US 20100152283A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0152283 A1 Gant (43) Pub. Date: Jun. 17, 2010

(54) Publication Classification MODULATORS OF CANNABINOD (51) Int. Cl. RECEPTORS A63L/352 (2006.01) C07D 3II/80 (2006.01) (52) U.S. Cl...... 514/454; 549/390 (75) Inventor: Thomas G. Gant, Carlsbad, CA (US) (57) ABSTRACT The present invention relates to new tetrahydrocannabinol modulators of receptors, pharmaceutical com Correspondence Address: positions thereof, and methods of use thereof. GLOBAL PATENT GROUP - APX 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) Formula I

(73) Assignee: AUSPEX PHARMACEUTICALS, INC., Vista, CA (US)

(21) Appl. No.: 12/640,107

(22) Filed: Dec. 17, 2009

Related U.S. Application Data (60) Provisional application No. 61/138,517, filed on Dec. 17, 2008. US 2010/0152283 A1 Jun. 17, 2010

TETRAHYDROCANNABINOL abdominal pain, nausea, Vomiting, amnesia, anxiety, ataxia, MODULATORS OF CANNABINOD confusion, depersonalization, dizziness, euphoria, hallucina RECEPTORS tion, paranoid reaction, Somnolence, abnormal thinking, con junctivitis, hypotension, diarrhea, fecal incontinence, myal gia, depression, nightmares, speech difficulties, tinnitus, and 0001. This application claims the benefit of priority of vision difficulties. U.S. provisional application No. 61/138,517, filed Dec. 17, 2008, the disclosure of which is hereby incorporated by ref DEUTERIUM KINETIC ISOTOPE EFFECT erence as if written herein in its entirety. 0005. In order to eliminate foreign substances such as 0002 Disclosed herein are new tetrahydrocannabinol therapeutic agents, the animal body expresses various compounds, pharmaceutical compositions made thereof, and enzymes, such as the cytochrome Paso enzymes (CYPs), methods to modulate cannabinoid receptor activity in a Sub esterases, proteases, reductases, dehydrogenases, and ject are also provided for, for the treatment of disorders such monoamine oxidases, to react with and convert these foreign as chemotherapy-induced emesis, pain, neuropathic pain, Substances to more polar intermediates or metabolites for multiple Sclerosis, spasticity, Alzheimer's disease, nausea, renal excretion. Such metabolic reactions frequently involve Vomiting, affective disorders, anorexia nervosa, dementia, the oxidation of a carbon-hydrogen (C H) bond to either a major depressive disorder, cachexia, HIV wasting syndrome, carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. Tourette's syndrome, and emesis. The resultant metabolites may be stable or unstable under 0003 (Marinol R, THC, delta-9-tetrahydro physiological conditions, and can have substantially different cannabinol, delta-9-THC, SP-104, ElevatR, CompassiaR), pharmacokinetic, pharmacodynamic, and acute and long CAS # 1972-08-3), (-)-(6aR,10aR)-6,6,9-trimethyl-3-pen term toxicity profiles relative to the parent compounds. For tyl-6a, 7.8.10a-tetrahydro-6H-benzocchromen-1-ol, is a most drugs, such oxidations are generally rapid and ulti cannabinoid receptor . Dronabinol is commonly pre mately lead to administration of multiple or high daily doses. scribed for the treatment of chemotherapy-induced emesis, 0006. The relationship between the activation energy and cachexia, emesis, and anorexia nervosa (Drug Report for the rate of reaction may be quantified by the Arrhenius equa Dronabinol, Thompson Investigational Drug Database (Aug. tion, k=Ae'. The Arrhenius equation states that, at a 12, 2008); Beal et al., J. Pain Symptom Management 1995, given temperature, the rate of a chemical reaction depends 10(2), 89-97: Meiri et al., Curr. Med. Res. Opin. 2007, 23(3), exponentially on the activation energy (E). 533-43; Struwe et al., Ann. Pharmacother: 1993, 27, 827-31; 0007. The transition state in a reaction is a short lived state and Volicer et al., Int. J. Geriatric Psych. 1997, 12,913-19). along the reaction pathway during which the original bonds Dronabinol has also shown promise in treating pain, neuro have stretched to their limit. By definition, the activation pathic pain, multiple Sclerosis, spasticity, Alzheimer's dis energy E for a reaction is the energy required to reach the ease, nausea; Vomiting, affective disorders, dementia, major transition state of that reaction. Once the transition state is depressive disorder, HIV wasting syndrome, Tourette's syn reached, the molecules can either revert to the original reac drome, asthma, and glaucoma (Drug Report for Dronabinol, tants, or form new bonds giving rise to reaction products. A Thompson Investigational Drug Database (Aug. 12, 2008); catalyst facilitates a reaction process by lowering the activa Ashton et al., Curr. Opin. Invest. Drugs 2008, 9(1), 65-75; tion energy leading to a transition state. Enzymes are Baker et al., Nature 2000, 404, 84-87; Beal et al., J. Pain examples of biological catalysts. Symptom Management 1995, 10(2), 89-97: Rice, Curr: Opin. 0008 Carbon-hydrogen bond strength is directly propor Invest. Drugs 2001, 203), 399-414; Struwe et al., Ann. Phar tional to the absolute value of the ground-state vibrational macother: 1993,27,827-31; and Volicer et al., Int. J. Geriatric energy of the bond. This vibrational energy depends on the Psych. 1997, 12,913-19). mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (H), a Dronabinol C-D bond is stronger than the corresponding C–H bond. If a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), then Substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of 0004 Dronabinol is subject to CYP2C9-, CYP2C19-, and tritium for hydrogen results in yet a stronger bond than deu CYP3A4-mediated oxidation of the allylic methyl and meth terium and gives numerically larger isotope effects. ylene groups to form 11-hydroxy-delta-9-tetrahydrocannab I0009 Deuterium (H or D) is a stable and non-radioactive inol, 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid, isotope of hydrogen which has approximately twice the mass and 8-hydroxy-delta-9-tetrahydrocannabinol (Perez-Reyes, of protium (H), the most common isotope of hydrogen. J. Clin. Pharmacol. 1981, 21, 178S-189S; and Wall et al., Deuterium oxide (DO or “heavy water) looks and tastes like Clin. Pharmacol. Ther: 1983,34(3), 352-63). Adverse effects HO, but has different physical properties. associated with dronabinol administration include: asthenia, 0010 When pure DO is given to rodents, it is readily palpitations, tachycardia, Vasodilation, facial flushing, absorbed. The quantity of deuterium required to induce tox US 2010/0152283 A1 Jun. 17, 2010

icity is extremely high. When about 0-15% of the body water ings. Various deuteration patterns can be used to (a) reduce or has been replaced by DO, animals are healthy but are unable eliminate unwanted metabolites, (b) increase the half-life of to gain weight as fast as the control (untreated) group. When the parent drug, (c) decrease the number of doses needed to about 15-20% of the body water has been replaced with D.O. achieve a desired effect, (d) decrease the amount of a dose the animals become excitable. When about 20-25% of the needed to achieve a desired effect, (e) increase the formation body water has been replaced with DO, the animals become of active metabolites, if any are formed, (f) decrease the so excitable that they go into frequent convulsions when production of deleterious metabolites in specific tissues, and/ stimulated. Skin lesions, ulcers on the paws and muzzles, and or (g) create a more effective drug and/or a safer drug for necrosis of the tails appear. The animals also become very polypharmacy, whether the polypharmacy be intentional or aggressive. When about 30% of the body water has been not. The deuteration approach has the strong potential to slow replaced with DO, the animals refuse to eat and become the metabolism of dronabinol and attenuate interpatient vari comatose. Their body weight drops sharply and their meta ability. bolic rates drop far below normal, with death occurring at 0014 Novel compounds and pharmaceutical composi about 30 to about 35% replacement with D.O.The effects are tions, certain of which have been found to modulate cannab reversible unless more than thirty percent of the previous inoid receptors have been discovered, together with methods body weight has been lost due to D.O. Studies have also of synthesizing and using the compounds, including methods shown that the use of DO can delay the growth of cancer cells for the treatment of cannabinoid receptor-mediated disorders and enhance the cytotoxicity of certain antineoplastic agents. in a patient by administering the compounds as disclosed 0011 Deuteration of pharmaceuticals to improve pharma herein. cokinetics (PK), pharmacodynamics (PD), and toxicity pro 0015. In certain embodiments of the present invention, files has been demonstrated previously with some classes of compounds have structural Formula I: drugs. For example, the DKIE was used to decrease the hepa totoxicity of halothane, presumably by limiting the produc

