4-Methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalenes

Abstract

The invention relates to 4-methyl-2,3,5,9,9b-pentaaza-cyclopenta[a]naphthalene derivatives of general formula (I) which are inhibitors of phosphodiesterase 2 and/or 10, useful in treating central nervous system diseases and other diseases. In addition, the invention relates to processes for preparing pharmaceutical compositions as well as processes for manufacture the compounds according to the invention.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         A is selected from the group A a  consisting of 
       
       
         
           
           
               
               
           
         
         
           wherein above mentioned phenyl-, pyridinyl-, pyrimidinyl-, pyridazinyl and pyrazinyl groups are substituted with R 1  and R 2 ; 
         
         R 1  is selected from the group R 1a  consisting of
 H, halogen, NC—, C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl and R 8 —(CH 2 ) n —O— with n=0, 1, 2, 3 or 4,
 wherein above mentioned C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl and R 8 —(CH 2 ) n —O— groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO— and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-; 
 
 
         R 2  is selected from the group R 2a  consisting of
 H, HO—, halogen, C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl, heteroaryl, R 8 —(CH 2 ) n —O— with n=0, 1, 2, 3 or 4, and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O— with m=0, 1 or 2 and o=0, 1 or 2,
 wherein above mentioned C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl, heteroaryl, R 8 — (CH 2 ) n —O— and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO—, optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-; 
 
 
         R 3  is selected from the group R 3a  consisting of
 H, halogen, NC—, C 1-4 -alkyl- and C 3-6 -cycloalkyl-,
 wherein the above mentioned C 1-4 -alkyl- and C 3-6 -cycloalkyl-groups may optionally be substituted with 1 to 9 substituents independently selected from the group consisting of halogen, NC—, HO—, C 1-3 -alkyl- and C 1-3 -alkyl-O—; 
 
 
         R 4 , R 5  are selected independently of each other from the group R 4a /R 5a  consisting of
 H, halogen, NC—, HO—, C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-8 -cycloalkyl-, C 3-8 -cycloalkyl-C 1-3 -alkyl-, C 3-8 -cycloalkyl-O—, heterocyclyl-O—, heterocyclyl, heteroaryl, R 7 —CH 2 —O— and R 7 —(CH 2 ) 2 —O—,
 wherein above mentioned C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-8 -cycloalkyl-, C 3-8 -cycloalkyl-C 1-3 -alkyl-, C 3-8 -cycloalkyl-O—, heterocyclyl-O—, heterocyclyl, heteroaryl, R 7 —CH 2 —O— and R 7 —(CH 2 ) 2 —O-groups, may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms, substituted C 1-2 -alkyl-, and optionally with 1 to 5 halogen atoms substituted C 1-2 -alkyl-O—; 
 
 
         R 6  is selected from the group R 6a  consisting of
 H, NC—, C 1-6 -alkyl-, C m -cycloalkyl-, C 3-8 -cycloalkyl-C 1-3 -alkyl- and C 3-8 -cycloalkyl-O—
 wherein above mentioned C 1-6 -alkyl- groups may optionally be substituted with 1-3 halogen atoms; 
 
 
         R 7  is selected from the group R 7a  consisting of
 H, carbocyclyl, heterocyclyl and heteroaryl,
 wherein above mentioned carbocyclyl, heterocyclyl and heteroaryl-groups may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of HO—, optionally with 1 to 3 halogen atoms substituted C 1-4 -alkyl-, optionally with 1 to 3 halogen atoms substituted C 1-4 -alkyl-O— and halogen; 
 
 
         R 8  is selected from the group R 8a  consisting of
 C 3-6 -cycloalkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl and pyridyl,
 wherein above mentioned C 3-6 -cycloalkyl, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl and pyridyl groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO—, fluorine and optionally with 1 to 7 halogen atoms substituted C 1-3 -alkyl-; 
 
 
         or a tautomer or salt thereof. 
       
     
     
         2 . A compound according to  claim 1 , wherein
 R 2  is selected from the group R 2a1  consisting of
 HO—, C 1-6 -alkyl-, C 1-6 -alkyl-O—, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl-, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl, heteroaryl, R 8 —(CH 2 ) n —O— with n=0, 1, 2, 3 or 4, and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O— with m=0, 1 or 2 and o=0, 1 or 2
 wherein above mentioned C 1-6 -alkyl- and C 1-6 -alkyl-O-groups are substituted with 1 to 5 substituents independently selected from the group consisting of HO—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, 
 and 
 wherein above mentioned C 1-6 -alkyl- and C 1-6 -alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-, 
 and 
 wherein above mentioned C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl-, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl, heteroaryl, R 8 —(CH 2 ) n —O— and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO—, optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         3 . A compound according to  claim 1 , wherein
 R 3  is selected from the group R 3a1  consisting of
 C 3-6 -cycloalkyl-,
 wherein the above mentioned C 3-6 -cycloalkyl-group may optionally be substituted with 1 to 9 substituents independently selected from the group consisting of halogen, NC—, HO—, C 1-3 -alkyl- and C 1-3 -alkyl-O—. 
 
