Pharmaceutical compositions comprising poh derivatives

Abstract

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.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a perillyl alcohol carbamate. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the perillyl alcohol carbamate is perillyl alcohol conjugated with a therapeutic agent. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the therapeutic agent is a chemotherapeutic agent. 
     
     
         4 . The pharmaceutical composition of  claim 3 , 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. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is administered before, during or after radiation. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is administered before, during or after the administration of a chemotherapeutic agent. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly. 
     
     
         9 . 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. 
     
     
         10 . 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. 
     
     
         11 . 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. 
     
     
         12 . A method for treating a disease in a mammal, comprising the step of delivering to the mammal a therapeutically effective amount of a perillyl alcohol carbamate. 
     
     
         13 . The method of  claim 12 , wherein the disease is cancer. 
     
     
         14 . The method of  claim 13 , wherein the cancer is a tumor of the nervous system. 
     
     
         15 . The method of  claim 14 , wherein the tumor is a glioblastoma. 
     
     
         16 . The method of  claim 12 , further comprising the step of treating the mammal with radiation. 
     
     
         17 . The method of  claim 12 , further comprising the step of delivering to the mammal a chemotherapeutic agent. 
     
     
         18 . The method of  claim 12 , wherein the perillyl alcohol carbamate is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly. 
     
     
         19 . The method of  claim 12 , wherein the perillyl alcohol carbamate is perillyl alcohol conjugated with a therapeutic agent. 
     
     
         20 . The method of  claim 19 , wherein the therapeutic agent is a chemotherapeutic agent. 
     
     
         21 . The method of  claim 20 , 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. 
     
     
         22 . The method of  claim 19 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         23 . The method of  claim 12 , wherein the perillyl alcohol carbamate 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. 
     
     
         24 . 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. 
     
     
         25 . The process of  claim 24 , wherein the second reactant is dimethyl celocoxib. 
     
     
         26 . The process of  claim 25 , wherein the reaction is carried out in the presence of acetone and a catalyst of potassium carbonate. 
     
     
         27 . The process of  claim 24 , wherein the second reactant is rolipram. 
     
     
         28 . The process of  claim 27 , wherein the reaction is carried out in the presence of tetrahydrofuran and a catalyst of n-butyl lithium. 
     
     
         29 . The process of  claim 24 , wherein the perillyl chloroformate is prepared by reacting perillyl alcohol with phosgene.