tion of reactive species such as trifluoroacetylchloride. How (I) ever, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic Switching. Metabolic Switching occurs when Xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the rela tively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class. 0012 Dronabinol is a cannabinoid receptor agonist. The carbon-hydrogen bonds of dronabinol contain a naturally occurring distribution of hydrogen isotopes, namely "H or protium (about 99.984.4%), H or deuterium (about or a pharmaceutically acceptable salt thereof, wherein: 0.0156%), and H or tritium (in the range between about 0.5 0016 R-R are independently selected from the group and 67 tritium atoms per 10' protium atoms). Increased consisting of hydrogen and deuterium; and levels of deuterium incorporation may produce a detectable 0017 at least one of R-Ro is deuterium. Deuterium Kinetic Isotope Effect (DKIE) that could effect 0018 Certain compounds disclosed herein may possess the pharmacokinetic, pharmacologic and/or toxicologic pro useful cannabinoid receptor modulating activity, and may be files of dronabinol in comparison with dronabinol having used in the treatment or prophylaxis of a disorder in which naturally occurring levels of deuterium. cannabinoid receptors play an active role. Thus, certain 0013 Based on discoveries made in our laboratory, as well embodiments also provide pharmaceutical compositions as considering the literature, dronabinol is metabolized in comprising one or more compounds disclosed herein together humans at the allylic methyl and methylene groups, and the with a pharmaceutically acceptable carrier, as well as meth n-pentylbeny Zlic methylene group. The current approach has ods of making and using the compounds and compositions. the potential to prevent metabolism at these sites. Other sites Certain embodiments provide methods for modulating can on the molecule may also undergo transformations leading to nabinoid receptor activity. Other embodiments provide meth metabolites with as-yet-unknown pharmacology/toxicology. ods for treating a cannabinoid receptor-mediated disorderina Limiting the production of these metabolites has the potential patient in need of Such treatment, comprising administering to decrease the danger of the administration of such drugs and to said patient a therapeutically effective amount of a com may even allow increased dosage and/or increased efficacy. pound or composition according to the present invention. All of these transformations can occur through polymorphi Also provided is the use of certain compounds disclosed cally-expressed enzymes, exacerbating interpatient variabil herein for use in the manufacture of a medicament for the ity. Further, some disorders are best treated when the subject prevention or treatment of a disorder ameliorated by modu is medicated around the clock or for an extended period of lating cannabinoid receptor activity. time. For all of the foregoing reasons, a medicine with a 0019. The compounds as disclosed herein may also con longer half-life may result in greater efficacy and cost sav tain less prevalent isotopes for other elements, including, but US 2010/0152283 A1 Jun. 17, 2010 not limited to, 'Cor'C for carbon, S.S, or S for sulfur, 0039 All publications and references cited herein are 'N for nitrogen, and ''O or "O for oxygen. expressly incorporated herein by reference in their entirety. 0020. In certain embodiments, the compound disclosed However, with respect to any similar or identical terms found herein may expose a patient to a maximum of about in both the incorporated publications or references and those 0.000005% DO or about 0.00001% DHO, assuming that all explicitly put forth or defined in this document, then those of the C-D bonds in the compound as disclosed herein are terms definitions or meanings explicitly put forth in this docu metabolized and released as DO or DHO. In certain embodi ment shall control in all respects. ments, the levels of DO shown to cause toxicity in animals is 0040. As used herein, the terms below have the meanings much greater than even the maximum limit of exposure indicated. caused by administration of the deuterium enriched com 0041. The singular forms “a”, “an', and “the may refer to pound as disclosed herein. Thus, in certain embodiments, the plural articles unless specifically stated otherwise. deuterium-enriched compound disclosed herein should not 0042. The term “about’, as used herein, is intended to cause any additional toxicity due to the formation of DO or qualify the numerical values which it modifies, denoting Such DHO upon drug metabolism. a value as variable within a margin of error. When no particu 0021. In certain embodiments, the deuterated compounds lar margin of error, such as a standard deviation to a mean disclosed herein maintain the beneficial aspects of the corre value given in a chart or table of data, is recited, the term sponding non-isotopically enriched molecules while Substan “about’ should be understood to mean that range which tially increasing the maximum tolerated dose, decreasingtox would encompass the recited value and the range which icity, increasing the half-life (T), lowering the maximum would be included by rounding up or down to that figure as plasma concentration (C) of the minimum efficacious well, taking into account significant figures. dose (MED), lowering the efficacious dose and thus decreas 0043. When ranges of values are disclosed, and the nota ing the non-mechanism-related toxicity, and/or lowering the tion “from n ... to n' or “n-n' is used, where n and n are probability of drug-drug interactions. the numbers, then unless otherwise specified, this notation is 0022. In certain embodiments, if R-Rs are deuterium, intended to include the numbers themselves and the range then at least one of Re-Ro is deuterium. between them. This range may be integral or continuous 0023. In other embodiments, if R-R, and Ras-Rs are between and including the end values. deuterium, then at least one of R-R and Ro-R is deute 0044) The term “deuterium enrichment” refers to the per rium. centage of incorporation of deuterium at a given position in a 0024. In other embodiments, if Ras-Rao are deuterium, molecule in the place of hydrogen. For example, deuterium then at least one of R-R is deuterium. enrichment of 1% at a given position means that 1% of mol 0025. In other embodiments, if R-Rs are deuterium, then ecules in a given sample contain deuterium at the specified at least one of Ro-Ro is deuterium. position. Because the naturally occurring distribution of deu 0026. In other embodiments, if R-R are deuterium, terium is about 0.0156%, deuterium enrichment at any posi then at least one of R-R and Ris-Ro is deuterium. tion in a compound synthesized using non-enriched starting 0027. In other embodiments, if R-R, R-R-7, and materials is about 0.0156%. The deuterium enrichment can Ro-R are deuterium, then at least one of R-R, R-Rs. be determined using conventional analytical methods known Ris-Rio, and R22-Rao is deuterium. to one of ordinary skill in the art, including mass spectrometry 0028. In other embodiments, if R-R and Ro-R are and nuclear magnetic resonance spectroscopy. deuterium, then at least one of R-R, R-R, and R-R-so 0045. The term “is/are deuterium, when used to describe is deuterium. a given position in a molecule such as R-R or the symbol “D’, when used to represent a given position in a drawing of 0029. In other embodiments, if R-R. R. and Ro-R a molecular structure, means that the specified position is are deuterium, then at least one of R-R, R-Rs, R7-R. enriched with deuterium above the naturally occurring distri and R-Ro is deuterium. bution of deuterium. In one embodiment deuterium enrich 0030. In other embodiments, if R-R are deuterium, ment is no less than about 1%, in another no less than about then at least one of R-R and Ra-Ro is deuterium. 5%, in another no less than about 10%, in another no less than 0031. In other embodiments, if R-R are deuterium, then about 20%, in another no less than about 50%, in another no at least one of Ra-Ro is deuterium. less than about 70%, in another no less than about 80%, in 0032. In other embodiments, if R and Ro-R are deu another no less than about 90%, or in another no less than terium, then at least one of R-Rs, R7-Ro, and R-Ro is about 98% of deuterium at the specified position. deuterium. 0046. The term “isotopic enrichment” refers to the per 0033. In other embodiments, if R7-R are deuterium, centage of incorporation of a less prevalent isotope of an then at least one of R-R and Ro-Ro is deuterium. element at a given position in a molecule in the place of the 0034. In other embodiments, if Rs-R are deuterium, then more prevalent isotope of the element. at least one of R-R, and R-Ro is deuterium. 0047. The term “non-isotopically enriched’ refers to a 0035. In other embodiments, if Ro-R are deuterium, molecule in which the percentages of the various isotopes are then at least one of R-R and R-Ro is deuterium. Substantially the same as the naturally occurring percentages. 0036. In other embodiments, if R-R. R. Rs, and Ro are 0048 Asymmetric centers exist in the compounds dis deuterium, then at least one of Rs. R-7, R. R. and R-Ro is closed herein. These centers are designated by the symbols deuterium. “R” or “S”, depending on the configuration of substituents 0037. In other embodiments, if R and Ra are deuterium, around the chiral carbon atom. It should be understood that then at least one of R-R and Rs-Ro is deuterium. the invention encompasses all Stereochemical isomeric 0038. In other embodiments, if R is deuterium, then at forms, including diastereomeric, enantiomeric, and epimeric least one of R-R and Re-Ro is deuterium. forms, as well as D-isomers and L-isomers, and mixtures US 2010/0152283 A1 Jun. 17, 2010

