WO2013119304A2 - Pharmaceutical compositions comprising deuterium-enriched perillyl alcohol, iso-perillyl alcohol and derivatives thereof - Google Patents

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.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING PEOTE HJ -EN.RICHEP PERILLYL ALCOHOL. ISO-PERILLYL ALCOHOL AND DERIVATIVES THEREOF

Cross Reference to Related Applications

This application claims priority to U.S. Provisional Application No. 61/562,105 (filed on

November 21, 201 ! }, and U.S. Application No, 13/566,73! (filed on August s, 2012), each of which is incorporated herein b reference in its entirety.

Field of the Invention

The present invention relates to deuterium-enriched periliyl alcohol (POH), deuterium nriched isoperiilyl alcohol (iso-POH) and derivatives thereof.

Background of the Invention

Malignant gliomas, the most common form of central nervous system (CMS) cancers, are currently considered essentially incurable. Among the various malignant gliomas, anaplastic astrocytomas (Grade ill) and glioblastoma multiforme (GBM; Grade IV) have an especialiy poor prognosis due to their aggressive growth and resistance to currently available therapies. The present standard of care for malignant gliomas consists of surgery, ionizing radiation, and chemotherapy. Despite recent advances in medicine, the past 50 years have not seen any significant improvement in prognosis for malignant gliomas. Wen et ai Malignant gliomas in adults, New England J Med„ 359: 92-507, 2008. Stapp et a!., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England_, J_Med._;. 352: 987-996, 2005.

The poor response of tumors, including malignant gliomas, to various types of chemotherapeutic agents is often due to intrinsic drug resistance. Additionally, acquired resistance of initially well-responding tumors and unwanted side effects are other problems that Irequeoily ihwart long-term treatment using chemotherapeutic agents. Periliyl alcohol (POH), a naturally occurring monoterpene, has been suggested to be an effective agent against a variety of cancers, including CNS cancer, breast cancer, pancreatic cancer, lung cancer, melanomas and colon cancer. Gould, M., Cancer chemopreven ion and therapy by monoterpenes, Environ. Health Perspeet. 1997 June; 105 (Supp! 4); 977 --979. Hybrid molecules containing both periliyl alcohol and retinoids were prepared to increase apoptosis-indueirig activity. Das et ah. Design and synthesis of potential new apoptosis agents: hybrid compounds containing periilyl alcohol and new constrained retinoids, Tetrahedron Letters 2010, 51 , 1462-4466..

However, POH is rapidiv metabolized. In order to improve performance over periilyl alcohol and its derivatives, e.g., rising a lower dose, there is a need to prepare deuterated forms of peri!lyl alcohol, including isomers or analogs, such as perriilyi alcohol or isoperiS !yl alcohol conjugated with other therapeutic agents, and use this material in the treatment of cancers such as malignant gliomas, as well as other brai disorders such as Parkinson's and Alzbeiraer's disease.

The present disclosure provides for a deutenum--ennched compound of Formula or Formula H

F rmula I Formula liar a pharmaceutically acceptable salt thereof; hemn: R_X, R₂, R.$, A, ¾, ¾» R7, Rs, R¾ Rio, Ru, t2, i¾ ¾ > ¾s a d , are iadependemly selected from the group consisting of hydrogen--

I and deuterium, and at least one of ;., f¾, ¾, R4, R ¾ R?, R*_> R¾ R-o, R\ Ru-, Rn, Rw, and R.;6 is deuterium.

For example, the demermm-enricied com may be the one of the following.

The present disclosure provides far s deuterium-enriched perillyl alcohol or isoperiil.y.1 alcohol,

The present deuterium-enriched compounds maybe conjugated with a therapeutic agent to form a carbamate. The present disclosure also provides tor a deuterium-enriched perillyl alcohol carbamate or isoperiliyi alcohol carbamate. For example, perillyl alcohol or isoperiliyl alcohol is conjugated with a therapeutic agent to form a carbamate. The therapeutic agent may be a chemotherapeuiic agent, including, but not limited to, a DMA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, a enzyme inhibitor, and. a receptor antagonist. For example, the therapeutic agent can be dimethyl ce!oeoxtb (D C), temo o!omide (TMZ or rolipram.

in the deuterium-enriched compound, the abundance of deuterium may be at least about 10%, at least about 20% or at least about 30%.

The present disclosure also provides for a pharmaceutical composition comprising the present deuterium-enriched compound. The pharmaceutical composition may further comprise a ehemoiherapeutic agent selected from the group consisting of a D A alkylating agent, a topoisosnera.se inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, and a receptor antagonist. For example, the

pharmaceutical composition may further comprise a therapeutic agent such as dimethyl celocoxib (DMC), te ozoiomide (TMZ) and rolipram.

The present disclosure further provides for a method for treating a disease in a mammal, comprising the step of administering to the mammal a therapeuticall effective amount of a deuterium-enriched perillyl alcohol, a deuterium-enriched isoperiliyl alcohol, s deuterium- enriched perillyl alcohol carbamate, and/or a deuterium-enriched isoperiliyl alcohol carbamate. The present disclosure provides for a method for treating a disease in a mammal, comprising the step of adttitnislering to the mamma! a pharmaceutical composition disclosed in the present disclosure.

The methods may further comprise the step of treating the mammal with radiation, and/or th step of administering to th mamma! a chemotherapeuiic agent. The pharmaceutical composition or deuterium-enriched, compound may be administered before, during or after radiation and/or the administration of a cheraomerapeutie agent. The chemotherapeuttc agent may be a DNA alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enzyme inhibitor, or a receptor antagonist. For example, the chemotherapeutic agent may be dimethyl celocoxib (DMC), temozolomide (TMZ) or rolipram.

The disease may be cancer, such as a tumor of the nervous system (e.g., glioblastoma).

The pharmaceutical composition or deuterium-enriched compound may be administered by inhalation, infratiasaliy, orally, intravenously, subcutaneously or intramuscularly.

The pharmaceutical composition or deuterium-enriched compound may he administered using a nasal delivery device, such as an intranasal inhaler, an intranasal spray device, an atomizer, a nebulizer, a metered dose inhaler (MDff a pressurized dose inhaler, an insufflator, a unit dose container, a pump, a dropper, a squeeze bottle and a bi-directional device.

Detailed Description of the Invention

The present invention pro ides for deuterium-enriched compounds and pharmaceutical compositions comprising the deuterium-enriched compounds. Specifically, the present invention provides for deuterium-enriched monoterpenes or sesquiterpenes (e.g., deuterium-enriched perillyl alcohol) and deuterit i-enrkhed isomers or analogs of monoterpenes or sesquiterpenes (e.g., deuterium-enriched isoperiliyl alcohol).

The present invention also provides for deuterium-earkhed derivatives of monoterpenes or sesquiterpenes, such as a deuterium-enriched perillyl alcohol derivative. For example, the deuterium-enriched periHyl alcohol derivative may be a deuterium-enriched perillyl alcohol carbamate. The perillyl alcohol derivative may be perillyl alcohol conjugated with a. therapeutic agent such as a chemotherapetitic agent.

The present invention further provides for deuterium-enriched derivatives of isomers or analogs of monoterpenes or sesquiterpenes, such as a deuterium-enriched isoperiliyl alcohol derivative. For example, the deuterium-enriched isoperiliyl. alcohol derivative ma be a deuterium-enriched isoperiliyl alcohol carbamate. The isoperiliyl alcohol derivative may be isoperiliyl alcohol conjugated with therapeutic agent, such as a chemotherapeutie agent.

Also encompassed by the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a deuterium-enriched compound of the present invention (or a pharmaceutical ly acceptable salt thereof) and a pharmaceutically acceptable carrier.

The invention provides for .methods of using the deuterium-enriched compounds or the pharmaceutical compositions to treat a disease, such as cancer or other nervous system disorders. The compounds or pharmaceutical compositions of the present invention may be administered alone, or in combination with radiation, surgery or chemotherapeutie agents. The deuterium- enriched molecule may also be co-administered with antiviral agents, anti-inilammatoiy agents or antibiotics. The agents may be administered concurrently or sequentially. The compounds of the present invention can be administered before, during or after the administration of the other acti ve agent(s).

One of ordinary skill in the art recognizes that in alt chemical compounds with an H atom, the E atom represents a mixture of ^!0 (hydrogen- 1 , proiium) and D (deuterium, hydrogen- 2, Ή), with about 0,015% being D. Thus., a deuterium-enriched compound (or a deuterated compound) has a level of deuterium greater than its natural abundance of 0,015%, As used herein, all percentages given for the abundance of deuterium are mole percentages.

The isomer or analog of nionoterpene or sesquiterpene can be an isoperillyi alcohol (iso- POH). Isoperillyi alcohols include any isomers or analogs of peri!!yl alcohol. In one embodiment, the isoperillyi alcohol is (4-isopropyhdene cyclohex- b-enyi)niethanoL Other examples of isoperillyi alcohol include, but are not limited to, (4~isopropyl eyclohex.a~L3~ dienyl)meihanoL (4-isopropyl cyclohexa~l .4-dienyl)meihanoL (4-isopropylphenyl)meihanoI and (4-isopfopenylpheny!_.in ethanol,

The present invention provides for deuterium-enriched isoperillyi alcohol where the compound is enriched, with deuterium in at least one position, in one embodiment, the deisteri«ra-e?mched isoperillyi alcohol is represented by Formula I shown below;

ormula 1 or a pharmaceutically acceptable salt thereof; wherein: R_{, R;₅ R_Sf R,_$, R_;. R_{;. R_?, §, R_¾ Rio., Rn_< Ri2, Ru_> R«_> ;.? and R½ are independently selected from, the group consisting of hydrogen-! (^!H) and deuterium; and at least one of Ru R₂, ¾, R₄, R_¾ ¾_> R?_> Rs, R>, RK>, R», }2, B_> ^₅ R.i? and R_Si; is deuterium..

Non-limitirsg examples of the deuterium-ennched isoperillyi alcohol are illustrated as follows.

The deuterium-enriched isoperillyi alcohol may be prepared by oxidation of commercially sourced perillyl alcohol or isoperillyi. alcohol followed by reduction of the o dised intermediates using de ieriioK-enricbed hydride reducing agents or by use of deuterohydrogen gas with a suitable catalyst or by other means.

The present invention provides for deuterium-enriched perillyl alcohol wherein the compound is enriched with deuterium in at least one position. In one embodiment, the deuterium-enriched perillyl. alcohol is represented by Formula I 1 , shown below.

f ormula or a pharmaceutically acceptable salt thereof; wherein; ¾ , ¾. 8.3, 4, ¾ R<;, R¾ R«_÷ ¾, Ru>, RH_> R.t2_> Rts, t4₅ -s and ½ are independently selected tram tine group consisting of hydrogen- 1 (¾) and deuterium; an at least one of Rn R?_> R,*_> ¾, R$, R«, R?_< 9, Rm_> Rn_> ¾ ?._> Ri.i_> Rw_> Ris and Rjft is deuterium.

Non-limiting examples of the deutetium-enriched perillyl alcohol are illustrated, as fol ows.

The term "is/are deuterium," when used to describe a given position in a molecule such as R_t, ¾ j, , *_> R?, R», RK>, n, i¾_> Rj* RSS and R^ or the symbol "D " when used to represent a g ves position in. a drawmg of a . molecular structure, means that the specified position is enriched with deuterium greater than its natural abundance of 0.015%,

The term "abundance of deuterium" herein refers to the mole percentage of incorporation of deuterium (IX or ~H) at a given position in a. molecule in the place of hydrogen, for example, tine abundance of deuterium of about 6% at a given positron means that about 6% of molecules in a given sample contain deuterium at the specified -position.

