Benzoquinoline inhibitors of vesicular monoamine transporter 2

Abstract

The present invention relates to new benzoquinoline inhibitors of vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions thereof, and methods of use thereof.

What is claimed is: 
     
         1 . A method of treatment of a VMAT2-mediated disorder comprising the administration of a therapeutically effective amount of a composition comprising compounds of structural Formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 in each compound of Formula I, R 1 -R 27  are independently selected from the group consisting of hydrogen and deuterium; 
 the composition has deuterium enrichment of at least 10% at each of the positions R 1 -R 6  in the compounds of Formula I; and 
 the positions R 7 -R 27  in the compounds of Formula I are not isotopically enriched. 
 
     
     
         2 . The composition as recited in  claim 1  wherein R 1 -R 6  each have deuterium enrichment of no less than 50%. 
     
     
         3 . The composition as recited in  claim 1  wherein R 1 -R 6  each have deuterium enrichment of no less than 90%. 
     
     
         4 . The composition as recited in  claim 1  wherein R 1 -R 6  each have deuterium enrichment of no less than 98%. 
     
     
         5 . The method as recited in  claim 1  wherein said VMAT2-mediated disorder is a chronic hyperkinetic movement disorder. 
     
     
         6 . The method as recited in  claim 5  wherein said chronic hyperkinetic movement disorder is Huntington's disease. 
     
     
         7 . The method as recited in  claim 5  wherein said chronic hyperkinetic movement disorder is chorea related to Huntington's disease. 
     
     
         8 . A method of treatment of a VMAT2-mediated disorder comprising the administration of a therapeutically effective amount of a compound having the structural formula: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein each position represented as D has deuterium enrichment of no less than about 10%. 
     
     
         9 . The compound as recited in  claim 8  wherein each position represented as D has deuterium enrichment of no less than about 50%. 
     
     
         10 . The compound as recited in  claim 8  wherein each position represented as D has deuterium enrichment of no less than about 90%. 
     
     
         11 . The compound as recited in  claim 8  wherein each position represented as D has deuterium enrichment of no less than about 98%. 
     
     
         12 . The method as recited in  claim 8  wherein said VMAT2-mediated disorder is a chronic hyperkinetic movement disorder. 
     
     
         13 . The method as recited in  claim 12  wherein said chronic hyperkinetic movement disorder is Huntington's disease. 
     
     
         14 . The method as recited in  claim 12  wherein said chronic hyperkinetic movement disorder is chorea related to Huntington's disease.