Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists

Abstract

The present invention relates to 1-aza-bicycloalkyl derivatives of formula (I), wherein X is CH 2 or a single bond; Y is a group of formula (II, III, IV) and wherein R has the meanings as defined in the specification, which compounds are alpha 7 nicotinic acetylcholine receptor (nAChR) agonists; to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.

1 . An aza-bicycloalkyl derivative of formula I  
     
       
         
         
             
             
         
       
     
     wherein 
 X is CH 2  or a single bond;  
 Y is a group of formula  
                     
 R is a substituted or unsubstituted C 5 -C 10 aryl or substituted or unsubstituted hetero-C 5 -C 10 aryl, N(R 1 )(R 4 ), or N(R 2 )(CHR 3 R 4 );  
 each of R 1 , R 2  and R 3  is independently H, C 1 -C 4 alkyl, or CF 3 ; and  
 R 4  is a substituted or unsubstituted C 5 -C 10 aryl or substituted or unsubstituted hetero-C 5 -C 10 aryl;  
 in free base or acid addition salt form.  
 
   
   
       2 . An aza-bicycloalkyl derivative of formula I according to  claim 1  wherein 
 X is CH 2  or a single bond;    Y is a group of formula                          and    R is phenyl, naphthyl, tetrahydronaphthyl, indanyl, thienyl, benzothienyl, furanyl, benzofuranyl and isobenzofuranyl, which in each case can be unsubstituted or mono-, di- or trisubstituted by 
 halogen, cyano, formyl, acetyl, C 1 -C 3 alkoxycarbonyl, N,N-di-(C 1 -C 3 alkyl) carbamoyl, phenyl, phenoxy, methylendioxy, ethylendioxy; or  
 C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkinyl or C 1 -C 4 alkoxy, which radicals themselves can be unsubstituted or mono-, di- or trisubstituted by halogen;  
   In free base or acid addition salt form.    
   
   
       3 . An aza-bicycloalkyl derivative of formula I according to  claim 1  wherein 
 X is CH 2  or a single bond;    Y is a group of formula                          and    R is    (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy, 
 C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or  
 C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen,  
   (b) naphthyl, indanyl, tetralinyl or    (c) furanyl, benzofuranyl, isobenzofuranyl, benzothienyl or thienyl,    in free base or acid addition salt form.    
   
   
       4 . An aza-bicycloalkyl derivative of formula I according to  claim 1  wherein 
 X is CH 2  or a single bond;    Y is a group of formula                          R is    (a) phenyl which is unsubstituted or mono-, di- or trisubstituted by halogen, cyano, methylendioxy, 
 C 1 -C 4 alkyl, which is unsubstituted or mono-, di- or trisubstituted by halogen, or  
 C 1 -C 4 alkoxy, which is unsubstituted or mono-, di- or trisubstituted by halogen,  
   (b) naphthyl, or    (c) furanyl, benzofuranyl, isobenzofuranyl, or thienyl,    in free base or acid addition salt form.    
   
   
       5 . A process for the preparation of an aza-bicycloalkyl derivative 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  
     
       
         
         
             
             
         
       
     
     wherein X is as defined in  claim 1 ,  
     and recovering the so obtained compound of formula I in free base or acid addition salt form.  
   
   
       6 . The aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical.  
   
   
       7 . The aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form, for use in the prevention and treatment of psychotic and neurodegenerative disorders.  
   
   
       8 . A pharmaceutical composition comprising an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.  
   
   
       9 . The use of an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the prevention and the treatment of psychotic and neurodegenerative disorders.  
   
   
       10 . The use of an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  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.  
   
   
       11 . 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 an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form.  
   
   
       12 . An aza-bicycloalkyl derivative according to any one of  claims 1  to  4  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.  
   
   
       13 . The use of an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  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.  
   
   
       14 . 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 an aza-bicycloalkyl derivative according to any one of  claims 1  to  4  in free base or pharmaceutically acceptable acid addition salt form.