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Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor

An alkyl and alkenyl technology, applied in the field of medicine, can solve problems such as the difficulty of EGFR tyrosine kinase inhibitors

Active Publication Date: 2014-08-06
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 to catalyze the biochemical process of transferring phosphate groups from ATP to protein tyrosine residues, the above-mentioned reversible EGFR tyrosine kinase inhibitors compete with ATP and The combination of EGFR tyrosine kinase, and due to the high concentration of intracellular ATP (mM level), it is difficult for reversible EGFR tyrosine kinase inhibitors with high activity in vitro to be effective in animal pathological models

Method used

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  • Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor
  • Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor
  • Zinc binding group-containing irreversible EGFR tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0129] (1) Preparation of intermediate 1

[0130] Suspend raw material 1 potassium carbonate in the middle chamber of raw material 2, add 50% aqueous sodium hydroxide solution, and heat the mixed solution to 70 °C for reaction. After the reaction is completed, pour the mixed solution into water and stir thoroughly, filter, wash with water, and dry under reduced pressure. Intermediate 1 was obtained.

[0131] (2) Preparation of Intermediate 2

[0132] Dissolve the intermediate 1 in an appropriate amount of tetrahydrofuran, add the catalyst Raney nickel for reduction, filter after the reaction is completed, and remove the solvent by rotary evaporation to obtain the intermediate 2.

[0133] (3) Preparation of Intermediate 3

[0134] Dissolve the tetrahydrofuran solution of intermediate 2 in an appropriate amount of dichloromethane, add triethylamine, add raw material 3 at 0 °C, and stir for reaction. After the reaction is completed, separate and purify by chromatography to obta...

experiment example

[0156] Experimental example The in vitro enzymatic activity experiment of the compound of the present invention

[0157] Test product: the compound of the present invention, its chemical name, structural formula and preparation refer to the examples of each compound.

[0158] Control drug: CUDC-101, compound 12 in patent US7547781, prepared with reference to patent example 8, its structural formula is: .

[0159] Experimental method Determination of inhibitory activity of HDAC enzyme

[0160] 1. Preparation of test reagents

[0161] 1x buffer (50 mM hydroxyethylpiperazineethanesulfonic acid, pH=7.4, 100 mM potassium chloride, 0.001% Tween-20, 0.05% bovine serum albumin, 20 μM trichloroethyl phosphate)

[0162] 2. Compound Serial Dilution

[0163] ① 0.15 mM DMSO (dimethyl sulfoxide) compound solution: 15 μL of 10 mM compound solution was added to 985 μL of 100% DMSO.

[0164] ② Serially dilute the compound on a 96-well plate: Dilute the compound 4 times (20 μL of 0.15 mM...

Embodiment 1

[0194] Example 1 (E)-N 1 -(4-((3-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-N 8 Preparation of -Hydroxyoct-2-enedioamide (Compound 1)

[0195]

[0196] (1) Preparation of tert-butyl diethylphosphonoacetate

[0197]

[0198] A mixed solution of triethyl phosphite (1.66 g, 10 mmol) and tert-butyl bromoacetate (1.93 g, 10 mmol) was stirred at 100 °C for 3 hours. After the reaction was completed, the product was concentrated under reduced pressure to obtain the product (2.48 g, Yield 98%).

[0199] (2) Preparation of ethyl 6-oxohexanoate

[0200]

[0201] Pyridinium chlorochromate (21.5 g, 0.1 mol) was added to a solution of ethyl 6-hydroxyhexanoate (3.20 g, 20 mmol) in dichloromethane (40 mL), stirred at room temperature for about 6 hours, and the reaction mixture was subjected to preparative chromatography The product was isolated and purified (2.6 g, yield 82%).

[0202] (3) Preparation of (E)-1-tert-butyl 8-ethyl octa-2-enedioate

[0203] ...

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to a zinc binding group-containing irreversible EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor shown as general formula (I), its deuterated compounds, pharmaceutically acceptable salts or stereoisomers, wherein R1, R2, R3, R4, R5, R6, R7, W, X, L, T, and n are defined as the specification. The invention also relates to a preparation method of the compounds, pharmaceutical preparations containing the compounds, and application of the compounds in preparation of drugs treating and / or preventing tumors. (formula I).

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an irreversible EGFR tyrosine kinase inhibitor containing a zinc binding group, its deuterated substance, its pharmaceutically acceptable salt or its stereoisomer, the preparation method of these compounds, containing these compounds pharmaceutical preparations, and the use 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 tu...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D405/12C07D401/12A61K31/517A61P35/00A61P35/02
CPCC07D239/94C07D401/12C07D403/12C07D405/12
Inventor 吴永谦
Owner BEIJING AOHE DRUG RES INST
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