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Substituted pyridin-2-ylamine analogues

A technology of substituents and haloalkyl groups is applied in the field of probes for detecting and locating capsaicin receptors, and can solve problems such as limited therapeutic use and burning pain.

Inactive Publication Date: 2006-08-30
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the use of agonists may cause burning pain, thus limiting its therapeutic use

Method used

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  • Substituted pyridin-2-ylamine analogues
  • Substituted pyridin-2-ylamine analogues
  • Substituted pyridin-2-ylamine analogues

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0283] Preparation of representative substituted pyridin-2-ylamine analogs

[0284] This example illustrates representative substituted pyridin-2-ylamine analogs.

[0285] A. [4,6-bis(2-trifluoromethyl-benzyloxy)-[1,3,5]triazin-2-yl]-(4-trifluoromethyl-phenyl)amine

[0286] 1. (4,6-dichloro-[1,3,5]triazin-2-yl)-(4-trifluoromethyl-phenyl)amine

[0287]

[0288] Add diisopropylethylamine (1.39 g, 0.0108 mol). After adding 4-trifluoromethyl-phenylamine (1.74 g, 0.0108 mol) dropwise to the mixture, the reaction was stirred at 0° C. for 2 hours, and then at room temperature for 16 hours. After diluting the reaction mixture with ethyl acetate, water (2x), saturated NaHCO 3 (1x) and brine (1x) washes. Organic layer with Na 2 SO 4 After drying, concentration was performed under reduced pressure. The concentrated residue was purified by preparative plate chromatography (eluent: 20% ethyl acetate / hexane) to give the title compound.

[0289] 2. [4,6-bis(2-trifluoromethyl-benz...

Embodiment 2

[0320] N 4 Preparation of -(4-tert-butyl-phenyl)-6-(2-trifluoromethyl-benzyloxy)-pyrimidine-2,4-diamine

[0321] 1.N 4 -(4-tert-butyl-phenyl)-6-chloro-pyridine-2,4-diamine

[0322]

[0323] After adding 4-tert-butyl-phenylamine (1.82 g, 0.0122 mol) to a solution of 4,6-dichloro-pyrimidin-2 ylamine (2.0 g, 0.0122 mol) in acetonitrile, the mixture was stirred at 70° C. 16 hours. Then cooled to room temperature, concentrated, in saturated NaHCO 3 Partition between aqueous solution and ethyl acetate. The organic layer was washed with brine, washed with Na 2 SO 4 Dry, then concentrate under reduced pressure. The concentrated residue was purified by flash chromatography (mobile phase 25% ethyl acetate / hexanes) to afford the title compound.

[0324] 2.N 4 -(4-tert-butyl-phenyl)-6-(2-trifluoromethyl-benzyloxy)-pyrimidine-2,4-diamine

[0325]

[0326] NaH (51 mg, 1.28 mmol, 60% suspension in mineral oil) was added to a solution of (2-trifluoromethyl-phenyl)methanol (300...

Embodiment 3

[0328] Representative substituted pyridin-2-ylamine analogs

[0329] Various changes may be made to the starting materials and other procedures may be used to produce other compounds provided herein by using routine modifications. The compounds listed in Table I were prepared using the method described. In marked "IC 50 "*" in the column of the field indicates the IC determined as described in Example 6 50 at a concentration of 1 micromolar or less (i.e., cells exposed to IC 50 The concentration of capsaicin required to reduce the fluorescent response produced by capsaicin by 50% is 1 micromolar or less). The mass spectrometry data in the columns marked with the "MS" field are electrospray mass spectrometry (Electospray MS) data, in positive ion mode with a conical voltage of 15 or 30 volts (V), by using a Waters 600 motor, Waters Micromass Time-of-Flight LCT (Micromass Time-of-Flight LCT) of 996-type photodiode array detector, Gilson215 automatic sampler and Gilson 841 mi...

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Abstract

Substituted pyridin-2-ylamine analogues are provided, of the formula: wherein variables are as described herein. Such compounds are ligands that may be used to modulate specific receptor activity in vivo or in vitro, and are particularly useful in the treatment of conditions associated with pathological receptor activation in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for using such compounds to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Description

technical field [0001] The present invention relates to substituted pyridin-2-ylamine analogs which are capsaicin receptor modulators and to the use of said compounds in the treatment of diseases associated with capsaicin receptor activation. The invention further relates to the use of said compounds as probes for the detection and localization of capsaicin receptors. Background technique [0002] Painful or nociceptive stimuli are mediated by the nerve endings of a specific group of sensory neurons called "nociceptors." Various physical and chemical stimuli induce the activation of such neurons in mammals, leading to the recognition of potentially noxious stimuli. However, inappropriate or overactivation of nociceptive receptors produces debilitating acute or chronic pain. [0003] Neuropathic pain involves the transmission of pain messages in the absence of stimuli and is typically caused by damage to the nervous system. In most cases, the pain occurs as a result of sen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D251/46C07D401/14C07D403/04C07D251/42C07D401/04C07D239/46C07D413/04C07D251/16C07D251/52C07D251/50C07D251/54C07D239/48C07D401/12A61K31/53A61K31/506
CPCC07D401/12C07D251/54C07D239/48C07D251/52C07D251/46A61K31/506A61K31/53C07D239/47C04B35/632C07D401/04A61P1/00A61P1/04A61P3/04A61P9/10A61P11/00A61P11/06A61P11/14A61P13/02A61P15/00A61P17/02A61P17/04A61P19/02A61P21/00A61P25/00A61P25/02A61P25/06A61P29/00A61P35/00A61P39/02A61P43/00
Inventor R·巴克他瓦特沙拉姆J·W·达罗S·德洛姆巴尔特X·郑
Owner NEUROGEN
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