The abundance of deuterium in the present deuterium-enriched, compound may be at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, about 0.5% to about 1 0% , about 1 % to about 1 0%, about 5% to about 100%, about 6% t about 100%, about 7% to about 100%, about 1 % to about 100%, about 20% to about 1 0%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 1 0%, about 80% to about 1 0%, or about 90% to about 100%. Deuterium enrichment can be determined using analytical methods, such as mass spectrometry, nuclear magnetic resonance spectroscopy and infrared spectrometry, m one embodiment, deuterium enrichment is determined by ¾ NM . The deuterium-enriched peril!yl alcohol of the present invention may h synthesized with deuterium incorporated in place of hydrogen a toms. For example, the deuterium may be incorporated in place of hydrogen atoms at the carbinol side chain where metabolic: degradation takes place in vivo. The deuterium atoms retard or slow down the metabolic processes when compared with the rate of metabolism for conventional perillyl alcohol or isoperiliyi alcohol. Without being limited to any specific physiologic mechanism, it is believed that this slow-down is due to the kinetic isotope effects at the active site of perillyl alcohol dehydrogenase enzyme. Deuterium can also be incorporated at a number of different centers in the molecule, in an embodiment, deuterium is incorporated at the carbinol moiety where 1, 2 or 3 deuterium atoms can be incorporated in plac e of hydrogen atoms to give any of the isotopic analogs of perillyl alcohol or isoperiliyi alcohol.

Because of its slower metabolism, the deuterated forms of perillyl alcohol or isoperiliyi alcohol will demonstrate significant improvement in the therapeutic effectiveness as compared with conventional non-deuterated material. The deuterium-enriched compounds described herein may contain one or more deuterium atoms. The compounds may be partially or fully deuterated. Any chemical compound described herein may be deuterium-enriched.

Monoterpenes include terpenes that consist of two isoptene units. Monoterpenes may be linear (acyclic) or contain rings. Derivatives of monoterpenoids are also encompassed by the present invention. Monoterpenoids maybe produced by biochemical modifications such as oxidation or rearrangement of monoterpenes. Examples of monoterpenes and monoterpenoids include, perillyl alcohol (S(-)) and (R( )), ocimene, myrcene. geranioL citral, citxoneliol, citronelial, linalooi, puisne, terpineof terpinen, iiraooene, terphienes, phellandrenes, terpinolene, tcrpinen-4-ol (or tea tree oil), pmene, terpiiieol, terpinen; the terpenoids such as /?~cynieoe which is derived from monocyclic terpenes such as menthol, thymol and carvacroJ; bicyclic monoterpenoi&s such as camphor, bonieol and eucal ptol,

Monoterpenes may be distinguished by the structure of a carbon skeleton and may be grouped into acyclic rooriOterpenes (e.g., myrcene, (Z|- and (E)-Qcmiene, linaiool, geraniol, n rol, ch onellol, myrcenol, geranial, eitral a, neral, eitral b, citronellal, etc.), monocyclic monoterpenes (e.g., limonene, terpmene, phellandrene, terpinolene, menthol, carveol, etc.), bicyclic monoterpenes (e.g., phiene, myrtenol, myrtenaL verbanol, verbanon, .pinocarveol, carene, sabinene, caniphene, thujene, etc.) and tricyclic monoterpenes (e.g. iricyclene). See Encyclopedia of Chemical Technology, Fourth Edition, Volume 23, page 834-835,

A specific example of a monoterpene is perillyl alcohol (FOR).

Sesquiterpenes of the present invention include terpenes that consist of three isoprene units. Sesquiterpenes may be linear (acyclic) or contain rings. Derivatives of sesquiterpenoids are also encompassed by the present invention. Sesquiterpenoids ma be produced by biochemical modifications such as oxidation or rearrangement of sesquiterpenes. Examples of sesquiterpenes include famesol, farnesal, farnesylie acid and nerolidol. PCX Application Nos. PCT/OS201 1/027051 and PCT/US2 1 1/049392. U.S. Application No, 13/040,059. All these applications are incorporated herein by reference in their entirety.

The present invention also provides for deuterium-enriched derivatives of monoterpenes or sesquiterpenes, such as a deuterium-enriched perillyl alcohol derivative. For example, the deuterium-enriched perillyl alcohol derivati e may be a deuterium-enriched perillyl alcohol carbamate. The perillyl alcohol derivative may he perillyl alcohol, conjugated with a therapeutic agent such as a chemotherapeutic agent.

Tile present invention further provides for deuterium-eniiehed derivatives of isomers or analogs of monoterpenes or sesquiterpenes, such as a deuterium-enriched isoperiiiyl alcohol derivative. For example, the deuterium-enriched isoperiiiyl alcohol derivative ma be a deuterium-enriched isoperiiiyl alcohol carbamate. The perillyl alcohol derivative may be isoperiiiyl alcohol conjugated with a therapeutic agent such as a chemotherapeutic agent.

The derivatives ma be deuterated at any desired atom position, including the atom positions of perillyl alcohol or isoperiiiyl alcohol, as well as the atom positions of the therapeutic agent conjugated with the perillyl alcohol or isoperiiiyl ale oho i. A deuterium-enriched compound can be prepared by, e.g., exchanging hydrogens with deuterium, or synthesizing the compound with deuteiium-enriched starting materials or intermediates. In one embodiment, deuterium can be introduced by deuterium-contaiouig reagents including, but not limited to, lithium aluminium deuteride, deuterium gas or other reagents. In another embodiment, depending on the desired sites of deuteration, deiitermm from i¾0 can be exchanged directly into finished drug compounds or into reagents that are used to synthesize drug molecules.

The deuterated derivatives of monoterpene or sesquiterpene (or deuterated. derivatives of isomers or analogs of monoterpene or sesquiterpene) include, but are not limited to, carbamates, esters, ethers, alcohols and aldehydes of the monoterpene or sesquiterpene (or of isomers or analogs of monoterpene or sesquiterpene). The present invention also provides for derivatives and conjugates of a deuterium enriched periilyl alcohol or isoperiHyl alcohol

Derivatives include, but are not limited to, carbamates, esters, ethers, alcohols and aldehydes of a monoterpene or sesquiterpene (e.g., POH), or of the isomer or analog of a monoterpene or sesquiterpene (e.g ., iso-POH). Alcohols may be derivatized to carbamates, esters, ethers, aldehydes or acids.

Carbamates refer to a class of chemical compounds sharing the functional group

based on a carbonyl group flanked by an oxygen and a nitrogen, R\ R² and R^'' can be a group such as alk i, aryl, etc., which can be substituted. The R groups on the nitrogen and the oxygen may form a ring. ^l-OH may be a monoterpene, e.g., POH or iso-POH. The R²-N-R^~ moiety may be a therapeutic agen t.

Carbamates may be synthesized, by reacting isocyanate and alcohol, or by reacting chloroformate with amine. Carbamates may be synthesized by reactions makin use of phosgene or phosgene equivalents. For example, carbamates may be synthesized by reacting phosgene gas, diphosgene or a solid phosgene precursor such as triphosgene with two amines or an amine and an alcohol. Carbamates (also known as urethanes) can also be made from reaction of a urea intermediate with, an alcohol. Dimethyl carbonate and dipheayi carbonate are also used for making carbamates. Alternatively, carbamates may be synthesized through the reaction of alcohol and/or amine precursors with an ester-substituted diary! carbonate, such as

bisn ethylsalicylcarbonate (BMSC). U.S. Patent Publication No. 201001 13819.

Carbamates may be synthesized by the following approach:

K -OH R . . ^:; . ·;■· R ; N H ~ Carbamate

Suitable reaction solvents include., but are not limited to, tetrahydrofhran, didilororoethane,, dic oroetbane, acetone, and diisopropyl ether. The reaction maybe performed at a temperature ranging from about -70^WC to about 80^1>C, or from about -65^1>C to about 30^1>C. The molar ratio of isoperillyl c oroformate (or perillyl ehioro formate) to the substrate R™ N¾ may range from about 1 : 1 to about 2:1, from about 1 : Ϊ to about 1,5: 1 , from about 2: 1 to about 1 : 1, or from about 1.05: 1 to about IJ : 1. Suitable ^'bases include, but are not limited, to, organic bases, such as triethylamme, potassium carbonate, N,N⁵-diisopropyl&&)yiamme, butyl lithium, and potassinm-t- butoxide.

Alternatively, carbamates may be synthesized by the following approach:

Suitable reaction solvents include, but are not limited to, dichloromethane, dkhloroet ane, toluene, diisopropy! ether, and tetrahydrofurau. The reaction may be performed at a temperature ranging from about ZS^C to about 1 !C C, or from, about 30*C to about 80^i!C, or about 5 °C. The molar ratio of isoperillyl. alcohol to the substrate R-^'NOO may range from about .1 : 1, to about 2:1 , from about 1 : 1 to about I..5: .1 , from about.2: 1 to about .1 : . , or from about . .05: .1 to about I ! : i . Esters of a monoterpene or sesquiterpene alcohol, or esters of the alcohol of the isomers or analogs of a monoterpene or sesquiterpene, can be deri ved f om an inorganic acid or an organic acid, inorganic acids include, but are not limited to, phosphoric acid, sulfuric acid, and nitric acid. Organic acids include, but are not limited to, carboxyiic acid suc as benzoic acid, tatty acid, acetic acid and propionic acid, and any therapeutic agent bearing at least one carboxyiic acid functional group. Examples of the esters of alcohols include, but are not limited to, carboxyiic acid esters (such as benzoate esters, fatty acid esters (e.g., palmitate ester, hnoleate ester, stearate ester, butyryi ester and oleate ester), acetates, propionates (or propanoates), and formates), phosphates, sulfates, and carbamates (e.g., N,N-dimethylajininocarbonyi).

I^'he derivatives of perillyl alcohol include, peril lyl alcohol carbamates, peril!yi alcohol esters, perillie aldehydes, dihydroperillie acid, peril! ic acid, periUic aldehyde derivatives, dihydroperiiiic acid esters and perillie acid esters. The derivatives of perillyl alcohol may also include its oxidative and nucleophilic/eiectrophilic addition derivatives, U.S. Patent Publication No. 20090031455. U.S. Patent Nos. 6,133,324 and 3,957,856.

The derivatives of isoperillyl alcohol include isoperillyl alcohol carbamates, isoperiily! alcohol esters, isoperiily! alcohol ethers, isoperiilic aldehydes, isoperiilic acid, isoperiilic aldehyde derivatives, and isoperiilic acid esters. The derivatives of isoperiily i alcohol may also include its oxidative and nttcleophiHc/electrophiKc addition derivatives. Few examples of derivatives of isoperillyl alcohol are reported in the chemistry literature. See U.S. Patent No, 5,994,598 and Japanese Patent No. 0 048264A,

In certai embodiments, a POH carbamate (or an iso-POH carbamate) is synthesized by a process comprising the step of reacting a first reactant of perillyl chloroformate (or isoperiily! chloroformate) with a second reactant such a dimethyl ceiocoxib (DMC), temozolomide (TMZ) and roli ram. The reaction may be carried out in the presence of telrahydrofuran and a base such as n-butyl lithium. Perillyl chloroformate (or isoperillyl chloroformate) may be made by reacting POH (or iso-POH) with phosgene. For example, POH (or iso-POH) conjugated with

teraozolomide through a carbamate bond may be synthesized by reacting teraozolomide with oxalyl chloride followed by reaction with perillyl alcohol (or iso-POH). The reaction may be carri d out in the presence of 1 ,2-dichloroethane. POH carbamates encompassed, by the present invention include, but not limited to, 4-this- .N '-4-isapropenyl cyclohex-l -enylmethyloxy carbonyl [5-(2.5~d.imethyi phenyl)-3~

trifliioromethyl pyrazoi- 1 -yl] enzenesullonam.ide, -(3-cydopentyloxy-4-methoxy phenyl)-2- oxo-pyrro idine- i -carboxy!ic acid 4-isopropenyl cyciohex- i -enylmethy! ester, and (3-rnethyl 4- oxo-3,4-dihydiOimidazo 5, 1 -d)[ 1 ,2,3 ,5 jtetra iae-8-carbooy}}carbainic acid-4-isopropenyl.

cyclohex-l -eny!merhyl ester.

Iso-POH carbamates encompassed by the present invention include, but are not limited to, (3-Methyl 4-oxo-3,4-dihydroimidazo|5J -d|il,2,3,5]tetrazine-S-carbony])-cai"bamic acid -4- isopropylidene cyciohex- 1 -enylmethy! ester, 4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-oxo- pyrrolidine-] -carhoxyiic acid 4-isopropySidene cyclohex-l -enylmethyl ester, 4-(Bis-N, ^,-4- isopropyiidene cyciohex- 1 -eny!methyloxy carbonyl i5-(2,5-diraethyl phenyl)-3-trifluoromethy! pyrazol-l -yfj benzenesalfonamide. The details of the chemical reactions generating these compounds are described in the Examples below.

