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Quinazoline-7-ether compounds and methods of use

A technology of compounds, solvates, applied in the field of pan-ErbB family kinase inhibitors, which can solve problems such as disease, uncontrolled cell proliferation or differentiation

Active Publication Date: 2014-04-09
JIANGSU KANION PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] When RTKs are inappropriately or constitutively activated, such as by overexpression or mutation, aberrant RTK activity leads to uncontrolled cell proliferation or differentiation and leads to disease

Method used

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  • Quinazoline-7-ether compounds and methods of use
  • Quinazoline-7-ether compounds and methods of use
  • Quinazoline-7-ether compounds and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] (E)-N-(4-((3-chloro-4-fluorophenyl)-7-(((3S,3aS,6R,6aS)-6-methoxyhexahydrofuro[3,2- b] Preparation of furan-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (1):

[0168]

[0169] Step 1: N-(3-chloro-4-fluorophenyl)-7-(((3S,3aS,6R,6aS)-6-methoxyhexahydrofuro[3,2-b]furan-3 Preparation of -yl)oxy)-6-nitroquinazolin-4-amine (1b):

[0170] at room temperature in N 2 (g) NaH (60% dispersion in mineral oil, 493 mg, 12.32 mmol) was added in portions to a stirred solution of dianhydro-D-glucitol (1.5 g, 10.26 mmol) in DMF (20 mL) under atmosphere middle. After 20 minutes, iodomethane (639 μL, 10.26 mmol) was added, the mixture was stirred for 30 minutes, cooled to 0 °C, after which DMF (20 mL) and NaH (493 mg, 12.32 mmol) were added gradually. After 20 minutes N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (500 mg, 1.48 mmol, according to Smaill, J.B. et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397) and after 30 minutes at 0 ° C by...

Embodiment 2

[0178] (E)-N-(7-((3-oxabicyclo[3.1.0]hexane-6-ylmethoxy)-4-((3-chloro-4-fluorophenyl)amino)quinone Preparation of oxazolin-6-yl)-4-(dimethylamino)but-2-enamide (2)

[0179]

[0180] Step 1: 7-((3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazoline - Preparation of 4-amine (2b).

[0181] at room temperature in N 2(g) Add NaH (60% dispersion in mineral oil, 480 mg, 12.0 mmol) in portions to stirred (3-oxa-bicyclo[3.1.0]hexan-6-yl)methanol under atmosphere (570 mg, 5.0 mmol; prepared according to the procedure described in WO2012 / 021591A1) in DMF (40 mL). After 20 minutes, the mixture was cooled to 0 °C before adding N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 1a (1.54 g, 4.6 mmol , prepared according to Smaill, J.B. et al., Journal of Medicinal Chemistry, 2000, 43, 1380-1397). After stirring for 30 min at 0 °C by slowly adding saturated NH 4 The reaction was quenched with Cl followed by extraction with EtOAc (100 mL). w...

Embodiment 3

[0186] (E)-N-(7-((1S,5S)-3-oxabicyclo[3.1.0]hexane-1-yl)methoxy)-4-((3-chloro-4-fluoro Preparation of phenyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (3)

[0187]

[0188] Step 1: Preparation of (1R,5S)-1-((benzyloxy)methyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (3b):

[0189] To stirred (1R,5S)-1-(hydroxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (3a, 100 mmol, according to Moon, H.R. et al. Nucleosides , Nucleotides and Nucleic Acids, 2007, 26, 975-978) in THF (200 mL) was added NaH (60% in mineral oil, 4.80 g, 120 mmol). After 10 minutes, BnBr (120 mmol) was added. After stirring at room temperature for 12 h, the reaction was cooled to 0 °C, and to the reaction was added saturated NH 4 Cl aqueous solution (50 mL) and water (50 mL). The mixture was extracted with ether (300 mL). Wash the organic layer with water (100mL), brine (50mL), wash over MgSO 4 Dry and concentrate. The residue was purified by column chromatography (0-20 ethyl acetate in hexanes) to obtai...

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Abstract

The invention provides quinazoline-7-ether derivatives, particularly 4-anilinyl-6- butenamido-quinazoline-7-ether derivatives that are inhibitors of the receptor protein tyrosine kinases (RTK). The compounds are useful in the treatment of diseases and disorders where RTK activity is implicated such as a hyperproliferative diseases (e.g., cancer). Also provided are methods of preparation of the quinazoline derivatives and methods of use as therapeutic agents alone or in a drug combination.

Description

[0001] This application claims priority from International Patent Application PCT / CN2011 / 074165 filed May 17, 2011, the entire contents of which are incorporated herein by reference. technical field [0002] The present invention relates to the field of medicine, in particular to the preparation of 4-anilino-6-butenamido-7-alkoxy-quinazoline derivatives and pharmaceutical compositions containing these derivatives, and their use as therapeutic agents, especially Use as a pan-ErbB family kinase inhibitor. Background technique [0003] Cell signaling is the basic mechanism. During signal transduction, extracellular stimuli are transmitted intracellularly to regulate various cellular processes including cell proliferation, differentiation, apoptosis, and cell migration. A large number of signal transductions are mediated by the binding of growth factors to protein tyrosine kinase transmembrane receptors (RTKs) of protein tyrosine kinases (PTKs). [0004] When RTKs are inapprop...

Claims

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Application Information

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IPC IPC(8): C07D405/12A61K31/517A61P35/00C07D493/04
CPCC07D405/12C07D493/04
Inventor 沈旺萧伟杰克·满张爱民郑晓玲王振中郭庆明李瑛光
Owner JIANGSU KANION PHARMA CO LTD
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