Novel quinazoline derivatives

A compound, prodrug technology, applied in the field of new quinazoline derivatives

Inactive Publication Date: 2012-09-19
张强 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, tabactin, a tyrosine kinase inhibitor, selectively attenuates the growth of athymic nude mice transplanted with human breast cancer expressing epidermal growth factor receptor tyrosine kinase (EGFR), but is less effective at inhibiting Recipient of another type of cancer growth is ineffective

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0581] (S,E)-N-(4-(3-Chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-(D 6 -Dimethylamino)but-2-enamide

[0582]

[0583] N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (2).

[0584] 230 mg of 1 (1.0 mmol) and 146 mg of 3-chloro-4-fluoroaniline (1.0 equiv) were suspended in 5 mL of isopropanol and heated at reflux for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under vacuum to give the crude product. The crude product was dissolved in dichloromethane and basified by 10% sodium hydroxide solution. The organic layer was separated and dried to give pure product 2 as a yellow solid in 100% yield. HPLC-MS: m / z: 337[M+1] + .

[0585] (S)-N-(3-Chloro-4-fluorophenyl)-6-nitro-7-(tetrahydrofuran-3-yloxy)quinazolin-4-amine (3).

[0586] 200 mg of 2 (0.6 mmol) was dissolved in 5 mL of DMF, 115 mg of potassium trimethylsilanolate (0.9 mmol) was added at room temperature, and stirred at room temperature for...

Embodiment 2

[0592] (S,E)-4-(D 6 -Dimethylamino)-N-(4-(3-ethynylanilino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)but-2-enamide

[0593]

[0594] As described in the scheme above, the compound was synthesized with (S)-N-(4-(3-chloro-4-fluoroanilino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl )-4-(D 6 -Dimethylamino)but-2-enamide was synthesized similarly, except that 3-ethynylaniline was used instead of 3-chloro-4-fluoroaniline. The final product was purified by HPLC to obtain 50 mg of product as a white solid. HPLC-MS: m / z: 464[M+1] + .

Embodiment 3

[0596] (E)-N-(4-(3-chloro-4-fluoroanilino)-7-((1-D)-tetrahydrofuran-3-yloxy)quinazolin-6-yl)-4-( Dimethylamino)but-2-enamide

[0597]

[0598] N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (2).

[0599] 230 mg of 1 (1.0 mmol) and 146 mg of 3-chloro-4-fluoroaniline (1.0 equiv) were suspended in 5 mL of isopropanol and heated at reflux for 4 hours. The mixture was cooled to room temperature and the solvent was evaporated under vacuum to give the crude product. The crude product was dissolved in dichloromethane and basified by 10% sodium hydroxide solution. The organic layer was separated and dried to give pure product 2 as a yellow solid. The yield is 100%. HPLC-MS: m / z: 337[M+1] + .

[0600] N-(3-Chloro-4-fluorophenyl)-6-nitro-7-(3-D-tetrahydrofuran-3-yloxy)quinazolin-4-amine (3).

[0601] 200 mg of 2 (0.6 mmol) was dissolved in 5 mL of DMF, 115 mg of potassium trimethylsiliconate (0.9 mmol) was added at room temperature and stirred for 15 min. Then,...

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Abstract

This disclosure concerns novel quinazoline compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful anticancer agents, especially in inhibiting the function of the EGF receptor tyrosine kinases, HERl tyrosine kinase, and HER2 tyrosine kinase. Thus, the disclosure also concerns a method of treating hyperproliferative diseases or conditions, such as various cancers and benign prostate hyperplasia (BPH), by use of these novel compounds or a composition comprising such novel compounds.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. $119(e) to U.S. Provisional Patent Application Serial No. 61 / 288,492, filed December 21, 2009, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to novel 4-anilinoquinazoline derivatives and stereoisomers, pharmaceutically acceptable salts or solvates and prodrugs thereof, which are used for hyperproliferative diseases such as various cancers and Treatment of benign prostatic hyperplasia (BPH). Background technique [0004] Cells may become oncogenic by converting part of their DNA into oncogenes (that is, activating genes that lead to the formation of malignant tumor cells). Many oncogenes encode proteins that are mutant tyrosine kinases capable of causing cellular transformation. Alternatively, overexpression of normal proto-oncogene tyrosine kinases may lead to proliferative disorders sometimes caused b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/08A61K31/517C07D413/08
CPCC07D401/12C07D239/94C07D405/14C07D403/12C07D405/12C07D405/04A61P13/08A61P35/00
Inventor 张强朱红文
Owner 张强
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