In certain embodiments, peril!yl alcohol derivatives may be peril!yl alcohol fatty acid esters, such as palmitoyi ester of POH and linoleoyl ester of POH; iso-perillyl alcohol derivatives may be isoperiiiyl alcohol fatty acid, esters, such as palmitoyi ester of iso-POH and linoleoyl ester of iso-POH.

The deuterium-enriched perillyl alcohol or isoperiiiyl alcohol may also be conjugated with other therapeutic moieties such as anti-cancer agents (such as temozolomide) by means of carbamate or other chemical linkage between the deuterated isoperiiiyl alcohol moiety and the other therapeutic moiety with net therapeutic advantage compared with either moiety or both moieties in their own right.

Tile monoterpene (or sesquiterpene) derivative may be a monoterpene (or sesquiterpene) conjugated with a therapeutic agent. A monoterpene (or sesqaiierpene) conjugate encompassed by the present in vention is a molecule having a monoterpene (or sesquiterpene) covalently bound via a chemical linking group to a therapeutic agent.

Tile derivative of an isomer or analog of monoterpene or sesquiterpene may be an isomer or analog of monoterpene or sesquiterpene conj ugated with a therapeutic agent. A conjugate encompassed b the present in vention may be a molecule having an isomer or analog of monoterpene or sesquiterpene covalently bound via a chemical linking group to a therapeutic agent.

The molar ratio of the monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) to the therapeutic agent in the conjugate may be 1 : 1 , t :2, 1 :3, ί :4, 2: 1, 3: 1 , 4: 1 , or any other suitable molar ratios. The monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) and the therapeutic agent may be covalently linked through carbamate, ester, ether bonds, or any other suitable chemical functional groups. When the monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesqifiterpene) and the therapeutic agent are conjugated through a carbamate bond, the therapeutic agent may be any agent bearing at least one carboxylic acid functional group, or any agent bearing at least, one amine functional group. In a specific example, a perillyl alcohol (or an iso-FOH conjugate is periiiyj alcohol (or iso-POH) covalently bound via a chemical linking group to a

chemotherapeutic agent. According to the present invention, the therapeutic agents that may be conjugated with a monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) include, but are not limited to, chemotherapeutic agents, therapeutic agents for treatment of CMS disorders (including, without limitation, primary degenerati e neurological disorders such as Alzheimer^'s, Parkinson's, multiple sclerosis, Attention-Deficit Hyperactivity Disorder or

ADHD, psychological disorders, psychosis and depression), immunotherapeutic agents, angiogenesis inhibitors, and anti-hyperten ive agents. Anti-cancer agents that may be conjugated with a monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) can have one or more of the following effects on cancer cells or the subject: cell death; decreased cell proliferation; decreased numbers of cells; inhibition of cell growth;

apoptosis; necrosis; mitotic catastrophe; cell cycle arrest; decreased ceil size; decreased cell division; decreased cell survival; decreased cell metabolism; markers of cell damage or

cytotoxicity; indirect indicators of cell damage or cytotoxicity such as tumor shrinkage;

improved survival of a subject; or disappearance of markers associated with undesirable, unwanted, or aberrant cell proliferation. U.S. Patent Publication No. 20080275057,

Chemotherapeutic agents include, but are not limited to, DNA alkylating agents, iopoisomerase inhibitors, endoplasmic reticulum stress inducing agents, a platinum compound, an antimetabolite, vineaikaloids, taxan.es, epothilones, enzyme inhibitors, receptor antagonists, tyrosine kinase inhibitors, boron .mdlosensitizers (i.e. velcade), and chemotherapeutic

combination therapi es .

Non-limitiitg examples of D A alkylating agents are nitrogen mustards, such as

Cyclophosphamide (Ifosfam de, Trofosiamide), Chlorambucil (Melphalan, Predru.raustine), Bendamiistine, Uramustme and Estramitstine: nitrosoureas, such as Carrmtstine (BCNU),

Loraustine (Semustine), Fote.raust.ine, Nimustine, Ranimustine and Streptozocin; alkyl

sulfonates, such as Busulfan (Mannosuifan, Treosulfan); Aziridines, such as Carboquone, Triaziquone, Iriethylenemel amine; Hydrazines {Procarbazine}; Triazenes such as Dacarbazine and Temozoto ide; Altretamine and Mitobron tol.

Non-limiting examples of Topoisomerase I inhibitors include Campothecin deri vatives including SN-38, ARC, NPC, campothecin, topotecan, exatecao mesylate, 9-nitrocamptothecin, 9-aminocamptothecm, iiirtoteean, rubifeean, siiatecan, gimatecan, diflomotecan, exfatecan, BN- 80927, DX-8951f, and MAG-CPT as decribed in Pommier Y. (2006) Nat. Rev. Cancer

6(10):789~802 and U.S. Patent Publication No. 200510250854; Protoberberine alkaloids and derivatives thereof including berberrubine and coralyne as described in Li et at (2000)

Biochemistry 39(24}:7107~71 16 and Gatto et al. (1996) Cancer Res. 15(I2):2795~280G;

PhenanthroHne derivatives including Benzo[i]phenanthridine, Nitidine, and fagaronine as described in Makhey et al. (2003) Bioorg . Med. Chem . 11 (8): 1809-1820; Terbenzimidazole and derivatives thereof as described in Xu (1998) Biochemistry 37(10) : 3558 ~3566 ; and

AnthracycHne derivatives including Doxorubicin, Daunorubkin, and Mitoxantrone as described in. Foglesong et al. (1992)

30(2):123~]2S, Crow et al. (1994) I

Med. Chem. 37( 1 ): 3.1 131 4, and Crespi et a!. ( 1 86) Bjochem._. Bio h s-_^Res. _Corpmun._. ! 36(2):52.I -8. Topoisomerase II inhibitors include, but are not limited to Etoposide and

Teniposide. Dual topoisomerase 1 and 11 inhibitors include, but are not limited to, Saintopin and other Naphtheeenediones, DACA and other Acridine-4-Carboxamindes, Intoplicine and oilier Benzopyridoindoles, TAS-J03 and other 7 -indeno 2,i-cjQuinoiine-7-ones, Pyrazoloacri dine, XR 1 ! 576 and other Benzophenazines, XR. 5944 and other Dimeric compounds, 7-oxo-71:l~ dibenzlfjjjlsoqiiinolines and 7-oxo-?H-benzo[e]pyri.raidmes, and Anthracenyl-amino Acid Conjugates as described in Denny and Bagnley (2003) Curr. Top. Med. Chem. 3( : 339-353. Some agents inhibit Topoisomerase 11 and have DNA intercalation activity such as, but not limited to, Antfaracyclines (Aclarubicm, !Daunarubicin, Doxorubicin, Epirubicia, Idarubictn, Amrubicin, Pirarubicin, Vairubicin, Zorubicin) and Antracenediones (Mitoxantione and

Pixantrone).

Examples of endoplasmic reticulum stress inducing agents include, but are not limited to, dimefhyl-celecoxib (KMC), nelf aavir, celecoxib, and boron radiosensitizers (i.e. veteade (Bortezomib)).

Platinum based compounds are a subclass of DNA alkylating agents. Non-limiting examples of such agents include Cisplatin, Nedaplatin, Oxaliplatin, Triplatin tetranitrate,

Satraplatin, Aroplatin, Lobapiatin, and J^'M-21 . (see McKeage et al. (1 97) J, Clin. Oncol. 201 :1232-1237 and m general, CHEMOTHERAPY FOR GYNECOLOGICAL NEOPLASM, CURRENT THERAPY AND NOVEL APPROACHES, in the Series Bask and Clinical

Oncology, Angioli et al. Eds., 2004).

"FOLFOX" is an abbreviation for a type of combination therapy that is used to treat colorectal cancer. It includes 5-FU, oxaliplatin and leiieovorm. information regarding this treatment is available on the National Cancer Institute's web site, cancer.gov, last accessed on January 16, 2008,

"FOLFOX/BV" is an abbreviation for a type of combination therapy that is used to treat colorectal cancer. This therapy includes 5-FU, oxaliplatin, ieucovorin and Bevacizumab.

Furtbennore, "XELO.X/BV" is another combination therapy used to treat colorectal cancer, which includes the prodrug to 5-FU, .known as Capeeitabine (.Xeloda) in combination with oxaliplatin and bevacizumab. Infonnation regarding these treatments are available on the National Cancer institute's web site, cancer.gov or from 23 the National Comprehensive Cancer Network's web site, iiccn.org, last accessed on May 27,2008,

Non-limiting examples of antimetabolite agents include Folic acid based, i.e.

dihydrofblate reductase inhibitors, such as Aminopterin, Methotrexate and Pemetrexed;

thymidylate synthase inhibitors, such as Raltitrexed, Pemetrexed; Purine based, i.e. an adenosine deaminase inhibitor, such as Pentostatin, a thiopur ine, such as Thioguanine and Mercaptopurine, a halogenated ribonucleotide reductase inhibitor, such as Cladribine, Ciofarabine, Fiudarabme, or a guanine/ guanosine: thiopurine, such as Thioguanine; or Pyriraidine based, i.e..

cytosine/eytidine: hypomethyiating agent, such as Azacitidine and Deeitabme, a DNA polymerase inhibitor, such as Cytarabine, a ribonucleotide reductase inhibitor, such as Gemcitabine, or a thymine/thymidioe: thymidylate synthase inhibitor, such as a Fiuorouracil (5-

FU). Equivalents to 5-FU include prodrugs, analogs and deri vati ve thereof such as 5* -deoxy-5- uorouridine (doxifluroidine), l-tetrah drofuran i-5-i uoiouiacil (ftorafur), Capecitabine

(Xeloda), S-l (MBMS-247616, consisting of tegafur and two modulators, a 5-chloro-2_<4- dihydroxypyridifte and potassium oxonate), ralitkrexed (tomudex), nolatrexed (Thymkaq,

AG337), LY23.15.14 and ZD9331 , as described for example in Papamicheal { .1 99} The

Oncologist 4:478-487.

Examples of vincalkaloids include, but are not limited to Vinblastine, Vincristine,

Vinf unine, Vindesine and Vinoreibine.

Examples of ta anes include but are not limited to docetaxei, Larotaxel Ortataxei,

Paciitaxel and Tesetaxel, An example of an epomilone is iabepilone.

Examples of enzyme inhibitors include, but are not limited to famesy!transferase

inhibitors (Tipiiaraib); CDK inhibitor f Alvocidib, Seliciclib); proteasome inhibitor

(Bor ezomib); phosphodiesterase inhibitor (Anagrelide; rolipram); IMP dehydrogenase inhibitor (Tiazofurine); and lipoxygenase inhibitor (Masoproco!). Examples of receptor antagonists include, but are not. limited, to ERA (Atrasentan); retinoid X receptor (Bexarotene}; and a sex steroid (Testolactone).

Examples of tyrosine kinase inhibitors include, but are not hmited to inhibitors to ErbB:

HERl/EGF (Eriot ib, Geiitmib, Lapatintb, Vandetamb, Sunitinib, Neratinih); HER2/neu

(Lapatinib, eratimb); RTK ciass 111: C-kit (Axitinib, Sunitinib, SorafeiiibK FLT3 (Lesiaurtinib).

PDGFR (Axitinib, Sunitinib, Sorafenib); and VEGFR (Vandetanib, Sernaxanib, Cediranib,

Axitinib, Sorafenib); bcr-abl (tmatinib, Nilotinib, Dasatinib); Sre {Bosutimb) and Janus kinase 2

(Lesta rtinib).

