Tocopherol derivatives and methods of use

Abstract

Tocol derivative compounds, compositions comprising these tocol derivatives and methods of using the tocol derivatives are provided herein. Specifically the tocol derivatives have a partially unsaturated hydrocarbon tail and are thus distinct from the tocopherols. The hydrocarbon tails do not have a trans carbon-carbon double bond in the second isoprene unit of the hydrocarbon tail and are distinct from the tocotrienols. The compounds are expected to allow improved interaction with the α-tocopherol transfer protein receptor than the tocotrienols and better bioactivity than the tocopherols.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . A composition comprising a compound of formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein R 1 , R 3 , and R 4  are selected from —H and —CH 3 ; R 5  is selected from —H and —CH 3 ; 
         R 2  is —OH; 
         Y is O; and 
         Z is a hydrocarbon side chain having 1 to 2 carbon-carbon double bonds and represented by formula (II) 
       
       
         
           
           
               
               
           
         
         wherein the numerals represent the numbering of the carbons in the chain, wherein the 1 to 2 carbon-carbon double bond is located between carbons 3′ and 4′, between carbons 11′ and 12′ or between both carbons 3′ and 4′ and carbons 11′ and 12′. 
       
     
     
         5 . The composition of  claim 4 , wherein the Torsion A angle between carbons 5′, 6′, 7′, and 8′ of the hydrocarbon tail of formula II and the Torsion B angle between carbons 6′, 7′, 8′, and 9′ of the hydrocarbon tail of formula II can adopt conformations between 30° and 90°. 
     
     
         6 . The composition of  claim 4 , wherein Z includes two double bonds. 
     
     
         7 . The composition of  claim 6 , wherein Z includes a double bond between the 3′ and 4′ carbons. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . The composition of  claim 4 , wherein the compound is over 80% in the RS structure. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . The composition of  claim 4 , wherein R 5  is —H. 
     
     
         17 . The composition of  claim 4 , wherein R 1 , R 3  and R 4  are all —CH 3 . 
     
     
         18 . The composition of  claim 4 , wherein R 3  and R 4  are —CH 3  and R 1  is —H. 
     
     
         19 . The composition of  claim 4 , wherein R 1  and R 4  are —CH 3  and R 3  is —H. 
     
     
         20 . The composition of  claim 4 , wherein R 1 , R 3  and R 4  are —H. 
     
     
         21 . The composition of  claim 4 , wherein the hydrocarbon tail allows farnesyl recognition. 
     
     
         22 . The composition of  claim 4 , wherein the hydrocarbon tail confers HMGCoA reductase inhibition activity. 
     
     
         23 . A pharmaceutical composition comprising the compound of  claim 4  and a pharmaceutically acceptable carrier. 
     
     
         24 . A method of treating a subject comprising administering an effective amount of the composition of  claim 23  to the subject. 
     
     
         25 . The method of  claim 24 , wherein the subject is in need of treatment with an antioxidant agent, an anti-inflammatory agent, an immunoregulatory agent, an anti-thromobotic agent, an anti-atherogenic agent, a hypocholesterolemic agent or an HMG-CoA reductase inhibitor. 
     
     
         26 . The method of  claim 24 , wherein the subject has a condition selected from the group consisting of radiation exposure, cancer, cardiovascular disease including but not limited to coronary artery disease, decreasing lipoprotein levels, decreasing cholesterol levels, decreasing triglycerides, age-related macular degeneration, cataracts, glaucoma, chronic pain, chronic fatigue syndrome, fever, edema, diabetes mellitus, signs of aging, rheumatoid diseases, septic shock, and Alzheimer's disease. 
     
     
         27 . The composition of  claim 4 , wherein R 5  is —CH 3 . 
     
     
         28 . The composition of  claim 4 , wherein R 1  and R 3  are —H and R 3  is —CH 3 .