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Heteroaryl substituted fused bicyclic heteroaryl compounds as GABAA receptor ligands

a technology of heteroaryl compounds and gabaa receptors, which is applied in the direction of heterocyclic compound active ingredients, biocide, drug compositions, etc., can solve the problems of compound known to exhibit a number of unwanted side effects, and achieve high selectivity and affinity to

Inactive Publication Date: 2006-01-19
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While benzodiazepines have enjoyed long pharmaceutical use as anxiolytics, these compounds are known to exhibit a number of unwanted side effects.

Method used

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  • Heteroaryl substituted fused bicyclic heteroaryl compounds as GABAA receptor ligands
  • Heteroaryl substituted fused bicyclic heteroaryl compounds as GABAA receptor ligands
  • Heteroaryl substituted fused bicyclic heteroaryl compounds as GABAA receptor ligands

Examples

Experimental program
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Effect test

example 1

SYNTHESIS OF 3-FLUORO-(1H-IMIDAZOL-2-YL)BENZENE

[0195]

[0196] Saturated ammonium hydroxide solution (30 mL) is slowly added to a solution of 3-fluorobenzaldehyde (12.4 g, 100 mmol) and glyoxal (17.5 mL of 40% wt in water, 120 mmol) in methanol (100 mL) at ambient temperature. After stirring for 24 hours, most of the solvent is removed at reduced pressure. Benzene is added and evaporated to remove residual water. The resulting dark oil is purified by chromatography on silica gel (2% MeOH / CH2Cl2) to obtain a tan solid. Trituration with ether / hexane provides 3-fluoro-(1H-imidazol-2-yl)benzene as a white solid. LRMS m / z (M+1) 163.2.

example 2

SYNTHESIS OF 3-CHLORO-4-FLUORO-(1H-IMIDAZOL-2-YL)BENZENE

[0197]

[0198] A mixture of 3-chloro-4-fluoro-benzaldehyde (0.032 mol), glyoxal (40% in water, 0.038 mol) and ammonium hydroxide (28% in water, 0.16 mol) in MeOH (60 mL) is stirred at room temperature overnight. Solvent is removed in vacuo and the residue is partitioned between water and CH2Cl2. The organic layer is washed with brine, dried (Na2SO4), and concentrated. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 / MeOH (95 / 5) to afford 3-chloro-4-fluoro-(1H-imidazol-2-yl)benzene as a yellow solid. 1H NMR (CDCl3) δ 7.88 (dd, 1H), 7.70 (m, 1H), 7.19 (t, 1H), 7.17 (s, 2H). LRMS m / z (M+1) 197.0.

example 3

SYNTHESIS OF 2,3,4-TRIFLUORO-(1H-IMIDAZOL-2-YL)BENZENE

[0199]

[0200] Saturated ammonium hydroxide solution (26 mL) is slowly added to a solution of 2,3,4-trifluorobenzaldehyde (5.0 g, 31.2 mmol) and glyoxal (10.75 mL of 40% wt in water, 93.7 mmol) in methanol (100 mL) at ambient temperature. After stirring for 24 hours, most of the solvent is removed at reduced pressure. Benzene is added and evaporated to remove residual water. The resulting dark oil is purified by chromatography on silica gel (5% MeOH / CH2Cl2) to obtain a tan solid. Trituration with ether / hexane provides 2,3,4-trifluoro-(1H-imidazol-2-yl)benzene as a white solid. LRMS m / z (M+1) 199.10.

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Abstract

This invention relates to heteroaryl substituted fused bicyclic heteroaryl compounds, such as heteroaryl substituted imidazopyridines, imidazopyrazines, imidazopyridizines, imidazopyrimidines, and imidazothiazoles, which may be described by Formula I or Formula II: The invention is particularly related to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. Processes for preparing compounds of Formula I and Formula II are disclosed. This invention also relates to the use of benzimidazoles, pyridylimidazoles and related bicyclic heteroaryl compounds of Formula I or Formula II in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.

Description

FIELD OF THE INVENTION [0001] This invention relates to heteroaryl substituted fused bicyclic heteroaryl compounds, such as heteroaryl substituted imidazopyridines, imidazopyrazines, imidazopyridizines, imidazopyrimidines, and imidazothiazoles, and more specifically to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases. This invention also relates to the use of these heteroaryl substituted imidazopyridines, imidazopyrazines, imidazopyridizines, imidazopyrimidines, and imidazothiazoles compounds and related compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections. BA...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04C07D471/02A61K31/519A61K31/503A61K31/4745A61K31/4355G01N33/48A61K31/4439A61K31/444A61K31/4985A61K31/5025A61K31/506A61P25/00A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00C07D471/04C07D513/04C12N15/09C12Q1/02G01N33/58G01N33/60
CPCC07D471/04C07D513/04C07D487/04A61P25/00A61P25/14A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00
Inventor HUTCHISON, ALANMAYNARD, GEORGEALBAUGH, PAMELAXIE, LINGHONGYUAN, JUNMITCHELL, SCOTTSINGH, VINODGHOSH, MANUKALI, GUIYINGLIU, NIAN
Owner NEUROGEN
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