"Lapatmib" (Tykerb®) is a dual EGFR and erbB~2 inhibitor. Lapatinib has been investigated as an anticancer monotherapy, as well as in combination with trastuzumab,

capecitabine, letrozole, paciitaxel and FOLFIRI (irinoteean, 5-tluorouracil and leucovorin), in a number of clinical trials. It is currently i n phase 111 testing for the oral treatment of metastatic breast, head and neck, lung, gastric, renal and bladder cancer,

A chemical, equivalent of lapatinib is a smal l .molecule or compound that is a tyrosine kinase inhibitor (TK1) or alternati vel a HBR-I inhibitor or a HER -2 inhibitor. Several T is have been found to have effective antitumor activity and have been approved or are in clinical trials. Examples of such include, but are not limited to, Zactima (ZD6474), Iressa (get nib), imatinih mesylate (ST.I571 ; Gleevec), er!o&nih (OS i- 1774; Tarceva}, eanertinib (CI 1033), semaxinib (SU5416), vataiamb (PT 7$7/ZK2225$4)₅. sorafeaib (BAY 43- 9006), sutenU SUl 124$) and lefltmomide (SUlOl).

PT /ZK is a tyrosin kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth facto (PDGF) receptor, c-KIT and e-Fms, Drevs (2003) rugs 6(8):787-794. PTK/ZK is a targeted drug that blocks angiogeaesis and lymphangiogenesis by inhibitin the activiiv of all known receptors that bind VEGF including VEGFR-1 (Flt- 1 ), VEGFR-2 (KDR/F!k-1) and VEGFR -3 (Flt-4 . The chemical names of PTK/ZK are l-[4-Chloroani].ino]-4-[4-pyridylmethyl] phthalaztne Succinate or 1 -

Phthalazinamine, N-(4 hlofC^heayl)-4-(4-pyridiaylmet yl)-butanedtoate (1: 1 }. Synonyms and analogs of PT /T are known as Vatalanib, CGP7 787D, PTK787/ZK 222584, CGP-79787, DE-00268, PTK-787, PTK787A, VEGFR-T inhibitor, ZK 222584 and ZK.

Cherootherapeuiie agents that can be conjugated with a monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) may also include arnsacrine, Trabeetedin, retinoids (Alitretmoin, Tretinoin), Arsenic trioxide, asparagine depieter Asparaginase

Pegaspargase), Celecoxib, Demecolcine, Elesclomol, Elsamitrucin, Etoglocid, Lonidaniine, Lucanthone, Mitoguazone, Mitotane, Oblimersen, Tenrsirolimus, and Vorinostat

A monoterpene or sesquiterpene (or an isomer or analog of monoterpene or

sesquiterpene) ma be conjugated with angiogeaesis inhibitors. Exampl es of angiogeaesis inhibitors include, but are not limited to, angiosfatio, angiozynie, antithrombm III, AG3340, VEGF inhibitors, baiimastat, bevacizumab (avastin), BMS-27529^'ί, CAi, 2C3, HuMV833

Canstatin, Capiopril, earboxyamidotriazole, cartilage derived inhibitor (GDI), CC-50I , 6-0- (diloroacetyl-carbonyl)-fumagilloi , COL-3, combretastatin, combretastatin A4 Phosphate, Dalteparin, EMD 1 21 74 (Cilengitide), endostatm, eriotinib, gefitinib (Iressa), genistem, haiofuginone hydrobrornide, Idl , Id3.. IM862, iroatinib mesylate, IMC-1C1 1 Inducible protein 10, mterferoa-alpha, interleukin 12, lavendustin A, LY3I7615 or AE-941 , marimastat, mspin, medroxpregesterotie acetate, Metis- 1 , Meth-2, 2-methoxyestradiol (2-ME). tieovastat, oteopontiti cleaved product, PEX, pigment epithelium growth factor (PEGF), platelet factor 4, prolactin fragment, proiiferin-related protein (PRP), PTK787/ZK 222584, ZD6474, recombinant human platelet, factor 4 (rPF4), restin, squalamine, SU545 , SU6668, SIJI 1248 suramin, Taxoi, Tecogalaa, thalidomide, hrombospoadin, TNP-47Q, troponin-!, vasostatin, VEGl, VEGF-Trap, and ZD64 4.

Non-limiting examples of angiogenesi inhibitors also include, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Fit- 1 (VEGFR1) and Flk-i/KDR (VEGFR2), inhibitors of epidermal-derived, fibrobiast-derived, or platelet derived growth factors, MMP (matrix metai!oprotease) inhibitors, integrin blockers, pentosan polysulfate, angiotensin II antagonists, cyclooxygeoase inhibitors (including non-steroidal anti-inflanimatary drugs

(NSA!Ds) such as aspirin and ibuprofen, as well as selective cyc!ooxygenase-2 inhibitors such as eeleeoxib and rofecoxib), and steroidal anti-int ammatories (such as corticosteroids,

mineraloeorticoicls, dexamethasone, prednisone, prednisolone, niethyipred, betamethasone).

Other therapeutic agents that modulate or inhibit angiogenesis include agents that modulate or inhibit the coagulation and fibrinolysis systems, including, but not limited to, heparin, low molecular weight heparins and carboxypepticlase U inhibitors (also known as inhibitors of active thrombin activatabie fibrinolysis inhibitor [TAP la]}. U.S. Patent Publication No. 20090328239. U.S. Patent No. 7,638,549.

Non-limiting examples of the anti-hypertensive agents include angiotensin converting enzyme inhibitors (e.g., captopril, enaiapril, delaprii etc.), angiotensin II antagonists (e.g., candesartan cilexetii, candesartan, iosartan (or Cozaar), Iosartan potassium, eprosaitan, valsaitan (or Diovan), termisartan, irbesartan, tasosartan, oimesartan, oimesartan medoxomil etc.), calcium antagonists (e.g., manidipine, nifedipine, amlodipine (or Amlodin), efonidipiiie, nicardipine etc.), diuretics, renin inhibitor (e.g., aliskiren etc.), aldosterone antagonists (e.g., spironolactone, eplerenoue etc.), beta-blockers (e.g., metoproiol (or Toporol), atenolol, propranolol, carvedilol, pindolol etc.), vasodilators (e.g., nitrate, soluble guarrylaie cyclase stimulator or activator, prostacycline etc.), angiotensin vaccine, clonidine and the like. U.S. Patent Publication No. 201001 13780.

Other therapeutic agents that may be conjugated with a monoterpene or sesquiterpene (or an isomer or analog of monoterpene or sesquiterpene) include, but are not limited to, Sertraline (Zoloft), Topiramate (Topamax), Duloxetine(Cymhalta), Sumatriptan (Imitrex), Pregabalin

(Lyrica), Lamotrigine (Lamictal), Valaciclovir (Valtrex), Tamsulosin (Flomax), Zidovudine (Combivir), Lamiwdme (Combivir), Efavirenz (Sustiva), Abacavir (Epzicom), Lopinavir

(Ka!etra), Pioglitazone (Actos), Desioratidine (Clarinex), Cetirizine (Zyrtec), Pentoprazole (Protonix), Lansoprazole (Prevadd), Rebeprazole (Aciphex), Moxifloxacin (Avelox),

Meloxicam (Mobic), Dorzoiaittide (Truspot), Diclofenac (Voltaren), Enlapril (Vasotec),

ontelukast (Singulair), Sildenafil (Viagra), Carvedilol (Coreg), Ramiprii (Delix), aod L-DOPA. Also encompassed by the presen t invention are admixtures and/or coformulations of the present deuterium-enriched compound and at least one therapeutic agent discussed above.

The purity of the present compounds may be assayed by gas chromatography (GC) or high pressure liquid chromatography (HPLC). Other techniques for assaying purity and for determining the presence of impurities include,, but are not limited to, mass spectrometry (MS). GC-MS, infrared spectroscopy (IR), nuclear magnetic resonance (NMR) spectroscopy, and thin layer chromatography (TLC). Chirai purity can be assessed by chiral GC or measurement of optical rotation.

The present compounds may be purified by methods such as crystallization, or by separating the compounds from impurities according to the unique physicochemiea! properties (e.g. , solubility or polarity) of compounds. Accordingly, the present compound can be separated by suitable separatio techniques known in the art, such as preparative chromatography,

(fractional) distillation, or (fractional) crystallization. The compounds and methods of the present invention may be used to inhibit the Ras protein. The Ras family is a protein family of small GTPases that are involved in cellular signal transduction. Activation of Ras signaling causes ceil growth, differentiation and survival.

Mtations in ras genes can permanently activate it and cause inappropriate transmission inside the cell even in the absence of extracellular signals. Because these signals result in cell growth and division, deregulated Ras signaling can ultimately lead to oncogenesis and cancer. Activating mutations in Ras are found in 20-25% of all human tumors and up to 90% in specific tumor types. Goodsell DS (1 99). Downward J., 'The molecular perspective: the ras oncogene".

Oncologist 4 (3): 263-4. (January 2003). "Targeting RAS signaling pathways in cancer therapy".

Nat. Rev. Cancer 3 (1): 1 1-22. Ras family members include, but are not limited to, HRAS; KRAS; NRAS; DIRAS 1 ; D1 AS2; D1RAS3; ERAS; GEM; MRAS; KIRASl ; N IRAS2; NRAS; RALA; RALB; RAP1 A; RAP I B; RAP2A; RAP2B; RAP2C: RASD1 ; RASD2; ASLI OA; RASLIOB; RASLl 3 A; RASL1 IB; RASL12; REM!: REM2; RERG; RERGL; RRAD; RRAS; and RRAS. Wennerberg K, Rossman KL, Der CJ (March 2005). "The Ras saperfaroily at a glance", ,1, . Cell, Sci, 1 18 (Pt 5): 843-6. The present deuterium-enriched compounds may be formulated into a pharmaceutical composition. The deuterium-enriched compound may be present in the pharmaceutical

composition in an amount ranging from about 0.01% (w w) to about 100% (w/w), from about 0.1% (w/w) to about 80% (w/w), from about 1% (w/w) to about 70% (w/w), from about 10% (w/w) to about 60% (w w), or from about 0.1 % (w/w) to about 20% (w/w).

The present compounds or pharmaceutical compositions may be administered, by any route known in the art, including, without limitation, inhalation, intranasal, oral, transdermal, ocular, intraperitoneal, inhalation, intravenous, ICV, intraei sternal injectio or infusion, subcutaneous, implant vaginal sublingual, urethral (e.g., urethral suppository), subcutaneous, intramuscular, intravenous, rectal, sub-lingual, mucosa!, ophthalmic, spinal, intrathecal, intra- articular, intra-arterial, sub~araehinokl, bronchial and lymphatic administration. Intranasal formulation can be delivered as a spray or in a drop; inhalation formulation, can be delivered using a nebulizer or similar device; topical formulation may be in the form of gel , ointment, cream, aerosol, etc; transdermal formulation may be administered via a transdermal patch or iontorphoresis. Compositions can also take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

To prepare such pharmaceutical compositions, one or more of compound of the present invention may be mixed with a pharmaceutical acceptable carrier, adjuvant and/or excipient, according to conventional pharmaceutical compounding techniques. Pharmaceutically

acceptabie carriers that can be used in the present compositions encompass any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents. The compositions can additionally contain solid pharmaceutical excipietUs such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monosiearaie, sodium, chloride, dried skim milk and the like. liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanoi and various oils. including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, pariiciiiari for injectable solutions, include water, saline, aqueous dextrose, and glycols. For examples of carriers, stabilizers and adjuvants, see Remington's Pharmaceutical Sciences, edited by E. W, Martin (Mack Publishing Company, 18th ed., 1990). Th compositions also can include stabilizers and preservatives.

The present invention also provides for a method of treating a disease comprising the step of administering to a patient a therapeutically effective amount of a deuterium-enriched compound, e.g., deuterium-enriched periliyl alcohol, deuterium-enriched isoperiilyi alcohol, a deuterium-enriched perii!y! alcohol carbamate or a deuterium-enriched isoperiilyi alcohol carbamate.

As used herein, the term "therapeutically effective amount" is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response treating a disorder or disease. Methods of determining the most effective means and dosage of administration can vary with the composition used for therapy, the purpose of the therapy, the target ceil being treated, and the subject being treated. Treatment dosages generally may be titrated to optimize safety and efficacy. Single or multiple administrations can be carried out with the dose le vel and pattern being selected by the treating physician. Suitable dosage formulations and methods of administering the agents can be readily determined by those of skill in the art. For example, the composition are administered at about 0.01 mg/kg to about 200 ma/ks, about 0.1 nis/kg to about 100 nis/kg. o about. 0.5 msi ks to about 50 ma ks. When the compounds described herein are co-administered with another agent or therapy, the effective amount may be less than when the agent is used alone.

