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Quinazoline derivatives and their preparation methods and applications in medicine

A pharmacy and drug technology, applied in the field of quinazoline derivatives and their preparation, to achieve the effect of excellent pharmacodynamic activity

Active Publication Date: 2019-10-29
HAISCO PHARMA GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Notably, in preclinical studies, irreversible dual inhibitors did not develop resistance as rapidly as gefitinib and erlotinib (Ercan, Zejnullahu et al., 2010, Oncogene, 29, 2346-2356; Chmielecki , Foo et al., 2011, Sci Transl Med, 3, 90ra59)

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1: 1-[4-[[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxymethyl]-1 -piperidinyl]propyl-2-en-1-one (compound 1)

[0149] 1-[4-[[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxymethyl]-1-piperidyl]prop-2-en-1-one

[0150]

[0151] The first step: tert-butyl 4-[(4-chloro-7-methoxy-quinazolin-6-yl)oxymethyl]piperidine-1-carboxylate (1B)

[0152] tert-butyl4-[(4-chloro-7-methoxy-quinazolin-6-yl)oxymethyl]piperidine-1-carboxylate

[0153] 1d (3.0g, 14.2mmol), triphenylphosphine (5.58g, 21.3mmol) and dichloromethane (50mL) were added to the reaction flask, protected by nitrogen, cooled to 0°C in an ice bath, and diazobiscarboxylic acid was added dropwise A solution of isopropyl ester (4.30 g, 21.3 mmol) in dichloromethane (10 mL) was added dropwise and allowed to react at room temperature for 30 minutes. 4-Hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (4.58 g, 21.3 mmol) was slowly added at 0° C., and the mixture was ra...

Embodiment 2

[0167] Example 2: 1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1 -piperidinyl]propyl-2-en-1-one (compound 2, compound 2 is 1-[(3R,4R)-4-[4-(3-chloro-2,4-difluoro-aniline) -7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidinyl]propyl-2-en-1-one and 1-[(3S,4S)-4- [4-(3-Chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidinyl]propyl-2- mixture of en-1-ones)

[0168] 1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidyl]prop-2-en-1- one

[0169]

[0170]

[0171] The first step: 4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-piperidine-1 - tert-butyl formate (2B, 2B is (3R,4R)-4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl] Oxy-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester and (3S,4S)-4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinone Azolin-6-yl]oxy-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester mixture)

[0...

Embodiment 3

[0187]Example 3: 1-[4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1- Piperidinyl] propyl-2-en-1-one (compound 3, compound 3 is 1-[(3R, 4S)-4-[4-(3-chloro-2,4-difluoro-aniline)- 7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidinyl]propyl-2-en-1-one and 1-[(3S,4R)-4-[ 4-(3-Chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidinyl]propyl-2-ene -1-ketone mixture)

[0188] 1-[4-[4-(3-chloro-2,4-difluoro-anilino)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-1-piperidyl]prop-2-en-1- one

[0189]

[0190] The first step: 4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl]oxy-3-fluoro-piperidine-1- tert-butyl formate (3B, 3B is (3R, 4S)-4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinazolin-6-yl]oxy tert-butyl-3-fluoro-piperidine-1-carboxylate and tert-(3S,4R)-4-[4-(3-chloro-2,4-difluoro-aniline)-7-methoxy-quinone Mixtures of oxazolin-6-yl]oxy-3-fluoro-piperidine-1-carboxylic acid butyl esters)

[0191] tert-butyl...

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Abstract

The present invention relates to a quinazoline derivative and its preparation method and application in medicine, specifically the present invention relates to a quinazoline derivative or its stereoisomer, hydrate, metabolite, solvate, pharmaceutical The acceptable salts, co-crystals or prodrugs relate to their preparation methods, their pharmaceutical compositions and their use in medicine, especially as EGFR / HER2 dual-target inhibitors.

Description

technical field [0001] The present invention relates to a quinazoline derivative and its preparation method and application in medicine, in particular to a novel quinazoline derivative or its stereoisomer and hydrate with EGFR / HER2 dual-target inhibitory effect , solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, pharmaceutical compositions thereof, and applications thereof in medicine. Background technique [0002] The receptor tyrosine kinase superfamily of cell surface receptors plays an important role in the regulation of cell signaling through extracellular growth factors. Receptor tyrosine kinases catalyze the transfer of a phosphate group from ATP to a tyrosine group on a substrate. When there is no ligand to activate receptor tyrosine kinases, these kinases are in the unphosphorylated monomeric state and their kinase domains assume an inactive configuration. When the ligand binds to the extracellular segment of the receptor tyrosine ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D403/12C07D405/14A61K31/517A61P35/00
CPCA61K31/517A61K45/06A61P35/00A61K2300/00
Inventor 李瑶徐波陈雷李升刘建余钱枚琳
Owner HAISCO PHARMA GRP INC
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