1',3'-Disubstituted-4-Phenyl-3,4,5,6-Tetrahydro-2H,1'H-[1,4']Bipyridinyl-2'-Ones

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.

1 . A compound having the formula (I) 
       
         
           
           
               
               
           
         
       
       or a stereochemically isomeric form thereof, wherein
 R 1  is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy; 
 R 2  is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl; 
 R 3  is hydrogen, fluoro, hydroxyl, hydroxyC 1-3 alkyl, hydroxyC 1-3 alkyloxy, fluoroC 1-3 alkyl, fluoroC 1-3 alkyloxy or cyano; and 
 Ar is phenyl substituted with n radicals R 4 , wherein n is 1, 2 or 3; 
 R 4  is selected from the group consisting of hydrogen, halo, C 1-3 alkyl, hydroxyC 1-3 alkyl, polyhaloC 1-3 alkyl, cyano, hydroxyl, amino, carboxyl, C 1-3 alkyloxyC 1-3 alkyl, C 1-3 alkyloxy, polyhaloC 1-3 alkyloxy, C 1-3 alkylcarbonyl, mono- and di(C 1-3 alkyl)amino, and morpholinyl; or 
 two vicinal R 4  radicals taken together form a bivalent radical of formula
   —N═CH—NH—  (a),
 
   —CH═CH—NH—  (b), or
 
   —O—CH 2 —CH 2 —NH—  (c); or
 
 R 3  and a R 4  radical in ortho position taken together form a bivalent radical of formula
   —CH 2 —O—  (d), or
 
   —O—CH 2 —  (e); or
 
 
 
 a pharmaceutically acceptable salt or a solvate thereof. 
 
     
     
         2 . The compound according to  claim 1  wherein
 R 1  is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl; 
 R 3  is hydrogen, fluoro or cyano; and 
 Ar is phenyl substituted with halo, trifluoromethyl, morpholinyl or hydroxyC 1-3 alkyl; 
 or a pharmaceutically acceptable salt or a solvate thereof 
 
     
     
         3 . The compound according to  claim 1  wherein
 R 1  is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl; 
 R 2  is chloro; 
 R 3  is hydrogen or fluoro; and 
 Ar is phenyl substituted with at least one halo, hydroxyC 1-3  alkyl, or a combination thereof; 
 or a pharmaceutically acceptable salt or a solvate thereof. 
 
     
     
         4 . The compound according to  claim 1  wherein
 R 1  is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl; 
 R 2  is chloro; 
 R 3  is hydrogen or fluoro; and 
 Ar is phenyl substituted with at least two fluoro groups; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . The compound according to  claim 1  wherein said compound is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         6 . The compound according to  claim 1  wherein said compound is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of a compound having the structure 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable carrier or excipient. 
       
     
     
         9 . A method for treating or preventing a central nervous system disorder in a human patient selected from the group of anxiety disorder, depression, psychotic disorder, or epilepsy or convulsive disorder, the method comprising administering to the patient in need thereof a compound of  claim 1 , or a pharmaceutically acceptable salt or a solvate thereof. 
     
     
         10 . The method of  claim 9 , wherein the central nervous system disorder is an anxiety disorder, selected from the group of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias. 
     
     
         11 . The method of  claim 10 , wherein the anxiety disorder is generalized anxiety disorder (GAD). 
     
     
         12 . The method of  claim 9 , wherein the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, schizoaffective disorder, and schizophreniform disorder. 
     
     
         13 . The method of  claim 13 , wherein the psychotic disorder is schizophrenia. 
     
     
         14 . The method of  claim 9 , wherein the central nervous system disorder is epilepsy or convulsive disorder. 
     
     
         15 . The method of  claim 14 , wherein the epilepsy or a convulsive disorder is generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, or epilepsy partialis continua. 
     
     
         16 . The method of  claim 9 , wherein the central nervous system disorder is depression. 
     
     
         17 . A method for treating or preventing a central nervous system disorder in a human patient selected from the group of anxiety disorder, psychotic disorder, or epilepsy or convulsive disorder, the method comprising administering to the patient in need thereof a compound of  claim 5 , or a pharmaceutically acceptable salt or a solvate thereof. 
     
     
         18 . The method of  claim 17 , wherein the central nervous system disorder is an anxiety disorder, selected from the group of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias. 
     
     
         19 . The method of  claim 18 , wherein the anxiety disorder is generalized anxiety disorder (GAD). 
     
     
         20 . The method of  claim 17 , wherein the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, schizoaffective disorder, and schizophreniform disorder. 
     
     
         21 . The method of  claim 20 , wherein the psychotic disorder is schizophrenia. 
     
     
         22 . The method of  claim 17 , wherein the central nervous system disorder is epilepsy or convulsive disorder. 
     
     
         23 . The method of  claim 22 , wherein the epilepsy or a convulsive disorder is generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilepticus, partial epilepsy with or without impairment of consciousness, infantile spasms, or epilepsy partialis continua. 
     
     
         23 . The method of  claim 17 , wherein the central nervous system disorder is depression.