Triazole compounds and their use as metabotropic glutamate receptor antagonists

A compound, halogenated alkyl technology, applied in the field of new compounds, which can solve problems such as increased release of neurotransmitters

Inactive Publication Date: 2007-08-15
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 a...

Method used

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

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preparation example Construction

[0271] The present invention also relates to the following compounds which can be used as intermediates in the preparation of compounds of formula I:

[0272] Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine

[0273] 4-Methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0274] 4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione

[0275] 4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0276] 4-(4-Methyl-5-methylsulfanyl-4H-[1,2,4]triazol-3-yl)-pyridine

[0277] 4-(4-Cyclopropyl-5-methylthio-4H-[1,2,4]triazol-3-yl)-pyridine

[0278] 4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

[0279] 4-(4-Cyclopropyl-5-methylsulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine

[0280] Methyl [(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio]acetate

[0281] [(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)thio]acetic acid

[0282] N'-(3-chlorophenyl)-2-[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]acetohydrazide...

Embodiment 1

[0308] Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine

[0309] 1000mg (4.35mmol) of N-amino-N', N"-dimethyl-guanidine hydrochloride (Henry; Smith; J.Amer.Chem.Soc.; 73; 1951; 1858) and 774mg (4.35mmol) A mixture of isonicotinoyl chloride hydrochloride in 3 ml of pyridine was heated at 160 °C for 5 minutes under microwave irradiation. Saturated K was added 2 CO 3 aqueous solution, the mixture was washed with CHCl 3 extraction. The combined organic layers were dried and concentrated. Recrystallization from ethanol, water and EA afforded 216 mg (26%) of the title compound. 1 H NMR (d6-DMSO): 2.85 (d, 3H) 3.45 (s, 3H) 6.25 (d, 1H) 7.65 (m, 2H) 8.67 (m, 2H)

Embodiment 2

[0311] 4-Methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione

[0312] 4-methyl-3-thiosemicarbazide (902mg, 8.58mmol), nicotinic acid (960mg, 7.80), EDCl (1.64g, 8.58mmol), HOBt (1.16g, 8.58mmol) in DMF (10mL) The solution was stirred overnight at room temperature. The reaction mixture was diluted with EA (100 mL), washed successively with 10% hydrochloric acid, water, saturated Na 2 CO 3 Aqueous, water and brine washes. The organic phase was dried (Na 2 SO 4 ), filtered and concentrated in vacuo. The residue was stirred in NaOH (53.4 mL, 66.7 mmol, 5% in water) at 60 °C overnight. The mixture was cooled to room temperature and the pH was adjusted to 6 using 1N hydrochloric acid. The aqueous phase was saturated with solid NaCl and extracted with EA. The combined organic phases were washed with brine, dried (Na 2 SO 4 ), filtered, concentrated, and dried in vacuo to give the title compound (180 mg). 1 H-NMR: 11.6(br s, 1H), 8.94(s, 1H), 8.83(dd, 1H), 7.98(m, ...

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Abstract

The present invention relates to new compounds of formula (I), wherein P, Q, X<1>, X<2>, X<3>, X<4> X<7>, X<8>, R<1>, R<2>, R<3>, m, n, and p are as defined as in formula (I), or salts, or hydrates thereof, processes for their preparation and new intermediates used in the preparation thereof, pharmaceutical compositions containing said compounds and to the use of said compounds in therapy, especially for the treatment of mGluR5 receptor mediated disorders, and for the treatment of neurological disorders, psychiatric disorders, gastrointestinal disorders and pain disorders.

Description

field of invention [0001] The present invention relates to a new class of compounds, pharmaceutical compositions comprising said compounds and the use of said compounds in therapy. The invention also relates to processes for the preparation of said compounds and novel intermediates for the preparation of said compounds. Background of the invention [0002] 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 main types, ionotropic glutamate receptors and metabolic type (metabotropic) glutamate receptors. [0003] Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate various intracellular second messenger systems upon binding glutamate. Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: phospholipase...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D413/14A61K31/4439A61P25/00A61P29/00A61P1/00C07D231/12C07D231/14C07D249/06C07D249/08C07D249/10C07D249/12C07D401/04
CPCC07D401/14C07D401/12C07D413/14C07D403/12C07D231/12C07D249/08C07D249/06C07D249/12C07D231/14C07D249/10C07D401/04A61P1/00A61P25/00A61P25/02A61P25/04A61P29/00A61P43/00A61K31/4196
Inventor L·爱德华兹M·伊萨克M·约翰松J·马尔姆贝里A·米尼迪斯K·斯塔夫A·斯拉西D·温斯博忻涛T·斯特法纳克
Owner ASTRAZENECA AB
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