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Irreversible EGFR inhibitors containing a zinc-binding group

An alkyl and hydroxyl technology, which is applied in the field of preparing medicines for treating and/or preventing tumors, can solve the problems of difficulty in EGF receptor tyrosine kinase inhibitors and the like

Active Publication Date: 2016-02-17
BEIJING AOHE DRUG RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the physiological function of protein tyrosine kinase (PTK) is the catalyst for the biochemical process of catalyzing the transfer of phosphate groups from ATP to protein tyrosine residues, the above-mentioned reversible EFG receptor tyrosine kinase inhibitors compete with ATP It binds to EFG receptor tyrosine kinase, and because of the high concentration of intracellular ATP (mM level), it is difficult for reversible EGF receptor tyrosine kinase inhibitors that exhibit high activity in vitro to be tested in animal pathological models Significantly effective

Method used

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  • Irreversible EGFR inhibitors containing a zinc-binding group
  • Irreversible EGFR inhibitors containing a zinc-binding group
  • Irreversible EGFR inhibitors containing a zinc-binding group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0206] Example 17 Preparation of-(6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yloxy)-N-hydroxyheptanamide (compound 1)

[0207] (1) Preparation of methyl 7-chloroheptanoate

[0208]

[0209] With stirring, methyl 7-hydroxyheptanoate (48 g, 300 mmol) was dissolved in SOCl 2 (120mL), DMF (5mL) was added, and the resulting thick suspension was heated to obtain a transparent yellow solution, which was refluxed for 18 hours, and excess SOCl was distilled off under reduced pressure. 2 To get a brown syrup, add toluene to azeotrope twice to remove excess SOCl 2 A brown solid was obtained, which was dissolved in a small amount of dichloromethane, quickly filtered through silica gel, and then rinsed with dichloromethane quickly, and the obtained yellow filtrate was concentrated under reduced pressure to obtain the target product (45 g, 84%).

[0210] (2) Preparation of 4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-ol

[0211]

[0212] Dissolve N-(3-chloro-4-fluoro...

Embodiment 2

[0233] Preparation of Example 26-(6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yloxy)-N-hydroxycaproamide (compound 2)

[0234] (1) Preparation of ethyl 6-(4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yloxy)hexanoate

[0235]

[0236] N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (10.08 g, 33 mmol) was dissolved in 1,4-dioxane (100 mL) , join K 2 CO 3 (20.7g, 150mmol), ethyl 6-hydroxyhexanoate (14.4g, 90mmol), heated to 100 ° C for 72 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain the target product (10.5g ,67%).

[0237] (2) Preparation of ethyl 6-(6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yloxy)hexanoate

[0238]

[0239] 6-(4-(3-Chloro-4-fluoroanilino)-6-nitroquinazolin-7-yloxy)ethyl hexanoate (10.5g, 22mmol) was dissolved in THF (100mL), added Catalyst RaneyNi (1.2g), feed H 2 Reduction reaction, fi...

Embodiment 38

[0254] Example 38 Preparation of-(6-acrylamido-4-(3-chloro-4-fluoroanilino)quinazolin-7-yloxy)-N-hydroxyoctylamide (compound 3)

[0255] (1) Preparation of methyl 8-(4-(3-chloro-4-fluoroanilino)-6-nitroquinazolin-7-yloxy)octanoate

[0256]

[0257] N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (11.08 g, 33 mmol) was dissolved in 1,4-dioxane (100 mL) , join K 2 CO 3 (20.7g, 150mmol), methyl 8-hydroxyoctanoate (24g, 138mmol), heated to 100 ° C for 72 hours, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography to obtain the target product (5.8g, 36 %).

[0258] (2) Preparation of methyl 8-(6-amino-4-(3-chloro-4-fluoroanilino)quinazolin-7-yloxy)octanoate

[0259]

[0260] 8-(4-(3-Chloro-4-fluoroanilino)-6-nitroquinazolin-7-yloxy)octanoic acid methyl ester (5.8g, 12mmol) was dissolved in THF (100mL), and the catalyst was added RaneyNi (1.2g), pass int...

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to zinc binding group-containing irreversible EGFR inhibitors represented by the general formula (I), and deuterated compounds, pharmaceutically acceptable salts or stereoisomers thereof, wherein R<1>, R<>2, R<3>, R<4>, R<5>, R<6>, R<7>, Y, W, X, T and n are defined in the specification. The invention also relates to a preparing method of the compounds, pharmaceutical preparations containing the compounds, and an application of the compounds in preparing medicines for treatment and / or prevention of tumor.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an irreversible EGFR inhibitor containing a zinc binding group, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, a preparation method of these compounds, a pharmaceutical preparation containing these compounds, And the application of these compounds in the preparation of medicines for treating and / or preventing tumors. Background technique [0002] Protein tyrosine kinases, a class of enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues located on protein substrates, play a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases and affect signaling through this process to regulate cell growth. However, under certain conditions, these receptors are either mutated or overexpressed, becoming abnormal, causing cells to multiply uncontrollably, leading to tumor growt...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94C07D403/12C07D401/12C07D471/08C07D453/06A61K31/517A61K31/5377A61P35/00A61P35/02
CPCC07D239/94C07D401/12C07D403/12C07D453/06C07D471/08
Inventor 吴永谦周岩
Owner BEIJING AOHE DRUG RES INST