   
     
     
         4 . A compound according to  claim 1 , wherein
 A is selected from the group A b  consisting of   
       
         
           
           
               
               
           
         
         
           wherein above mentioned phenyl- and pyridinyl- groups are substituted with R 1  and R 2 . 
         
       
     
     
         5 . A compound according to  claim 1 , wherein
 A is selected from the group A e  consisting of   
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound according to  claim 1 , wherein
 R 1  is selected from the group R 1b  consisting of
 H, halogen, C 1-6 -alkyl- and C 3-6 -cycloalkyl
 wherein above mentioned C 1-6 -alkyl- and C 3-6 -cycloalkyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO— and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         7 . A compound according to  claim 1 , wherein
 R 1  is selected from the group R 1c  consisting of
 H, H 3 C—, F 3 C—, F 2 HC—, FH 2 C—, fluorine, chlorine and bromine. 
   
     
     
         8 . A compound according to  claim 1 , wherein
 R 2  is selected from the group R 2b1  consisting of
 HO—, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl-, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, phenyl, heteroaryl, R 8 —(CH 2 ) n —O— with n=0, 1, 2 or 3 and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O— with m=0 or 1 and o=0 or 1
 wherein above mentioned C 1-4 -alkyl- and C 1-4 -alkyl-O— groups are substituted with 1 to 3 substituents independently selected from the group consisting of HO— and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, 
 and 
 wherein above mentioned C 1-4 -alkyl- and C 1-4 -alkyl-O-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-, 
 and 
 wherein above mentioned C 3-6 -cycloalkyl-, C 3-6 -cycloalkyl-C 1-3 -alkyl-, heterocyclyl, heterocyclyl-C 1-3 -alkyl-, R 8 —(CH 2 ) n —O— and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O-groups may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, HO—, optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         9 . A compound according to  claim 1 , wherein
 R 2  is selected from the group R 2d1  consisting of
 HO—, C 1-4 -alkyl-, C 1-4 -alkyl-O—, C 3-6 -cycloalkyl, C 3-6 -cycloalkyl-C 1-3 -alkyl-, a saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R 8 —(CH 2 ) n —O— with n=0, 1 or 2, and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O— with m=0 or 1 and o=0 or 1
 wherein above mentioned C 1-4 -alkyl- and C 1-4 -alkyl-O-groups are substituted with 1 to 5 substituents independently selected from the group consisting of HO—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, 
 and 
 wherein above mentioned C 1-4 -alkyl- and C 1-4 -alkyl-O-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-, 
 and 
 wherein above mentioned C 3-6 -cycloalkyl-, C 3-6 -cycloalkyl-C 1-3 -alkyl-, saturated 5 or 6 membered monocyclic heterocycle containing one heteroatom selected from N or O, R 8 —(CH 2 ) n —O— and R 8 —(CH 2 ) m —(CH)(CH 3 )—(CH 2 ) o —O— groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, HO—, optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-O—, and optionally with 1 to 7 fluorine atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         10 . A compound according to  claim 1 , wherein
 R 3  is selected from the group R 3b  consisting of
 H, C 1-3 -alkyl-, cyclobutyl- and cyclopropyl-,
 wherein the above mentioned C 1-3 -alkyl-, cyclobutyl- and cyclopropyl-groups may optionally be substituted with 1 to 7 substituents independently selected from the group consisting of halogen, C 1-3 -alkyl-O—, NC— and HO—. 
 
   
     
     
         11 . A compound according to  claim 1 , wherein
 R 3  is selected from the group R 3c  consisting of
 H, and H 3 C— and cyclopropyl-,
 wherein the above mentioned H 3 C— and cyclopropyl-groups may optionally be substituted with 1 to 3 fluorine atoms. 
 
   
     
     
         12 . A compound according to  claim 1 , wherein
 R 4 , R 5  are selected independently of each other from the group R 4b /R 5b  consisting of
 H, halogen, HO—, H 3 C—, F 3 C—, H 3 C—O—, F 2 HC—O—, FH 2 C—O—, F 3 C—O—, C 1-4 -alkyl-O—, R 7 —CH 2 —O— and R 7 —(CH 2 ) 2 —O—,
 wherein above mentioned C 1-4 -alkyl-O—, R 7 —CH 2 —O— and R 7 —(CH 2 ) 2 —O-groups, may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of halogen, optionally with 1 to 5 halogen atoms substituted C 1-2 -alkyl-, and optionally with 1 to 5 halogen atoms substituted C 1-2 -alkyl-O—. 
 
   
     
     
         13 . A compound according to  claim 1 , wherein
 R 4 , R 5  are selected from the group R 4d /R 5d  consisting of H—.   
     
