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Arylalkylamino-substituted quinazoline analogues

A technology of alkyl and amino groups, applied in the field of probes for detection and localization of capsaicin receptors, can solve the problems of limited therapeutic use, burning pain and the like

Inactive Publication Date: 2007-04-18
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, administration of the agonist itself may cause burning pain, limiting its therapeutic use

Method used

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  • Arylalkylamino-substituted quinazoline analogues
  • Arylalkylamino-substituted quinazoline analogues
  • Arylalkylamino-substituted quinazoline analogues

Examples

Experimental program
Comparison scheme
Effect test

example

[0299]The mass spectrometry data in this example and the following examples are electrospray MS, and the cone voltage (cone voltage) is 15V or 30V according to the positive ion mode, using the instrument Micromass Time-of-Flight LCT (Micromass, Beverly MA), equipped with Waters 600 pump , Waters 996 photodiode array detector, Gilson 215 autosampler and Gilson 841 microinjector. MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software was used. A sample volume of 1 μl was injected into a 50×4.6mm Chromolith SpeedROD C18 column, and a 2-phase linear gradient was used to elute at a flow rate of 6 ml / min. The total absorbance of the sample was measured in the 220-340nm UV range. The dissolution conditions are: mobile phase A-95 / 5 / 0.05 water / MeOH / TFA; mobile phase B-5 / 95 / 0.025 water / MeOH / TFA.

[0300] Gradient: time(minutes) %B

[0301] 0 10

[0302] 0.5 100

[0303] ...

example 1

[0307] Preparation of representative aralkylamino-substituted quinazoline analogs

[0308] This example illustrates representative aralkylamino-substituted quinazoline analogs [4-(2-fluoro-phenyl)-ethyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinoline Preparation method of oxazolin-4-yl]-amine (compound I).

[0309]

[0310] Take 4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline (10.8 mg, 35 micromoles) and 2-fluorophenethylamine (5.4 mg, 38.5 micromoles) in 392.5 µl CH 3 CN. DIEA (9.1 μL, 52.5 μmol) was added and the reaction mixture was heated at 45°C overnight. The reaction was cooled to room temperature and washed with 1N NaOH (200 μl). The organic phase was packed into a 0.5 g silica gel SPE column. Impurities were eluted with 4 mL 9 / 1 hexane / EtOAc. The product was collected from the eluate with 4 mL of EtOAc. The solvent was removed in vacuo to give [4-(2-fluoro-phenyl)-ethyl]-[7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]- Amine as a white soli...

example 2

[0312] Synthesis of other representative aralkylamino-substituted quinazoline analogs

[0313] This example illustrates the preparation of other representative substituted 2-aminoalkyl-quinazolin-4-ylamine analogs.

[0314] A. [2-Chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-phenethylamine (compound 4)

[0315]

[0316] 4-Chloro-2-chloromethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazoline (333 mg, 0.93 mmol) was dissolved in 5 mL of acetonitrile at room temperature. DIEA (162 μL, 0.93 μmol) was added followed by phenethylamine (117 μL, 0.93 μmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue is soluble in CH 2 Cl 2 Then pass through a 5 g silica gel SPE column. Unreacted starting material was removed by eluting with 5 mL of dichloromethane. The product is 95 / 5CH 2 Cl 2 / Methanol eluate collection. The solvent was removed in vacuo to give [2-chloromethyl-7-(3-trifluoromethyl-...

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Abstract

The present invention provides a quinazoline analog read by aramid amino substituted as shown in the right-sided general formula, a variation of this chemical formula as described herein. Formula I Such compounds are ligands that can be used to regulate specific receptor activity in vivo or in vivo, and are particularly suitable for the treatment of human, pet and domesticated animals pathological receptor activation related to the disease. And provide medical compositions for the treatment of such conditions and their use methods, and the use of such ligands for receptor localization studies.

Description

technical field [0001] The present invention generally relates to aralkylamino-substituted quinazoline analogs having pharmaceutically useful properties. The invention also relates to the use of these compounds in the treatment of conditions associated with capsaicin receptor activation, for the identification of other agents that bind to capsaicin receptors, and as a method for the detection and localization of capsaicin receptors. The purpose of the probe. Background of the invention [0002] Pain sensation, or nociception, is mediated by the peripheral terminals of specialized sensory neurons called "nociceptors." A variety of physical and chemical stimuli induce activation of these neurons in mammals, leading to recognition of potentially noxious stimuli. However, inappropriate or excessive activation of nociceptors can lead to acute or chronic pain that is excruciating. [0003] Neuropathic pain involves the transmission of pain signals in the absence of a stimulus, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/395A61K31/505C07D215/16C07D239/95C07D239/94C07D401/04C07D401/14C07D405/14C07D471/04C07D491/10
CPCC07D401/14C07D471/04C07D239/94C07D405/14C07D491/10C07D401/04A61P11/00A61P11/06A61P11/14A61P13/10A61P17/02A61P17/04A61P25/04A61P29/00A61P3/04A61P43/00A61P7/12
Inventor R·巴克他瓦特沙拉姆B·L·谢纳尔J·M·彼得森C·K·斯藤斯特罗
Owner NEUROGEN