25℃, 5h;

[0093] (i) i-PrOH, HCl, 80°C, 8h.

[0094] Wherein, the preparation method of compound 2h can be as follows:

[0095]

Embodiment 1

[0098] Embodiment 1: the synthesis of compound 1

[0099] Synthesis of Methyl 4-(N-Boc-4-piperidinemethoxy)-3-methoxybenzoate

[0100]

[0101] Weigh methyl trioxalate (1g, 5.49mmol) into a 100mL eggplant-shaped bottle, add anhydrous potassium carbonate (1.52g, 10.98mmol), add about 50mL of DMF, and stir at room temperature for about 15min. Add tert-butyl-4-((toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (2.75g, 7.41mmol), heat up to 95°C and reflux for 3h. TLC confirmed complete reaction. Extract with saturated sodium chloride / ethyl acetate, and dry with anhydrous sodium sulfate. Most of the solvent is removed by rotary evaporation with a water pump, and the residual DMF is removed by rotary evaporation at 70°C for about 20 minutes with a diaphragm pump. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate=8:1) to obtain 2 g of methyl 4-(N-Boc-4-piperidinemethoxy)-3-methoxybenzoate, the yield 86%. ...

Embodiment 2

[0127] Example 2 N-(4-fluoro-3-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-yl)amino)benzene base) benzamide

[0128]

[0129] Pale yellow solid, yield 45%. 1H NMR (400MHz, DMSO-d6): δ10.38(s, 1H), 9.58(s, 1H), 8.36(s, 1H), 8.05(d, J=7.2Hz, 1H), 7.87(d, J =7.2Hz, 2H), 7.84(s, 1H), 7.67-7.53(m, 4H), 7.31(t, J=12Hz, 1H), 7.18(s, 1H), 4.01(d, J=6Hz, 2H ),3.95(s,3H),2.83(d,J=11.2Hz,2H),2.21(s,3H),1.96(t,J=12Hz,3H),1.78(d,J=10.4Hz,2H) ,1.30-1.58(m,2H).13C NMR(100MHz,DMSO-d6)δ170.74,157.40,153.54,153.10,148.90,146.73,142.50,128.62,126.13,124.39,114.60,108.43,107.62,107.62, , 54.65, 48.55, 45.86, 42.02, 38.30, 36.20, 34.37, 28.22. HRMS (ESI) (m / z): [M+H] +, calcd for C29H33N8O3, 516.2433; found, 516.2410. HPLC purity: 95.36%, retained Time = 10.78min.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a quinazoline compound serving as an epidermal growth factor receptor (EGFR) triple mutation inhibitor and application of the quinazoline compound. Specifically, the inventiondiscloses a compound shown as the following formula I (please see the specifications for the formula), a drug composition containing the compound shown as the following formula I (please see the specifications for the formula) and application of the compound to treatment of EGFR mediated related diseases and preparation of drugs for treating the EGFR mediated related diseases.

Description

technical field [0001] The invention belongs to the field of medicine and drug synthesis, in particular, the invention relates to a quinazoline compound as an EGFR triple mutation inhibitor and its application. Background technique [0002] Epidermal growth factor receptor (EGFR, also known as HER-1 or c-erbB-1) is composed of 1186 amino acids, 170-kDa transmembrane glycoprotein. EGFR consists of three parts: the extracellular receptor region; the transmembrane region; and the intracellular tyrosine kinase region. EGFR is a member of the c-erbB family of receptor tyrosine kinases, which together with HER2 (c-erbB-2), HER3 (c-erbB-3) and HER4 (c-erbB-4) form the c-erbB family . The confirmed ligands that can bind to EGFR include: epidermal growth factor (EGF), transforming growth factor ɑ (TGFɑ), two-way regulator, heparin-binding EGF, cytokines, etc. In human tissues, EGF and TGFɑ are considered to be the two most important ligands of EGFR [2]. When the ligand binds to t...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D401/12C07F9/6558C07D403/12C07D239/94C07D401/14A61K31/517A61K31/5377A61K31/675A61P35/00
CPCC07D401/12C07F9/65583C07D403/12C07D239/94C07D401/14A61P35/00C07D413/14C07D413/12C07D403/14A61K31/517A61K31/675A61K31/5377C07F9/6558
Inventor 李洪林丁健徐玉芳谢华李倩男张弢赵振江
Owner EAST CHINA UNIV OF SCI & TECH
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com