Pyrido[3,2-e]pyrazines, their use as inhibitors of phospohodiesterase 10, and processes for preparing them

Abstract

The invention relates to pyrido[3,2-e]pyrazines, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10, as active compounds for treating diseases of mammals including a human which can be influenced by using the compounds according to the invention to inhibit phosphodiesterase 10 activity in the central nervous system. More particularly, the invention relates to the treatment of neurologic and psychiatric disorders, for example psychosis and disorders comprising cognitive deficits as symptoms.

1 - 40 . (canceled) 
     
     
         41 . A method comprising treating or preventing disorders associated with, accompanied by or caused by phosphodiesterase 10 hyperactivity or a disorder in which inhibiting phosphodiesterase 10 is of value by administering a therapeutically effective amount of a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein the bond between A and N is a single bond or a double bond; 
         A is C when the bond is a double bond and CH when the bond is a single bond; 
         m is 0 or 1; 
         n is 0 or 1; 
         R 1  and R 2  are independently selected from 
         H, 
         a cyclic radical; 
         C 1-8  alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical; 
         C 2-8  alkenyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical; 
         C 2-8  alkynyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3 -alkyl or a cyclic radical; 
         a saturated, monounsaturated or polyunsaturated carbocycle ring system with 3 to 8 atoms or a heterocyclic ring with 5 to 15 ring atoms, each optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical; and 
         R 3  is selected from 
         H, 
         a cyclic radical, 
         N 3 , 
         CN, 
         R 6 , OR 6 , SR 6 , SOR 6 , SO 2 R 6 , 
         NH(CO)OR 6 , N((CO)OR 6 ) 2 , NR 6 ((CO)OR 6 ), 
         NH—(C═O)—NH 2 , NR 6 —(C═O)—NH 2 , 
         NH—(C═O)—NHR 6 , NR 6 —(C═O)—NHR 6 , 
         NH—SO 2 R 6 , N(SO 2 R 6 ) 2  and NR 6 (SO 2 R 6 ), 
         wherein R 6  is independently, 
         a cyclic radical, 
         C 1-8  alkyl, C 3-8  cyclo(hetero)alkyl, 
         C 2-8  alkenyl, C 3-8  cyclo(hetero)alkenyl, 
         or C 2-8  alkynyl each optionally mono or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         R 7 , OR 7 , SR 7 , NHSO 2 R 7 , N(SO 2 R 7 ), or N(R 8 )SO 2 R 7 , 
         wherein R 7  is aryl, heteroaryl, aryl-C 1-5  alkyl, heteroaryl-C 1-5  alkyl, 
         wherein aryl is phenyl or naphthyl, heteroaryl is an aromatic heterocyclic ring system of 5 to 15 ring atoms containing at least one atom selected from N including N-oxide, S, and O and wherein aryl and heteroaryl are optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylaminio, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical and 
         R 8  is C 1-5  alkyl, optionally mono or polysubstituted with at last one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         R 4  is selected from 
         H, 
         halo, 
         a cyclic radical, 
         R 9    
         OH or OR 9 , 
         NH(C═O)—C 1-3  alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         NH 2 , NHR X  or NR 9 R 10 , 
         wherein R 9  and R 10  are independently selected from
 a cyclic radical, 
 C 1-6  alkyl or C 3-6  cyclo(hetero)alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
 aryl-C 1-5 -alkyl wherein aryl is phenyl, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical or 
 NR 9 R 10  together form a saturated or unsaturated five-, six- or seven-membered ring which can contain up to 3 heteroatoms, preferably N including N-oxide, S or O, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or aryl-C 1-5 -alkyl, wherein aryl is phenyl, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical, 
 
         and R 5  is selected from 
         H, 
         C 1-5  alkyl, C 3-6  cycloalkyl or (CO)—C 1-5  alkyl, optionally mono or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         or a pharmaceutically acceptable salt or prodrug thereof, wherein if m and n are 1, A and 
         N are not a double bond; 
         wherein if m is 1 and n is 0, A and N are not double bond; 
         wherein if n is 1 and m is 0, A and N are not a single bond; and 
         wherein if m and n are 0, A and N are not a single bond. 
       
       to a subject in need thereof. 
     
