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Substituted pyrimidin-4-ylamina analogues as vanilloid receptor ligands

A halogenated alkyl and alkyl technology, which can be used in the field of probes for detecting and locating capsaicin receptors, and can solve problems such as burning pain and limited therapeutic use.

Inactive Publication Date: 2006-08-23
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 pyrimidin-4-ylamina analogues as vanilloid receptor ligands
  • Substituted pyrimidin-4-ylamina analogues as vanilloid receptor ligands
  • Substituted pyrimidin-4-ylamina analogues as vanilloid receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0326] Preparation of [4-tert-butyl-phenyl][6-(3-methoxy-phenyl)pyrimidin-4-yl]amine

[0327] This example illustrates the preparation of a representative substituted pyrimidin-4-ylamine analog: [4-tert-butyl-phenyl]-[6-(3-methoxyphenyl)pyrimidin-4-yl]amine .

[0328] 1.1-(6-chloropyrimidin-4-yl)-3-methoxybenzene

[0329]

[0330] 4,6-Dichloropyrimidine (5g, 33.5mmol), 3-methoxy-phenylboronic acid (5.17g, 34.0mmol), tris(triphenylphosphine)palladium(0) (1.4g, 1.1mmol), A mixture of 2M potassium carbonate (35 mL) in toluene (150 mL) was heated at 80° C. for 8 hours under nitrogen. The reaction mixture was then cooled and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 100 mL), then the combined organic layers were washed with 4M NaOH (100 mL), water (100 mL) and brine (100 mL). followed by MgSO 4 After drying the organic layer, it was concentrated under reduced pressure. The concentrated residue was purified by flash chromatography (7...

Embodiment 2

[0335] Synthesis of other representative pyrimidin-4-ylamine analogs

[0336] A. [4-tert-butyl-phenyl]-[6-(3-methoxyphenyl)-5-methyl-2-morpholin-4-ylpyrimidin-4-yl]amine

[0337] 1.5-Methyl-2-morpholin-4-ylpyrimidine-4,6-diol

[0338]

[0339] A mixture of sodium methoxide (15mL, 45mmol), morpholinoformamidine hydrobromide (6.3g, 30mmol) and diethyl methylmalonate (5.22g, 30mmol) dissolved in methanol was heated at 50°C Heat for 2 hours. After cooling, it was concentrated under reduced pressure. The concentrated white gum was dissolved in water and acidified with concentrated sulfuric acid. The resulting white solid was collected by filtration, washed with water and air dried to give the title compound.

[0340] 2.4-(4,6-dichloro-5-methylpyrimidin-2-yl)morpholine

[0341]

[0342] 5-Methyl-2-morpholin-4-ylpyrimidine-4,6-diol (3.57g, 17mmol), N,N-diethylaniline (4.37g, 35mmol) and phosphorus oxychloride (phosphorus oxychloride) (25 mL) was heated at 90°C for 2 hours...

Embodiment 3

[0360] Other representative substituted pyrimidin-4-ylamine analogs

[0361] 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 Gilso...

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Abstract

Substituted pyrimidyl-4-ylamine analogues are provided, of the Formula: (I) wherein variables are as described herein. Such compounds are ligands that may be used to modulate Vanilloid 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 pyrimidin-4-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 s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D239/48C07D251/18C07D403/04A61K31/505A61P25/00C07D239/46C07D251/42C07D401/04
CPCC07D239/42C07D239/48C07D239/47C07D251/42C07D401/04A61P11/00A61P11/06A61P13/02A61P13/10A61P17/02A61P25/00A61P25/06A61P29/00A61P3/04A61P43/00
Inventor C·A·布卢姆H·布里尔曼K·J·霍杰茨
Owner NEUROGEN
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