Pharmaceutical compositions comprising perillyl alcohol derivatives
A pharmaceutical composition is provided which includes perillyl alcohol conjugated with a therapeutic agent and further includes and a hydrolyzable acylated aliphatic tail. A method of using the pharmaceutical composition is also provided for treating a condition or disease of a patient, e.g., cancer.
1. A compound of the Formula I;
wherein R is selected from the group consisting of a C 4 to C 28 linear or branched alkyl, linear or branched C 4 to C 28 alkeneyl and a linear or branched C 4 to C 28 alkynyl group; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein R is a C 4 to C 28 linear or branched alkeneyl containing 1, 2, 3, 4 or 5 double bonds or a linear or branched C 4 to C 28 alkynyl group containing 1, 2, 3, 4 or 5 triple bonds.
3. The compound according to claim 1 of the Formula II;
or a pharmaceutically acceptable salt thereof.
4. A method of treating melanoma in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of the compound according to claim 1 , 2 or 3 .
5. The method of claim 4 , wherein the compound is administered topically.
6. A pharmaceutical composition comprising a compound according to claim 1 , 2 or 3 .
7. A compound of the Formula III;
wherein R 1 is selected from a C 4 to C 28 linear or branched alkyl, linear or branched C 4 to C 28 alkeneyl or a linear or branched C 4 to C 28 alkynyl group; or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 wherein R 1 is a C 4 to C 28 linear or branched alkeneyl containing 1, 2, 3, 4 or 5 double bonds or a linear or branched C 4 to C 28 alkynyl group containing 1, 2, 3, 4 or 5 triple bonds.
9. The compound according to claim 7 of the Formula IV; or a pharmaceutically acceptable salt thereof
10. A pharmaceutical composition comprising a compound according to claim 7 , 8 or 9 .
11. A process for making a compound of the Formula I
comprising the steps of
a) reacting Temozolamide with oxalyl chloride in a halogenated solvent to give the isocyanate of Temozolamide Formula A
b) reacting the isocyanate of Temozolamide with perillyl alcohol in a halogenated solvent to afford a compound of Formula B
c) reacting the compound of Formula B with an acid chloride of the Formula C
wherein R is selected from the group consisting of a C 4 to C 28 linear or branched alkyl, linear or branched C 4 to C 28 alkeneyl containing 1, 2, 3, 4, or 5 double bonds or a linear or branched C 4 to C 28 alkynyl group; containing 1, 2, 3, 4 or 5 triple bonds in the presence of a base in an ethereal solvent to afford a compound of the Formula I.
12. The process according to claim 11 wherein the halogenated solvent is 1,2 dichloroethane.
13. The process according to claim 11 wherein the acid chloride is linoleic acid chloride.
14. The process according to claim 11 wherein the base is NaH.
15. The process according to claim 11 wherein the ethereal solvent is THF.