Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Quinazoline derivatives and their preparation methods and applications

A technology of quinazoline and derivatives, applied in the field of quinazoline derivatives and their preparation, can solve the problems of loss of drug efficacy, increase of EGFR and ATP binding ability and the like

Active Publication Date: 2019-05-24
GUANGZHOU HENOVCOM BIOSCI CO LTD
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the acquired drug resistance mechanisms, the most common one (accounting for 50% of the total number of drug-resistant patients) is the secondary mutation T790M of EGFR, that is, the threonine at position 790 is mutated to methionine, which can increase The binding ability of EGFR and ATP makes it difficult for drug molecules such as Gefitinib to compete with the binding of ATP and EGFR, thus losing its efficacy

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 derivatives and their preparation methods and applications
  • Quinazoline derivatives and their preparation methods and applications
  • Quinazoline derivatives and their preparation methods and applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Compound 7-1, N-(4-(4-((3-Chloro-4-fluorophenyl)amino)-7-(2-(dimethylamino)ethoxy)quinazolin-6-yl) - Preparation of 2-methylbutyl-3-yn-2-yl)acrylamide.

[0107] Synthesize as follows:

[0108]

[0109] Step (1) prepares compound 2 (that is, methyl 2-amino-4-fluoro-5-iodobenzoate) as follows:

[0110] Take a 250mL clean two-necked round-bottomed flask, add 50g of raw material 1 (322.58mmol), 100mL of tert-butanol and 50mL of water in turn, add 44.g (161.29mmol) of elemental iodine in batches under stirring, and then slowly dropwise add 40mL of 30% hydrogen peroxide , heated to 50°C in an oil bath for 2h. The reaction was monitored by TLC. After the reaction was completed, the system was cooled to room temperature, 50 mL of saturated aqueous sodium bisulfite solution was added, and then extracted three times with 150 mL of ethyl acetate. The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and recrystallized to...

Embodiment 2

[0123] Compound 7-2, N-(3-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-morpholinoethoxy)quinazolin-6-yl)propyl - Preparation of 2-yn-1-yl)acrylamides.

[0124] Referring to the preparation method of Example 1, N-(2-hydroxyethyl)morpholine is selected as the raw material in step (3), and the operation method is as in Example 1. The target compound 7-2.

[0125]

[0126] The characterization data for this target compound are: 1 H NMR (400MHz, DMSO-d 6 )δ9.84(s,1H),8.69(t,J=5.6Hz,1H),8.63(s,1H),8.56(s,1H),8.19(dd,J=6.9,2.6Hz,1H), 7.82(ddd,J=9.0,4.3,2.7Hz,1H),7.42(t,J=9.1Hz,1H),7.23(s,1H),6.27(dd,J=17.1,10.0Hz,1H),6.16 (dd, J=17.1, 2.3Hz, 1H), 5.66 (dd, J=10.0, 2.4Hz, 1H), 4.26-4.31 (m, 4H), 3.60 (q, J=4.7Hz, 4H), 2.79- 2.83(m,2H),2.57-2.62(m,4H).

Embodiment 3

[0128] Compound 7-3, N-(3-(4-((3-chloro-4-fluorophenyl)amino)-7-(2-(dimethylamino)ethoxy)quinazolin-6-yl) Preparation of propyl-2-yn-1-yl)acrylamide.

[0129] According to the method of Example 1, the target compound 7-3 is prepared by using compound 6-2 as a raw material in step 5).

[0130]

[0131] The characterization data for this target compound are: 1 H NMR (400MHz, DMSO-d 6 )δ9.93(s,1H),8.78(t,J=5.8Hz,1H),8.69(s,1H),8.56(s,1H),8.21(dd,J=7.0,2.6Hz,1H), 7.84(dt,J=7.5,3.4Hz,1H),

[0132] 7.42(t, J=9.1Hz, 1H), 7.22(s, 1H), 6.29(dd, J=17.1, 10.1Hz, 1H), 6.16(d, J=16.9Hz, 1H),

[0133] 5.66(dd, J=10.0, 2.4Hz, 1H), 4.21-4.29(m, 4H), 2.77(t, J=5.4Hz, 2H), 2.31(s, 6H).

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 derivative and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. The structure of the quinazoline derivative is as shown in a formula I. The quinazoline derivative or a pharmaceutically acceptable salt thereof has an irreversible inhibition effect on tyrosine kinase, the compound can inhibit two kinds of tyrosine kinase of EGFR and HER2 simultaneously, and the compound has good inhibitory activity on multiple cancer cell lines. Please see the formula I in the description.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a quinazoline derivative and a preparation method and application thereof. Background technique [0002] Epidermal growth factor receptor (EGFR) is a member of the ErbB protein family, and the other three subtypes are HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4), which are involved in cell proliferation and differentiation. It plays an important role in the process and is one of the most deeply studied tyrosine receptor proteins. EGFR widely exists in normal epidermal tissues such as skin, hair follicles and gastrointestinal tract, and plays an important role in maintaining normal physiological activities. However, overexpression or persistent activation of EGFR can lead to numerous cancers, and EGFR abnormalities are present in cancers including colorectal, lung, breast, and head and neck cancers. [0003] From 2003 to 2004, the EGFR small-molecule inhibitors G...

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
Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94C07D401/12A61P35/00A61P15/00A61P35/02
CPCC07D239/94C07D401/12
Inventor 张健存彭江灵李宏
Owner GUANGZHOU HENOVCOM BIOSCI CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com