Brain-penetrant chromone oxime derivative for the therapy of levodopa-induced dyskinesia

Abstract

The present invention provides a chromone oxime derivative of formula (I), which is a modulator of nervous system receptors sensitive to the neuroexcitatory amino acid glutamate and presents an advantageously high brain exposure upon oral administration, for the treatment or prevention of levodopa-induced dyskinesia. The present invention also provides an improved therapy of Parkinson's disease, using the chromone oxime derivative of formula (I) in combination with levodopa.

1 - 49 . (canceled) 
     
     
         50 . A method of treating or preventing levodopa-induced dyskinesia, the method comprising the administration of a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof to a subject in need thereof: 
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 50 , wherein said compound, or the pharmaceutically acceptable salt, solvate or prodrug thereof, has the (E)-configuration at the oxime group comprised in formula (I). 
     
     
         52 . The method of  claim 50 , wherein said compound, or the pharmaceutically acceptable salt, solvate or prodrug thereof, is in the form of a hydrochloride salt. 
     
     
         53 . The method of  claim 50 , wherein the method comprises orally administering said compound to said subject. 
     
     
         54 . The method of  claim 50 , wherein said subject is a human. 
     
     
         55 . A method of treating Parkinson's disease, the method comprising the administration of a compound of the following formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof: 
       
         
           
           
               
               
           
         
         in combination with levodopa or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof. 
       
     
     
         56 . The method of  claim 55 , wherein the compound of formula (I), or the pharmaceutically acceptable salt, solvate or prodrug thereof, has the (E)-configuration at the oxime group comprised in formula (I). 
     
     
         57 . The method of  claim 55 , wherein the compound of formula (I), or the pharmaceutically acceptable salt, solvate or prodrug thereof, is in the form of a hydrochloride salt. 
     
     
         58 . The method of  claim 55 , wherein the method comprises the simultaneous administration of said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         59 . The method of  claim 55 , wherein said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof are provided in a single pharmaceutical composition. 
     
     
         60 . The method of  claim 55 , wherein said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof are provided in separate pharmaceutical compositions. 
     
     
         61 . The method of  claim 55 , wherein the method comprises the sequential administration of said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof. 
     
     
         62 . The method of  claim 55 , wherein the method comprises orally administering said compound of formula (I) or the pharmaceutically acceptable salt, solvate or prodrug thereof and said levodopa or the pharmaceutically acceptable salt, solvate or prodrug thereof to said subject. 
     
     
         63 . The method of  claim 55 , wherein the method further comprises administering a levodopa decarboxylase inhibitor to said subject. 
     
     
         64 . The method of  claim 55 , wherein the method further comprises administering a catechol-O-methyl transferase (COMT) inhibitor to said subject. 
     
     
         65 . The method of  claim 55 , wherein the method further comprises administering a levodopa decarboxylase inhibitor and a catechol-O-methyl transferase (COMT) inhibitor to said subject. 
     
     
         66 . The method of  claim 63 , wherein the levodopa decarboxylase inhibitor is selected from the group consisting of carbidopa, benserazide, α-methyldopa, α-difluoromethyldopa, and pharmaceutically acceptable salts and solvates thereof. 
     
     
         67 . The method of  claim 64 , wherein the COMT inhibitor is selected from the group consisting of entacapone, tolcapone, nitecapone, opicapone, and pharmaceutically acceptable salts and solvates thereof. 
     
     
         68 . The method of  claim 55 , wherein said subject is a human.