Quinazoline-based egfr tyrosine kinase inhibitor containing a zinc-binding group

A technology of alkyl and hydroxyl, applied in the field of medicine, can solve the problem of drug resistance of tumors

Active Publication Date: 2016-05-11
BEIJING AOHE DRUG RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, their efficacy is limited to a small subset of specific patients due to the molecular heterogeneity of tumors
In addition, tumors rapidly become resistant to treatment with these tyrosine kinase inhibitors

Method used

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  • Quinazoline-based egfr tyrosine kinase inhibitor containing a zinc-binding group
  • Quinazoline-based egfr tyrosine kinase inhibitor containing a zinc-binding group
  • Quinazoline-based egfr tyrosine kinase inhibitor containing a zinc-binding group

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] The preparation of embodiment 17-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yloxy)-N-hydroxyheptanamide (compound 1)

[0172]

[0173] (1) Preparation of 3-iodotetrahydrofuran

[0174]

[0175] Add triphenylphosphine (52.4g, 0.2mol), imidazole (13.6g, 0.2mol) and iodine (50.7g, 0.2 mol), the reaction solution in N 2 Reflux overnight under protection with 0.2M Na 2 S 2 o 3 (30mL) to quench the reaction, the organic layer was separated, the aqueous phase was extracted three times with dichloromethane and the combined organic phase was washed with anhydrous MgSO 4 After drying, filtering and concentrating, a wet, yellow solid was obtained. The solid was added to pentane (100 mL) and stirred for 2 h. The insoluble solid was filtered and the filtrate was concentrated to obtain the target product (18.6 g, yield 94%).

[0176] (2) Preparation of methyl 3-hydroxy-4-(tetrahydrofuran-3-yloxy)benzoate

[0177]

[0178] 3,4-Dihydroxybenzoic ...

Embodiment 2

[0208] Example 2N 1 -(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-N 8 Preparation of -Hydroxysuberamide (compound 3)

[0209]

[0210] (1) Preparation of N-(3-chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine

[0211]

[0212]3-Hydroxytetrahydrofuran (0.88g, 10mmol) was dissolved in tetrahydrofuran (50mL), under ice-cooling conditions, sodium hydride (0.6g, 15mmol) was stirred for 1 hour, and then 7-fluoro-4-(3 -Chloro-4-fluoroaniline)-6-nitroquinazoline (3.36g, 10mmol) was dissolved in tetrahydrofuran (50mL) and added to the above reaction solution, refluxed for 24 hours, and purified by column to obtain 1.01g of the product. The rate is 25%.

[0213] (2) Preparation of N-(3-chloro-4-fluorophenyl)-6-amino-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine

[0214]

[0215] N-(3-chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine (2.02g, 5mmol) and Raney nickel (RaneyNi ) (0.2g) was a...

Embodiment 3

[0227] Example 3(S)-N 1 -(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-N 8 Preparation of -Hydroxysuberamide (Compound 4)

[0228]

[0229] (1) Preparation of (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine

[0230]

[0231] (S)-3-Hydroxytetrahydrofuran (0.88g, 10mmol) was dissolved in tetrahydrofuran (50mL), under ice-cooling conditions, sodium hydride (0.6g, 15mmol) was stirred for 1 hour, and then 7-fluoro- 4-(3-Chloro-4-fluoroaniline)-6-nitroquinazoline (3.36g, 10mmol) was dissolved in tetrahydrofuran (50mL) and added to the above reaction solution, refluxed for 24 hours, and purified by column to obtain the product 1.30 g, 32% yield.

[0232] (2) Preparation of (S)-N-(3-chloro-4-fluorophenyl)-6-amino-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine

[0233]

[0234] (S)-N-(3-Chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine (2.02g, 5mmol) and Ra RaneyNi (0.2g) was a...

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to a zinc binding group-containing quinazolinyl 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, and T 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

1. Technical field [0001] The invention belongs to the field of medical technology, in particular to quinazoline-based EGFR tyrosine kinase inhibitors containing zinc binding groups, deuterated products thereof, pharmaceutically acceptable salts thereof or stereoisomers thereof, and methods for preparing these compounds. Pharmaceutical preparations containing these compounds, and the use of these compounds in the preparation of drugs for treating and / or preventing tumors. 2. Background technology [0002] Epidermal growth factor receptor (EGFR) is a multifunctional glycoprotein widely distributed on the cell membrane of various human tissues, and is a homologue of the oncogene of avian erythroblastic leukemia virus (v-erb-b). Human EGFR / HER1 / ErbB-1 and HER2 (humanepidermalgrowthfactorreceptor-2) / ErbB-2 / Teu / p185, HER3 / ErbB-3, HER4 / ErbB-4, etc. are classified into the HER / ErbB family and belong to protein tyrosine kinases (PTKs). Clinical studies have shown that EGFR is over...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07D401/12C07D239/94A61K31/517A61P35/00A61P35/02
CPCC07D239/94C07D401/12C07D403/12C07D405/12C07D405/14
Inventor 吴永谦
Owner BEIJING AOHE DRUG RES INST
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