Utility of (+) epicatechin and their analogs

Abstract

The present invention pertains to the enhanced activity of (+) epicatechin over (−) epicatechin. The present invention is related to novel analogs of (+) epicatechin of the formula (I), which enhances the pharmacokinetics and therefore the pharmacodynamics of (+) epicatechin. The present invention is related to analogs of (+) epicatechin of the formula (I). The general structure of the analogs of the present invention may be represented by Formula (I): Formula (I) wherein A and B are independently OR1 and C and D are independently OH; wherein R1 is independently C1 to C10 lower straight or branched chain acyclic or cyclic alkyl, or is selected from the group comprising, hydroxy butyric acid, dichloroacetic acid; phenyl butyric acid; valproic acid.

1 .- 7 . (canceled) 
     
     
         8 . A method for treating a disease or a disorder associated with Electron Transport Chain, comprising administering to a subject in need thereof a therapeutically effective amount of (+)-epicatechin or an analog of (+) epicatechin of Formula (I), 
       
         
           
           
               
               
           
         
         wherein A and B are independently OR 1  and C and D are independently OH, or B is OR 1  and A, C and D are independently OH; wherein R 1  is independently C 2  to C 10  lower straight or branched chain acyclic or cyclic alkyl, or —C(═O)—(C 6 -C 9  alkyl), or, taken together with the oxygen to which it is attached, is selected from the group consisting of hydroxybutanoate, dichloroacetate, phenyl butanoate, phenyl propionate, and 2-propylpentanoate. 
       
     
     
         9 . The method of  claim 8 , wherein B is OR 1  and A, C and D are independently OH. 
     
     
         10 . The method of  claim 8 , wherein A and B are independently OR 1  and C and D are independently OH. 
     
     
         11 . The method of  claim 8 , wherein R 1 , taken together with the oxygen to which it is attached, is selected from the group consisting of hydroxybutanoate, dichloroacetate, phenyl butanoate, phenyl propionate, and 2-propylpentanoate. 
     
     
         12 . The method of  claim 8 , wherein R 1  is —C(═O)—(C 6 -C 9  alkyl). 
     
     
         13 . The method of  claim 8 , wherein the analog of (+) epicatechin is selected from the group comprising:
 i. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl octanoate;   ii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl octanoate;   iii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxychroman-5,7-diyl dioctanoate;   iv. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl heptanoate;   v. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl heptanoate;   vi. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxychroman-5,7-diyl diheptanoate;   vii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl decanoate;   viii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl decanoate;   ix. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxychroman-5,7-diyl bis(decanoate);   x. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxychroman-5,7-diylbis(2-propylpentanoate);   xi. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl 2-propylpentanoate;   xii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl 2-propylpentanoate;   xiii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxy-5-((3-phenylpropanoyl)oxy)chroman-7-yl 4-phenylbutanoate;   xiv. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl 3-phenylpropanoate;   xv. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl 4-phenylbutanoate;   xvi. (2S,3S)-2-(3,4-dihydroxyphenyl)-3-hydroxychroman-5,7-diyl bis(2,2-dichloroacetate);   xvii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,7-dihydroxychroman-5-yl 2,2-dichloroacetate; and   xviii. (2S,3S)-2-(3,4-dihydroxyphenyl)-3,5-dihydroxychroman-7-yl 2,2-dichloroacetate.   
     
     
         14 . The method of  claim 8 , wherein the disease or the disorder is associated with Electron Transport Chain, complex IV. 
     
     
         15 . The method of  claim 8 , wherein the disease or the disorder is selected from the group consisting of impaired cognition, a neurodegenerative disease, dystonia, sarcopenia, cardiomyopathy of aging or other diseases associated with mitochondrial dysfunction, ischemic vascular disease, immunodeficiency states, ataxia, pulmonary inflammation and fibrosis, infantile encephalomyopathy, epilepsy, Charcot-Marie-Tooth disease, exocrine pancreatic insufficiency, impaired wound healing, and growth of cancer cells. 
     
     
         16 . The method of  claim 15 , wherein the neurodegenerative disease is Alzheimer's or Leigh syndrome. 
     
     
         17 . The method of  claim 8 , wherein the (+)-epicatechin is free of catechin and other isomers of epicatechin.