3-(Heteroaryl-Oxy)-2-Alkyl-1-Aza-Bicycloalkyl Derivatives As Alpha. 7-Nachrligands For TheTreatment Of Cns Diseases

Abstract

The present invention relates to 1-aza-bicycloalkyl derivatives of formula (I) wherein the substituents are as defined in the specification, to processes for their production, their use as pharmaceuticals in the prevention and treatment of psychotic and neurodegenerative disorders. The claimed compounds act as nicotinic acelylcholine receptors (NACHR) ligands.

1 . A compound of formula I 
       
         
           
           
               
               
           
         
         wherein 
         A and B, independently of each other, represent hydrogen or C 1 -C 7 alkyl under the proviso that not both A and B can represent hydrogen at the same time, or 
         A and B together with the carbon atom to which they are attached form a C 3 -C 7 cycloalkyl group; and 
         X represents CH 2  or a single bond 
         Y represents a group of formula 
       
       
         
           
           
               
               
           
         
          wherein the left bond is attached to the oxygen and the right bond is attached to the R group; 
         R represents a substituted or unsubstituted C 5 -C 10 aryl; a substituted or unsubstituted C 5 -C 10 heteroaryl, a group N(R 1 )(R 5 ), or a group N(R 2 )(CHR 3 R 4 ); 
         R 1  representa hydrogen, C 1 -C 4 alkyl, or CF 3 ; 
         R 2  represents hydrogen, C 1 -C 4 alkyl, or CF 3 ; 
         R 3  represents hydrogen, C 1 -C 4 alkyl, or CF 3 ; 
         R 4  represents a substituted or unsubstituted C 5 -C 10 aryl or a substituted or unsubstituted C 5 -C 10 heteroaryl; 
         R 5  represents a substituted or unsubstituted C 5 -C 10 aryl or a substituted or unsubstituted C 5 -C 10 heteroaryl; 
         in free base or acid addition salt form. 
       
     
     
         2 . A compound of formula I according to  claim 1  wherein X is CH 2 . 
     
     
         3 . A compound of formula I according to  claim 1  wherein Y is a group of formula 
       
         
           
           
               
               
           
         
       
     
     
         4 . A process for the preparation of a compound of formula I as defined in  claim 1 , or a salt thereof, which comprises the step of reacting a compound of formula II
   Z-Y—R   (II)   wherein Y and R are as defined in  claim 1  and Z is a leaving group with a compound of formula III   
       
         
           
           
               
               
           
         
         and recovering the so obtained compound of formula I in free base or acid addition salt form. 
       
     
     
         5 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical. 
     
     
         6 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use in the prevention and treatment of psychotic and neurodegenerative disorders. 
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. 
     
     
         8 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the prevention and the treatment of psychotic and neurodegenerative disorders. 
     
     
         9 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for the manufacture of a medicament for the prevention and treatment of psychotic and neurodegenerative disorders. 
     
     
         10 . A method for the prevention and treatment of psychotic and neurodegenerative disorders, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form. 
     
     
         11 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use in the treatment or prevention of a disease or condition in which α7 nAChR activation plays a role or is implicated. 
     
     
         12 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the treatment or prevention of a disease or condition in which α7 nAChR activation plays a role or is implicated. 
     
     
         13 . A method for treating or preventing a disease or condition in which α7 nAChR activation plays a role or is implicated, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form. 
     
     
         14 . A product obtained according to the process of  claim 4  characterized in that (+)-trans-2-methyl-1-aza-bicyclo[2.2.2]octan-3-ol is used as starting material and Y represents pyrimidinyl or pyridazinyl. 
     
     
         15 . A product obtained according to the process of  claim 4 , characterized in that (−)-trans-2-methyl-1-aza-bicyclo[2.2.2]octan-3-ol is used as starting material and Y represents pyridinyl.