Metabotropic Glutamate Receptor Oxadiazole Ligands and Their Use as Potentiators

Abstract

Compounds of Formula (I) wherein R 1 , R 2 , R 3 R 4 and Q are as described in the specification, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

1 . A compound according to Formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is halo or C 1-3 haloalkoxyl; 
 R 2  is hydrogen or C 1-3 alkyl; 
 R 3  is C 1  or CH 3 ; 
 R 4  is hydrogen or C 1-3 alkyl; 
 Q is 
 
       
         
           
           
               
               
           
         
         R 5  is hydrogen or C 1-3 alkyl, 
         and n is 1 or 2, 
       
       wherein when n is 2 both R 5  moieties can be attached to the same carbon atom, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof. 
     
     
         2 . A compound according to  claim 1 , wherein R 1  is chloro or trifluoromethoxyl. 
     
     
         3 . A compound according to  claim 2 , wherein R 1  is chloro. 
     
     
         4 . A compound according to  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 4 , wherein Q is 
       
         
           
           
               
               
           
         
       
       and R 5  is H at each occurrence. 
     
     
         6 . A compound according to  claim 1 , wherein R 1  is chloro or trifluoromethoxyl and Q is 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound according to  claim 1 , wherein R 1  is chloro and Q is 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound according to  claim 1 , wherein R 1  is chloro or trifluoromethoxyl and Q is 
       
         
           
           
               
               
           
         
       
       where R 5  is H at each occurrence. 
     
     
         9 . A compound according to  claim 1 , wherein Q is 
       
         
           
           
               
               
           
         
       
       and R 5  is hydrogen or C 1-3 alkyl.
 or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof. 
 
     
     
         10 . A compound according to  claim 1  selected from:
 7-chloro-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;   7-chloro-2-(4-chlorobenzyl)-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydroisoindol-1-one;   7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;   2-(4-chlorobenzyl)-7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydroisoindol-1-one;   5-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)-[1,2,4]oxadiazol-3-yl]-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;   2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-(5-piperazin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-2,3-dihydro-isoindol-1-one;   2-[(S)-1-(4-chloro-phenyl)-ethyl]-5-{5-[(1S,4S)-1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)methyl]-[1,2,4]oxadiazol-3-yl}-7-methyl-2,3-dihydro-isoindol-1-one;   2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;   2-(4-chloro-benzyl)-7-methyl-5-[5-(2-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;   2-(4-chloro-benzyl)-7-methyl-5-[5-(3-methyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydroisoindol-1-one;   7-chloro-5-[5-(3,3-dimethyl-piperazin-1-ylmethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one;   7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one;   2-(4-chloro-benzyl)-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one, or   2-[(S)-1-(4-chloro-phenyl)-ethyl]-7-methyl-5-[5-(1-piperazin-1-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-2,3-dihydro-isoindol-1-one,   or a pharmaceutically acceptable salt, hydrate or solvate thereof.   
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         16 . A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a pharmaceutical composition according to  claim 11 . 
     
     
         17 . The method according to  claim 15 , wherein the neurological and psychiatric disorders are selected from cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine, migraine headache, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), mood disorders, depression, mania, bipolar disorders, circadian rhythm disorders, jet lag, shift work, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, and conduct disorder. 
     
     
         18 . The method according to  claim 17 , wherein the neurological and psychiatric disorders are selected from Alzheimer's disease, cerebral deficits secondary to prolonged status epilepticus, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), mood disorders, depression, mania, and bipolar disorders. 
     
     
         19 . A pharmaceutical composition comprising a compound according to  claim 10  and a pharmaceutically acceptable carrier or excipient. 
     
     
         20 . A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction selected from cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine, migraine headache, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), mood disorders, depression, mania, bipolar disorders, circadian rhythm disorders, jet lag, shift work, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, and conduct disorder, in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a compound according to  claim 10 .