Nurr1:rxr activating compounds for simultaneous treatment of symptoms and pathology of parkinson's disease

Abstract

The invention provides a series of substituted aryl pyrimidine compounds and the use of these compounds as therapeutics to treat or prevent neurodegenerative disorders, including Parkinson's disease. Compounds of the invention are also able to treat the symptoms of such diseases and therefore represent a new treatment modality for ameliorating chronic and acute conditions. The compounds of the invention are capable of selectively potentiating the activity of the Nurr1:RXRα heterodimer, and are able to treat diseases or conditions associated with aberrant Nurr1:RXRα function. The invention further provides methods for treating neurodegenerative disorders by administration of Nurr1:RXRα activating agents.

1 .- 9 . (canceled) 
     
     
         10 . A compound of formula 1e: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein n is 0 to 2, p is 0 to 2; 
         each R 1  is independently selected from the group consisting of halogen, cyanate, isocyanate, thiocyanate, isothiocyanate, selenocyanate, isoselenocyanate, alkoxy, trifluoromethoxy, azido, cyano, nitro, hydroxy, acyl, mercapto, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 7 , —SR 7 , and —N(R 8 )R 7 ; 
         each R 2  is independently selected from the group consisting of halogen, cyanate, isocyanate, thiocyanate, isothiocyanate, selenocyanate, isoselenocyanate, alkoxy, trifluoromethoxy, azido, cyano, nitro, hydroxy, acyl, mercapto, carboxyl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 7 , —SR 7 , and —N(R 8 )R 7 ; 
         R 4  is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aryl-alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted heteroaryl-alkyl, optionally substituted heterocyclolalkyl, OR 7 , and —N(R 8 )R 7 ; 
         R 5  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl; 
         each R 7  is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aryl-alkyl, and optionally substituted heterocyclyl; and 
         each R 8  is independently selected from the group consisting of hydrogen and optionally substituted alkyl; 
         R 10  is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryl-alkyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; and 
         R 11  is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted aryl-alkyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl. 
       
     
     
         11 . The compound of  claim 10 , wherein R 4  is methyl or trifluoromethyl. 
     
     
         12 . The compound of  claim 10 , wherein R 5  is hydrogen or alkyl. 
     
     
         13 . The compound of  claim 10 , wherein n is 0 or 1, and wherein p is 0 or 1. 
     
     
         14 . The compound of  claim 10 , wherein R 4  is haloalkyl. 
     
     
         15 . The compound of  claim 10 , wherein R 4  is trifluoromethyl. 
     
     
         16 . A compound of  claim 10  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         o) 
       
       or a salt or free base thereof. 
     
     
         17 . A pharmaceutical composition comprising a compound of  claim 10  and a pharmaceutically acceptable excipient. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein said pharmaceutical composition comprises an additional therapeutically active compound. 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein said additional therapeutically active compound is selected from the group consisting of levodopa (L-dihydroxyphenylalanine), L-aromatic amino acid decarboxylase (AADC) inhibitors, and catechol O-methyl transferase (COMT) inhibitors. 
     
     
         20 . A method of treating a neurodegenerative disorder in a human, or alleviating or preventing one or more symptoms of a neurodegenerative disorder in a human, said method comprising administering to the human an effective amount of a compound of  claim 10 . 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 20 , wherein said symptom is selected from the group consisting of bradykinesia and dyskinesias. 
     
     
         23 . The method of  claim 20 , wherein said symptom is selected from the group consisting of anxiety and depression. 
     
     
         24 . The method of  claim 20 , wherein said symptom is selected from the group consisting of learning difficulties, memory disorders, and attention deficit disorder. 
     
     
         25 . The method of  claim 20 , wherein said symptom is selected from the group consisting of insomnia and katalepsy. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 20 , wherein said disorder is Parkinson's disease. 
     
     
         28 . The method of  claim 20 , wherein the effective amount is sufficient to halt or prevent degeneration of neurons. 
     
     
         29 . The method of  claim 28 , wherein said neurons are dopaminergic midbrain neurons. 
     
     
         30 . The method of  claim 20 , wherein the effective amount is sufficient to increase the rate of dopamine biosynthesis. 
     
     
         31 .- 48 . (canceled)