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1',3'-disubstituted-4-pheny-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2'-ones

a technology of disubstituted phenyls and dipyridinyls, which is applied in the field of pyridinonederivatives, can solve problems such as glutamatergic neurotransmission imbalan

Inactive Publication Date: 2013-08-01
ADDEX PHARM SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

These pyridinone-derivatives demonstrate potential in treating anxiety, schizophrenia, epilepsy, and other neurological disorders by potentiating glutamate responses, offering a novel therapeutic approach with selective targeting of the mGluR2 subtype.

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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  • 1',3'-disubstituted-4-pheny-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2'-ones
  • 1',3'-disubstituted-4-pheny-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2'-ones
  • 1',3'-disubstituted-4-pheny-3,4,5,6-tetrahydro-2h,1'h-[1,4']bipyridinyl-2'-ones

Examples

Experimental program
Comparison scheme
Effect test

example 1

3′-Chloro-1′-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-one (E1)

[0169]

[0170]A solution of intermediate D18 (0.2 g, 0.65 mmol) and N-chlorosuccinimide (0.09 g, 0.65 mmol) in DCM (10 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by column chromatography (silica gel; 0-3% methanol / DCM as eluent). The desired fractions were collected and evaporated in vacuo and the resulting solid was recrystallized from diethyl ether to yield compound E1 (0.10 g, 47%) as a white solid.

[0171]Melting point: 170.8° C.

[0172]1H NMR (400 MHz, CDCl3) 8 ppm 0.35-0.42 (m, 2H), 0.57-0.64 (m, 2H), 1.19-1.33 (m, 1H), 1.85-2.00 (m, 4H), 2.64-2.76 (m, 1H), 2.85-2.99 (m, 2H), 3.76-3.87 (m, 4H), 6.05 (d, J=7.6 Hz, 1H), 7.19-7.29 (m, 4H), 7.29-7.38 (m, 2H).

example 2

1′-Butyl-3′-chloro-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-one (E2)

[0173]

[0174]A solution of intermediate D19 (0.43 g, 1.40 mmol) and N-chlorosuccinimide (0.19 g, 1.40 mmol) in DCM (10 ml) was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by column chromatography (silica gel; 0-3% methanol / DCM as eluent). The desired fractions were collected and evaporated in vacuo and the resulting solid was recrystallized from diethyl ether to yield compound E2 (0.39 g, 82%) as a white solid.

[0175]Melting point: 149.4° C.

[0176]1H NMR (400 MHz, CDCl3) 8 ppm 0.95 (t, J=7.3 Hz, 3H), 1.31-1.42 (m, 2H), 1.68-1.78 (m, 2H), 1.85-1.98 (m, 4H), 2.64-2.73 (m, 1H), 2.87-2.96 (m, 2H), 3.82 (br d, J=12.1 Hz, 2H), 3.93 (t, J=7.3 Hz, 2H), 6.03 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.19-7.28 (m, 3H), 7.29-7.37 (m, 2H).

example 3

3′-Bromo-1′-cyclopropylmethyl-4-phenyl-3,4,5,6-tetrahydro-2H,1′H-[1,4′]bipyridinyl-2′-one (E3)

[0177]

[0178]N-Bromosuccinimide (0.145 g, 0.82 mmol) was added to a solution of intermediate D18 (0.25 g, 0.82 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 1 hour. Subsequently, the solvent was evaporated in vacuo and the crude residue was purified by column chromatography (silica gel; 0-3% methanol / DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield compound E3 (0.20 g, 64%) as a white solid.

[0179]Melting point: 150° C.

[0180]1H NMR (500 MHz, DMSO-d6) 8 ppm 0.34-0.40 (m, 2H), 0.44-0.50 (m, 2H), 1.16-1.26 (m, 1H), 1.77 (qd, J=12.38, 3.61 Hz, 2H), 1.88 (br d, J=12.1 Hz, 2H), 2.68-2.78 (m, 1H), 2.91 (br t, J=11.9 Hz, 2H) 3.69 (br d, J=12.1 Hz, 2H), 3.74 (d, J=7.2 Hz, 2H), 6.21 (d, J=7.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.27-7.36 (m, 4H), 7.69 (d, J=7.5 Hz, 1H).

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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 as defined in the application and claims. 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 continuation application of U.S. application Ser. No. 12 / 677,618, filed on Sep. 12, 2008, which is a U.S. national phase application under 35 USC 371 of international application number PCT / EP2008 / 007551, filed Sep. 12, 2008, which claims priority to European Application No. 07116390.1, filed Sep. 14, 2007. Each application is hereby incorporated herein by reference in its entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to novel pyridinone-derivatives which are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (“mGluR2”) and 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 pharmaceutical compositions comprising such compounds, to processes to prepare such compou...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4545A61K45/06A61K31/5377C07D211/86C07D491/107
CPCC07D401/04C07D493/10A61K9/2018A61K9/2059A61K9/2013A61K31/4545A61K31/5377A61K45/06C07D211/86C07D491/107A61K31/444A61K9/0014A61K9/0019A61K47/10A61K9/08A61K9/10A61K47/44A61K9/2009A61K2300/00A61P25/00A61P25/06A61P25/08A61P25/10A61P25/12A61P25/14A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P25/36A61P3/04A61P9/10
Inventor CID-NUNEZ, JOSE MARIATRABANCO-SUAREZ, ANDRES AVELINOMACDONALD, GREGOR JAMESDUVEY, GUILLAUME ALBERT JACQUESLUTJENS, ROBERT JOHANNESFINN, TERRY PATRICK
Owner ADDEX PHARM SA
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