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5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5

The technology of a compound, flupyridine, is applied in the field of new compounds, which can solve problems such as increasing the release of neurotransmitters

Inactive Publication Date: 2007-01-31
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 activation of presynaptic mGluRs has also been shown to occur, leading to increased neurotransmitter release

Method used

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  • 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5
  • 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5
  • 5-fluoro-, chloro- and cyano-pyridin-2-yl-tetrazoles as ligands of the metabotropic glutamate receptor-5

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] Example 1: 3-Fluoro-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl] benzonitrile

[0126] The chlorination was prepared from sodium nitrite (0.06g) in ethanol (2mL), water (1mL) and 3-amino-5-fluorobenzonitrile (0.10g) in 10% aqueous HCl (2mL) at 5°C Diazonium. This solution was added dropwise to N′-[(1E)-(5-fluoropyridin-2-yl)methylene]-4-methylbenzenesulfonyl hydrazide (0.15g) in pyridine ( 5mL) in the solution so that the temperature is kept below 5°C. The reaction mixture was stirred for 2 hours, then concentrated, and the resulting product was dissolved in CH 2 Cl 2 Partition between (100 mL) and water (50 mL). The organic phase was washed with water (50mL) and brine (50mL), then dried (Na 2 SO 4 ), filtered and concentrated. The residue was recrystallized from EtOAc to obtain 40 mg of the title compound as a yellow solid.

[0127] 1 H NMR: 7.56 (m, 1H), 7.67 (m, 1H), 8.33 (m, 1H), 8.42 (m, 1H), 8.47 (m, 1H), 8.73 (m, 1H).

[0128] 3-amino-5-fluorobenzonitrile

[0129] T...

Embodiment 2

[0138] Example 2: 3-[5-(5-chloropyridin-2-yl)-2H-tetrazol-2-yl]-5-fluorobenzonitrile

[0139] Similar to 3-fluoro-5-[5-(5-fluoropyridin-2-yl)-2H-tetrazol-2-yl] benzonitrile, from 3-amino-5-fluorobenzonitrile (0.14g) And N'-[(1E)-(5-chloropyridin-2-yl)methylene]-4-methylbenzenesulfonyl hydrazide (0.22 g) to prepare the title compound to obtain 67 mg of the title compound as an orange solid.

[0140] 1 H NMR: 7.56 (m, 1H), 7.95 (m, 1H), 8.31-8.37 (2H), 8.47 (m, 1H), 8.83 (m, 1H).

[0141] N′-[(1E)-(5-chloropyridin-2-yl)methylene]-4-methylbenzenesulfonyl hydrazide

[0142] Similar to N′-[(1E)-(5-fluoropyridin-2-yl)methylene]-4-methylbenzenesulfonyl hydrazide, from 5-chloropyridine-2-carbaldehyde [J.Med.Chem. 1970, 1124-30] (1.0 g) and p-toluenesulfonyl hydrazide (1.0 g) prepared the title compound to obtain 0.54 g of the title compound as a white solid.

[0143] 1H NMR: 2.44 (s, 3H), 7.34 (m, 2H), 7.69 (m, 1H), 7.80 (d, 1H), 7.86-7.91 (3H), 8.16 (br s, 1H), 8.51 (m, 1H).

Embodiment 3

[0144] Example 3: 6-[2-(3-cyano-5-fluorophenyl)-2H-tetrazol-5-yl] nicotinonitrile

[0145] Dissolve 3-[5-(5-bromopyridin-2-yl)-2H-tetrazol-2-yl]-5-fluorobenzonitrile (WO03 / 029210) (0.03g) in DMF (3mL), And bubbling argon for 15 minutes. Add zinc cyanide (0.01g) and Pd (PPh 3 ) 4 (0.03g), the reaction was stirred at 80°C for 16 hours. CH for reaction mixture 2 Cl 2 (20mL) Dilute and use NH 4 Cl (10mL) and brine (10mL) washed, then dried (Na 2 SO4), filtered and concentrated to obtain a yellow solid, which was purified by recrystallization from EtOAc:hexane to obtain 7 mg of the title compound as a white solid.

[0146] 1 H NMR: 7.59 (m, 1H), 8.25 (m, 1H), 8.34 (m, 1H), 8.47 (m, 1H), 8.53 (m, 1H), 9.13 (m, 1H).

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Abstract

The present invention relates to new compounds of formula I, wherein Z, Q, X1, X2, R1 and R2, are as defined as in formula I, or salts, solvates or solvated salts thereof, processes for their preparation, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.

Description

Technical field [0001] The present invention relates to a novel compound, a pharmaceutical composition containing the compound, and the use of the compound in therapy. The invention further relates to a method of preparing the compound. technical background [0002] Glutamate is the main excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate exerts its effect on central nerve cells by binding to central nerve cells and thereby activating cell surface receptors. Based on the structural characteristics of the receptor protein, the way the receptor converts signals into the cell, and the pharmacological properties, these receptors are divided into two main categories, ion-transfer glutamate receptors and metabotropic glutamate receptors. [0003] Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate various intracellular secondary messenger systems after binding to glutamate. The activation of mGluRs in intact mammalian...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D213/84A61K31/4439A61P25/04
CPCC07D213/84C07D401/04A61P1/00A61P11/00A61P11/06A61P13/12A61P17/02A61P19/02A61P21/04A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P27/02A61P27/06A61P27/16A61P29/00A61P3/00A61P43/00A61P9/04A61P9/10A61K31/4439
Inventor D·温斯博L·爱德华兹M·伊萨克D·A·麦莱奥德A·斯拉西忻涛T·M·斯托尔曼
Owner ASTRAZENECA AB
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