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Substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues

a technology of phenylaminoquinazolin and methanol, which is applied in the field of substitution of (7-pyridyl-4phenylaminoquinazolin-2-yl)methanol analogues, can solve the problems of acute or chronic pain, more debilitating, and damage to the nervous system, and achieve the effect of inhibiting the binding of vanilloid ligands and reducing the calcium conductance of cellular capsaicin

Inactive Publication Date: 2008-06-26
NEUROGEN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inappropriate or excessive activation of nociceptors, however, can result in debilitating acute or chronic pain.
Neuropathic pain involves pain signal transmission in the absence of stimulus, and typically results from damage to the nervous system.
Neuropathic pain is typically burning, shooting and unrelenting in its intensity and can sometimes be more debilitating that the initial injury or disease process that induced it.
Existing treatments for neuropathic pain are largely ineffective.
Opiates, such as morphine, are potent analgesics, but their usefulness is limited because of adverse side effects, such as physical addictiveness and withdrawal properties, as well as respiratory depression, mood changes, and decreased intestinal motility with concomitant constipation, nausea, vomiting, and alterations in the endocrine and autonomic nervous systems.
In addition, neuropathic pain is frequently non-responsive or only partially responsive to conventional opioid analgesic regimens.
Treatments employing the N-methyl-D-aspartate antagonist ketamine or the alpha(2)-adrenergic agonist clonidine can reduce acute or chronic pain, and permit a reduction in opioid consumption, but these agents are often poorly tolerated due to side effects.
However, agonist application may itself cause burning pain, which limits this therapeutic use.

Method used

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  • Substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues

Examples

Experimental program
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Effect test

example 1

Preparation of [2-Isopropoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Compound 1)

[0132]This Example illustrates the preparation of a representative substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogue.

1. 2-p-tolyl-3-trifluoromethyl-pyridine

[0133]

[0134]To a de-gassed mixture of 2-chloro-3-(trifluoromethyl)-pyridine (70.1 mmol), p-tolylboronic acid (70.6 mmol), and 2M Na2CO3 (175.0 mmol), in ethylene glycol dimethyl ether (DME; 200 mL) under nitrogen add Pd(PPh3)4 (2.8 mmol). Stir the mixture at 80° C. overnight, concentrate, and extract with EtOAc. Dry over Na2SO4, concentrate under vacuum, and pass through a silica gel pad to give 2-p-tolyl-3-trifluoromethyl-pyridine.

2. 2-(4-methyl-3-nitro-phenyl)-3-(trifluoromethyl)-pyridine

[0135]

[0136]To a solution of 2-p-tolyl-3-trifluoromethyl-pyridine (8.4 mmol) in H2SO4 (6 mL) cautiously add fuming HNO3 (2 ml). Stir the mixture for 60 minutes at room temperature. Pour the mi...

example 2

Preparation of Additional Representative Compounds

[0151]This Example illustrates the preparation of additional representative substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues.

A. [7-(3-Chloro-pyridin-2-yl)-2-methoxymethyl-pyrido [2,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine (Compound 2)

1. 2-Acetyl-3-chloropyridine

[0152]

[0153]Dissolve 3-chloro-2-cyanopyridine (10.0 g, 0.072 mol, Chem. Pharm. Bull. (1985) 33:565-571) in anhydrous THF (200 mL) under N2 atmosphere and cool in an ice bath. Add drop wise 3.0 M MeMgI in diethyl ether (48 ml, 0.14 mol) to the reaction mixture and stir in an ice bath for 2 hours. Pour the reaction mixture over ice cold water, acidify the mixture with 2.0 N aq. HCl to pH 2 to 3. Extract the reaction mixture with EtOAc (3×100 mL) and dry over anhydrous MgSO4. Filter, concentrate under vacuum and then filter through a pad of silica gel using 20% ethyl acetate / hexane as eluent. Removal of solvent under reduced pressure gives pure...

example 3

Representative Substituted (7-Pyridyl-4-Phenylamino-Quinazolin-2-yl)-Methanol Analogues

[0192]Using routine modifications, the starting materials may be varied and additional steps employed to produce other compounds provided herein. Compounds listed in Table I were prepared using such methods. Mass spectroscopy data in the column labeled “MS” is Electrospray MS, obtained in positive ion mode with a 15V or 30V cone voltage, using a Micromass Time-of-Flight LCT, equipped with a Waters 600 pump, Waters 996 photodiode array detector, Gilson 215 autosampler, and a Gilson 841 microinjector. MassLynx (Advanced Chemistry Development, Inc; Toronto, Canada) version 4.0 software was used for data collection and analysis. Sample volume of 1 microliter was injected onto a 50×4.6 mm Chromolith SpeedROD C18 column, and eluted using a 2-phase linear gradient at 6 ml / min flow rate. Sample was detected using total absorbance count over the 220-340 nm UV range. The elution conditions were: Mobile Phas...

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Abstract

Substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues are provided. 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 them to treat such disorders are provided, as are methods for using such ligands for receptor localization studies.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 10 / 892,741, filed Jul. 16, 2004, pending, which claims the benefit of and priority to U.S. Provisional Application 60 / 488,551, filed Jul. 16, 2003. The contents of each of these applications are incorporated by reference herein in their entirety.FIELD OF THE INVENTION[0002]This invention relates generally to substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues that are modulators of capsaicin receptors, and to the use of such compounds for treating conditions related to capsaicin receptor activation. The invention further relates to the use such compounds as probes for detecting and localizing capsaicin receptors.BACKGROUND OF THE INVENTION[0003]Pain perception, or nociception, is mediated by the peripheral terminals of a group of specialized sensory neurons, termed “nociceptors.” A wide variety of physical and chemical stimuli induce activation of ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D401/04C07D401/14C12N5/00A61P3/04A61P43/00A61P25/00C07D471/04A61K31/506A61K31/517C07D405/14
CPCC07D401/04C07D405/14C07D401/14A61P3/04A61P25/00A61P43/00
Inventor BAKTHAVATCHALAM, RAJAGOPALBLUM, CHARLES A.BRIELMANN, HARRYDE LOMBAERT, STEPHANEZHENG, XIAOZHANG
Owner NEUROGEN CORP
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