     
         14 . A compound according to  claim 1 , wherein
 R 6  is selected from the group R 6b  consisting of
 H, C 1-4 -alkyl- and cyclopropyl-,
 wherein above mentioned C 1-4 -alkyl-group may optionally be substituted with 1-9 fluorine and/or chlorine atoms. 
 
   
     
     
         15 . A compound according to  claim 1 , wherein
 R 6  is selected from the group R 6c  consisting of
 H and C 1-2 -alkyl-,
 wherein above mentioned C 1-2 -alkyl- group may optionally be substituted with 1-5 fluorine and/or chlorine atoms. 
 
   
     
     
         16 . A compound according to  claim 1 , wherein
 R 6  is selected from the group R 6e  consisting of
 H 3 C—, FH 2 C—, F 2 HC— and F 3 C—. 
   
     
     
         17 . A compound according to  claim 1 , wherein
 R 7  is selected from the group R 7b  consisting of
 H, phenyl, heteroaryl, cycloalkyl and heterocyclyl
 wherein above mentioned phenyl, heteroaryl, cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen, and optionally with 1 to 3 halogen atoms substituted C 1-3 -alkyl-O—. 
 
   
     
     
         18 . A compound according to  claim 1 , wherein
 R 7  is selected from the group R 7c  consisting of
 H and phenyl,
 wherein above mentioned phenyl group may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of halogen and optionally with 1 to 3 halogen atoms substituted C 1-3 -alkyl-O—. 
 
   
     
     
         19 . A compound according to  claim 1 , wherein
 R 8  is selected from the group R 8b  consisting of
 C 3-6 -cycloalkyl, heterocyclyl and heterocyclyl-C 1-3 -alkyl-,
 wherein above mentioned C 3-6 -cycloalkyl, heterocyclyl and heterocyclyl-C 1-3 -alkyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO—, fluorine and optionally with 1 to 7 halogen atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         20 . A compound according to  claim 1 , wherein
 R 8  is selected from the group R 8b1  consisting of
 C 3-6 -cycloalkyl and a saturated 4 to 6 membered monocyclic heterocycle containing one or two heteroatoms selected from N or O,
 wherein above mentioned C 3-6 -cycloalkyl and heterocyclyl-groups may optionally be substituted with 1 to 5 substituents independently selected from the group consisting of HO—, fluorine and optionally with 1 to 7 halogen atoms substituted C 1-3 -alkyl-. 
 
   
     
     
         21 . A pharmaceutical composition containing a compound according to  claim 1  or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 
     
     
         22 . A method for treating (1) disorders comprising the symptom of cognitive deficiency; (2) organic, including symptomatic, mental disorders, dementia; (3) mental retardation; (4) mood [affective] disorders; (5) neurotic, stress-related and somatoform disorders including anxiety disorders; (6) behavioural and emotional disorders with onset usually occurring in childhood and adolescence, attention deficit hyperactivity syndrome (ADHD) and Autism spectrum disorders; (7) disorders of psychological development, developmental disorders of scholastic skills; (8) schizophrenia and other psychotic disorders; (9) disorders of adult personality and behaviour; (10) mental and behavioural disorders due to psychoactive substance use; (11) extrapyramidal and movement disorders; (12) episodic and paroxysmal disorders, epilepsy; (13) Systemic atrophies primarily affecting the central nervous system, ataxia; (14) Behavioural syndromes associated with physiological disturbances and physical factors; (15) sexual dysfunction comprising excessive sexual drive; (16) factitious disorders; (17) Treatment, amelioration and/or prevention of cognitive impairment being related to perception, concentration, cognition, learning or memory; (18) Treatment amelioration and/or prevention of cognitive impairment being related to age-associated learning and memory impairments; (19) Age-associated memory losses; (20) Vascular dementia; (21) Craniocerebral trauma; (22) Stroke; (23) Dementia occurring after strokes (post stroke dementia); (24) Post-traumatic dementia; (25) General concentration impairments; (26) Concentration impairments in children with learning and memory problems; (27) Alzheimer's disease; (28) Lewy body dementia; (29) Dementia with degeneration of the frontal lobes; including Pick's syndrome; (30) Parkinson's disease; (31) Progressive nuclear palsy; (32) Dementia with corticobasal degeneration; (33) Amyotropic lateral sclerosis (ALS); (34) Huntington's disease; (35) Multiple sclerosis; (36) Thalamic degeneration; (37) Creutzfeld-Jacob dementia; (38) HIV dementia; (38) Schizophrenia with dementia or Korsakoff's psychosis; (39) Sleep disorders; (40) Bipolar disorder; (41) Metabolic syndrome; (42) Obesity; (43) Diabetis mellitus; (44) Hyperglycemia; (45) Dyslipidemia; (46) Impaired glucose tolerance; (47) Disease of the testes, brain, small intestine, skeletal muscle, heart, lung, thymus or spleen and (48) pain disorders, which method comprises administering a therapeutically effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, to a patient suffering from such condition.