thereof. Individual stereoisomers of compounds can be pre peutic disorder described in the present disclosure. Such pared synthetically from commercially available starting administration encompasses co-administration of these materials which contain chiral centers or by preparation of therapeutic agents in a Substantially simultaneous manner, mixtures of enantiomeric products followed by separation Such as in a single capsule having a fixed ratio of active such as conversion to a mixture of diastereomers followed by ingredients or in multiple, separate capsules for each active separation or recrystallization, chromatographic techniques, ingredient. In addition, Such administration also encom direct separation of enantiomers on chiral chromatographic passes use of each type of therapeutic agent in a sequential columns, or any other appropriate method known in the art. manner. In either case, the treatment regimen will provide Starting compounds of particular stereochemistry are either beneficial effects of the drug combination in treating the commercially available or can be made and resolved by tech disorders described herein. niques known in the art. Additionally, the compounds dis 0055. The term “cannabinoid receptor” refers to a class of closed herein may exist as geometric isomers. The present G-protein coupled receptors. Two types of high-affinity can invention includes all cis, trans, syn, anti, entgegen (E), and nabinoid receptors have been identified: 1) CB1 receptors Zusammen (Z) isomers as well as the appropriate mixtures (Devane et al., Mol. Pharmacol. 1988, 34,605-613; Matsuda thereof. Additionally, compounds may exist as tautomers; all et al., Nature 1990, 346,561-564; Shire et al., J. Biol. Chem., tautomeric isomers are provided by this invention. Addition 1995, 270, 3726-3731; and Ishac et al., Br. J. Pharmacol. ally, the compounds disclosed herein can exist in unsolvated 1996, 118, 2023-2028), and 2) CB2 receptors (Munro et al., as well as Solvated forms with pharmaceutically acceptable Nature 1993, 365, 61-65). Both CB1 and CB2 are coupled to Solvents such as water, ethanol, and the like. In general, the the inhibitory G-protein alpha-subunit Receptor activation Solvated forms are considered equivalent to the unsolvated thus leads to inhibition of adenylate cyclase and activation of forms. mitogen activated protein kinase (MAPK) (Parolaro, D., Life 0049. The term “bond refers to a covalent linkage Sci. 1999, 65, 637–44). CB1 receptors can also modulate ion between two atoms, or two moieties when the atoms joined by channels, including: (1) inhibiting N-, and P/R-type calcium the bond are considered to be part of larger substructure. A channels, (2) stimulating inwardly rectifying K channels, and bond may be single, double, or triple unless otherwise speci (3) enhancing the activation of A-type K channels. CB 1 fied. A dashed line between two atoms in a drawing of a receptors are primarily, but not exclusively, expressed in the molecule indicates that an additional bond may be present or CNS and are believed to mediate the CNS effects of endog absent at that position. enous (e.g., anandamide, 2-arachidonylglycerol 2-AG) and 0050. The term “disorder as used herein is intended to be exogenous . CB1 receptors are also located on generally synonymous, and is used interchangeably with, the central and peripheral nerve terminals and, when activated, terms “disease”, “disorder, and “condition' (as in medical seem to Suppress the neuronal release of a number of excita condition), in that all reflect an abnormal condition of the tory and inhibitory transmitters including acetylcholine, human or animal body or of one of its parts that impairs noradrenaline, dopamine, 5-hydroxytryptamine, gamma normal functioning, is typically manifested by distinguishing aminobutyric acid, glutamate and aspartate (Pertwee et al., signs and Symptoms. Pharmacol. Ther: 1997, 129, 74; Ong et al., Neuroscience, 0051. The terms “treat”, “treating, and “treatment” are 1999,92, 1177; and Pertwee et al., Progr: Neurobiol., 2001, meant to include alleviating or abrogating a disorder or one or 63, 569). CB2 receptor expression was originally thought to more of the symptoms associated with a disorder, or allevi be restricted to the periphery, mainly in lymphoid organs and ating or eradicating the cause(s) of the disorder itself. As used cells of the immune system, including spleen, thymus, ton herein, reference to “treatment of a disorder is intended to sils, bone marrow, pancreas and mast cells with particularly include prevention. The terms “prevent”, “preventing, and high levels in B-cells and natural killer cells (Galiegue et al., “prevention” refer to a method of delaying or precluding the Bur: J. Biochein 1995, 54, 232). Recent studies, however, onset of a disorder; and/or its attendant symptoms, barring a demonstrate that CB2 is expressed in the brain stem, cortex, Subject from acquiring a disorder or reducing a subject's risk cerebellum and hippocampus (Onaivi et al., Ann. N.Y. Acad. of acquiring a disorder. Sci. 2006, 1074, 514-36; and Van Sickle et al., Science 2005, 0052. The term “therapeutically effective amount” refers 310, 329-32). In addition, there is both electophysiological to the amount of a compound that, when administered, is and in situ hybridization data that demonstrate expression of sufficient to prevent development of, or alleviate to some CB2 receptors in the dorsal root ganglion and primary sen extent, one or more of the symptoms of the disorder being sory afferent fibers in the spinal cord (Elmes et al., Eur: J. treated. The term “therapeutically effective amount” also Neurosci. 2004, 20, 2311-20; Wotherspoon et al., Neuro refers to the amount of a compound that is sufficient to elicit science 2005, 135,235-45; and Zhanget al., Eur: J. Neurosci. the biological or medical response of a cell, tissue, system, 2003, 17, 2750-54). animal, or human that is being sought by a researcher, Veteri 0056. The term “cannabinoid receptor-mediated disor narian, medical doctor, or clinician. der, refers to a disorder that is characterized by abnormal 0053. The term “subject” refers to an animal, including, cannabinoid receptor activity, or normal cannabinoid recep but not limited to, a primate (e.g., human, monkey, chimpan tor activity that when modulated ameliorates other abnormal Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, biochemical processes. A cannabinoid receptor-mediated hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, disorder may be completely or partially mediated by modu miniature pig), equine, canine, feline, and the like. The terms lating cannabinoid receptor activity. In particular, a cannab “subject' and “patient” are used interchangeably herein in inoid receptor-mediated disorder is one in which modulating reference, for example, to a mammalian Subject, such as a cannabinoid receptor activity results in some effect on the human patient. underlying disorder e.g., administration of a cannabinoid 0054 The term “combination therapy’ means the admin results in Some improvement in at least istration of two or more therapeutic agents to treat a thera Some of the patients being treated. US 2010/0152283 A1 Jun. 17, 2010

