2,4-Thiazolidinedione Derivatives in the Treatment of Central Nervous System Disorders

Abstract

The present invention provides 5-(4-(2-(5-(1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione and novel stereoisomers of said compound for use in the treatment of central nervous system (NS)disorders.

1 - 27 . (canceled) 
     
     
         28 . A method of reducing the risk of developing or reducing the recurrence of a central nervous system disorder, comprising administering to a subject in need thereof a dosage form comprising an effective amount of a compound of formula (1) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein the central nervous system disorder is selected from the group consisting of a neurodegenerative disease, a neuroinflammatory disease, and a traumatic brain injury. 
       
     
     
         29 . The method according to  claim 28 , wherein the compound of formula (1) is:
 compound (2): (R)-5-(4-(2-(5-((R)-1-hydroxvethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;   compound (3): (R)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;   compound (4): (S)-5-(4-(2-(5-((R)-1-hydroxyethylpyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione; or   compound (5): (S)-5-(4-(2-(5-((S)-1-hydroyethyl)pyridine-2-yl)ethoxy)benzy)thiazolidine-2,4-dione;   or a pharmaceutically acceptable salt thereof.   
     
     
         30 . A method of reducing the risk of developing or reducing the recurrence of a central nervous system disorder, comprising administering to a subject in need thereof an effective amount of a mixture of two or more compounds selected from the group consisting of
 compound (2): (R)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;   compound (3): (R)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione:   compound (4): (S)-5-(4-(2-(5-((R)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione; and   compound (5): (S)-5-(4-(2-(5-((S)-1-hydroxyethyl)pyridine-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione;   or a pharmaceutically acceptable salt thereof,   wherein the central nervous system disorder is selected from the group consisting of a neurodegenerative disease, a neuroinflammatory disease, and a traumatic brain injury.   
     
     
         31 . The method according to  claim 30 , wherein the mixture comprises
 (a) said compound (2) and said compound (3), or a pharmaceutically acceptable salt thereof; or   (b) said compound (4) and said compound (5), or a pharmaceutically acceptable salt thereof; or   (c) said compound (2) and said compound (4), or a pharmaceutically acceptable salt thereof; or   (d) said compound (3) and said compound (5), or a pharmaceutically acceptable salt thereof.   
     
     
         32 . (canceled) 
     
     
         33 . The method according to  claim 28 , wherein the central nervous system disorder is a neurodegenerative disease. 
     
     
         34 . The method according to  claim 33  wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), leukodystrophy, degenerative ataxia, multiple system atrophy, and a motor neuron disease. 
     
     
         35 . The method according to  claim 34 , wherein the neurodegenerative disease is a leukodystrophy, wherein said leukodystrophy is adrenoleukodystrophy (ALP or X-ALD). 
     
     
         36 - 38 . (canceled) 
     
     
         39 . The method according to  claim 34 , wherein the neurodegenerative disease is Parkinson's disease, multiple sclerosis, or ALS. 
     
     
         40 . The method according to  claim 34 , wherein the neurodegenerative disease is a degenerative ataxia, wherein said degenerative ataxia is Friedreich's ataxia. 
     
     
         41 . The method of  claim 34 , wherein the neurodegenerative disease is a motor neuron disease selected from the group consisting of progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis (PLS), progressive muscular atrophy, spinal muscular atrophy (SMA), post-polio syndrome (PPS)-Marie-Tooth disease, Guillan-Barré syndrome, and adrenomyeloneuropathy (AMN). 
     
     
         42 . The method according to  claim 30 , wherein the central nervous system disorder is a neurodegenerative disease. 
     
     
         43 . The method according to  claim 42 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Huntington's chorea, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, leukodystrophy, degenerative ataxia, multiple system atrophy, and a motor neuron disease. 
     
     
         44 . The method according to  claim 43 , wherein the neurodegenerative disease is leukodystrophy or degenerative ataxia, wherein said leukodystrophy and said degenerative ataxia are adrenoleukodystrophy (ALD or X-ALD) and Friedreich's ataxia, respectively. 
     
     
         45 . The method according to  claim 28 , wherein no more than 1% of the total number of hydrogen atoms per mole of the compound of formula (1) are in the form of the  2 H isotope. 
     
     
         46 . The method according to  claim 28 , wherein the compound of formula (1) is administered to the subject in an oral dosage form. 
     
     
         47 . The method according to  claim 46 , wherein the oral dosage form is a solid oral dosage form, an oral solution, or an oral suspension. 
     
     
         48 . The method according to  claim 46 , wherein the oral dosage form is selected from the group consisting of tablets, capsules, pills and granules. 
     
     
         49 . The method according to  claim 28 , wherein the dosage form is suitable for topical, epicutaneous, subcutaneous, transdermal, intramuscular, parenteral, ocular, rectal, vaginal, inhalation, buccal, sublingual, or intranasal delivery. 
     
     
         50 . The method according to  claim 30 , wherein no more than 1% of the total number of hydrogen atoms per mole of each of the two or more compounds in the mixture are in the form of the  2 H isotope. 
     
     
         51 . The method according to  claim 30 , wherein the mixture is optically active.