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Novel pyridinone derivatives and their use as positive allosteric modulators of mglur2-receptors

a technology of mglur2-receptors and derivatives, which is applied in the direction of biocide, drug composition, metabolic disorders, etc., can solve problems such as glutamatergic neurotransmission imbalan

Inactive Publication Date: 2013-05-02
ADDEX PHARM SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about new chemical compounds that can help treat or prevent neurological and psychiatric diseases caused by excessive glutamate in the brain. These compounds work by improving the function of a specific type of receptor called the mGluR2, which is involved in these diseases. This invention includes methods for making these compounds, pharmaceutical compositions containing them, and their use in treating these mGluR2-related diseases.

Problems solved by technology

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

Method used

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  • Novel pyridinone derivatives and their use as positive allosteric modulators of mglur2-receptors
  • Novel pyridinone derivatives and their use as positive allosteric modulators of mglur2-receptors
  • Novel pyridinone derivatives and their use as positive allosteric modulators of mglur2-receptors

Examples

Experimental program
Comparison scheme
Effect test

example 1

1-(4-Chloro-2-fluorobenzyl)-5-(6-methoxypyridin-3-yl)pyridin-2(1H)-one (Final Compound 6-51)

[0588]

Step 1: 5-Bromopyridin-2(1H)-one

[0589]According to Scheme 1 Step 1: A mixture of 2-hydroxypyridine (1 eq, 100 mmol, 10.0 g) in AcOH (100 mL) was treated with NBS (1.06 eq, 110 mmol, 19.8 g) at room temperature for 4 hours. The mixture was concentrated, azeotroped twice with EtOH then the solid was taken up in hot EtOH (100 mL). After cooling to room temperature, the precipitate was removed by filtration and recrystallized from EtOH to provide 5-bromopyridin-2(1H)-one (51.7 mmol, 9.00 g, 49%) as a pale brown solid. Rf=0.60 (AcOEt / MeOH / NEt3 100 / 15 / 1); LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=0.59-2.46 min; MS m / z (CI) [MH]+=174, 176.

Step 2: 1-(4-Chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one

[0590]According to Scheme 1 Step 2: K2CO3 (10 eq, 0.11 mmol, 16.0 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (1.5 eq, 17.0 mmol, 3.90 g) was added to a solution of 5-bromopyridin-2(1H)-one ...

example 2

1-(4-Chlorobenzyl)-5-(4-(3-hydroxypropyl)phenyl)pyridin-2(1H)-one (Final Compound 2-16)

[0594]

Step 1: 1-(4-Chlorobenzyl)-5-bromopyridin-2(1H)-one

[0595]According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 29.0 mmol, 5.00 g, Example 1 Step 1) and 4-chlorobenzyl bromide (1.2 eq, 34.0 mmol, 7.10 g) according to the procedure described for Example 1 Step 2. After concentration of the solvent, water was added. The aqueous phase was extracted with AcOEt and the combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was recristallized with pentane / Et2O 50 / 50 to afford 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (26.2 mmol, 7.82 g, 91%) as a white solid.

[0596]LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=4.18 min; MS m / z (CI) [MH]+=299, 301.

Step 2: 1-(4-Chlorobenzyl)-5-(4-(3-hydroxypropyl)phenyl)pyridin-2(1H)-one

[0597]According to Scheme 3 Method A: To a solution of 1-(4-chlorobenzyl...

example 3

N-(3-(1-Isopentyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methanesulfonamide (Final Compound 8-02)

[0598]

Step 1: 5-Bromo-1-isopentylpyridin-2(1H)-one

[0599]According to Scheme 1 Step 2: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 0.01 μmol, 1.73 g) and 1-isopentylbromide (1 eq, 0.01 mmol, 1.51 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours under reflux in acetonitrile. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column SiO2) using CH2Cl2 / AcOEt (80 / 20) as the eluent to afford 5-bromo-1-isopentylpyridin-2(1H)-one (6.23 mmol, 1.52 g, 62%) as a brown oil.

Step 2: N-(3-(1-Isopentyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)methanesulfonamide

[0600]According to scheme 3 Method A: The title compound was prepared from 5-bromo-1-isopentylpyridin-2(1H)-one (1 eq, 0.41 mmol, 0.10 g) and 3-(methylsulfonamido)phenylboronic acid (1.5 eq, 0.61 mmol, 0.13 g) according to the procedure descr...

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Abstract

The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I)wherein all radicals are defined in the application. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional application of U.S. application Ser. No. 11 / 575,433, filed on Mar. 16, 2007, which is a U.S. national phase application under 35 USC 371 of international application number PCT / EP2005 / 054636, filed Sep. 16, 2005, which claims priority to Great Britain application no. 0420722.1, filed Sep. 17, 2004, all of which are hereby incorporated herein by reference in their entireties for all purposes.SUMMARY OF THE INVENTION[0002]The present invention relates to novel compounds, in particular novel pyridinone-derivatives that are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention is also directed to the pharmaceutical compositions, the processes to prepare such compounds...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D213/64C07F7/10C07D217/24C07D241/18C07D401/04C07D401/10C07D401/12C07D405/04C07D405/06C07D409/04C07D409/10C07D409/12C07D413/06C07D413/12C07D417/04C07D417/06C07D417/12C07F7/08
CPCC07D213/64C07F7/10C07D217/24C07D241/18C07D401/04C07D401/10C07D401/12C07D405/04C07D405/06C07D409/04C07D409/10C07D409/12C07D413/06C07D413/12C07D417/04C07D417/06C07D417/12C07F7/0812A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P25/36A61P3/04A61P43/00C07D211/76A61K31/4412
Inventor IMOGAI, HASSAN JULIANCID-NUNEZ, JOSE MARIADUVEY, GUILLAUME ALBERT JACQUESNHEM, VANTHEAFINN, TERRY PATRICK
Owner ADDEX PHARM SA
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