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Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

A compound and composition technology, applied in anti-inflammatory agents, metabolic diseases, non-central analgesics, etc., can solve obstacles to mGluR physiology, pharmacology and treatment, limited value, lack of efficacy and selection of mGluR agonists and antagonists sexual issues

Inactive Publication Date: 2007-05-02
ASTRAZENECA AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] From the above description, it is clear that currently available mGluR agonists and antagonists are of limited value due to lack of potency and selectivity
Furthermore, most currently available compounds are amino acids or amino acid derivatives with very limited bioavailability, which hinders in vivo studies to evaluate the physiology, pharmacology and therapeutic potential of mGluRs

Method used

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  • Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
  • Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists
  • Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Embodiment 1: synthetic amidoxime intermediate

[0094] Pyridin-2-ylamidoxime

[0095]

[0096] Using the method of Shine et al., J.Heterocyclic Chem. (1989) 26:125-128, hydroxylamine hydrochloride (7.65g, 110mmol) in ethanol (100mL) was dissolved in sodium hydroxide solution (11mL, 10N, 110mmol )deal with. A precipitate formed rapidly and the reaction mixture was stirred at room temperature for 30 minutes. The inorganic precipitate was filtered off and washed with ethanol (100 mL). The filtrate was combined with the ethanol washes and treated with 2-cyanopyridine (10.4 g, 100 mmol). The reaction mixture was heated to reflux for 20 hours. The volatiles were then removed in vacuo to afford 13.3 g (97%) of pyridin-2-ylamidoxime.

[0097] 3-Methoxybenzamide oxime

[0098]

[0099] Using the general procedure for the synthesis of amidoximes, hydroxylamine hydrochloride (7.65 g, 110 mmol), sodium hydroxide (11 mL, 10 N,...

Embodiment 2

[0120] Embodiment 2: synthetic carboxylic acid intermediate

[0121] 3-Chloro-5-cyanobenzoic acid

[0122]

[0123] Methyl 3,5-dichlorobenzoate (14.66g, 71.5mmol), zinc cyanide (5.04g, 42.9mmol), zinc (zinc powder, 0.21g, 3.21mmol), [1,1′-di( Diphenylphosphino) ferrocene] dichloropalladium (II) complex with dichloromethane (1:1) (1.3g, 1.57mmol) in N,N-dimethylformamide (70mL) The mixture was heated to reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Purification by silica gel chromatography afforded 2.34 g (17%) of methyl 2-chloro-5-cyanobenzoate. The intermediate ester was treated with sodium hydroxide solution (7.5 ml, 4N solution, 30 mmol) in methanol (50 mL) and stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic solution was washed with 5% HCl and brine. Removal of the solvent afforded 1.8 g (83%) ...

Embodiment 3

[0132] The crude methyl 3-chloro-5-cyanobenzoate was treated with sodium hydroxide solution (45 ml, 4N solution, 180 mmol) in methanol (350 mL) at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate. The organic solution was washed with 5% hydrochloric acid and brine. Purification by silica gel chromatography afforded 7.0 g (54%) of 3-fluoro-5-cyanobenzoic acid. Example 3: Synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from acid chlorides

[0133] Generally a modification of the method given by Shine et al. in J. Heterocyclic Chem. (1989) 26: 125-128 is used. 3,5-disubstituted-1,2,4-oxadiazoles are usually prepared by adding the acid chloride to a solution of amidoxime in pyridine, then heating the reaction mixture to reflux, or placing it in a sealed tube and heat. Oxadiazoles are generally isolated by precipitation with cold water and filtration or extraction with organic solvents. Purify the oxadiazole by chr...

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Abstract

Compound of formula (II) wherein X, Y, and Z are independently selected from the group consisting of N, O, S, C, and CO wherein at least one of X, Y, and Z is a heteroatom; Ar<1> and Ar<2> are independently selected from the group consisting of a heterocyclic or fused heterocyclic moiety and an aromatic moiety; act as antagonist at metabotropic glutamate receptors, and are useful for treating neurological diseases and disorders.

Description

field of invention [0001] The present invention provides compounds that are active at metabotropic glutamate receptors and are useful in the treatment of neurological and psychiatric diseases and disorders. Background of the invention [0002] Recent advances in elucidating the neurophysiological roles of metabotropic glutamate receptors have established these receptors as promising drug targets in the treatment of acute and chronic neurological and psychiatric disorders and diseases. However, a major challenge in achieving this goal is the development of metabotropic glutamate receptor subtype-selective compounds. [0003] Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate exerts its effects on central neurons by binding to and thereby activating cell surface receptors. These receptors have been divided into two classes, ionotropic and metabotropic glutamate receptors, based on the structural ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/04C07D401/04A61K31/4439A61K31/4725A61K31/497A61P25/00A61KA61K31/4245A61K31/4709A61PA61P9/10A61P25/06A61P25/08A61P25/14A61P25/16A61P25/28A61P29/00C07DC07D403/04
CPCC07D413/04C07D401/04A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P29/00A61P29/02A61P3/08A61P43/00A61P9/00A61P9/10
Inventor B·C·范瓦格宁T·M·斯托尔曼S·T·莫埃S·M·舍汉D·A·麦莱奥德D·L·史密斯M·B·伊萨尔克A·斯拉斯
Owner ASTRAZENECA AB
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