Condensed indoline derivatives and their use as 5HT, in particular 5HT2C, receptor ligands

Abstract

A chemical compound of formula (I) wherein R 1 and R 2 are independently selected from hydrogen and alkyl; R 3 is alkyl; R 4 and R 5 are selected from hydrogen and alkyl; R 6 and R 7 are independently selected from hydrogen, halogen, hydroxyl, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and A is a 5- or 6-membered ring optionally containing one or more heteroatoms wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated, and pharmaceutically acceptable salts, addition compounds and prodrugs thereof; and the use thereof in therapy, particularly as an agonist or antagonist of a 5HT receptor, particularly a 5HT 2C receptor, for instance in the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, and sleep apnea, and particularly for the treatment of obesity.

1 . A method of treating a condition treatable by agonism of the 5HT2 receptor comprising administering a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  and R 2  are independently selected from hydrogen and alkyl;  
         R 3  is alkyl;  
         R 4  and R 5  are selected from hydrogen and alkyl;  
         R 6  and R 7  are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and  
         A is a 5 or 6-membered ring containing one heteroatom selected from N, wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated,  
         or a pharmaceutically acceptable salt, addition compound or prodrug thereof.  
       
     
     
         2 . A method of treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes insipidus, or sleep apnea comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  and R 2  are independently selected from hydrogen and alkyl;  
         R 3  is alkyl;  
         R 4  and R 5  are selected from hydrogen and alkyl;  
         R 6  and R 7  are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and  
         A is a 5 or 6-membered ring containing one heteroatom selected from N, wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated,  
         or a pharmaceutically acceptable salt, addition compound or prodrug thereof.  
       
     
     
         3 . A method according to  claim 2 , wherein the disorders of the central nervous system are selected from the group consisting of depression, atypical depression, bipolar disorders, anxiety disorders, obsessive-compulsive disorders, social phobias or panic states, sleep disorders, sexual dysfunction, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or other pain, raised intracranial pressure, epilepsy, personality disorders, age-related behavioural disorders, behavioural disorders associated with dementia, organic mental disorders, mental disorders in childhood, aggressivity, age-related memory disorders, chronic fatigue syndrome, drug and alcohol addiction, obesity, bulimia, anorexia nervosa and premenstrual tension.  
     
     
         4 . A method according to  claim 2 , wherein the damage to the central nervous system is by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases.  
     
     
         5 . A method according to  claim 4 , wherein said toxic or infective CNS disease is encephalitis or meningitis.  
     
     
         6 . A method according to  claim 2 , wherein the cardiovascular disorder is thrombosis.  
     
     
         7 . A method according to  claim 2 , wherein the gastrointestinal disorder is dysfunction of gastrointestinal motility.  
     
     
         8 . A method of treatment according to  claim 2 , wherein said disorder is obesity.  
     
     
         9 . A method according to  claim 2 , wherein said treatment is prophylactic treatment.  
     
     
         10 . A method of making a pharmaceutical composition, comprising combining a compound of formula (I):  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  and R 2  are independently selected from hydrogen and alkyl;  
         R 3  is alkyl;  
         R 4  and R 5  are selected from hydrogen and alkyl;  
         R 6  and R 7  are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, amino, alkylamino, dialkylamino, alkoxy, aryloxy, alkylthio, alkylsulfoxyl, alkylsulfonyl, nitro, carbonitrile, carbo-alkoxy, carbo-aryloxy and carboxyl; and  
         A is a 5 or 6-membered ring containing one heteroatom selected from N, wherein the atoms of the ring A, other than the unsaturated carbon atoms of the phenyl ring to which the ring A is fused, are saturated or unsaturated,  
         or a pharmaceutically acceptable salt, addition compound or prodrug thereof.