Transdermal formulations may be prepared by incorporating the active agent in a thixotropio or gelatinous carrier such as a celiulosie medium, e.g., methyl cellulose or hydroxyethyJ cellulose, with the resulting formulation then being packed in a transdermal device adapted to be secured in dermal contact with, the skin of a wearer. If the composition is in the form of a gel, the compositio may be rubbed onto a membrane of the patient, for example, the skin, preferably intact, clean, and dry skin, of the shoulder or upper arm and or the upper torso, and maintained thereon for a period of time sufficien for delivery of the present compound to the blood serum of the patient. The composition of the present invention in gel form ma be contained in a tube, a sachet, or a metered pump. Such a tube or sachet may contain one unit dose, or more than one unit dose, of the composition. A metered pump may be capable of dispensing one metered dose of the composition.

Th is invention also provides the compositions as described above for intranasal

administration. As such, the compositions can further comprise a permeation enhancer. Southall et al. Developments_. jn as _.D_.n^_.Deliyery, 2000. The present compound may be administered iotranasally as an aerosol, in a liquid form such as a solution, an emulsion, a suspension, drops, or in a solid form such as a powder, gel, or ointment.

Devices to deliver intranasal medications are well known in the art. Nasal drug delivery can be carried out using devices including, but not limited to, intranasal inhalers, intranasal spray devices, atomizers, nasal spray bottles, unit dose containers, pumps, droppers, squeeze bottles, nebulizers, metered dose inhalers (MDI), pressurized dose inhalers, insufflators, and bidirectional devices. The nasal delivery device can he metered to administer an accurate effective dosage amount to the nasal cavity. The nasal delivery device can be for single unit delivery or multiple unit delivery. In a specific example, the Via ase Electronic Atomizer from Kurve

Technology (Beth ell , Washington) can be used in th is invention . The compounds of the present invention may also be delivered through a tube, a catheter, a syringe, a paektaii, a pledget, a nasal tampon or by submucosal infusion. U.S. Patent Publication Nos. 20090326275,

20090291894, 20090281522 and 20090317377.

The present compound can be formulated as aerosols using standard procedures. The compound may be formulated with or without solvents, and formulated with or without carriers. The formulation may be a solution, or may be an aqueous emulsion with one or more surfactants. For example, an aerosol spray may be generated from pressurized container with a suitable propellent such as, dichiorodifluoromethane, tric oroiluoroffiethane, dichloiotetratluoroethane, hydrocarbons, compressed air, nitrogen, carbon dioxide, or other suitable gas. The dosage unit can be determined by providing a valve to deliver a metered amount. Pump spray dispensers can dispense a metered dose or a dose having a specific particle or droplet size. As used herein, the term "aerosol" refers to a suspension of fine solid particles or liquid solution droplets in a gas. Specifically, aerosol includes a gas-borne suspension of droplets of a monoterpene (or

sesquiterpene), as ma be produced in an suitable device, such as an MDI, a nebulizer, or a mist sprayer. Aerosol also includes a dry powder composition of the composition of the instant invention suspended in air or other carrier gas. Gonda ( 1 90) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313. Raeburn et a!., (1 92) Pharmacol. Toxicol. Methods 27: 143- 159.

The present compound may be delivered to the nasal cavity as an aerosol, such as liquid aerosol, or a solid aerosol. The present compound may be delivered to the nasal cavity as a powder in a form such as microspheres delivered by a nasal insufflator. The present compound may be absorbed to a solid surface, for example, a carrier. The powder or microspheres may be administered in a dry, air-dispensable form. The powder or microspheres may be stored in a container of the insufflator. Alternatively the powder or microspheres may be filled into a capsule, such as a gelatin capsule, or other single dose unit adapted for nasal administration.

The pharmaceutical composition can. be delivered to the nasal cavity by direct placement of the compositio in the nasal cavity, for example, in the form of a gei, an ointment, a nasal emulsion, a lotion, a cream, a nasal tampon, a dropper, or a bioatlhesive strip. In certain embodiments, it can be desirable to prolong the residence time of the pharmaceutical composition in the nasal cavity, for example, to enhance absorption. Thus, the pharmaceutical composition can optionally be formulated with a bioadhesive polymer, a gum (e.g., xanthan gum), ehitosan (e.g., highly purified cationic polysaccharide), pectin (or any carbohydrate that thickens like a gel or emulsifies when applied to nasal mucosa), a microsphere (e.g., starch, albumin, dextran, cyclodexttin), gelatin, a liposome, carhamer, polyvinyl alcohol, alginate, acacia, chitosans and/or cellulose (e.g., methyl or propyl; hydroxy! or carboxy; carboxymethyl or hydroxylpropyl).

Hie composition containing the presen compound can be administered by oral inhalation into the respiratory tract, i.e., the lungs.

Typical delivery systems for iuhakb!e agents include nebulizer inhalers, dry po wder inhalers (DPI), and metered-dose inhalers (MDi).

Nebulizer devices produce a stream of high velocity air that causes a therapeutic agent: in the form of liquid to spray as a mist The therapeutic agent is formulated in a liquid form such as a solution or a suspension of particles of suitable size, hi one embodiment, the particles are micronized. The terra "micronized" is defined as having about 90% or more of the particles with a diameter of less than about 10 um. Suitable nebulizer devices are provided commercially, for example, by PARI GmbH (Sternberg, Germany). Other nebulizer devices include espimat (Boehriuger Ingeiheira) and those disclosed in, for example, U.S. Patent Nos. 7,568,480 and 6,123,068. and WO 97/12687. The present compound can be formulated for use in a nebulizer device as an aqueous solution or as a liquid suspension.

DPI devices typically administer a therapeutic agent in the form of a free flowing powder that can be dispersed in a patient's air-stream during inspiration. DPI devices which use an external energy source may also be used m the present invention. In order to achieve a free flowing powder, the present compound can be formulated with a suitable exeipient (e.g., lactose). A dry powder formulation can be made, for example, by combinin dry lactose having a particle size between about I pm and 1 0 μηι with mieronized particles of the present, compound and dry blending. Alternatively, the compound can be formulated without exeipients. The formulation is loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder deli ery device. Examples of DPI devices provided commercially include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g., U.S. Patent No.

5,035,237); Diskus (GlaxoSmim Mne) (see, e.g., U.S. Patent No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Dei.) (see, e.g., U.S. Patent No. 4,524,769); and Rotahaler

(GlaxoSmith line) (see, e.g., U.S. Patent No. 4,353,365 ), Further examples of suitable DPI devices are described in U.S. Patent Nos. 5,415,1 2, 5,239,993, and 5,715,810 and references therein.

MDI de vices typically discharge a measured amount of the stored composition using compressed propellent gas. Formulations for MDI administration include a solution or suspension of an acti v e ingredien t in a liquefied propeliant. Examples of propellents include hydrofluoroalklanes (HFA), such as 1 , 1 ,1,2-tetraflu.oroethane (HFA 134a) and 1,1 ,1,2,3,3,3- heptafluoro-n-propane (HFA 227), and chlorofluorocarbons. such as CCI₃F. Additional components of HFA formulations for MDI administration include co-sol vents, such as ethanol pentane, water; and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin. (See, for example, U.S. Patent No. 5,225,183, EP 0717987, and WO 92/22286). The formulation is loaded into an aerosol canister, which forms a portion of an MDI device. Examples of MD I devices developed specifically for use with HFA propellents are provided in U.S. Patent Nos. 6,006,745 and 6,143,227. For examples of processes of preparing suitable formulations and devices suitable for inhalation dosing see U.S. Patent Nos. 6,268,533, 5,983,956, 5,874,063, and 6,221,398, and WO 99/53901 , WO 00/61108, WO 99/55319 and WO 00/30614. The present compound or pharmaceutical composition may be encapsulated in liposomes or microcapsules for delivery via inhalation. A liposome is a vesicle composed of a lipid bi layer membrane and an aqueous interior. The lipid membrane may be made of phospholipids, examples of which include phosphatidylcholine such as lecithin and lysoleeithin; acidic

phospholipids such as phosphatidy!serine and phosphatidylglycerol; and sphmgophospholipids such as phosphatidyl ethanolarnine and sphingomyelin. Alternatively, cholesterol may be added. A microcapsule is a particle coated, with a coating material. For example, the coating material may consist of a mixture of a film-forming polymer, a hydrophobic plastieizer, a surface activating agent or/and a lubricant nitrogen-containing polymer. U.S. Patent Nos. 6,313,176 and 7,563,768.

The present compound or pharmaceutical composition may also be used alone or in combination with other ehemotherapentic agents via topical application for the treatment of localized cancers such as breast cancer or melanomas. The present compound ma also be used in combination with narcotics or analgesics for transdermal delivery of pain medication.

This invention also provides the compound or the compositions as described above for ocular administration. As such, the compositions can further comprise a permeation enhancer. For ocular administration, the compositions described herein can be formulated as a solution, emulsion, suspension, etc. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos.

6,261,547; 6, 197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841 ; 5,077,033; 4,882.150; and 4,738,851.

Hie present compound or pharmaceutical composition can be given alone or in combination, with other drugs for the treatment of the above diseases for a short or prolonged period of lime. The present compound or pharmaceutical compositions can be administered to a mammal, preferably a human. Mammals include, but are not limited to, murines, rats, rabbit, simians, hovines, ovine, porcine., canines, feline, farm animals, sport animals, pets, equine, and primates.

The present compounds or compositions can be administered alone, or may be coadministered together with radiation or another agent (e.g., a cheniotherapeutic agent), to treat disease such as cancer. Treatments maybe sequential, with the present compounds or compositions being administered before or after the administration of other agents. For example, a deuterium-enriched perillyi alcohol (or isoperillyi alcohol) may be used to sensitize a cancer patient to radiation or chemotherapy. Alternatively, agents may be administered concurrently.

The present deuterium-enriched compounds may be used in combination with radiation therapy. In one embodiment, the present invention provides for a method of treating tumor cells, such as malignant glioma cells, with radiation, where the cells are treated with an effective amount of a deuterium-enriched compound of the present invention (such as deuterkmi-enriched perillyi alcohol or deuterium-enriched isoperillyi alcohol), and then exposed to radiation.

Treatment by the compounds of the present invention may be before, during and or after radiation. For example, the compounds of the present in vention may be administered

continuously beginning one week prior to the initiation of radiotherapy and continued for two weeks after the completion of radiotherapy. U.S. Patent os, 5,587,402 and 5,602, 184.

In one embodiment, the present invention provides for a method of treating tumor cells, such as malignant glioma cells, with chemomerapeutical agent, where the cells are treated, with an effective amount of a deuterium-enriched compound of the present invention (such as deuterium-enriched perillyi alcohol or deuterium-enriched isoperillyi. alcohol), and then exposed to chemotherapeutical agent. Treatment by the compounds of the present invention may be before, during and/or after chemotherapy. The compounds or pharmaceutical compositions of the present invention may be used for the treatment of nervous system cancers, such as a malignant glioma (e.g., astrocytoma, anaplastic astrocytoma, glioblastoma multiforme), retinoblastoma, pi!ocytic astrocytomas (grade J), meningiomas, metastatic brain tumors, neuroblastoma, pituitary adenomas, skull base meningiomas, and skull base cancer,

Cancers that can be treated by the present compounds or pharmaceutical compositions include, but are not limited to, lung cancer, ear, nose and throat cancer, leukemia, colon cancer, melanoma, pancreatic cancer, mammary cancer, prostate cancer, breast cancer, hematopoietic cancer, ovarian cancer, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; breast cancer; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer;

cancer of the head and neck: gastric cancer; intra-epithelial neoplasm; kidney cancer; larynx caacer; leakemia including acute myeloid leiikemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia; liver cancer; lymphoma mcluding Hodgkin's and Nk>n~ Hodgkin's lymphoma; myeloma; fibroma, neuroblastoma; oral cavity cancer (e.g., lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma;

rhabdomyosarcoma; rectal cancer; renal cancer; cancer of the respiratory system; sarcoma; skin cancer; stomach cancer; testicular cancer; thyroid cancer; uterin e cancer; cancer of the urinary system, as well as other carcinomas and sarcomas. U.S. Patent No. 7,601,355.

