Tetrahydrocarbazole Inhibitors Of SIRT1 Receptors

Abstract

Described are deuterium-substituted tetrahydrocarbazole compounds of Formulae I, II, or III which are inhibitors of sirtuin 1 (SIRT1). Also described are pharmaceutical compositions comprising the deuterium-substituted tetrahydrocarbazole compounds, and methods of use thereof.

What is claimed is: 
     
         1 . A method of treating a SIRT1-mediated disorder comprising administering a therapeutically effective amount of a compound of Formula III to a patient in need thereof, wherein the compound of Formula III is: 
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof, wherein:
 R 1 -R 7  are, independently, hydrogen or deuterium; 
 at least one of R 1 -R 7  is deuterium; and 
 at least one of R 1 -R 7  has deuterium enrichment of no less than about 10%. 
 
     
     
         2 . The method of  claim 1 , wherein the disorder is Huntington's disease. 
     
     
         3 . The method of  claim 1 , further comprising administering an additional therapeutic agent to the patient. 
     
     
         4 . The method of  claim 3 , wherein the additional therapeutic agent is a drug for treating an abnormal involuntary movement, a drug for treating a movement disorder, a drug for treating multiple sclerosis, an antipsychotic, an antidepressant, or a mood stabilizer. 
     
     
         5 . The method of  claim 3 , wherein the additional therapeutic agent is laquinimod. 
     
     
         6 . The method of  claim 1 , wherein the disorder is an autoimmune disease. 
     
     
         7 . The method of  claim 6 , wherein the autoimmune disease is multiple sclerosis. 
     
     
         8 . The method of  claim 1 , wherein the disorder is an inflammatory disease. 
     
     
         9 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are deuterium. 
     
     
         10 . The method of  claim 1 , wherein R 7  is deuterium. 
     
     
         11 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are deuterium. 
     
     
         12 . The method of  claim 1 , wherein at least one of R 1 -R 7  has deuterium enrichment of no less than about 50%. 
     
     
         13 . The method of  claim 1 , wherein at least one of R 1 -R 7  has deuterium enrichment of no less than about 90%. 
     
     
         14 . The method of  claim 1 , wherein at least one of R 1 -R 7  has deuterium enrichment of no less than about 98%. 
     
     
         15 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof. 
     
     
         16 . The method of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt, prodrug, or solvate thereof. 
     
     
         17 . The method of  claim 16 , wherein each position represented as D has deuterium enrichment of no less than about 10%. 
     
     
         18 . The method of  claim 17 , wherein each position represented as D has deuterium enrichment of no less than about 50%. 
     
     
         19 . The method of  claim 18 , wherein each position represented as D has deuterium enrichment of no less than about 90%. 
     
     
         20 . The method of  claim 19 , wherein each position represented as D has deuterium enrichment of no less than about 98%.