0057 The term “cannabinoid receptor modulator, refers composition thereof, which is administered to a subject for to the ability of a compound disclosed herein to alter the treating, preventing, or ameliorating one or more symptoms function of cannabinoid receptor. A cannabinoid receptor of a disorder. modulator may activate the activity of a cannabinoid receptor, 0062. The term “release controlling excipient” refers to an may activate or inhibit the activity of a cannabinoid receptor excipient whose primary function is to modify the duration or depending on the concentration of the compound exposed to place of release of the active Substance from a dosage form as the cannabinoid receptor, or may inhibit the activity of a compared with a conventional immediate release dosage cannabinoid receptor. Such activation or inhibition may be form. contingent on the occurrence of a specific event. Such as 0063. The term “nonrelease controlling excipient” refers activation of a signal transduction pathway, and/or may be to an excipient whose primary function do not include modi manifest only in particular cell types. The term “cannabinoid fying the duration or place of release of the active Substance receptor modulator, also refers to altering the function of a from a dosage form as compared with a conventional imme cannabinoid receptor by increasing or decreasing the prob diate release dosage form. ability that a complex forms between a cannabinoid receptor 0064. The term “prodrug” refers to a compound functional and a natural binding partner. A cannabinoid receptor modu derivative of the compound as disclosed herein and is readily lator may increase the probability that such a complex forms convertible into the parent compound in vivo. Prodrugs are between the cannabinoid receptor and the natural binding often useful because, in Some situations, they may be easier to partner, may increase or decrease the probability that a com administer than the parent compound. They may, for instance, plex forms between the cannabinoid receptor and the natural be bioavailable by oral administration whereas the parent binding partner depending on the concentration of the com compound is not. The prodrug may also have enhanced solu pound exposed to the cannabinoid receptor, and or may bility in pharmaceutical compositions over the parent com decrease the probability that a complex forms between the pound. A prodrug may be converted into the parent drug by cannabinoid receptor and the natural binding partner. In some various mechanisms, including enzymatic processes and embodiments, modulation of the cannabinoid receptor may metabolic hydrolysis (See Harper, Progress in Drug Research be assessed using the method described in Yao et al., Brit. J. 1962, 4, 221–294; Morozowich et al. in “Design of Biophar Pharmacol. 2006, 149, 145-154; and Steffens et al., Brit. J. maceutical Properties through Prodrugs and Analogs. Roche Ed., APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers Pharmacol. 2004, 141, 1193–1203. in Drug in Drug Design, Theory and Application. Roche Ed., 0058. The term “therapeutically acceptable” refers to APHA Acad. Pharm. Sci. 1987: "Design of Prodrugs.” Bund those compounds (or salts, prodrugs, tautomers, Zwitterionic gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, forms, etc.) which are suitable for use in contact with the 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997,27, tissues of patients without excessive toxicity, irritation, aller 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; gic response, immunogenecity, are commensurate with a rea Gaignault et al., Pract. Med. Chem. 1996, 671-696; sonable benefit/risk ratio, and are effective for their intended Asgharnejad in “Transport Processes in Pharmaceutical Sys US tems. Amidon et al., Ed., Marcell Dekker, 185-218, 2000; 0059. The term “pharmaceutically acceptable carrier, Balant et al., Eur: J. Drug Metab. Pharmacokinet. 1990, 15, “pharmaceutically acceptable excipient”, “physiologically 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, acceptable carrier, or “physiologically acceptable excipi 39, 183-209: Browne, Clin. Neuropharmacol. 1997, 20, 1-12; ent” refers to a pharmaceutically-acceptable material, com Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, position, or vehicle, such as a liquid or Solid filler, diluent, Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. excipient, solvent, or encapsulating material. Each compo Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug nent must be “pharmaceutically acceptable' in the sense of Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods being compatible with the other ingredients of a pharmaceu Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. tical formulation. It must also be suitable for use in contact 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. with the tissue or organ of humans and animals without exces Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. sive toxicity, irritation, allergic response, immunogenecity, or Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. other problems or complications, commensurate with a rea Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and sonable benefit/risk ratio. See, Remington. The Science and Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. Practice of Pharmacy, 21st Edition; Lippincott Williams & Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs Wilkins: Philadelphia, Pa., 2005, Handbook of Pharmaceu 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, tical Excipients, 5th Edition; Rowe et al., Eds. The Pharma 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 ceutical Press and the American Pharmaceutical Association: 148; Valentino and Borchardt, Drug Discovery Today 1997.2, 2005; and Handbook of Pharmaceutical Additives, 3rd Edi 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, tion; Ash and Ash Eds. Gower Publishing Company: 2007; 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, Pharmaceutical Preformulation and Formulation, Gibson 497-507. Ed., CRC Press LLC: Boca Raton, Fla., 2004). 0065. The compounds disclosed herein can exist as thera 0060. The terms “active ingredient”, “active compound', peutically acceptable salts. The term “pharmaceutically and “active Substance' refer to a compound, which is admin acceptable salt, as used herein, represents salts or Zwitteri istered, alone or in combination with one or more pharma onic forms of the compounds disclosed herein which are ceutically acceptable excipients or carriers, to a Subject for therapeutically acceptable as defined herein. The salts can be treating, preventing, or ameliorating one or more symptoms prepared during the final isolation and purification of the of a disorder. compounds or separately by reacting the appropriate com 0061 The terms “drug”,99 “therapeutic&g agent, and “chemo pound with a suitable acid or base. Therapeutically accept therapeutic agent” refer to a compound, or a pharmaceutical able salts include acid and basic addition salts. For a more US 2010/0152283 A1 Jun. 17, 2010 complete discussion of the preparation and selection of salts, The pharmaceutical compositions may also be formulated as refer to “Handbook of Pharmaceutical Salts, Properties, and a modified release dosage form, including delayed-, Use.” Stah and Wermuth, Ed. (Wiley-VCH and VHCA, Zur extended-, prolonged-, Sustained-, pulsatile-, controlled ich, 2002) and Berge et al., J. Pharm. Sci. 1977, 66, 1-19. accelerated- and fast-, targeted-, programmed-release, and 0066 Suitable acids for use in the preparation of pharma gastric retention dosage forms. These dosage forms can be ceutically acceptable salts include, but are not limited to, prepared according to conventional methods and techniques acetic acid, 2,2-dichloroacetic acid, acylated amino acids, known to those skilled in the art (see, Remington. The Science adipic acid, alginic acid, ascorbic acid, L-aspartic acid, ben and Practice of Pharmacy, supra; Modified-Release Drug Zenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, Deliver Technology, Rathbone et al., Eds. Drugs and the boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- Pharmaceutical Science, Marcel Dekker, Inc.: New York, (1S)-camphor-10-Sulfonic acid, capric acid, caproic acid, N.Y., 2002; Vol. 126). caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclo 0069. The compositions include those suitable for oral, hexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disul parenteral (including Subcutaneous, intradermal, intramuscu fonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic lar, intravenous, intraarticular, and intramedullary), intraperi acid, formic acid, fumaric acid, galactaric acid, gentisic acid, toneal, transmucosal, transdermal, rectal and topical (includ glucoheptonic acid, D-gluconic acid, D-glucuronic acid, ing dermal, buccal, Sublingual and intraocular) L-glutamic acid, C-OXO-glutaric acid, glycolic acid, hippuric administration although the most Suitable route may depend acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, upon for example the condition and disorder of the recipient. (+)-L-lactic acid, (t)-DL-lactic acid, lactobionic acid, lauric The compositions may conveniently be presented in unit dos acid, maleic acid, (-)-L-malic acid, malonic acid, (+)-DL age form and may be prepared by any of the methods well mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic known in the art of pharmacy. Typically, these methods acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naph include the step of bringing into association a compound of thoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, the Subject invention or a pharmaceutically salt, prodrug, or oxalic acid, palmitic acid, pamoic acid, perchloric acid, phos solvate thereof (“active ingredient') with the carrier which phoric acid, L-pyroglutamic acid, Saccharic acid, salicylic constitutes one or more accessory ingredients. In general, the acid, 4-amino-salicylic acid, sebacic acid, Stearic acid, suc compositions are prepared by uniformly and intimately cinic acid, Sulfuric acid, tannic acid, (+)-L-tartaric acid, thio bringing into association the active ingredient with liquid cyanic acid, p-toluenesulfonic acid, undecylenic acid, and carriers or finely divided solid carriers or both and then, if Valeric acid. necessary, shaping the product into the desired formulation. 0067 Suitable bases for use in the preparation of pharma 0070 Formulations of the compounds disclosed herein ceutically acceptable salts, including, but not limited to, inor Suitable for oral administration may be presented as discrete ganic bases, such as magnesium hydroxide, calcium hydrox units such as capsules, cachets or tablets each containing a ide, potassium hydroxide, Zinc hydroxide, or sodium predetermined amount of the active ingredient; as a powder or hydroxide; and organic bases, such as primary, secondary, granules; as a solution or a suspension in an aqueous liquid or tertiary, and quaternary, aliphatic and aromatic amines, a non-aqueous liquid; or as an oil-in-water liquid emulsion or including L-arginine, benethamine, benzathine, choline, a water-in-oil liquid emulsion. The active ingredient may also deanol, diethanolamine, diethylamine, dimethylamine, be presented as a bolus, electuary or paste. dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, 0071 Pharmaceutical preparations which can be used ethanolamine, ethylamine, ethylenediamine, isopropy orally include tablets, push-fit capsules made of gelatin, as lamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, well as Soft, sealed capsules made of gelatin and a plasticizer, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, Such as glycerol or Sorbitol. Tablets may be made by com methylamine, piperidine, piperazine, propylamine, pyrroli pression or molding, optionally with one or more accessory dine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, ingredients. Compressed tablets may be prepared by com quinoline, isoquinoline, secondary amines, triethanolamine, pressing in a suitable machine the active ingredient in a free trimethylamine, triethylamine, N-methyl-D-glucamine, flowing form such as a powder or granules, optionally mixed 2-amino-2-(hydroxymethyl)-1,3-propanediol. and with binders, inert diluents, or lubricating, surface active or tromethamine. dispersing agents. Molded tablets may be made by molding in 0068 While it may be possible for the compounds of the a suitable machine a mixture of the powdered compound Subject invention to be administered as the raw chemical, it is moistened with an inert liquid diluent. The tablets may also possible to present them as a pharmaceutical composi optionally be coated or scored and may be formulated so as to tion. Accordingly, provided herein are pharmaceutical com provide slow or controlled release of the active ingredient positions which comprise one or more of certain compounds therein. All formulations for oral administration should be in disclosed herein, or one or more pharmaceutically acceptable dosages suitable for Such administration. The push-fit cap salts, prodrugs, or Solvates thereof, together with one or more Sules can contain the active ingredients in admixture with pharmaceutically acceptable carriers thereof and optionally filler Such as lactose, binders such as starches, and/or lubri one or more other therapeutic ingredients. Proper formulation cants such as talc or magnesium Stearate and, optionally, is dependent upon the route of administration chosen. Any of stabilizers. In soft capsules, the active compounds may be the well-known techniques, carriers, and excipients may be dissolved or Suspended in Suitable liquids, such as fatty oils, used as Suitable and as understood in the art; e.g., in Reming liquid paraffin, or liquid polyethylene glycols. In addition, ton's Pharmaceutical Sciences. The pharmaceutical compo stabilizers may be added. Dragee cores are provided with sitions disclosed herein may be manufactured in any manner Suitable coatings. For this purpose, concentrated Sugar Solu known in the art, e.g., by means of conventional mixing, tions may be used, which may optionally contain gum arabic, dissolving, granulating, dragee-making, levigating, emulsi talc, polyvinyl pyrrolidone, carbopol gel, polyethylene gly fying, encapsulating, entrapping or compression processes. col, and/or titanium dioxide, lacquer Solutions, and Suitable US 2010/0152283 A1 Jun. 17, 2010

organic solvents or solvent mixtures. Dyestuffs or pigments etration through the skin to the site of inflammation Such as may be added to the tablets or dragee coatings for identifica gels, liniments, lotions, creams, ointments or pastes, and tion or to characterize different combinations of active com drops suitable for administration to the eye, ear or nose. pound doses. 007.9 For administration by inhalation, compounds may 0072 The compounds may be formulated for parenteral be delivered from an insufflator, nebulizer pressurized packs administration by injection, e.g., by bolus injection or con or other convenient means of delivering an aerosol spray. tinuous infusion. Formulations for injection may be presented Pressurized packs may comprise a suitable propellant Such as in unit dosage form, e.g., in ampoules or in multi-dose con dichlorodifluoromethane, trichlorofluoromethane, dichlo tainers, with an added preservative. The compositions may rotetrafluoroethane, carbon dioxide or other suitable gas. In take Such forms as Suspensions, solutions or emulsions in oily the case of a pressurized aerosol, the dosage unit may be or aqueous vehicles, and may contain formulatory agents determined by providing a valve to deliver a metered amount. Such as Suspending, stabilizing and/or dispersing agents. The Alternatively, for administration by inhalation or insufflation, formulations may be presented in unit-dose or multi-dose the compounds according to the invention may take the form containers, for example sealed ampoules and vials, and may ofa dry powder composition, for example a powder mix of the be stored in powder form or in a freeze-dried (lyophilized) compound and a suitable powder base such as lactose or condition requiring only the addition of the sterile liquid starch. The powder composition may be presented in unit carrier, for example, saline or sterile pyrogen-free water, dosage form, in for example, capsules, cartridges, gelatin or immediately prior to use. Extemporaneous injection solu blister packs from which the powder may be administered tions and Suspensions may be prepared from sterile powders, with the aid of an inhalator or insufflator. granules and tablets of the kind previously described. 0080 Preferred unit dosage formulations are those con 0073 Formulations for parenteral administration include taining an effective dose, as herein below recited, oran appro aqueous and non-aqueous (oily) sterile injection Solutions of priate fraction thereof, of the active ingredient. the active compounds which may contain antioxidants, buff ers, bacteriostats and solutes which render the formulation I0081 Compounds may be administered orally or via isotonic with the blood of the intended recipient; and aqueous injection at a dose of from 0.1 to 500 mg/kg per day. The dose and non-aqueous sterile Suspensions which may include Sus range for adult humans is generally from 5 mg to 2 g/day. pending agents and thickening agents. Suitable lipophilic Tablets or other forms of presentation provided in discrete Solvents or vehicles include fatty oils such as sesame oil, or units may conveniently contain an amount of one or more synthetic fatty acid esters, such as ethyl oleate or triglycer compounds which is effective at Such dosage or as a multiple ides, or liposomes. Aqueous injection Suspensions may con of the same, for instance, units containing 5 mg to 500 mg. tain Substances which increase the Viscosity of the Suspen usually around 10 mg to 200 mg. Sion, such as Sodium carboxymethyl cellulose, Sorbitol, or I0082. The amount of active ingredient that may be com dextran. Optionally, the Suspension may also contain Suitable bined with the carrier materials to produce a single dosage stabilizers or agents which increase the solubility of the com form will vary depending upon the host treated and the par pounds to allow for the preparation of highly concentrated ticular mode of administration. Solutions. I0083. The compounds can be administered in various 0074. In addition to the formulations described previously, modes, e.g. orally, topically, or by injection. The precise the compounds may also be formulated as a depot prepara amount of compound administered to a patient will be the tion. Such long acting formulations may be administered by responsibility of the attendant physician. The specific dose implantation (for example Subcutaneously or intramuscu level for any particular patient will depend upon a variety of larly) or by intramuscular injection. Thus, for example, the factors including the activity of the specific compound compounds may be formulated with Suitable polymeric or employed, the age, body weight, general health, sex, diets, hydrophobic materials (for example as an emulsion in an time of administration, route of administration, rate of excre acceptable oil) or ion exchange resins, or as sparingly soluble tion, drug combination, the precise disorder being treated, derivatives, for example, as a sparingly soluble salt. and the severity of the disorder being treated. Also, the route 0075 Forbuccal or sublingual administration, the compo of administration may vary depending on the disorder and its sitions may take the form of tablets, lozenges, pastilles, or severity. gels formulated in conventional manner. Such compositions I0084. In the case wherein the patient's condition does not may comprise the active ingredient in a flavored basis such as improve, upon the doctor's discretion the administration of Sucrose and acacia or tragacanth. the compounds may be administered chronically, that is, for 0076. The compounds may also be formulated in rectal an extended period of time, including throughout the duration compositions such as Suppositories or retention enemas, e.g., of the patient's life in order to ameliorate or otherwise control containing conventional Suppository bases such as cocoa but or limit the symptoms of the patient’s disorder. ter, polyethylene glycol, or other glycerides. I0085. In the case wherein the patient's status does 0077 Certain compounds disclosed herein may be admin improve, upon the doctor's discretion the administration of istered topically, that is by non-systemic administration. This the compounds may be given continuously or temporarily includes the application of a compound disclosed herein Suspended for a certain length of time (i.e., a "drug holiday'). externally to the epidermis or the buccal cavity and the instil I0086 Once improvement of the patient's conditions has lation of Sucha compound into the ear, eye and nose, such that occurred, a maintenance dose is administered if necessary. the compound does not significantly enter the blood stream. Subsequently, the dosage or the frequency of administration, In contrast, Systemic administration refers to oral, intrave or both, can be reduced, as a function of the symptoms, to a nous, intraperitoneal and intramuscular administration. level at which the improved disorder is retained. Patients can, 0078 Formulations suitable for topical administration however, require intermittent treatment on a long-term basis include liquid or semi-liquid preparations Suitable for pen upon any recurrence of symptoms. US 2010/0152283 A1 Jun. 17, 2010

0087 Disclosed herein are methods of treating a cannab inoid receptor-mediated disorder comprising administering to a Subject having or Suspected of having Such a disorder, a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt, Solvate, or pro drug thereof. CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, 0088 Cannabinoid receptor-mediated disorders, include, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and but are not limited to, chemotherapy-induced emesis, pain, CYP51. neuropathic pain, multiple Sclerosis, spasticity, Alzheimer's 0093 Examples of monoamine oxidase isoforms in a disease, nausea, vomiting, affective disorders, anorexia ner mammalian Subject include, but are not limited to, MAO Vosa, dementia, major depressive disorder, cachexia, HIV and MAO. wasting syndrome, Tourette's syndrome, emesis, and/or any 0094. The inhibition of the cytochrome Paso isoform is disorder which can lessened, alleviated, or prevented by measured by the method of Ko et al., British Journal of administering a cannabinoid receptor modulator. Clinical Pharmacology 2000, 49,343-351. The inhibition of 0089. In certain embodiments, a method of treating a can the MAO isoform is measured by the method of Weyler et nabinoid receptor-mediated disorder comprises administer al., J. Biol. Chem. 1985, 260, 13199-13207. The inhibition of ing to the Subject a therapeutically effective amount of a the MAO isoform is measured by the method of Uebelhack compound as disclosed herein, or a pharmaceutically accept et al., Pharmacopsychiatry 1998, 31, 187-192. able salt, Solvate, or prodrug thereof, so as to affect: (1) 0.095 Examples of polymorphically-expressed cyto decreased inter-individual variation in plasma levels of the chrome Paso isoforms in a mammalian Subject include, but are compound or a metabolite thereof (2) increased average not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. plasma levels of the compound or decreased average plasma 0096. The metabolic activities of liver microsomes, cyto levels of at least one metabolite of the compound per dosage chrome Paso isoforms, and monoamine oxidase isoforms are unit; (3) decreased inhibition of, and/or metabolism by at measured by the methods described herein. least one cytochrome Paso or monoamine oxidase isoform in 0097 Examples of improved disorder-control and/or dis the Subject; (4) decreased metabolism via at least one poly order-eradication endpoints, or improved clinical effects morphically-expressed cytochrome Paso isoform in the Sub include, but are not limited to, reduced nausea intensity and ject; (5) at least one statistically-significantly improved dis Vomiting, weight gain or reduced weight loss, increased appe order-control and/or disorder-eradication endpoint; (6) an tite, improved Cohen-Mansfield agitation inventory scores, improved clinical effect during the treatment of the disorder, reduced pain, improved Visual Analog Scale scores (Drug (7) prevention of recurrence, or delay of decline or appear Report for Dronabinol, Thompson Investigational Drug ance, of abnormal alimentary or hepatic parameters as the Database (Aug. 12, 2008); Ashton et al., Curr. Opin. Invest. primary clinical benefit, or (8) reduction or elimination of Drugs 2008, 9(1), 65-75; Beal et al., J. Pain Symptom Man deleterious changes in any diagnostic hepatobiliary function agement 1995, 10(2), 89-97: Meiri et al., Curr. Med. Res. endpoints, as compared to the corresponding non-isotopi Opin. 2007, 23(3), 533-43: Struwe et al., Ann. Pharmacother. cally enriched compound. 1993, 27, 827-31; and Volicer et al., Int. J. Geriatric Psych. 0090. In certain embodiments, inter-individual variation 1997, 12,913-19). in plasma levels of the compounds as disclosed herein, or 0098. Examples of diagnostic hepatobiliary function end metabolites thereof, is decreased; average plasma levels of points include, but are not limited to, alanine aminotrans the compound as disclosed herein are increased; average ferase (ALT), serum glutamic-pyruvic transaminase plasma levels of a metabolite of the compound as disclosed (“SGPT), aspartate aminotransferase (“AST' or “SGOT), herein are decreased; inhibition of a cytochrome Paso or ALT/AST ratios, serum aldolase, alkaline phosphatase monoamine oxidase isoform by a compound as disclosed (ALP), ammonia levels, bilirubin, gamma-glutamyl herein is decreased; or metabolism of the compound as dis transpeptidase (“GGTP” “Y-GTP or “GGT), leucine ami closed herein by at least one polymorphically-expressed nopeptidase (“LAP), liver biopsy, liver ultrasonography, cytochrome Paso isoform is decreased; by greater than about liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa 5%, greater than about 10%, greater than about 20%, greater tobiliary endpoints are compared to the stated normal levels than about 30%, greater than about 40%, or by greater than as given in “Diagnostic and Laboratory Test Reference', 4' about 50% as compared to the corresponding non-isotopi edition, Mosby, 1999. These assays are run by accredited cally enriched compound. laboratories according to standard protocol. 0091 Plasma levels of the compound as disclosed herein, 0099 Besides being useful for human treatment, certain or metabolites thereof, may be measured using the methods compounds and formulations disclosed herein may also be described by Li et al. Rapid Communications in Mass Spec useful for veterinary treatment of companion animals, exotic trometry 2005, 19, 1943-1950; Coulter et al., Drug Testing animals and farm animals, including mammals, rodents, and and Analysis 2009, 1(5), 234-239; Jagerdeo et al., Rapid the like. More preferred animals include horses, dogs, and Communications in Mass Spectrometry 2009, 23(17), 2697 Cats. 2705; Chu et al., Journal of Analytical Toxicology 2002, 26(8), 575-581; Thomas et al., Journal of Pharmaceutical Combination Therapy and Biomedical Analysis 2007, 45(3), 495-503; and any ref 0100. The compounds disclosed herein may also be com erences cited therein and any modifications made thereof. bined or used in combination with other agents useful in the 0092. Examples of cytochrome Paso isoforms in a mam treatment of cannabinoid receptor-mediated disorders. Or, by malian subject include, but are not limited to, CYP1A1, way of example only, the therapeutic effectiveness of one of CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, the compounds described herein may be enhanced by admin CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, istration of an adjuvant (i.e., by itself the adjuvant may only US 2010/0152283 A1 Jun. 17, 2010

