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 .- 20 . (canceled) 
     
     
         21 . A method of treating a central nervous system disorder that is an anxiety disorder, a psychotic disorder, a personality disorder, a substance-related disorder, an eating disorder, a mood disorder, migraine, epilepsy, a convulsive disorder, a childhood disorder, a cognitive disorder, neurodegeneration, neurotoxicity, or ischemia, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is C 1-6 alkyl; or is 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 unsubstituted phenyl or phenyl substituted with n radicals R 4 ;
 wherein n is 1, 2 or 3; and 
 each R 4  is independently 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(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, or morpholinyl; or 
 two vicinal R 4  radicals taken together form a bivalent radical of formula:
   —N═CH—NH—;  (a)
 
   —CH═CH—NH—; or  (b)
 
   —O—CH 2 —CH 2 —NH— ( c ); or  (c)
 
 
 
         R 3  and a R 4  radical in ortho position taken together form a bivalent radical of formula
   —CH 2 —O—; or  (a)
 
   —O—CH 2 —;  (b)
 
 
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         22 . The method of  claim 21 , 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 unsubstituted phenyl or phenyl substituted with halo, trifluoromethyl, morpholinyl, or hydroxyC 1-3 alkyl.   
     
     
         23 . The method of  claim 21 , 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 unsubstituted phenyl or phenyl substituted with at least one halo or hydroxyC 1-3  alkyl, or a combination thereof, or wherein Ar is phenyl substituted with at least two fluoro groups.   
     
     
         24 . The method of claim  1 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         25 . The method of claim  1 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 21 , wherein the central nervous system disorder is an anxiety disorder, wherein the anxiety disorder is agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), a phobia, or a social phobia. 
     
     
         27 . The method of  claim 21 , wherein the central nervous system disorder is a psychotic disorder, wherein the psychotic disorder is schizophrenia, schizoaffective disorder, or schizophreniform disorder. 
     
     
         28 . The method of  claim 21 , wherein the central nervous system disorder is a personality disorder, wherein the personality disorder is obsessive-compulsive personality disorder or schizoid, schizotypal disorder. 
     
     
         29 . The method of  claim 21 , wherein the central nervous system disorder is a substance-related disorder that is alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence, or opioid withdrawal. 
     
     
         30 . The method of  claim 21 , wherein the central nervous system disorder is an eating disorder that is anorexia nervosa or bulimia nervosa. 
     
     
         31 . The method of  claim 21 , wherein the central nervous system disorder is a mood disorder that is bipolar disorder (I or II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, or a substance-induced mood disorder. 
     
     
         32 . The method of  claim 21 , wherein the central nervous system disorder is migraine. 
     
     
         33 . The method of  claim 21 , wherein the central nervous system disorder is epilepsy or convulsive disorder. 
     
     
         34 . The method of  claim 33 , 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. 
     
     
         35 . The method of  claim 21 , wherein the central nervous disorder is a childhood disorder, wherein the childhood disorder is attention-deficit/hyperactivity disorder. 
     
     
         36 . The method of  claim 21 , wherein the central nervous system disorder is a cognitive disorder, wherein the cognitive disorder is delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, substance-induced persisting dementia, or mild cognitive impairment. 
     
     
         37 . A pharmaceutical composition comprising a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is C 1-6 alkyl; or is 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 unsubstituted phenyl or phenyl substituted with n radicals R 4 ; 
 wherein n is 1, 2 or 3; and 
 each R 4  is independently 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(C 1-3 alkyl)amino, di(C 1-3 alkyl)amino, or morpholinyl; or 
 two vicinal R 4  radicals taken together form a bivalent radical of formula:
   —N═CH—NH—;  (a)
 
   —CH═CH—NH—; or  (b)
 
   —O—CH 2 —CH 2 —NH— ( c ); or  (c)
 
 
 R 3  and a R 4  radical in ortho position taken together form a bivalent radical of formula
   —CH 2 —O—; or  (a)
 
   —O—CH 2 —;  (b)
 
 
 or a pharmaceutically acceptable salt or a solvate thereof, and 
 a pharmaceutically acceptable excipient. 
 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a solvate thereof. 
       
     
     
         39 . The pharmaceutical composition of  claim 37 , wherein the compound of Formula (I) is: