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 . A tocol derivative compound comprising a chroman group and a hydrocarbon tail, the hydrocarbon tail having three isoprene units, wherein at least one isoprene unit is unsaturated between carbon 2 and 3 of the isoprene unit and wherein the second isoprene unit in the hydrocarbon tail does not include a trans carbon-carbon double bond. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein the compound has formula (I) 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein R 1 , R 3 , R 4  and R 5  are each independently —H, halogen, —OH, —OCH 3 , or a branched or unbranched, substituted or unsubstituted, saturated or unsaturated C 1 -C 20  alkyl; R 2  is an ester, —OH, —NHR 6 , —CO 2 H, —C(R 6 ) 2 CO 2 H or a branched or =branched, substituted or unsubstituted, saturated or unsaturated C 1 -C 6  alkyl; 
         R 6  is —H, halogen, —OH, or a branched or unbranched, substituted or unsubstituted, saturated or unsaturated C 1 -C 20  alkyl; 
         Y is O, S or NH; and 
         Z is a hydrocarbon side chain having 1 to 3 carbon-carbon double bonds and represented by formula (II) 
       
       
         
           
           
               
               
           
         
         wherein the numerals represent the numbering of the carbons in the chain, wherein the dotted lines between carbons 1′, 2′, 3′, 4′ and 16′, and between 15′, 8′, 9 10′, 11′, 12′, 13′, and 14′ represent a position for an optional carbon-carbon bond and the dotted line between carbon 7′ and 8′ represent a single bond, a cis carbon-carbon double bond or a cyclopropyl group including both carbon 7′ and 8′ and an additional carbon not shown in formula II. 
       
     
     
         5 . The compound 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 compound of  claim 4 , wherein Z includes two double bonds. 
     
     
         7 . The compound of  claim 6 , wherein Z includes a double bond between the 3′ and 4′ carbons. 
     
     
         8 . The compound of  claim 4 , wherein Z includes a cis double bond between the 7′ and 8′ carbons. 
     
     
         9 . The compound of  claim 8 , wherein Z includes three double bonds. 
     
     
         10 . The compound of  claim 4 , wherein Z includes a cyclopropyl group including the 7′ and 8′ carbons. 
     
     
         11 . The compound of  claim 10 , wherein Z has one of the two following structures: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein the compound is a racemic mixture of stereoisomers. 
     
     
         13 . The compound of  claim 1 , wherein either isomer is in enantiomeric excess of over 50% the compound is over 80% in the RS structure. 
     
     
         14 . The compound of  claim 4 , wherein R 2  is an ester selected from —O(CO)CH 3 , —O(CO)heterocyclic, O(CO) carbocyclic, —O(CO)(R 7 )COOH, —O(CO)R 8 , wherein R 7  is selected from a branched or unbranched, saturated or unsaturated, substituted or unsubstituted C 1 -C 20  alkyl and R 8  is selected from —H, and a branched or unbranched, saturated or unsaturated, substituted or unsubstituted C 1 -C 20  alkyl. 
     
     
         15 . The compound of  claim 4 , wherein R 2  is —OH and wherein R 5  is —H. 
     
     
         16 . (canceled) 
     
     
         17 . The compound of  claim 4 , wherein R 1 , R 3  and R 4  are all CH 3 . 
     
     
         18 . The compound of  claim 4 , wherein R 3  and R 4  are CH 3  and R 1  is H. 
     
     
         19 . The compound of  claim 4 , wherein R 1  and R 4  are CH 3  and R 3  is H. 
     
     
         20 . The compound of  claim 4 , wherein R 1 , R 3  and R 4  are H. 
     
     
         21 . The compound of  claim 1 , wherein the hydrocarbon tail allows farnesyl recognition. 
     
     
         22 . The compound of  claim 1 , wherein the hydrocarbon tail confers HMGCoA reductase inhibition activity. 
     
     
         23 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         24 . A method of treating a subject comprising administering an effective amount of a composition comprising the compound of  claim 1  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 inn unoregulatory 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.