have minimal therapeutic benefit, but in combination with ide, flumethiazide, hydroflumethiazide, bendroflumethiaz another therapeutic agent, the overall therapeutic benefit to ide, methylchlorothiazide, trichloromethiazide, polythiazide, the patient is enhanced). benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, 0101 Such other agents, adjuvants, or drugs, may be furosenilde, musolimine, bumetanide, triamterene, administered, by a route and in an amount commonly used amiloride, and spironolactone; thrombolytic agents, such as therefor, simultaneously or sequentially with a compound as tissue plasminogen activator (tPA), recombinant tRA, strep disclosed herein. When a compound as disclosed herein is tokinase, urokinase, prourokinase, and anisoylated plasmino used contemporaneously with one or more other drugs, a gen streptokinase activator complex (APSAC); anti-diabetic pharmaceutical composition containing such other drugs in agents, such as biguanides (e.g. metformin), glucosidase addition to the compound disclosed herein may be utilized, inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repa but is not required. glinide), Sulfonylureas (e.g., glimepiride, glyburide, and glip 0102. In certain embodiments, the compounds disclosed izide), thioZolidinediones (e.g. troglitaZone, rosiglitaZone herein can be combined with one or more anti-emetics or and pioglitaZone), and PPAR-gamma ; mineralocor analgesics. ticoid receptor antagonists, such as Spironolactone and 0103) In certain embodiments, the compounds disclosed eplerenone; growth hormone secretagogues; aP2 inhibitors; herein can be combined with one or more anti-emetics, phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., including, but not limited to, , , cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil. , , and palomosetron, , Vardenafil); protein tyrosine kinase inhibitors; antiinflamma , , , , tories; antiproliferatives, such as methotrexate, FK506 (tac , , , , rolimus, Prograf), mycophenolate mofetil: chemotherapeutic , , , promethaZ agents; immunosuppressants; anticancer agents and cyto ine, hydroxy Zine, dronabinol, , , hyos toxic agents (e.g., alkylating agents, such as nitrogen mus cine, , , casopitant, trimethobenza tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria mide, and . Zenes); antimetabolites, such as folate antagonists, purine 0104. In certain embodiments, the compounds disclosed analogues, and pyrridine analogues; antibiotics, such as herein can be combined with one or more analgesics, includ anthracyclines, bleomycins, mitomycin, dactinomycin, and ing, but not limited to, carbamazepine, , pregaba plicamycin; enzymes, such as L-asparaginase; farnesyl-pro tein transferase inhibitors; hormonal agents, such as gluco lin, acetaminophen, acetylsalicyclic acid, ibuprofen, and corticoids (e.g., cortisone), estrogens/antiestrogens, andro naproXen. gens/antiandrogens, progestins, and luteinizing hormone 0105. The compounds disclosed herein can also be admin releasing hormone anatagonists, and octreotide acetate; istered in combination with other classes of compounds, microtubule-disruptor agents, such as ecteinascidins; micro including, but not limited to, norepinephrine reuptake inhibi tubule-stablizing agents, such as pacitaxel, docetaxel, and tors (NRIs) such as ; dopamine reuptake inhibi epothilones A-F; plant-derived products. Such as Vinca alka tors (DARIs). Such as methylphenidate; serotonin-norepi loids, epipodophyllotoxins, and taxanes; and topoisomerase nephrine reuptake inhibitors (SNRIs), such as ; inhibitors; prenyl-protein transferase inhibitors; and sedatives. Such as diazepham; norepinephrine-dopamine cyclosporins; steroids. Such as prednisone and dexametha (NDRIs), such as ; serotonin Sone; cytotoxic drugs, such as azathiprine and cyclophospha norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti Such as ; monoamine oxidase inhibitors, such as bodies or soluble TNF receptor, such as etanercept, ; hypothalamic phospholipids; endothelin convert rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) ing enzyme (ECE) inhibitors, such as phosphoramidon; opio inhibitors, such as celecoxib and rofecoxib; and miscella ids. Such as tramadol; thromboxane receptor antagonists, neous agents such as, hydroxyurea, procarbazine, mitotane, Such as ifetroban; potassium channel openers; thrombin hexamethylmelamine, gold compounds, platinum coordina inhibitors, such as hirudin; hypothalamic phospholipids; tion complexes, such as cisplatin, satraplatin, and carbopl growth factor inhibitors, such as modulators of PDGF activ atin. ity; platelet activating factor (PAF) antagonists; anti-platelet 0106 Thus, in another aspect, certain embodiments pro agents, such as GPIb/IIIa blockers (e.g., abdximab, eptifi vide methods for treating cannabinoid receptor-mediated dis batide, and tirofiban), P2Y (AC) antagonists (e.g., clopi orders in a human or animal Subject in need of such treatment dogrel, ticlopidine and CS-747), and aspirin; anticoagulants, comprising administering to said subject an amount of a Such as warfarin; low molecular weight heparins, such as compound disclosed herein effective to reduce or prevent said enoxaparin; Factor VIIa Inhibitors and Factor Xa Inhibitors: disorder in the subject, in combination with at least one addi renin inhibitors; neutral endopeptidase (NEP) inhibitors: tional agent for the treatment of said disorder. In a related vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as aspect, certain embodiments provide therapeutic composi omapatrilat and gemopatrilat; HMG CoA reductase inhibi tions comprising at least one compound disclosed herein in tors, such as pravastatin, lovastatin, atorvastatin, simvastatin, combination with one or more additional agents for the treat NK-104 (a.k.a. itavastatin, niSvastatin, or nisbastatin), and ment of cannabinoid receptor-mediated disorders. ZD-4522 (also known as rosuvastatin, or atavastatin or vis astatin): squalene synthetase inhibitors; fibrates; bile acid General Synthetic Methods for Preparing Compounds sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium 0107 Isotopic hydrogen can be introduced into a com channel blockers, such as amlodipine besylate; potassium pound as disclosed herein by synthetic techniques that channel activators; alpha-muscarinic agents; beta-muscarinic employ deuterated reagents, whereby incorporation rates are agents, such as carvedilol and metoprolol, antiarrhythmic pre-determined; and/or by exchange techniques, wherein agents: diuretics, such as chlorothlazide, hydrochlorothiaz incorporation rates are determined by equilibrium conditions, US 2010/0152283 A1 Jun. 17, 2010 10 and may be highly variable depending on the reaction condi and/or procedures found in WO 2007041167; WO tions. Synthetic techniques, where tritium or deuterium is 2004O92101; U.S. Pat. No. 7,323,576; Nikas et al., Tetrahe directly and specifically inserted by tritiated or deuterated dron, 2007. 63(34), 81 12-23; Trost et al., Org. Lett. 2007, reagents of known isotopic content, may yield high tritium or 9(5), 861-63; Siegel et al., J. Org. Chem. 1991, 56(24), 6865 deuterium abundance, but can be limited by the chemistry 72; Handrick et al., Tet. Lett. 1979, (8), 681-4, which are required. Exchange techniques, on the other hand, may yield hereby incorporated in their entirety, and references cited lower tritium or deuterium incorporation, often with the iso therein and routine modifications thereof. Compounds as dis tope being distributed over many sites on the molecule. closed herein can also be prepared as shown in any of the 0108. The compounds as disclosed herein can be prepared following schemes and routine modifications thereof. by methods known to one of skill in the art and routine 0109 The following schemes can be used to practice the modifications thereof, and/or following procedures similar to present invention. Any position shown as hydrogen may be those described herein and routine modifications thereof, optionally substituted with deuterium.

