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 treating a VMAT2-mediated disorder comprising administering to a subject in need of treatment a dosage unit comprising a therapeutically effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
         or a salt or diasteromer thereof, wherein: 
         each position designed as D has deuterium enrichment above the naturally occurring distribution of deuterium; and 
         the administration results in decreased average plasma levels in the subject of at least one metabolite of said compound, as compared to administration of the corresponding non-deuterium enriched compound. 
       
     
     
         2 . The method of  claim 1 , wherein the metabolite is a deleterious metabolite. 
     
     
         3 . The method of  claim 1 , wherein the half-life of the compound is increased, as compared to the half-life of the corresponding non-deuterium enriched compound. 
     
     
         4 . The method of  claim 1 , wherein the half-life of the compound is increased by at least 5%, as compared to the half-life of the corresponding non-deuterium enriched compound. 
     
     
         5 . The method of  claim 1 , comprising administering to the subject a mixture of diastereomers of the compound. 
     
     
         6 . The method of  claim 1 , comprising administering to the subject a single diastereomer of the compound. 
     
     
         7 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 1%. 
     
     
         8 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 5%. 
     
     
         9 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 10%. 
     
     
         10 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 20%. 
     
     
         11 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 50%. 
     
     
         12 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 70%. 
     
     
         13 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than about 90%. 
     
     
         14 . The method of  claim 1 , wherein each position designed as D has deuterium enrichment of no less than 98%. 
     
     
         15 . The method of  claim 1 , wherein said VMAT2-mediated disorder is a chronic hyperkinetic movement disorder. 
     
     
         16 . The method of  claim 15 , wherein said chronic hyperkinetic movement disorder is Huntington's disease. 
     
     
         17 . The method of  claim 15 , wherein said chronic hyperkinetic movement disorder is chorea related to Huntington's disease.