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 in a subject comprising administering to the subject 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%. 
       
     
     
         2 . The method as recited in  claim 1  further comprising the administration of an additional therapeutic agent. 
     
     
         3 . The method as recited in  claim 2  wherein the additional therapeutic agent is olanzapine or pimozide. 
     
     
         4 . The method as recited in  claim 2  wherein the additional therapeutic agent is a benzodiazepine or an antipsychotic. 
     
     
         5 . The method as recited in  claim 4  wherein the benzodiazepine is alprazolam, adinazolam, bromazepam, camazepam, clobazam, clonazepam, clotiazepam, cloxazolam, diazepam, ethyl loflazepate, estizolam, fludiazepam, flunitrazepam, halazepam, ketazolam, lorazepam, medazepam, dazolam, nitrazepam, nordazepam, oxazepam, potassium clorazepate, pinazepam, prazepam, tofisopam, triazolam, temazepam, or chlordiazepoxide. 
     
     
         6 . The method as recited in  claim 4  wherein the antipsychotic is chlorpromazine, levomepromazine, promazine, acepromazine, triflupromazine, cyamemazine, chlorproethazine, dixyrazine, fluphenazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine, periciazine, thioridazine, mesoridazine, pipotiazine, haloperidol, trifluperidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, fluanisone, oxypertine, molindone, sertindole, ziprasidone, flupentixol, clopenthixol, chlorprothixene, thiothixene, zuclopenthixol, fluspirilene, pimozide, penfluridol, loxapine, clozapine, olanzapine, quetiapine, tetrabenazine, sulpiride, sultopride, tiapride, remoxipride, amisulpride, veralipride, levosulpiride, lithium, prothipendyl, risperidone, clotiapine, mosapramine, zotepine, pripiprazole, or paliperidone. 
     
     
         7 . The method as recited in  claim 1 , wherein each position represented as D has deuterium enrichment of no less than about 20%. 
     
     
         8 . The method as recited in  claim 1 , wherein each position represented as D has deuterium enrichment of no less than about 50%. 
     
     
         9 . The method as recited in  claim 1 , wherein each position represented as D has deuterium enrichment of no less than about 70%. 
     
     
         10 . The method as recited in  claim 1 , wherein each position represented as D has deuterium enrichment of no less than about 80%. 
     
     
         11 . The method as recited in  claim 1 , wherein each position represented as D has deuterium enrichment of no less than about 90%.