The present invention also provides methods of treatin CNS disorders, including, without limitation, primary degenerative neurological disorders such as Alzheimer's,

Parkinson^'s, psychological disorders, psychosis and depression. Autism may also be treated by the present compositions and methods. Treatment may consist of the use of a compound of the present invention alone or in combination with current medications used in the treatment of Parkinson's, Alzheimer's, or psychological disorders.

The present invention also provides a method of improving immunomodulatory therapy responses, comprising the steps of exposing ceils to an effective amount of compound (such as deuterium-enriched perillyi alcohol or deuterium-enriched isoperillyl alcohol) or pharmaceutical compositions of the present invention, before or during immunomodulatory treatment. PrefeiTed immunomodulatory agents are cytokines, such itUerleukins, lymphokines, monokines, interfereons and chemokines.

The invention also provides a method for inhibiting the growth of a cell in vitm. ex vivo or in vivo, where a cell, such as a cancer cell, is contacted with an effecti ve amount of the present compound as described herein.

Pathological cells or tissue such as hyperproliferatrve cells or tissue maybe treated by contacting the cells or tissue with an effective amount of the compound or composition of this invention. The cells, such as cancer cells, can be primary cancer cells or can be cultured cells available from tissue banks such as the American Type Culture Collection (ATCC). The

pathological cells can be cells of a systemic cancer, gliomas, meningiomas, pituitary adenomas, or a CNS metastasis from a systemic cancer, lung cancer, prostate cancer, breast cancer, hematopoietic cancer or ovarian cancer. The cells can be from a vertebrate, preferably a mammal, more preferably a human. U.S. Patent Publication No. 2004/0087651. Balassian ei al (2002) knera. 1. Mol. Med. 10:785-788. Thorne, et al. (2004) Nenroscieuce 127:481 -496. Ferneries, et al (2005 } Oncology Reports 13:943-947. Da Fonseca, et al. (2008) Surgical Neurology 70:259267. Da Fonseca, et al. (2008) Arch. Irnnrnnol. ^'then Exp. 56:267-276.

Hashixnme, et al. (2008) euroncoiogy 10; 1 12-120.

Efficacy of the present composition can be delenn ned usin methods well known in. the an. For example, the eytojucity of the present com ound may be studied by ΜΎΤ [3-(4,5- diniethylthia ol-2~yl)--2,5-cliplienyl ietrazoikrm bromide] cytotoxicity assay. MTT assay is based on the principle of uptake of MIT, a ietrazohoni salt, by mctaboliealSy active cells where it is metabolized into a blue colored formazon product, which can be read spectrometrically. I of Il MS Qgic i s h di 05: 55 63, 1 83, The cytoxicity of the present compound m y be studied by colony formation assay. Functional assays for inhibition of VEGF secretion and IL-8 secretion may be performed via E1.JSA. Ceil cycle block by the present compound may be studied by standard propidium iodide (Pi) staining and flow cytometry, invasion inhibition may be studied by Boyden chambers. In this assa a layer of reconstituted basement membrane, Matrigei, is coated onto chemotaxis filters and acts as a barrier to the migration of cells in the Boyden. chambers. Only cells with invasive capacity can cross the Matrigei barrier. Other assays met ode, but are not limited to, cell viability assays, apopfosis assays, and morphological assays.

The following are examples of the present invention and are not to be construed as iiniiti.o¾? .

Example 1 Synthesis of Beutera ed periilyt akofeat

Scheine~j :

S-foPerisis^ehyde Liduurn. alumkmm deuteride (LAD, 1.0 M. in. TEIF. 2Ϊ .2 mL, 213 mmol) was added slowly to a cold solution of ( Penliadehyde (1, 2,0g, .13.3 rnmol) in dry THF (20 mL) while maintaining the temperature below 10 °C under b½. The reaction mixture was slowly warmed to room temperature and then heated to reflux for 2.0 h. The reaction mixture was quenched with saturated sodium sulfate solution carefully and the resulting lithium salts were filtered and washed with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and the resulting oil was passed through a Thomson single StEP 40 g column and e luted wit .7% ethyl acetate/he&anes ( 120 mL). The clean fractions were combined and concentrated under vacuum to give compound 2 as colorless oil. Weight: 1 ,?8 g. Yield: 88%, Ή-NM^'R (400 Ml¾ CDC ): i 1.48 ( , J.R), .7.3 (s, 3H), .84-1.99 (m, 2H), 2.1 1 (m_f 4H), 3.99 (d, 1 H), 4.71 (m, 2HX 5.71 (hs, IH). MS (APQ rve mode): Molecular ion peak was observed.

Scheme-2

S-(-) Methyl Penmate

Synthesis of{S)~4~fcopropenyi~J~cychhexe -]-me†hm-(x,a '-d2-oi (2}

Lithium al«min.u.m deuteiide (LAD. 1.0 M in THF., 16,6 mL, 16.6 mmol) was added slowly to a cold solution of CoV ethy iperi ilate (1 , 2 ,0g, 1. 1, mmol} in dry THF (20 mL) while maintaining the temperature below 10 *€ under N>, The reaction mixture was slowly warmed to room temperature and then stirred at room, temperature for 2.0 h. The reaction mixture was quenched with saturated sodium sulfate solution carefully and the resulting lithium salts were filtered and washed with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and the resulting oil was passed through, a Thomson single StEP 40 g column and eluted with 5% ethyl acetaie/hexanes ( 1 0 mL). The clean tractions were combmed and concentrated snider vacuum to give compound 2 as colorless oil. Weight: 1.34 g. Yield; 79%, ' H-NMR (400 MH , CDCh): S 1.45-1.49 (m, ! H), 1.73 (s, 3H), 1.84-1.98 (m, 2HT 2.1 1-2,1? (m, 4E), 4.71 (m, 2H), 5.69 (bs, IH). MS (APCI rve mode): Molecular ion peak was observed .

Synthe of {8}-4-i8opwp l-l Glohexene-i-deutem meihan-a-d!-αί (2)

Lithium aluminum deuteride (LAD, ! ,0 M in THF, 21.2 mL, 213 mmol) will be added slowly to a cold solution of (5 Peri11adehyde (1, 2.0g, 13.3 mmol) in dry THF (20 mL) while maintaining the temperature below 10 °C under b . The reaction mixture will be slowly warmed to room temperature and heated to reflux for 2.0 h. The reaction will be quenched with 5% sodium deuteroxide in ¾0 (6.0 mL) carefully. The resulting lithium salts will, be filtered and washed with ethyl acetate. The organic layer will be dried over sodium sulfate and filtered. The filtrate will be concentrated and. the resulting oily residue will be passed through a Thomson single St^'EP 40 g column and will be e!uted with 7% ethyl acetate hexanes (.120 mL). The clean fractions will be combined and concentrated uuder acuum to give compound 2 as colorless oil.

Sc eme~4;

S-H fcfethyt Perflate

Synthesis (>f{S)~4~lsop penyI~ I-cyc ex e- ! -deni ro meth n~a_r '~d2~ol (2)

Lithium aluminum deuteride (LAD. 1.0 M in THF, 16.6 mL, .16.6 mmol) will be added slowly to a cold solution of Methylperiilate (t , 2.0g, 11 mmol) in. dry THF (20 mL) while maintaining the temperature below 10 °C under ¾. The reaction mixture will be slowly warmed to room temperature and then stirred at room temperature for 2.0 h. The reaction mixture will be queuched with 5% sodium deuteroxide in D;0 (6.0 mL) carefully. The resulting lithium salts will he filtered and washed with ethyl acetate. The organic layer will be dried over sodium sulfate and filtered.. The filtrate will be concentrated. The resulting oily residue will be passed through a Thomson single StEP 40 g column and will be elated with ?% ethyl acetate/hexaues (120 mL). The clean fractions will be combined and concentrated under vacuum to give compound 2 as colorless oil.

Example 2 Synthesis of Deliberated b»-perifiyl alcohol: 4-isi^ropylide«e~ i~cydo!iexeije~ i~ otethao-«,«^'-d2~oI

Scheme.

Synthesis o

ester (2):

A 2.5 M s lution of n-Buty^'l lithium in hexanes (5.6 mL, M l mmol) was added to a solution of diisopropyiarnine (1.98 ml-, 14..1 mmol) in dry THF (30 mL) at -78 °C over a period of 0.5 hr. After stirring tor 1.0 h at -78 *C_> a solution of ketone (J, 1 g, 9.4 mmol) in dry THF (1 mL) was added over a period of 1.0 min while maintaining the temperature below ~78°C. The reaction mixture was stirred for 1.0 at -78 *€. A solutio of pheuyltriflimide (3.53g, 9.86 mmol) in dry THF (15 mL) was added slowly while maintaining the temperature below -78 °C, The reaction mixture was slowly warmed to 0 *C, maintained for 2.0 h at 0 °C and then quenched with saturated ammonium chloride solution. The separated organic layer was -washed wit water (1.5 mL), brine (I S mL) and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum. The resulting residue was purified, by column, chromatography. [Column dimensions: diameter: 6.0 cm, height: 12 cm, silica: 200 mesh, elated with hexanes (200 ml,)] The similar fractions were combined and concentrated under vacuum which gave 2 as an oil. Weight: 0.9 g. Weight yield; 38%. 1H-NMR (400 MHz, CDCb h 0 1 M is, 3H). 1.71 is, 3H), 2.37 (ra, 2H), 2.46 (m, 2H), 2.91 (rm 2H), 5.73 (m, I Fl), MS (APCi +ve mode) Molecular ion peak was observed. S^■ynthesis i>f4~isopropyiiiicne cyciohex-J-etw carbvxyh^'c ciii methyl ester 0}:

To a solution of compound 2 (0.2g, 0.74 mmol) in H 'N-dimeihy!fora¾tt»ide (.1.5 mL) were added methanol (1.0 mL), triethylamine (0.1? mL_> 1.2 mroot}, 1 , 3- bis(dtphenylphosphi»o)propa»e (0.03 g, 0.07 mmol) and palladium acetate (0.04g, 0,07 mmol). The reaction mixture was degassed arid then stirred at room temperature under carbon monoxide (^'balloon pressure) for 5 h. The reaction mixture was diluted with ethyl acetate ( 15 mL) and washed with 0,5 HQ (15 mL), brine (15 ml) and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum and tire resulting residue was purified by column chromatography. [Column dimensions: diameter; 6,0 cm, height; 12 cm, silica; 200 mesh, elutecl wit.h bexao.es (100 mL) followed by ethyl acetate: hexara.es (2%_:, 1 0 ml,)]. The similar fractions were combined and concentrated under vacuum which gave a oil. Weight: 0.07 g. Yield: 52%.

Synthesis f 'isopr pyl{d ne-I-cyci h(- ce^e~ 'm (h ~a,ci '~d2~o! (4)

Lithium aluminum denteride (1.0 M in THF, 16.6 mL, 16.6 mmol) will be added slowly to a cold solution of methyl ester (3, 2.0g, 1 1 mmol) in dry THF (20 mL) while maintaining the temperature below 10 °C under N₂. The reaction, mixture will be slowly warmed to room temperature and then, stirred at room temperature for 2.0 h. The reaction mixture will be quenched with saturated sodium sulfate solution carefully. The resulting lithium salts will be filtered and washed with ethyl, acetate. The organic layer will be dried over sodium sulfate and filtered. The filtrate will be concentrated and the resulting oil will be purified by column chromatograph to obtain compound 4.

Example 3 Synthesis sf Deuterated ssQ~§>erIIyi aleohoh 4~Is0|>ro| yiHfene~l~€yeio exeue~l~ den tero m eia&n-^a'-dl-ol

Scheme:

Li hium aluminum deuteride ( 1.0 M in THF, 16,6 mL, 1 .6 mrool) will be added slowly to a cold solution of Methyl ester (3. 2.0g, 1 1 mmoi) in dry THF (20 mL) while maintaining the temperature below 10 °C under ^' %. The reaction mixture will be slowly warmed to room temperature and then it will he stirred at room temperature for 2.0 h. The reaction mixture will be Quenched with 5% sodium deuteroxide m ¾0 (6.0 mL) carefully. The resulting lii!iiura salts will be filtered, and washed with ethyl acetate. The organic layer will be dried over sodium sulfate and filtered. The filtrate will be concentrated and the resulting oily residue will be purified by column chromatography to obtain compound 4A. xample 4 Synthesis of Oeistera ed Iso-periliyi alcohol: 4~fs»pr«pyMdeBe-l~cyclobexe«e-I~ m t b n -owl Lei

Symh& qf 4-m>propyikkn cy hhex~/~ nyi methanol (5)

Methyl ester (3, 1 ,0 g, 5.54 mmoL) in dry THF ( 10 ml) was added to lithium aluminum hydride (0.25 g, 6.6 rnrnoL) in dry THF (20 mL) at .10 °C over a period of 5 mm. The mixture was slowly heated to reflux and maintained for 2.0 h. The reaction mixture wa cooled and quenched with saturated sodium sulfate solution (2,0 mL). The lithium salts were filtered and washed with hot ethyl, acetate. The organic layer was dried over sodium sulfate, f ltered and concentrated under vacuum to give a colorless oil. Weight: 0.67 g. Yield: 80%. Ti-N!vlR (400 MHz, CDC!?_.): S 1.65 (s, 3H), 1.69 ($, 3i¾ 1.77 (bs, OH), 2.09 (m_> 2H), 2,33 (t, 2B), 2.79 (br s_> 2H); MS (APCI ·Η¾ mode): m/e: 152 ( 7 3.5%), 1.35.07 ( 100 %}, 1.07.12 (5%).

>rw/^;w/v qf4-iSf>prop)4kien ~cychhex~ I~em carhiUdehyde (6):

Dry DMSO (0,5 mi will be added to a cold solution of oxalyl chloride (0.67 mL, 7.8 mmol) in dieldorornethatie ( 15 ml.) at -78 °C and the mixture will be stirred for 20 min. Aleoho^' (5, 1.0g, 6.5 rnmoi), in 5 nit of DC will be added over 1.0 min mid the mixture will be stirred .for 1.0 h followed by ie addition of trietlrylam e (0.8 mL). The reaction mixture will be stirred for 0,5 h and then warmed to room temperature. Water (20 mL) will be added and the DCM layer will be separated. The aqueous layer will be extracted with DCM (20 mL) and separated. The combined DCM layer will be washed with water, separated, and will be dried, over sodium sulfate. The filtered organic layer will be concentrated under acu m and the sult nt residue wdl be purified by column chromatography to obtain compound 6.

Synthesis of 4-isopropyiidem- 1 -eydohexene- 1 ~methan~ -dl -of (7):

Lithium aluminum deuteride (1 ,0 M in TRF, 21,2 mL, 21.3 mmol) will be added slowly to a cold solution of adebyde (6, 2.0g, 133 mmol) m dryTHF (20 mL) while maintaining the temperature below 10 °C under ! The reaction mixture will be slowly warmed to room temperature and then heated to reflux for 2, h. The reaction mixture will be quenched, with saturated sodium sulfate solution carefully. The resulting lithium salts will, be filtered and washed with ethyl acetate. The organic layer will be dried over sodium sulfate and filtered. The filtrate will be concentrated and the resulting oil will, be purified by column chromatography to obtain compound 7.

Example 5 Synthesis of Deu erated iso~perii!yi ¾ko oL 4~!sopro|>yik!eoe -1 -cyc!ohexeae-l- deutero eife a rw¾~d 1 -ol

Scheme;

Li hium aluminum deuteride (1.0 M in THF, 21.2 mL, 2.1.3 mmol) will be added slowly to a cold solution of aldehyde (¾, 2.0g, 13.3 mmol) in dry THF (20 ml.,) while maintaining the temperature belo 10 °C under N₂. The reaction, mixture will be slowly warmed to room temperature aud then it will be heated to reflux for 2.0 li. The reaction will be quenched with 5% sodium deuteroxide in jO (6.0 mL) carefully and (he resulting lithium salts will be filtered, washed with ethyl acetate. The organic layer will be dried over sodium sulfate and filtered. The ill Irate will be concentrated and the resulting oily residue will be purified by column

chromatography to obtain compound 7 A.

Example 6 Synthesis of Dimethyl Celeeoxlb bisFOII Carharoate (4~(b s- , ^'~4~isoprope?3yl cydohex~l~eB h»ethylexy car osn l [5~(2,S-dimetfry! pfeeayih3~tfifla»r i«etbyi pyraa*l™!~ yl) ben¾enes«If »8.n«de)

The reaction scheme is the following:

Dimethyl eaSecoxsb

Phosgene

DMC-POH

Phosgene (20% in toluene. 13 ml. 26.2 mmol) was added to a mixture of peri I ly I alcohol

(2.0 grams, 13, 1 mmol} and potassium carbonate (5.4 grams, 39. 1 mmol) in dr toluene (30 nit) over a period of 30 mkmtes while maintaining the temperature between 10°€ to 15° C, The reaction mixture was allowed to warm to room temperature and stirred for 8,0 hours under j, The reaction mixture was quenched with water (30 mL) and the organic layer was separated, The aqueous layer was extracted with tolnene (20 .mL) and the combmed organic layer was washed with water (50 mL x.2}.. brine (15%, 30 mL) and drred over sodium sulfate (20 grams). The filtered organic layer was concentrated under vacuum to gi ve penllyl ehloro brmate as an oil Weight: 2.5 grams; Yield: 89%. H-NMR (400 MHz, CIX¾): «5 1.5 (m, 1H), 1.7 (s, 3H), 1.8 (ro, IH), 2.0 (m, 1H), 2.2 (m, 4H), 47 (dd, 4H); 5.87 (m, 1H).

Periifyl c oroibrmate (0, 1 1 grams, 0,55 ramol) was added slowly to a mixture of dimethyl ce!ecoxib (0.2 grams, 0.50 mmol) an potassium carbonate (0.13 grams, 1 .0 mmol) in dry acetone (10 mL) o ver a period of 5 minutes under Hz- The reaction mixture was heated to reflux and maintained for 3 hours. Since TLC analysis indicated the presence of dimethyl celecoxib (> 60%), another 1.0 equivalent of peril lyi chioroforraate was added and re fluxed for an additional 5 hours. Hie reaction mixture was cooled and acetone was concentrated under vacuum to give a residue.

The resulting residue was suspended in water ( I S mL) and extracted with ethyl acetate

(3 15 mL). The combined organic layer was washed with water (20 mL) followed by brine 05%, 20 ml.) and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum to give a residue which was purified by column chromatography [column dimensions: diameter: 1 .5 cm, height 1 0 cm, silica: 230-400 mesh] and eluted with hexanes ( 100 mL) followed by a mixture of hexanes; ethyl acetate (95:5, 100 mL). The hexane ethyl acetate fractious were combined and concentrated under vacuum to give a gummy mass.

The product POH carbamate exhibited a weight of 120 mg and a yield of 31%. H~ ^;MR (400 MHz, CDC1. : 9 0.9 (m, 2H)_f 1.4 (m, 2H), 1.7 (m, ?H*), 1 .95 (m, 8H*), 2.1 (m, 4H)_S 2.3 (s, 3H), 4.4 (d, 2H), 4.7 (dd, 2H), 5.6 (br d, 2H), 6.6 (s, 1 H), 7.0 ( br s, 1 H), 7.12 (d, 1 H), 7.19 (d_t ί H), 7,4 id, 2H), 7.85 (d, 2H); MS, m/e: 751 .8 (M* 3%), 574.3 (100%), 530.5 (45%), 396 (6%). * .B. further 2H overlapping .from presumed impurity discounted in NMR integration.

Hie product POH carbamate may be partially or fully deuterated. For example, one or more of the H atoms may be deuterium . Example 7 Synthesis of Temozolomide POH Carbamate (3-niethyi 4-oso-3,4-

acid-4-isopropeuyl cyelohex- 1 -en yl methyl ester)

The reaction scheme is the following:

Oxaiyl chloride (0.13 grams, 1.0 mmol) was added slowly to a mixture oftemoiioiomide (OChem Incorporation, 0.1 grams, 0.5 mmol) in L2<lkIiloroeiha.ue (10 mL) over a period of 2 minutes while maintaining the temperature at .1 ^ft€ under Na. The reaction, mixture was allowed to warm to room temperature and then healed to reflux for 3 ^'hours. The excess of oxaiyl chloride and I ,2-dichlotoetiiane were removed by concentration under vacuum. The resulting residue was re-dissolved ia 1,2-dichlorethane ( 15 mL) and the reaction mixture was cooled to Hf C under N₂. A solution of perill i alcohol (0.086 grams, 0.56 mmol) in ,2-dichloroethane (3 ml..} was added over a period of 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 14 hoars. I _>2- iehlofoethane was concentrated under vacuum io give a residue, which was triturated with hexanes. The resulting yellow solid was filtered and washed with hexanes. Weight: 170 mg; Yield: 89%. ^SH-NMK (400 MH , COCK): <? 1 .4-2.2 (m, 10H), 4,06 (s, 3H), 4.6-4.8 (m, 4H), 5.88 (hr s, 1H) 8.42 (s, 1H), 9.31 (br s, 1 H); MS, no molecular too peak was observed, m/e: 314 (100%), 286.5 ( 17%), 136 (12%).

Alternatively, teniosolomide POM carbamate was synthesized according to the following procedure. Oxaiyl chloride (0.1 3 grams, 1 .0 mmol) was added slowly to a mixture of temozoiomide (OChem Incorporation, 0, 1 grams, 0,5 mmoi) in 1 ,2-dschloroei.hane (1.0 mL) over a period of 2 minutes while maintaining the temperature at .} ⁽) "€ under ₂. The reaction mixture was allowed, to warn? to room temperature and then heated to reflux for 3 hours. The excess of oxai l chloride and 1 ,2-diehleroethane were removed by concentration under vacuum. The resulting residue was re-dissolved in 1 2-dichioreihane (.15 mL) and the eaction mixture was cooled to 10 ^: C under o¾. A solution of perillyi alcohol (0.086 grams, 0.56 mmol) in 1 ,2- dichioroethane (3mL) was added over a period of 5 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. 1 ,2-Dichloroethane was concentrated under vacuum to give a residue, which was purified by a short silica-plug column (column dimensions: diameter: 2 cm, height: 3 cm, silica: 230-400 mesh) and elated with a mixture of hexanes/ethyl acetate (1 : 1 , 100 mL). The hexane ethyl acetate fractions were combined and concentrated under vacuum to give a hite solid residue which was triturated with heptanes and filtered to obtain a white solid. Weight: 1 70 rag; Yield; 89%, ^!H-NMR (400 MHz, CDC13): 1.4- 2.2 Cm, iOHl 4.06 (s. 3H1 4.6-4,8 Cm, 4H1 5.88 (br s, I B), 8,42 (s, IB), 9,31 (br s, I H): MS, no molecular ion peak was observed, /e: 314 (100%), 286.3 (i 7%), 136 (12%).

The product POM carbamate may be partially or fully deuierated. For ex m l , one or more of the H stor may be deuterium.

Example 8 Synthesis of Rolipram PCM Carbamate {4~(3~cyeioperrtyl«xy^~mefhox p enyl)~2~o.so~p¥rroMdirui-l-earboxy!k* acid 4 soprspeny1 cycto^'hex-l-eayteelfey ester)

The reaction scheme is the following:

chloroforrrvate

Phosgene

Toluene Γ ^Η T

Pefiiiy! alcohol

Phosgene (20% in toluene, 13 ml, 26,2 nunol) was added to a mixture of periHyi alcohol

(2.0 grams, 1 .1 m ol) and. otassium, carbonate (5,4 grams, 39, 1 mrnol) in dry toluene (30 mL) over a period of 30 minutes while maintaining the temperature between iff C to 15"C. The reaction mixture was allowed to warm to room temperature and stirred for 8.0 hours under N-j. The reaction mixture was quenched with water (30 mL) and the organic layer separated. The aqueous layer was extracted with toluene (20 m.L) and the combined organic layer washed with water (50 mL x 2), brine ( 15%, 30 mL) and dried over sodium sulfate (20 grams). The filtered organic layer was concentrated under vacuum to give pefiiiy! ch rofbrrnate as an oil. Weight 2.5 grams; Yield; 89%. ^SB~NMR (400 MHz, CDC¾): 3 1 ,5 (ra, 111), ! .? (s_t 3H), i .8 (m, i E), 2.0 (ra, 1 :1), 2.2 (m, 4H), 4.7 (άά, 4H); 5.S7 (ra, I B).