     
         42 . A method comprising treating or preventing central nervous system disorder by administering a therapeutically effective amount of a compound of formula (II) 
       
         
           
           
               
               
           
         
         wherein the bond between A and N is a single bond or a double bond; 
         A is C when the bond is a double bond and CH when the bond is a single bond; 
         m is 0 or 1; 
         n is 0 or 1; 
         R 1  and R 2  are independently selected from 
         H, 
         a cyclic radical; 
         C 1-8  alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical; 
         C 2-8  alkenyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical; 
         C 2-8  alkynyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3 -alkyl or a cyclic radical; 
         a saturated, monounsaturated or polyunsaturated carbocycle ring system with 3 to 8 atoms or a heterocyclic ring with 5 to 15 ring atoms, each optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical; and 
         R 3  is selected from 
         H, 
         a cyclic radical, 
         N 3 , 
         CN, 
         R 6 , OR 6 , SR 6 , SOR 6 , SO 2 R 6 , 
         NH(CO)OR 6 , N((CO)OR 6 ) 2 , NR 6 ((CO)OR 6 ), 
         NH—(C═O)—NH 2 , NR 6 —(C═O)—NH 2 , 
         NH—(C═O)—NHR 6 , NR 6 —(C═O)—NHR 6 , 
         NH—SO 2 R 6 , N(SO 2 R 6 ) 2  and NR 6 (SO 2 R 6 ), 
         wherein R 6  is independently, 
         a cyclic radical, 
         C 1-8  alkyl, C 3-8  cyclo(hetero)alkyl, 
         C 2-8  alkenyl, C 3-8  cyclo(hetero)alkenyl, 
         or C 2-8  alkynyl each optionally mono or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         R 7 , OR 7 , SR 7 , NHSO 2 R 7 , N(SO 2 R 7 ), or N(R 8 )SO 2 R 7 , 
         wherein R 7  is aryl, heteroaryl, aryl-C 1-5 alkyl, heteroaryl-C 1-5  alkyl, 
         wherein aryl is phenyl or naphthyl, heteroaryl is an aromatic heterocyclic ring system of 5 to 15 ring atoms containing at least one atom selected from N including N-oxide, S, and O and wherein aryl and heteroaryl are optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical and 
         R 8  is C 1-5  alkyl, optionally mono or polysubstituted with at last one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         R 4  is selected from 
         H, 
         halo, 
         a cyclic radical, 
         R 9 , 
         OH or OR 9 , 
         NH(C═O)—C 1-3  alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         NH 2 , NHR 9  or NR 9 R 10 , 
         wherein R 9  and R 10  are independently selected from
 a cyclic radical, 
 C 1-6  alkyl or C 3-6  cyclo(hetero)alkyl, optionally mono- or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
 aryl-C 1-5 -alkyl wherein aryl is phenyl, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical or 
 NR 9 R 10  together form a saturated or unsaturated five-, six- or seven-membered ring which can contain up to 3 heteroatoms, preferably N including N-oxide, S or O, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or aryl-C 1-5 -alkyl, wherein aryl is phenyl, optionally mono- or polysubstituted with at least one of halo, amino, C 1-3  alkylamino, di-C 1-3  alkylamino, nitro, C 1-3  alkyl, O—C 1-3  alkyl or a cyclic radical, 
 
         and R 5  is selected from 
         H, 
         C 1-5  alkyl, C 3-6  cycloalkyl or (CO)—C 1-5  alkyl, optionally mono or polysubstituted with at least one of halo, OH, O—C 1-3  alkyl or a cyclic radical, 
         or a pharmaceutically acceptable salt or prodrug thereof, wherein if m and n are 1, A and 
         N are not a double bond; 
         wherein if m is 1 and n is O, A and N are not double bond; 
         wherein if n is 1 and m is O, A and N are not a single bond; and 
         wherein if m and n are O, A and N are not a single bond. 
       
       to a subject in need thereof, wherien the bond between A and N is a double bond. 
     
