[(1h-indol-5-yl) - heteroaryloxy] - (1-aza-bicyclo [3.3.1] nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders

Abstract

The present invention relates to 1-aza-bicycloalkyl derivatives of Formula (I) wherein the substituents are as defined in the specification and to processes for their production to pharmaceutical compositions comprising them and to their use in the manufacture of a medicament for the treatment and/or delay of progression of psychotic and nemodegenerative disorders.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 X represents hydrogen or hydroxyl and 
 Y represents one of the following groups: 
 
       
         
           
           
               
               
           
         
       
       in free base or acid addition salt form. 
     
     
         2 . A compound according to  claim 1 , wherein the compound is (4S,5R)- 4- [5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane. 
     
     
         3 . A compound according to  claim 1 , wherein the compound is 5-{2-[(4S,5R)-(1-Aza-bicyclo[3.3.1 ]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indol-2-one. 
     
     
         4 . A compound according to  claim 1 , wherein the compound is (4S,5R)- 4- [6-(1H-Indol-5-yl)-pyrimidin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane. 
     
     
         5 . A compound according to  claim 1 , wherein the compound is (4S,5R)- 4- [5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane. 
     
     
         6 . A compound according to  claim 1 , wherein the compound is (4S,5R)- 4- [6-(1H-Indol-5-yl)-pyrimidin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane. 
     
     
         7 . A compound according to  claim 1 , wherein the compound is 5-{6-[(4S,5R)-(1-Aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazine-3-yl}-1,3-dihydro-indol-2- one. 
     
     
         8 . A process for preparation of a compound of formula (I) according to  claim 1  comprising the steps of i) reacting a compound of formula (IX) 
       
         
           
           
               
               
           
         
       
       wherein Y is as defined above and z represents a leaving group with a compound of formula (X) 
       
         
           
           
               
               
           
         
       
       where R represents H, C 1 -C 4 alkyl or both RO represent together with the B to which they are attached a heterocyclic moiety, X is as defined above, and
 ii) recovering the so obtained compound of formula (I). 
 
     
     
         9 . A process for preparation of a compound of formula (I) according to  claim 1  comprising the steps of
 i) reacting a compound of formula (XI) 
 
       
         
           
           
               
               
           
         
       
       with a compound of formula (XII) 
       
         
           
           
               
               
           
         
       
       wherein X and Y are as defined above and PG is a suitable protecting group,
 ii) subsequent deprotection of the so obtained compound and 
 iii) recovering the so obtained compound of formula (I) in free base or acid addition salt form. 
 
     
     
         10 . The compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use as a pharmaceutical. 
     
     
         11 . The compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use in the prevention, treatment and/or delay of progression of psychotic and neurodegenerative disorders. 
     
     
         12 . 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. 
     
     
         13 . 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. 
     
     
         14 . 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, treatment and/or delay of progression of psychotic and neurodegenerative disorders. 
     
     
         15 . A method for the prevention, treatment and/or delay of progression 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. 
     
     
         16 . A compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, for use in the prevention, treatment and/or delay of progression of a disease or condition in which nAChR α7 activation plays a role or is implicated. 
     
     
         17 . The use of a compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form, as a pharmaceutical for the prevention, treatment and/or delay of progression of a disease or condition in which nAChR α7 activation plays a role or is implicated. 
     
     
         18 . A method for treating or preventing a disease or condition in which nAChR α7activation 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 compound of  claim 1  in free base or pharmaceutically acceptable acid addition salt form. 
     
     
         19 . A combination comprising:
 a compound of formula (I)   
       
         
           
           
               
               
           
         
       
       wherein
 X represents hydrogen or hydroxyl and 
 Y represents one of the following groups: 
 
       
         
           
           
               
               
           
         
       
       as the first active ingredient and
 a second therapeutic compound as the second active ingredient, 
 wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt. 
 
     
     
         20 . The combination of  claim 19 ,
 wherein the second active ingredient is selected from the group consisting of benzodiazepines, selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), conventional antipsychotics, atypical antipsychotics, buspirone, carbamazepine, oxcarbazepine, gabapentin, and pregabalin.