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'1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5

A 5-membered ring, SO2 technology, used in anti-inflammatory agents, anti-toxic agents, non-central analgesics, etc., can solve problems such as increased release of neurotransmitters

Inactive Publication Date: 2007-01-10
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Evidence suggests that this excitation is due to direct activation of postsynaptic mGluRs, but it has also been demonstrated that activation of presynaptic mGluRs occurs, leading to increased neurotransmitter release

Method used

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  • '1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5
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  • '1,2,4' oxadiazoles as modulators of metabotropic glutamate receptor-5

Examples

Experimental program
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preparation example Construction

[1092] Preparation of compound of formula IX

[1093]

[1094] Under alkaline conditions, using a suitable base such as sodium bicarbonate or triethylamine, at a suitable temperature (0°C-100°C), in a solvent such as toluene, pass between the compound of formula VI and the compound of formula VII. , 3-dipolar cycloaddition reaction can prepare the compound of formula IX, where R 7 Independently selected from M 1 -(R 2 ) n -P-(R 1 ) m1 , M 2 -(R 3 ) n -X 4 -Q-(R 4 ) m2 And M 2 -(R 3 ) n -G, where G is a leaving group or a group that can be subsequently converted into a leaving group. The synthesis of the compound of formula VI has previously been described in the literature, for example Kim, Jae Nyoung; Ryu, Eung K; J. Org. Chem. (1992), 57, 6649-50. Using the substituted nitromethane of formula VIII, in the presence of a base such as triethylamine, at high temperature (50-100° C.), through activation with an electrophile such as PhNCO, it is also possible to achieve 1 with the d...

Embodiment 1

[1175] 6-methylpyridine-4-carboxylic acid

[1176] Put a spherical flask filled with hydrogen with 2-chloro-6-methylpyridine-4-carboxylic acid (2g, 12.0mmol), 10% (weight) palladium activated carbon (0.5g), and triethylamine (4.8ml) Connect to a flask of ethanol (24 ml), and then stir overnight at room temperature. The reaction mixture was filtered through Celite, washed with methanol and concentrated. The residue was triturated with dichloromethane and then filtered to give 6-picoline-4-carboxylic acid (white solid); 1.05 g (66%). 1 H NMR (MeOD) δ (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60 (d, 1H), 2.55 (s, 3H).

Embodiment 2

[1178] 1-cyano-3-ethylbenzene

[1179] Blow argon into a solution of 1-bromo-3-ethylbenzene (2.5g, 13.5mmol) in DMF (37ml) for 10 minutes, then add zinc cyanide (1.75g, 14.9mmol) and tetrakis(triphenyl) Phosphine) Palladium(O) (1.56 g, 1.35 mmol). After stirring overnight at 80°C, the reaction mixture was diluted with ethyl acetate (35 ml) and then filtered through Celite to remove the precipitate. The filtrate was washed with water (3x), saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained product was purified by flash column chromatography (using 2% ethyl acetate / hexane) to obtain a colorless liquid (1.42 g). GC-MS (M+): 131.18.

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Abstract

The present invention relates to new compounds of formula (I), a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. In particular, there are compounds according to the present invention that are potent and selective for the mGluR Group I receptor and more particularly for mGluR5. Thus, it is expected that the compounds of the invention are well suited for the prevention and / or treatment of mGluR5 receptor-mediated disorders such as acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders.

Description

Invention field [0001] The present invention relates to a new class of compounds, pharmaceutical preparations containing the compounds, and therapeutic uses of the compounds. The present invention also relates to the preparation method of the compound and the new intermediate prepared in it. Background of the invention [0002] Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate acts on central neurons by binding to cell surface receptors and thus activating the receptors. According to the structural characteristics of the receptor protein, the way the receptor transmits signals into the cell, and the pharmacological characteristics, these receptors have been divided into two categories, namely ionotropic glutamate receptors and metabotropic glutamate receptors. Receptor. [0003] Metabotropic glutamate receptor (mGluR) is a G protein-coupled receptor, which activates various intracellular second messenger systems after bindi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/12C07D413/14C07D417/14A61K31/4245A61P25/00C07D271/00
CPCC07D413/14C07D417/14C07D413/12A61P19/02A61P19/06A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P27/02A61P27/16A61P29/00A61P39/00A61P43/00A61P9/00
Inventor ARORA JALAJ EDWARDS LOUISE ISAAC METHVIN MCLEOD DONALD A. SLASSI ABDELMALIK STEFANAC TOMISLAV STORMANN THOMAS M. WENSBO DAVID XIN TAO GYBACK HELENA JOHANSSON MARTIN KERS ANNIKA MALMBERG JOHN MINIDIS AYNGVE ULRIKA OSTERWALL CHRISTOFFER
Owner ASTRAZENECA AB
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