     
         43 . A method according to  claim 42 , wherein the disorder is neurological or psychiatric disorder including schizophrenia or other psychotic disorder; an affective disorder; a neurosis, a stress-related disorder, a somatofonn disorder, and anxiety disorder; an eating disorder; a sexual dysfunction; a disorder of adult personality and behavior; a disorder usually first diagnosed in infancy, childhood or adolescence, mental retardation; a disorder of psychological development; a disorder comprising the symptom of a cognitive deficit in a mammal and a factitious disorder. 
     
     
         44 . A method according to  claim 43 , wherein the schizophrenia and other psychotic disorders are continuous or episodic schizophrenia selected from the group consisting of, paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorder; schizotypal disorder; a persistent delusional disorder; an acute psychotic disorder, a transient psychotic disorder, a persistent psychotic disorder; an induced delusional disorder; a schizoaffective disorder; puerperal psychosis and other and unspecified nonorganic psychosis. 
     
     
         45 . A method according to  claim 43 , wherein the affective disorder is a manic episode associated to bipolar disorder, a single manic episode, hypomania, mania with psychotic symptoms; a bipolar affective disorder; a depressive disorder, a depressive disorder with postpartum onset, a depressive disorder with psychotic symptoms; a persistent affective disorder and premenstrual dysphoric disorder. 
     
     
         46 . A method according to  claim 43 , wherein the disorder is a phobic anxiety disorder selected from the group consisting of agoraphobia and social phobia primarily but not exclusively related to psychosis; a panic disorder, a general anxiety disorder; an obsessive compulsive disorder; reaction to sever stress and adjustment disorder, a dissociative disorder and depersonalisation-derealization syndrome. 
     
     
         47 . A method according to  claim 43 , wherein the disorder is a specific personality disorder of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; a mixed personality disorder; a habit and impulse disorder or disorders of sexual preference. 
     
     
         48 . A method according to  claim 43 , wherein the disorder is a hyperkinetic disorder, attentional deficit/hyperactivity disorder (AD/HD), a conduct disorder; a mixed disorder of conduct and emotional disorder; a nonorganic enuresis, a nonorganic encopresis; a stereotyped movement disorder; attention deficit disorder without hyperactivity, excessive masturbation, excessive nail-biting, excessive nose-picking and excessive thumb-sucking; a schizoid disorder of childhood and a pervasive development disorder. 
     
     
         49 . A method according to  claim 43 , wherein the disorder is a disorder of speech and language or a developmental disorder of scholastic skill. 
     
     
         50 . A method according to claim  63 , wherein the disorder is a cognitive deficit primarily but not exclusively related to psychosis; age-associated memory impairment, Parkinson's disease, Alzheimer's disease, multi infarct dementia, Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy Huntington's disease, HIV disease, cerebral trauma, drug abuse and mild cognitive disorder. 
     
     
         51 . A method according to claim  63 , wherein the disorder is associated with a malfunction of basal ganglia is a focal dystonia, a multiple-focal or segmental dystonia, torsion dystonia, hemispheric, generalized and tardive dyskinesia, akathisias, or a dyskinesia. 
     
     
         52 . A method according to claim  63 , wherein the disorder is a symptomatic mental disorder, an organic delusional disorder, a presenil or senile psychosis associated to dementia, to psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; personality and a behavioral disorder due to brain disease, damage and dysfunction. 
     
     
         53 . A method according to claim  63 , wherein the disorder is a mental and behavioural disorder due to a psychoactive compound. 
     
     
         54 . A method according to claim  63 , wherein the learning and memory capacities are enhanced in a mammal. 
     
     
         55 . A method according to claim  63 , wherein the active agent is administered to a human or an animal.