Deuterium Substituted Fumarate Derivatives

Abstract

Provided is a compound of formula (I): or a pharmaceutically acceptable salt thereof. Also provided is a method of activating the Nrf2 pathway, comprising contacting cells with a sufficient amount of a compound of formula (I) described herein. Also provided is a method of treating a neurodegenerative disease, comprising administering to a subject in need of treatment for the neurodegenerative disease an effective amount of a compound of formula (I) described herein.

1 . A compound of formula (I) 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 each of R 1  and R 2 , independently, is hydrogen, deuterium, deuterated methyl, deuterated ethyl, C 1-6  aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 
 each of R 3  and R 4 , independently, is hydrogen or deuterium, provided that the compound of formula (I) contains at least one deuterium atom and that R 1  and R 2  are not hydrogen at the same time. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is hydrogen or —CH 3 . 
     
     
         3 . The compound of  claim 2 , wherein R 2  is —CH 2 D, —CHD 2 , or —CD 3 . 
     
     
         4 . The compound of  claim 1 , wherein R 1  is —CD 3 . 
     
     
         5 . The compound of  claim 4 , wherein R 2  is —CH 2 D, —CHD 2 , or —CD 3 . 
     
     
         6 . The compound of  claim 1 , wherein at least one of R 3  and R 4  is deuterium. 
     
     
         7 . The compound of  claim 6 , wherein both of R 3  and R 4  are deuterium. 
     
     
         8 . The compound of  claim 6 , wherein R 2  is hydrogen, —CH 3 , —CH 2 D, —CHD 2 , or —CD 3 . 
     
     
         9 . The compound of  claim 1 , wherein R 1  is —CD 2 CD 3 . 
     
     
         10 . The compound of  claim 9 , wherein R 2  is H, —CH 3 , —CH 2 D, —CHD 2 , or —CD 3 . 
     
     
         11 . A compound of formula (I) wherein the compound is ( 2 H 6 )dimethyl fumaric acid ester, ( 2 H 3 )methyl fumaric acid ester, ( 2 H 3 )dimethyl fumaric acid ester, or dimethyl fumaric(2,3- 2 H 2 ) acid ester. 
     
     
         12 . A method of activating the Nrf2 pathway, comprising contacting cells with a sufficient amount of a compound of  claim 1 . 
     
     
         13 . A method of treating a neurodegenerative disease, comprising administering to a subject in need of treatment for the neurodegenerative disease an effective amount of a compound of  claim 1 . 
     
     
         14 . The method of  claim 13 , wherein the neurodegenerative disease is MS, ALS, Parkinson's disease, Huntington's disease, or Alzheimer's disease.