Substituted Isoindolones and Their Use as Metabotropic Glutamate Receptor Potentiators

Abstract

The present invention is directed to compounds of formula I: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and n are as defined for formula I in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.

1 . A compound according to formula I: 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is a 3- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein said ring may be substituted by one or more A; 
 R 2  and R 3  are H; 
 R 4  and R 6  are H; 
 R 5  is C 0-6 -alkylheteroaryl, wherein any cyclic moiety is substituted by one or more B; 
 R 7  is selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, or C 1-6 -alkyl; 
 R 8  and R 9  are H; 
 A is selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C 1-6 -alkyl, and C 1-6 -alkylhalo; 
 B is selected from the group consisting of C 1-6 -alkylheterocycloalkyl, OC 0-6 -alkylheterocycloalkyl, C 1-6 -alkylheteroaryl and OC 1-6 -alkylheteroaryl; 
 
         and
 n is 1; 
 
         or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof. 
       
     
     
         2 . (canceled) 
     
     
         3 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
         4 - 6 . (canceled) 
     
     
         7 . 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 . 
     
     
         8 . 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 3 . 
     
     
         9 . The method according to  claim 7 , 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. 
     
     
         10 . The method according to  claim 9 , 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. 
     
     
         10 . The method according to  claim 8 , 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, 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. 
     
     
         11 . The method according to  claim 10 , 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, mood disorders, depression, mania, and bipolar disorders.