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Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors

a technology of metabotropic glutamate receptor and allosteric modulation, which is applied in the direction of drug composition, biocide, metabolic disorder, etc., can solve the problem of glutamatergic neurotransmission imbalan

Inactive Publication Date: 2010-06-10
ADDEX PHARM SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, glutamate is at the center of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.

Method used

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  • Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
  • Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors
  • Novel heteroaromatic derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-(2-Chlorophenyl)-3-(3-methyl-1H-pyrazol-4-yl)-1,2,4-thiadiazol-5-amine (Final Compound 1-3)

tert-Butyl 4-cyano-3-methyl-1H-pyrazole-1-carboxylate

[0156]According to Scheme 1 Step 1: To a solution of 3-methyl-1H-pyrazol-4-carbonitrile (9.34 mmol, 1.00 g) in DCM (20 mL) were sequentially added DIEA (9.34 mmol, 1.60 mL), (Boc)2O (9.34 mmol, 2.04 g) and DMAP (0.93 mmol, 0.11 g). After stirring for 14 hours at room temperature, the reaction mixture was quenched with water. The aqueous phase was extracted with DCM. The organic phase was washed with a saturated solution of NaHCO3 and brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane / AcOEt (85:15) as eluent to afford tert-butyl 4-cyano-3-methyl-1H-pyrazole-1-carboxylate (7.96 mmol, 1.65 g, 85%) as a white solid.

[0157]LC (Zorbax SB-C18, 3.5 μm, 4.6×50 mm Column): RT=3.72 min; MS m / z ES+=108 (M+-Boc).

3-Methyl-1H-pyrazo...

example 2

3-(3-Propyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine (Final Compound 1-9)

Ethyl 1-(4-methoxybenzyl)-3-propyl-1H-pyrazole-4-carboxylate and ethyl 1-(4-methoxybenzyl)-5-propyl-1H-pyrazole-4-carboxylate

[0166]According to Scheme 1 Step 1: A suspension of ethyl 5-propyl-1H-pyrazole-4-carboxylate (2.74 mmol, 500 mg), 1-(bromomethyl)-4-methoxybenzene (2.74 mmol, 0.39 mL) and K2CO3 (2.74 mmol, 379 mg) in acetonitrile (10 mL) was heated at 70° C. overnight. Water was added and the aqueous phase was extracted with AcOEt. The organic phase was washed with water and brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane / AcOEt (80:20) as eluent to afford a mixture of ethyl 1-(4-methoxybenzyl)-3-propyl-1H-pyrazole-4-carboxylate and of ethyl 1-(4-methoxybenzyl)-5-propyl-1H-pyrazole-4-carboxylate (2.15 mmol, 650 mg, 78%) as an orange oil.

[0167]LC (Zorbax SB-C18,...

example 3

3-(3-Methyl-1H-pyrazol-4-yl)-N-(pyridin-2-yl)-1,2,4-thiadiazol-5-amine (Final Compound 1-5)

1-(4-Methoxybenzyl)-3-methyl-1H-pyrazol-4-carbonitrile and 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-carbonitrile

[0176]According to Scheme 1 Step 1: Triphenylphosphine (11 mmol, 2.9 g), (4-methoxyphenyl)methanol (10 mmol, 1.4 g) and di-tert-butylazodicarboxylate (11 mmol, 2.6 g) were added to a solution of 3-methyl-1H-pyrazol-4-carbonitrile (9.3 mmol, 1.0 g), in DCM (40 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with a saturated solution of NH4OH and brine. Then the organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The resulting crude product was purified by flash chromatography over silica gel using cyclohexane / AcOEt (90:10) as eluent to yield a mixture of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-carbonitrile and of 1-(4-methoxybenzyl)-5-methyl-1H-pyrazol-4-carbonitrile (9.3 mmol, 2.1 g...

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Abstract

The present invention relates to novel compounds of Formula (I), wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4, M1, M2, M3, Am and Bn are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors.The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

Description

SUMMARY OF THE INVENTION[0001][0002]The present invention relates to novel compounds of Formula (I), wherein X1, X2, X3, X4, Y1, Y2, Y3, Y4, M1, M2, M3, Am and Bn are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.BACKGROUND OF THE INVENTION[0003]Glutamate is the major amino-acid transmitter in the mammalian central nervous system (CNS). Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration and regulat...

Claims

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Application Information

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IPC IPC(8): A61K31/497A61K31/4439A61K31/433C07D417/14C07D401/04C07D417/04A61P25/28A61P1/04A61P1/00A61P27/02A61P3/10A61P29/00A61P35/00A61P25/00A61P9/10A61P25/06A61P25/24A61K31/427C07D401/14A61K31/4545
CPCA61P1/00A61P1/04A61P1/06A61P1/12A61P3/10A61P9/10A61P25/00A61P25/02A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P27/02A61P29/00A61P35/00A61P43/00C07D417/04C07D417/14
Inventor BOLÉA, CHRISTELLECALANIRE, SYLVAIN
Owner ADDEX PHARM SA
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