Pirazino(AZA)indole derivatives

Abstract

Chemical compounds of formula (I): and pharmaceutically acceptable salts and addition compounds and prodrugs thereof are useful in therapy, particularly for the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes inspidus, and sleep apnea.

1 . A chemical compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  to R 3  are independently selected from hydrogen and lower alkyl;  
 X 1  is selected from N and C—R 4 ;  
 X 2  is selected from N and C—R 5 ;  
 X 3  is selected from N and C—R 6 ;  
 X 4  is selected from N and C—R 7 ;  
 R 4 , R 5  and R 7  are independently selected from hydrogen, halogen, hydroxy, alkyl, aryl, alkoxy, aryloxy, alkoyl, aryloyl, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino, nitro, cyano, carboalkoxy, carboaryloxy and carboxy; and  
 R 6  is selected from hydrogen, halogen, alkyl, aryl, aryloxy, alkylthio, arylthio, alkylsulfoxyl, arylsulfoxyl, alkylsulfonyl, arylsulfonyl, amino, alkylamino, dialkylamino and cyano;  
 with the proviso that R 4  to R 7  are not all selected as hydrogen,  
 and pharmaceutically acceptable salts and addition compounds and prodrugs thereof.  
 
     
     
         2 . A compound according to  claim 1  wherein R 1  is selected from hydrogen and methyl.  
     
     
         3 . A compound according to  claim 1  or  2  wherein R 2  is hydrogen.  
     
     
         4 . A compound according to  claim 1 ,  2  or  3  wherein R 3  is selected from hydrogen and methyl.  
     
     
         5 . A compound according to any preceding claim wherein X 2  is C—R 5 .  
     
     
         6 . A compound according to any preceding claim wherein X 3  is C—R 6 .  
     
     
         7 . A compound according to any preceding claim wherein X 4  is C—R 7 .  
     
     
         8 . A compound according to any preceding claim wherein X 1  is C—R 4 .  
     
     
         9 . A compound according to any preceding claim wherein two of R 4 , R 5 , R 6  and R 7  are hydrogen.  
     
     
         10 . A compound according to  claim 9  wherein R 4  and R 6  are hydrogen.  
     
     
         11 . A compound according to any of  claims 1  to  8  wherein two of R 4 , R 5 , R 6  and R 7  are independently selected from hydrogen, chlorine, fluorine, trifluoromethyl and bromine.  
     
     
         12 . A compound according to any of  claims 1  to  8  wherein three of R 4 , R 5 , R 6  and R 7  are hydrogen.  
     
     
         13 . A compound according to  claim 12  wherein R 4 , R 6  and R 7  are hydrogen.  
     
     
         14 . A compound according to any of  claims 1  to  8  wherein R 4  is hydrogen.  
     
     
         15 . A compound according to any of  claims 1  to  8  wherein R 5  is halogen.  
     
     
         16 . A compound according to any of  claims 1  to  8  wherein R 6  is hydrogen.  
     
     
         17 . A compound according to any of  claims 1  to  8  wherein R 7  is halogen.  
     
     
         18 . A compound according to  claim 1  which is selected from: 
 (RS) 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (RS) 9-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (RS) 7-chloro-8-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (10aR) 7-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (RS) 7-bromo-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (3S, 10aR) 8-chloro-2-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole,  
 (10aR) 8-chloro-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole and  
 (3S, 10aR) 8-chloro-2-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole.  
 
     
     
         19 . A compound of formula (I) as set out in any one of  claims 1  to  18  for use in therapy.  
     
     
         20 . The use of a compound of formula (I) as set out in any of  claims 1  to  18  in the manufacture of a medicament for the treatment of disorders of the central nervous system; damage to the central nervous system; cardiovascular disorders; gastrointestinal disorders; diabetes inspidus, and sleep apnea.  
     
     
         21 . A use according to  claim 20  wherein the disorders of the central nervous system are selected from 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.  
     
     
         22 . A use according to  claim 20  wherein the damage to the central nervous system is by trauma, stroke, neurodegenerative diseases or toxic or infective CNS diseases.  
     
     
         23 . A use according to  claim 22  wherein said toxic or infective CNS disease is encephalitis or meningitis.  
     
     
         24 . A use according to  claim 20  wherein the cardiovascular disorder is thrombosis.  
     
     
         25 . A use according to  claim 20  wherein the gastrointestinal disorder is dysfunction of gastrointestinal motility  
     
     
         26 . A use according to  claim 20  wherein said medicament is for the treatment of obesity.  
     
     
         27 . A use according to any one of  claims 20  to  26  wherein said treatment is prophylactic treatment.  
     
     
         28 . A method of treatment of any of the disorders set out in  claims 20  to  25  comprising administering to a patient in need of such treatment an effective dose of a compound of formula (I) as set out in any one of  claims 1  to  18 .  
     
     
         29 . A method of treatment according to  claim 28  wherein said disorder is obesity.  
     
     
         30 . A method according to  claim 28  or  29  wherein said treatment is prophylactic treatment.  
     
     
         31 . A method of preparing a compound of formula (I) as set out in any one of  claims 1  to  18 .  
     
     
         32 . A pharmaceutical composition comprising a compound of formula (I) as set out in any one of  claims 1  to  18  in combination with a pharmaceutically acceptable carrier or excipient.  
     
     
         33 . A method of making a composition according to  claim 32  comprising combining a compound of formula (I) as set out in any one of  claims 1  to  18  with a pharmaceutically acceptable carrier or excipient.  
     
     
         34 . A process for the preparation of a compound of formula (I) according to any of  claims 1  to  18 , said process comprising the steps of: 
 (i) treating a compound of formula (IX) as described herein with an aldehyde and then exposing to acid to obtain a compound of formula (X) as described herein, and  
 (ii) reduction of a compound of formula (X).