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Quinazoline derivatives useful in cancer treatment

A compound and solvate technology, which is applied in the field of quinazoline derivatives for the treatment of cancer, can solve the problems of loss of DNA binding and sequence-specific transcription regulation functions, conformational changes in domains, etc.

Inactive Publication Date: 2008-09-10
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Based on the central DBD map, most of these mutations appear to result in intradomain conformational changes, loss of DNA binding and sequence-specific transcriptional regulation functions

Method used

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  • Quinazoline derivatives useful in cancer treatment
  • Quinazoline derivatives useful in cancer treatment
  • Quinazoline derivatives useful in cancer treatment

Examples

Experimental program
Comparison scheme
Effect test

preparation Embodiment 2

[0346] 5-bromo-2-[chloro-(2,4-dichlorophenyl)methyl]pyridine

[0347]

[0348] A. 2,4-dichloro-N-methoxy-N-methylbenzamide

[0349]

[0350] 2,4-Dichlorobenzoyl chloride (11.59 g, 7.76 mL, 55.3 mmoles) and N,O-dimethylhydroxylamine hydrochloride (4.91 g, 50.3 mmoles) were dissolved in dry dichloromethane (550 mL) , and the mixture was cooled to 0 °C under argon. Anhydrous pyridine (8.76 g, 8.96 mL, 110.6 mmoles) was added dropwise to the stirred solution at 0°C, and the mixture was stirred at 0°C for 6 hours. The mixture was evaporated to dryness and the residue was partitioned between ether-dichloromethane (1:1) and brine. The organic layer was dried (MgSO 4 ), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (60×5 cm) with 1% (10% concentrated NH 4 OH / methanol)-dichloromethane as eluent afforded the title compound (11.78 g, 100%) as a colorless oil: ESMS: m / z 234.0 (MH + ); measured value:

[0351] C, 46.16; H, 3.55; Cl,...

preparation Embodiment 3

[0367] A. (6-bromopyridin-3-yl)-(2,4-dichlorophenyl)methanone

[0368]

[0369] 2,5-Dibromopyridine (10.8 g, 45.6 mmoles) was dissolved in anhydrous ether (541 mL), and the mixture was stirred at -78°C under argon. 2.5M n-BuLi / hexane (21.5 mL, 54.7 mmoles) was added dropwise at -78°C over 10 minutes, and the mixture was stirred at -78°C for 40 minutes. 2,4-Dichloro-N-methoxy-N-methylbenzamide (10.64 g, 45.61 mmoles) (prepared as described above in Preparative Example 2, Step A) was dissolved in anhydrous diethyl ether over 10 minutes. (8 ml) was added dropwise to the stirred solution, and the mixture was stirred at -78°C for 1 hour. The mixture was allowed to warm to -10°C. Add saturated NH 4 Cl aqueous solution (108 mL), the mixture was stirred and allowed to warm to 25 °C. The ether layer was separated and dried (MgSO 4 ), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (30 x 5 cm) with 2% ethyl acetate / hexane as eluent to ...

preparation Embodiment 4

[0380] 5-bromo-2-[chloro-(3,5-dichlorophenyl)methyl]pyridine

[0381]

[0382] A. 3,5-dichloro-N-methoxy-N-methylbenzamide

[0383]

[0384] Dissolve 3,5-dichlorobenzoyl chloride (10.0 g, 47.7 mmoles) and N, O-dimethylhydroxylamine hydrochloride (4.23 g, 43.4 mmoles) in anhydrous dichloromethane (475 mL) under argon The mixture was cooled to 0°C under air. Anhydrous pyridine (7.55 g, 7.79 mL, 95.5 mmoles) was added dropwise to the stirred solution at 0°C, and the mixture was stirred at 0°C for 5 hours. The mixture was evaporated to dryness and the residue was partitioned between ether-dichloromethane (1:1) and brine. The organic layer was dried (MgSO 4 ), filtered and evaporated to dryness. The residue was chromatographed on a silica gel column (60×5 cm) with 0.75% (10% concentrated NH 4 OH / methanol)-dichloromethane as eluent afforded 3,5-dichloro-N-methoxy-N-methylbenzamide (9.66 g, 95%) as a colorless oil: FABMS: m / z 234.2 (MH + ); HRFABMS: m / z 234.0090 (MH + )...

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Abstract

The present invention provides compounds of Formula (I) (wherein R<1>, R<2>, R<3>, L, and X are as defined herein), or a pharmaceutically acceptable salt, solvate or ester thereof. The present invention also provides compositions comprising these compounds that are useful for treating cellular proliferative diseases, disorders associated with activity of mutants of p53, or in causing apoptosis of cancer cells.

Description

field of invention [0001] The present invention relates to compounds and compositions useful for treating cell proliferative diseases, conditions associated with p53 active mutations, or causing apoptosis of cancer cells. The compound of the present invention can restore the biochemical and biological activities of the mutant p53 and cause cancer cell apoptosis. Background of the invention [0002] Cancer is the leading cause of death in the United States and worldwide. Cancer cells are commonly characterized by constitutive proliferative signaling, defects in cell cycle checkpoints, and defects in apoptotic pathways. There is a great need to develop new chemotherapeutic drugs that can block cell proliferation and enhance tumor cell apoptosis. [0003] The p53 tumor suppressor protein belongs to a superfamily of transcription factors that includes its homologues p63 and p73. p53 is involved in a variety of cellular activities that are beneficial to ensure genome stability...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D239/90C07D401/12C07D403/12C07D405/12C07D409/12C07D409/14C07D413/12A61K31/517A61P35/00
CPCC07D401/12C07D239/94C07D239/90C07D403/12C07D409/12C07D405/12C07D409/14C07D413/12A61P1/04A61P19/02A61P29/00A61P31/10A61P35/00A61P37/02A61P37/04A61P37/06A61P43/00A61P9/04
Inventor A·K·马拉姆斯B·塔斯马哈帕特拉B·R·诺伊斯塔德特M·德马H·A·瓦卡罗
Owner SCHERING AG
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