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4-anilino quinazoline derivatives as antiproliferative agents

A kind of derivative, the technology of quinazoline, applied in the medicine of solid tumor disease, the field of preparation of described quinazoline derivatives, can solve the problems such as unpublished

Inactive Publication Date: 2007-07-25
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] No disclosure of 4-(2,3-dihaloanilino) quinazoline compounds in the prior art

Method used

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  • 4-anilino quinazoline derivatives as antiproliferative agents
  • 4-anilino quinazoline derivatives as antiproliferative agents
  • 4-anilino quinazoline derivatives as antiproliferative agents

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0861] 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)oxy]quinazoline

[0862]

[0863] 1- Methyl-3-pyrrolidinol (658 μl, 6.0 mmol) and triphenylphosphine (1572 mg, 6.0 mmol). The suspension was cooled to below 0°C under nitrogen atmosphere. A solution of di-tert-butyl azodicarboxylate (1380 mg, 6 mmol) in DCM (20 ml) was added dropwise over 15 minutes. The resulting light brown solution was warmed to room temperature and stirred overnight. The solution was evaporated and the residue was purified by chromatography eluting with 0-5% methanol in DCM. Appropriate fractions were combined, evaporated and the crude product (230mg) redissolved in 1:1 methanol / DCM (5ml). Etherified HCl (1M, 1.14ml) was added and the mixture was evaporated. Crystallization from methanol / ether gave the title product as the hydrochloride salt as a white crystalline solid (154 mg, 16%);

[0864] 1 H NMR (hydrochloride):

[0865] ...

Embodiment 2

[0868] 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline

[0869]

[0870] With 6-{[(1-tert-butoxycarbonyl)piperidin-4-yl]oxyl}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (reference implementation Example 3; 350mg, 0.70mmol) was dissolved in trifluoroacetic acid (5ml) and the solution was left for 2 hours. Excess trifluoroacetic acid was evaporated and the residue was azeotroped twice with DCM. The residue was purified by chromatography with 0-4% (7:1 MeOH / conc. NH 4 OH aq) in DCM for elution. Evaporation of the appropriate fractions gave the product as an off-white solid (270 mg, 96%);

[0871] 1 H NMR: 1.53-1.64 (m, 2H), 2.00-2.05 (m, 2H), 2.64-2.72 (m, 2H), 3.00-3.07 (m, 2H), 3.92 (s, 3H), 4.60 (m, 1H), 7.20(s, 1H), 7.26(ddd, 1H), 7.47(dd, 1H), 7.50(dd, 1H), 7.82(s, 1H), 8.34(s, 1H), 9.56(s, 1H );

[0872] mass spectrometry : 403.2, 405.2.

Embodiment 3

[0874] 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-[(piperidin-4-yl)methoxy]quinazoline

[0875]

[0876] Using 6-{[(1-tert-butoxycarbonyl)piperidin-4-yl]methoxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (reference Example 4) The procedure described in Example 2 was repeated. The title compound was obtained in 91% yield;

[0877] 1 H NMR: 1.45-1.61 (m, 2H), 1.95-2.00 (m, 2H), 2.18 (m, 1H), 2.92 (m, 2H). 3.25-3.35 (m, 2H), 3.93 (s, 3H) , 4.03(d, 2H), 7.20(s, 1H), 7.26(dd, 1H), 7.46(dd, 1H), 7.50(dd, 1H), 7.89(s, 1H), 8.36(s, 1H), 8.72(br.s, 1H), 9.74(s, 1H);

[0878] mass spectrometry : 417.4, 419.

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Abstract

The invention concerns quinazoline derivatives of Formula (I) wherein each of Q<1>, Z, R<1> and Q<2> have any of the meanings defined in the description; processes for their preparation, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours which are sensitive to inhibition of erbB receptor tyrosine kinases.

Description

[0001] This application is a Chinese patent application (National Application No. 03811739.8, International Application No. PCT / GB03 / 01306) divisional application. technical field [0002] The present invention relates to certain novel quinazoline derivatives or pharmaceutically acceptable salts thereof, these compounds have antitumor activity and can therefore be used in methods of treatment for human or animal bodies. The present invention also relates to methods for preparing said quinazoline derivatives, pharmaceutical compositions containing these derivatives and their use in methods of treatment, such as in the preparation of solid tumors for the prevention or treatment of warm-blooded animals (such as humans). Use in medicine for disease. Background technique [0003] Many current treatment regimens for diseases caused by abnormal regulation of cell proliferation, such as psoriasis and cancer, employ compounds that inhibit DNA synthesis and cell proliferation. The c...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D401/12C07D401/14C07D403/14C07D491/04A61K31/517A61P35/00
Inventor R·H·布拉博里L·F·A·亨内奎恩J·G·凯特尔
Owner ASTRAZENECA AB
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