Pharmaceutical compositions comprising POH derivatives
The present invention provides for a derivative of monoterpene or sesquiterpene, such as a perillyl alcohol derivative. For example, the perillyl alcohol derivative may be a perillyl alcohol carbamate. The perillyl alcohol derivative may be perillyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agent. The present invention also provides for a method of treating a disease such as cancer, comprising the step of delivering to a patient a therapeutically effective amount of a derivative of monoterpene (or sesquiterpene). The route of administration may vary, and can include, inhalation, intranasal, oral, transdermal, intravenous, subcutaneous or intramuscular injection.
1. A pharmaceutical composition comprising a compound comprising perillyl alcohol conjugated with a chemotherapeutic agent with a carbamate linkage.
2. The pharmaceutical composition of claim 1 , wherein the chemotherapeutic agent is selected from the group consisting of a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, and a receptor antagonist.
3. The pharmaceutical composition of claim 1 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.
4. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is administered before, during or after radiation.
5. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is administered before, during or after the administration of another chemotherapeutic agent.
6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.
7. The pharmaceutical composition of claim 1 , wherein the perillyl alcohol carbamate is 4-Bis-N,N′-4-isopropenyl cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide.
8. The pharmaceutical composition of claim 1 , wherein the perillyl alcohol carbamate is 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester.
9. The pharmaceutical composition of claim 1 , wherein the perillyl alcohol carbamate is 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.
10. A method for treating a tumor of the central nervous system in a mammal, comprising the step of delivering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising a compound comprising perillyl alcohol conjugated with a chemotherapeutic agent with a carbamate linkage.
11. The method of claim 10 , wherein the tumor is a glioblastoma.
12. The method of claim 10 , further comprising the step of treating the mammal with radiation.
13. The method of claim 10 , further comprising the step of delivering to the mammal a chemotherapeutic agent.
14. The method of claim 10 , wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly.
15. The method of claim 10 , wherein the chemotherapeutic agent is selected from the group consisting of a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, and a receptor antagonist.
16. The method of claim 10 , wherein the chemotherapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.
17. The method of claim 10 , wherein the compound comprising perillyl alcohol conjugated with a chemotherapeutic agent with a carbamate linkage is selected from the group consisting of (a) 4-(bis-N,N′-4-isopropenyl cyclohex-1-enylmethyloxy carbonyl [5-(2,5-dimethyl phenyl)-3-trifluoromethyl pyrazol-1-yl] benzenesulfonamide; (b) 4-(3-cyclopentyloxy-4-methoxy phenyl)-2-oxo-pyrrolidine-1-carboxylic acid 4-isopropenyl cyclohex-1-enylmethyl ester; and (c) 3-methyl 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbonyl)-carbamic acid-4-isopropenyl cyclohex-1-enylmethyl ester.
18. A process for making a POH carbamate, comprising the step of reacting a first reactant of perillyl chloroformate with a second reactant selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.
19. The process of claim 18 , wherein the second reactant is dimethyl celocoxib.
20. The process of claim 19 , wherein the reaction is carried out in the presence of acetone and a catalyst of potassium carbonate.
21. The process of claim 18 , wherein the second reactant is rolipram.
22. The process of claim 21 , wherein the reaction is carried out in the presence of tetrahydrofuran and a catalyst of n-butyl lithium.
23. The process of claim 18 , wherein the perillyl chloroformate is prepared by reacting perillyl alcohol with phosgene.