Capsaicin receptor ligands

a capsaicin receptor and ligand technology, applied in the field of compounds, can solve problems such as side effects

Inactive Publication Date: 2004-09-09
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most currently marketed analgesic compounds act centrally, and often have side effects.

Method used

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  • Capsaicin receptor ligands
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Examples

Experimental program
Comparison scheme
Effect test

example 1

(R)-4-(3-Chloro-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid (4-sec-butyl-phenyl)-amide

[0262] Part A: Synthesis of (R)-1-(3-Chloro-pyridin-2-yl)-3-methylpiperazi-ne: 26

[0263] Dissolve 2,3-dichloropyridine (8.5 g, 0.057 moles) and (R)-(-)-2-methylpiperazine (5.75 g, 0.057 moles) in N,N-dimethylacetamide (125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K.sub.2CO.sub.3 (23.75 g, 0.172 moles) to this mixture and stir at 135-140.degree. C. for 48 h. New spot noticed in TLC (5% MeOH / CHCl.sub.3 / 1% NEt.sub.3) along with absence of starting materials. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3.times.200 mL) and wash the combined organic extract with brine (2.times.150 mL). Dry over MgSO.sub.4, concentrate under vacuum to afford crude product (20.0 g) as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil (10 g, bp 112-115.degree. C. / 0.1 torr). NMR (CDCl.s...

example 2

(R)-(-)-4-(3-Chloro-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid (4-trifluoromethyl-phenyl)-amide

[0269] 29

[0270] Dissolve Part A material of example 1 (0.2756 g, 1.3 mmoles) in toluene (1.5 mL) under nitrogen at room temperature. Add drop wise 4-trifluoromethylphenyl isocyanate (0.2431 g, 1.3 mmoles) dissolved in toluene (50 mL) to the mixture over a period of 30 mins and stir at room temperature for 3 hours. Evaporate the solvent from reaction mixture under vacuum to afford colorless oil. Crystallize the oil from 1:1 Et.sub.2O / hexane (2.0 mL) to afford white solid.

[0271] NMR (CDCl.sub.3): .delta. 1.45-1.47 (d, 3H, J=1.7 Hz), 2.97-3.01 (t, 1H), 3.06-3.10 (m, 1H), 3.47-3.50 (m, 1H), 3.75-3.85 (m, 2H), 3.92-3.95 (m, 1H), 4.37-4.38 (m, 1H), 6.59 (bs, 1H), 6.88-6.91 (dd, 1H), 7.52-7.56 (m, 4H), 7.61-7.63 (dd, 1H), 8.19-8.21 (dd, 1H).

[0272] Mass spectrum (ESI): 399.3 (M+H).

[0273] Analysis calcd. for C.sub.18H.sub.18ClF.sub.3N.sub.4O: C, 54.21; H, 4.55; Cl, 8.89; F, 14.29; N, 14.05...

example 3

(R)-3-Chloro-pyridin-2-yl)-2-methyl-piperazine-1-carboxylic acid 4-tert-butyl-phenyl ester

[0274] Part A: Synthesis of (R)-4-(3-Chloro-pyridin-2-yl)-2-methylpiperazi-ne-1-carbonyl chloride: 30

[0275] Dissolve Part A material of Example 1 (1.06 g, 5.0 mmole)) in CH.sub.2Cl.sub.2 (50 mL) and saturated NaHCO.sub.3 (50 mL) under nitrogen at room temperature. Add drop wise 20% COCl.sub.2 in toluene (5.0 mL) at room temperature and stir overnight. Separate the organic layer, extract the aq. layer with CH.sub.2Cl.sub.2 (2.times.15 mL) and dry (MgSO.sub.4). Evaporate the organic layer under vacuo to afford yellow oil.

[0276] Part B: Title Compound: 31

[0277] Dissolve Part A material of Example 3 (136 g, 0.5 mmole)) in pyridine (2.0 mL) under nitrogen at room temperature. Add 4-tert.butylphenol to the reaction mixture at room temperature and stir overnight. Evaporate the reaction mixture under vacuo, partition between water / CH.sub.2Cl.sub.2 (20 mL) and dry (MgSO.sub.4). Evaporate the organic lay...

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Abstract

Disclosed are diaryl piperazines and related compounds. These compounds are selective modulators of capsaicin receptors, including human capsaicin receptors, that are, therefore, useful in the treatment of a chronic and acute pain conditions, itch and urinary incontinence. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds of the invention are also useful as probes for the localization of capsaicin receptors and as standards in assays for capsaicin receptor binding and capsaicin receptor mediated cation conductance. Methods of using the compounds in receptor localization studies are given.

Description

RELATED APPLICATION INFORMATION[0001] This application claims the benefit of priority under 35 U.S.C. section 119(e) to Provisional Patent Application 60 / 280,223, filed Mar. 30, 2001, 60 / 230,726, filed Sep. 7, 2000, and 60 / 219,529, filed Jul. 20, 2001. These applications are hereby incorporated by reference in their entirety.BACKGOUND OF THE INVENTION[0002] 1. Field of the Invention[0003] This invention relates compounds that bind with high selectivity and high affinity to Vanilloid Receptors, especially Type I Vanilloid Receptors, also known as capsaicin receptors or VR1 Receptors. In an important aspect the invention provides capsaicin receptor, preferably human VR1 receptor, antagonists that are not capsaicin analogs (e.g., they do not contain a phenyl ring with two oxygen atoms bound to two adjacent ring carbons), are free of agonist activity, and exhibit an unprecedented level of affinity for the VR1 receptor. In another aspect, the invention provides aryl piperazines and relat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/496A61K31/497A61P11/08A61P13/02A61P17/02A61P19/02A61P25/02A61P25/04A61P25/06A61P27/02A61P29/00A61P43/00C07D213/74C07D213/75C07D217/22C07D241/20C07D295/194C07D401/04C07D401/14C07D403/04C07D405/12C07D405/14C07D407/14C07D417/12C07D417/14
CPCC07D213/74C07D213/75C07D417/12C07D241/20C07D405/12C07D217/22A61P11/00A61P11/08A61P13/02A61P17/02A61P19/02A61P25/02A61P25/04A61P25/06A61P27/02A61P29/00A61P43/00C07D401/04
Inventor BAKTHAVATCHALAM, RAJAGOPALHUTCHISON, ALANDESIMONE, ROBERT W.HODGETTS, KEVIN J.KRAUSE, JAMES E.WHITE, GEOFFREY G.
Owner NEUROGEN
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