Butyl lithium (2,5 M, 0. 18 niL, 0.45 mmol) was added to a solution of rolipram (GL synthesis, inc., 0.1 grams, 0.36 mmol) in dry THF at -72° C over a period of 5 nimistes under Nj. After the reaction mixture was stirred for 1 ,0 hoars at -72" C, perdlyi ehloroiormate {dissolved in 4 mL THF) was added over & period of 15 minutes while maintaining the temperature at -72€. The reaction mixture was stirred for 2.5 hours and quenched with saturated ammonium chloride (5 mL), The reaction- mixture was allowed to warm to room temperature and extracted with ethyl acetate (2 1 5 mL), The combined organic layer was washed with water (15 mL), brine f 15%, 1 S mL), and titers dried over sodium sulfate. The filtered organic layer was concentrated to give an oil which was purified by column chromatography [column dimensions; diameter: 1 ,5 em, height: 10 em, silica.: 230-400 mesh] and elated with mixture of 8% ethyl, acetate/hexaues (100 mL) followed by 12% ethyl acetate/hexanes (100 mL). The 12% ethyl acetate hexanes fractions were combined and concentrated under vacuum to yield a gammy solid. Weight: 142 mg; Yield: 86%. ³H~NMR (400 MHz, CDCh): S \ .5 (m, IH), 1.6 (m, 2H), 1.7 (s, 3H), 1.9 (m, 6H), 2,2 (m, 5H), 2.7 (m, IB), 2.9 (m, I B), 3,5 (m, IH), 3.7 (m, IH), 3.8 (s, 3H), 4.2 (m, l id), 4,7 (si, 6H), 5.8 (br s, .11:1), 6,8 (m, 3H); S, m/e: 452.1 ( ^' 53%), 274. 1 (100%), 206.0 (55%).

The product POB carbamate may be partially or fully deuterated. For example, one or more of the H atoms may be deuterium.

Example 9 Synthesis of lso~FOH Conjugated with Tetne*oIa.mkle (TM )

The reaction scheme is the .following:

Preparation

carb mi cid -4-imptvpyiktene cy hkvx- 1 -enylmeikyl ester: Oxalyl chloride (0.26 g, 2.0 mmol) will be added slowly to s mixture of Temoxola ide (Source; OChem incorporation, tot # 071 Π85Α; 0.2 g, 1 ,0 mmol) HI i,2- ikbfoi >ethafte (.15 mL) over & -period of 5 min while maintaining the temperature at 10 °C -under b½. The reaction mixture will be allowed to warm io room temperature and then heated to reflux, for 2.5 h. The excess of oxalyl chloride and 1 ,2-dic oroet!iaae will be removed by concentration voider vacuum. The resulting residue will he redissoKed in 1 ,2-diehioroe haae (20 mL) and the reaction mixture cooled to 5^';iC under Nj. A solution of isoperi!Syl alcohol (0,17 g, 1 , 12 mmol) in L2"dieb!oroethane (5 mL) will be added over a period of 10 min. The reaction mixture will be allowed to warm to room temperature and stirred for 12 h. L2-Dich!oroeihane will be concentrated under vacuum to give a residue which will e triturated with hexanes. The resulting pale yellow solid will he filtered and washed with hexanes.

The product iso-POH carbamate may be partially or fully deuterated. For example, one or more of die H atoms may be deuterium.

Example JO Synt esis of Iso-POH Conjugated with R lipr m

The reaction scheme is as follows.

isoperi S alcohol

Prejjarmk

Phosgene (20% in toluene, 19.5 ml 39.4 mmol) will be added to a mixture of isoperillyl alcohol (3.0 g, 1 .7 mmol) and potassium carbonate (8.. I g, 58.6 mmol) in dry toluene (45 mL) over a period of 45 min while maintaining the temperature between 1.0-1.2 C. The reaction mixture will be allowed to warm to room temperature and stirred for 10 h tinder r%. The reaction mixture will be quenched with water (40.mL) and the organic layer separated. The aqueous layer will be extracted with toluene (30 mL) and the combined organic iayer washed wrth water (40 mL x 2), brine (10%, 40 mL), and dried over sodium sulfate (25 g). The filtered organic layer will be concentrated under vacuum to give isoperillyi chloroformate as an oil.

Butyl lithium (2.5 M, 0.36 mL, 0,90 mraol) will be added to a solution of rolipram (Source: GL synthesis. Inc. Lot # GLS-SH- 10809; 0.2g, 0.72 ramol) in dry THF (8 mL) at -72 °C over a period of 10 min under N?. After the reaction mixture being stirred for 1.0 h at -72 °C isoperillyi chloroformate (0,16 g, 0.76 mrnol dissolved in 4 mL THF) will be added over a period of 1.0 min while maintaining the temperature at -72 ^l'C, The reaction mixture will be stirred for 3 h and quenched with saturated ammonium chloride (10 mL). The reaction mixture will be allowed to warm to room temperature and extracted with ethyl acetate (2x20 mL). The combined organic layer will be washed with water (20 mL), brine ( 10%, 25 mL), and dried o ver sodium sulfate. The filtered organic layer will, be concentrated to give an oil which will be purified by column chromatography [Column dimensions: dia; 1.5 cm, height; 15 cm, silica; 230-400 mesh] and elated with a mixture of 5% ethyl acetate hexanes (120 mL) followed by 1.0% ethyl acetate/hexanes (1.50 mL). The 10% ethyl acetate /hexanes fractions will be combined and concentrated under vacuum to give a gummy solid.

The product iso-POH carbamate may be partially or fully deuterated. For example, one or more of the H atoms may be deuterium.

Example 11 Synthesis of Dimethyl Celecoxib bis iso-POH carbamate conjugate

The reaction scheme is as follows.

Oimst ! cetecoxib

Phc-sgerte

DMC bis-fcoPOH Toiusns

!scperiiiyi steobof

Preparation of4-(Bi$~N,N ^!~4-i$epropyiktem cyc hex- i~enyf .ethy xy earhonyi (5-(2,5- dsmeiky! pkenyi}~3~irifh<oromethyi pyrazoi~i-yli henzenesiiifbn mi :

Phosgene (20% m toluene, 19.5 ml. 39,4 mmol) will be added to a mix r of isoperillyl alcohol (3.0 g, 19.7 mmol) and potassium carbonate (8, 1 g, 58.6 mmol) in dry toluene (45 mL) over a period of 45 mm while nudutainiog the temperature between 10-12 "(1 The reaction mixture will be allowed to warm io room, temperature and stirred for 10 fa under h½. The reaction mixture will be quenched with water (40 ml.) and the organic layer separated. The aqueous layer will be extracted with toluene (30 mL) and the combined organic layer washed with water (40 mL x 2), brine (10%, 40 mL}, and dried, over sodium sulfate (25 g). The filtered organic layer will be concentrated under vacuum to give isoperillyi chloroformate as oil.

Isoperillyl chloroformate (0.22 g, 1.0 mmol) will be added slowly to a mixture of dimethyl celecoxib (0.2 g, 0.50 mmol) and potassium carbonate (0, 14 g, 1.0 mmol) in dry acetone (25 mL) over a period of 5 min under ?*¾. The reaction mixture will he heated to reflux and maintained for 4 h. The reaction mixture will be cooled and the acetone concentrated under vacuum. The resulting residue will be suspended in. water (25 ml.,} and. extracted with ethyl acetate (3x20 ail,}. The combined organic layer will be washed with water (40 ml), followed by brine (1.0%, 30 mL), and dried over sodium sulfate. The filtered organic layer will be concentrated under vacuum to gi e a residue which will be purified by column chromatography [Column dimensions: dla: 1.5 cm, height: 15 cm, silica: 230-400 mesh] and eluted with, hexanes (100 mL) .followed by a mixture of bexanes ethyi acetate (95:5, 100 mL). The hexane/ethyl acetate fractions will he combined and concentrated under vacuum io give a gummy mass. The product iso-POH carbamate may be partially or fully deuterated. For example, one or more of the H atoms may be deuterium.

The scope of the present invention is not li mited by what lias been specifi cally shown and described hereinabove. Those skilled in the art will recognize that there are suitable alternatives to the depicted examples of materials, configurations, constructions and dimensions. Numerous references, including patents and various publications, are cited and discussed in the description of this invention. The citation and discussion of such references is provided merely to clarify the description of the present invention and is not an admission that any reference is prior art to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entirety. Variations, modifications and other implementations of what is described here in will occur to those of ordinary skil l in the art without departing from the spirit and scope of the invention . While certain embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications may be made without departing from the spirit and scope of the invention. The matter set forth in the foregoing description and accompanying drawings is offered by way of illustration only and not as a limitation.

Claims

What is cl imed is:

-enriched c m ound of Formula I or Formula II

Formula !! or a pharmaceutically acceptable salt thereof; wherein; s, ¾_> R_:¾, *, Rs> R?, ¾ R9, ¾o_> B.jj_> ^'B-r>_> R _> u, Ri5 atid Ru; te independently selected from the group consisting of hydrogen- I and. deuterium, and ai least one ofR?₅ R₂, R *> Rs_> Rs, R?, Rs, K Ru>, o, R*2_> Ru, Ru, Rw and is deuterium; and wherein the abundance of deuterium is at least about 10%.

The deuterium-enriched compound of claim 1 selected from the group consisting oi:

3. A deuterium-enriched periilyl alcohol or isoperillyi alcohol wherein the abundance of deuterium is at least about 10%.

4. The detitedmtt-e.tt.ricn.ed compound of claims L 2 or 3, conjugated with a therapeutic agent to form, a carbamate.

5. A deuterium-enriched periilyl alcohol carbamate or isoperillyl alcohol carbamate, wherein the abundance of deuterium is at least about 10%.

6. The deuterium-enriched compound of any of claims 1 - 5, wherein the abundance of deuterium is at least arxnrt 20% or at least about 30%.

7. The dented um-enriched compound of claim 5, wherein periilyl alcohol or isoperillyl alcohol is conjugated with a therapeutic agent to form a carbamate,

8. The dented um-enriched compound, of claims 4 or 7, wherein the therapeutic agent is a chemotherapettfk agent selected, from the group consisting of a D A alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducing agent, a platinum compound, an antimetabolite, an enxy e inhibitor, and a receptor antagonist.

9. The dented um-enriched compound of claims 4 or 7, wherein the therapeutic agent is selected from the group consisting of dimethyl, celocoxib (D C), temozolomide (TMZ) and roli ram,

10. A pharmaceutical composition comprising the deuterium-enriched compound of any of claims I.—3.

1 1. 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 e z me inhibitor, and a receptor antagonist.

12. The pharmaceutical composition of claim 10, further comprising a therapeutic agent selected from die group consisting of dimethyl celocoxih (DMC), temozo!omide (TMZ) and rolipram.

13. A pharmaceutical composition comprising the deuterium-enriched compound of any of claims 4 - 9.

14. A method for treating a disease in a mammal, comprising the step of

administering to the mamma! a pharmaceutical composition comprising a therape tic ally effective amount of a deuterium-enriched periiiyl alcohol a deuterium-enriched isoperi!Iyi alcohol a deuterium-enriched periliyi alcohol carbamate, and/or a deuterium-enriched isoperiliyl alcohol carbamate.

15. A method for treating a disease in a mammal, comprising the step of

administering to the mammal a pharmaceutical composition of any of claims 10 ~ 13.

16. The method of claims 14 or 15, 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 cla ims 14 or 15, wherein the pharmaceutical composition is administered by inhalation, intranasally, orally, intravenously, subcutaneousJy or

intramuscularly.

20. The method of claims 14 or 15, 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 claims 14 or 15, 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 iopoisomerase 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 chetnotherapeutic agent is selected from the group consisting of dimethyl celocoxib (DMC)„ temozolomide (TMZ) and rolipram.

26. The method of claims 14 or 15, 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 inhal er, 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.