Pharmaceutical Compositions Comprising Deuterium-Enriched Perillyl Alcohol, Iso-Perillyl Alcohol and Derivatives Thereof

Abstract

The present invention, provides for a deuterium-enriched monoterpene or sesquiterpene such as perillyl alcohol, or a deuterium-enriched isomer or analog of monoterpenes or sesquiterpenes, such as isoperillyl alcohol. The present invention also provides for a deuterium-enriched derivative of a monoterpene or sesquiterpene, such as a perillyl alcohol carbamate or a deuterium-enriched derivative of an isomer or analog of a monoterpene or sesquiterpene, such as an isoperillyl alcohol carbamate. The deuterium-enriched derivative may be perillyl alcohol or isoperillyl 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 deuterium-enriched compound.

1 . A deuterium-enriched compound of Formula I or Formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein: R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  are independently selected from the group consisting of hydrogen-1 and deuterium, and at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15  and R 16  is deuterium; and wherein the abundance of deuterium is at least about 10%. 
       
     
     
         2 . The deuterium-enriched compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A deuterium-enriched perillyl alcohol or isoperillyl alcohol, wherein the abundance of deuterium is at least about 10%. 
     
     
         4 . The deuterium-enriched compound of  claim 1 , conjugated with a therapeutic agent to form a carbamate. 
     
     
         5 . A deuterium-enriched perillyl alcohol carbamate or isoperillyl alcohol carbamate, wherein the abundance of deuterium is at least about 10%. 
     
     
         6 . The deuterium-enriched compound of  claim 1 , wherein the abundance of deuterium is at least about 20% or at least about 30%. 
     
     
         7 . The deuterium-enriched compound of  claim 5 , wherein perillyl alcohol or isoperillyl alcohol is conjugated with a therapeutic agent to form a carbamate. 
     
     
         8 . The deuterium-enriched compound of  claim 4 , wherein the therapeutic agent is a chemotherapeutic agent 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. 
     
     
         9 . The deuterium-enriched compound of  claim 4 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         10 . A pharmaceutical composition comprising the deuterium-enriched compound of  claim 3 . 
     
     
         11 . The pharmaceutical composition of  claim 10 , further comprising a chemotherapeutic agent 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. 
     
     
         12 . The pharmaceutical composition of  claim 10 , further comprising a therapeutic agent selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         13 . A pharmaceutical composition comprising the deuterium-enriched compound of  claim 5 . 
     
     
         14 . A method for treating a disease in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of a deuterium-enriched perillyl alcohol, a deuterium-enriched isoperillyl alcohol, a deuterium-enriched perillyl alcohol carbamate, and/or a deuterium-enriched isoperillyl alcohol carbamate. 
     
     
         15 . A method for treating a disease in a mammal, comprising the step of administering to the mammal a pharmaceutical composition of  claim 10 . 
     
     
         16 . The method of  claim 14 , wherein the disease is cancer. 
     
     
         17 . The method of  claim 16 , wherein the cancer is a tumor of the nervous system. 
     
     
         18 . The method of  claim 17 , wherein the disease is glioblastoma. 
     
     
         19 . The method of  claim 14 , wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneously or intramuscularly. 
     
     
         20 . The method of  claim 14 , further comprising the step of treating the mammal with radiation. 
     
     
         21 . The method of  claim 20 , wherein the pharmaceutical composition is administered before, during or after radiation. 
     
     
         22 . The method of  claim 14 , further comprising the step of administering to the mammal a chemotherapeutic agent. 
     
     
         23 . The method of  claim 22 , wherein the pharmaceutical composition is administered before, during or after the administration of a chemotherapeutic agent. 
     
     
         24 . The method of  claim 22 , 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. 
     
     
         25 . The method of  claim 22 , wherein the chemotherapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         26 . The method of  claim 14 , wherein the pharmaceutical composition is administered using a nasal delivery device. 
     
     
         27 . The method of  claim 26 , wherein the nasal delivery device is selected from the group consisting of an intranasal inhaler, an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDI), a pressurized dose inhaler, an insufflator, a unit dose container, a pump, a dropper, a squeeze bottle and a bi-directional device. 
     
     
         28 . The deuterium-enriched compound of  claim 3 , conjugated with a therapeutic agent to form a carbamate. 
     
     
         29 . The deuterium-enriched compound of  claim 3 , wherein the abundance of deuterium is at least about 20% or at least about 30%. 
     
     
         30 . The deuterium-enriched compound of  claim 5 , wherein the abundance of deuterium is at least about 20% or at least about 30%. 
     
     
         31 . The deuterium-enriched compound of  claim 7 , wherein the therapeutic agent is a chemotherapeutic agent 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. 
     
     
         32 . The deuterium-enriched compound of  claim 7 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram. 
     
     
         33 . The deuterium-enriched compound of  claim 28 , wherein the therapeutic agent is a chemotherapeutic agent 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. 
     
     
         34 . The deuterium-enriched compound of  claim 28 , wherein the therapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC), temozolomide (TMZ) and rolipram.