Scheme I O R24 COCH R18 R18 R19 R17 R19 R17 O

R R23 R22 R R R R 16N2. Rs 2 20 I6 20 I6 --> R R15 O -- R R15 R R22 R22 7 S R21 R23 O R23 OH R18 R19 R20 R-V2'-3COCH R-2COH 1 3 4

10 US 2010/0152283 A1 Jun. 17, 2010 11

-continued

11

0110 Compound 1 is reacted with compound 2 and hyd at RandR, these protons may be replaced with deuterium roquinone in an appropriate solvent, Such as toluene, to give selectively or non-selectively through a proton-deuterium compound 3. Compound 3 is reacted with an appropriate exchange method known in the art. hydroxide base. Such as hydroxide, in an appropriate Solvent, such as water, to give compound 4. Compound 4 is 0114. The following compounds can generally be made resolved with an appropriate chiral amine. Such as (+)-me using the methods described above. thyl-benzylamine, in an appropriate solvent, such as acetone,

to give an intermediate salt that upon aqueous workup gives enantiomerically enriched compound 5. Compound 5 is reacted with an appropriate esterifying reagent, Such as dim ethyl sulfate, in the presence of an appropriate base. Such as potassium carbonate, in an appropriate solvent, such as acetone, to give compound 6. Compound 6 is reacted with compound 7 in an appropriate solvent, such as tetrahydrofu ran, to give compound 8. Compound 8 is reacted with com pound 9 in the presence of an appropriate acid, such as cam phorsulfonic acid, in an appropriate solvent, such as dichloromethane, to give compound 10. Compound 10 is cyclized in the presence of an appropriate catalyst, Such as a mixture of Zinc chloride and magnesium Sulfate, in an appro priate solvent, such as dichloromethane, to give a compound 11 of Formula I. 0111 Deuterium can be incorporated into different posi tions synthetically, according to the synthetic procedures as shown in Scheme I, by using appropriate deuterated interme diates. For example, to introduce deuterium at one or more positions of Rs-R, compound 1 with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R-Ra, compound 2 with the corresponding deuterium Substitution can be used. To intro duce deuterium at one or more positions of Rs-Ro com pound 7 with the corresponding deuterium Substitutions can be used. To introduce deuterium at one or more positions of R-R, compound 9 with the corresponding deuterium Sub stitutions can be used. 0112 Deuterium can also be incorporated into various positions having an exchangeable proton, Such as the hydroxyl O—H. via proton-deuterium equilibrium exchange. For example, to introduce deuterium at R, this proton may be replaced with deuterium selectively or non-selectively through a proton-deuterium exchange method known in the art 0113 Deuterium can also be incorporated into various positions having an aromatic proton via proton-deuterium equilibrium exchange. For example, to introduce deuterium US 2010/0152283 A1 Jun. 17, 2010 12

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0115 Changes in the metabolic properties of the com pounds disclosed herein as compared to their non-isotopi cally enriched analogs can be shown using the following assays. Compounds listed above which have not yet been made and/or tested are predicted to have changed metabolic properties as shown by one or more of these assays as well. Biological Activity Assays 0116. In vitro Liver Microsomal Stability Assay 0117 Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-gener ating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chlo ride). Test compounds are prepared as solutions in 20% aceto nitrile-water and added to the assay mixture (final assay con centration 5 microgram per mL) and incubated at 37°C. Final concentration of acetonitrile in the assay should be <1%. Aliquots (50 uL) are taken out at times 0, 15, 30, 45, and 60 minutes, and diluted with ice cold acetonitrile (200 uL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 minutes to precipitate proteins. Supernatants are trans US 2010/0152283 A1 Jun. 17, 2010

ferred to microcentrifuge tubes and stored for LC/MS/MS Determination of Dronabinol in Whole Blood by GC-MS analysis of the degradation half-life of the test compounds. I0123. The procedure is carried out as described in Chu et In Vitro Metabolism Using Human Cytochrome Paso al., Journal of Analytical Toxicology 2002, 26(8), 575-581, Enzymes which is hereby incorporated by reference in its entirety. 0118. The cytochrome Paso enzymes are expressed from the corresponding human cDNA using a baculovirus expres Detection of Dronabinol in Whole Blood by GC-MS sion system (BD Biosciences, San Jose, Calif.). A 0.25 mil 0.124. The procedure is carried out as described in Thomas liliter reaction mixture containing 0.8 milligrams per millili et al., Journal of Pharmaceutical and Biomedical Analysis ter protein, 1.3 millimolar NADP", 3.3 millimolar glucose 2007, 45(3), 495-503, which is hereby incorporated by refer 6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, ence in its entirety. 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound as disclosed herein, the corresponding non-isoto CB2 Radioligand Binding Assay pically enriched compound or standard or control in 100 0.125. The procedure is carried out as described in Yao et millimolar potassium phosphate (pH 7.4) is incubated at 37° al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby C. for 20 minutes. After incubation, the reaction is stopped by incorporated by reference in its entirety. the addition of an appropriate solvent (e.g., acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, CB1 Radioligand Binding Assay 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is 0.126 The procedure is carried out as described in Yao et analyzed by HPLC/MS/MS. al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby incorporated by reference in its entirety. CB2 Cyclase Functional Assay Cytochrome P4so Standard I0127. The procedure is carried out as described in Yao et CYP1A2 Phenacetin al., Brit. J. Pharmacol. 2006, (149), 145-154, which is hereby CYP2A6 Coumarin incorporated by reference in its entirety. CYP2B6 'C-(S)-mephenytoin CYP2C8 Paclitaxel CB1 cAMP Assay CYP2C9 Diclofenac I0128. The procedure is carried out as described in Steffens CYP2C19 'C-(S)-mephenytoin et al., Brit. J. Pharmacol. 2004, (141), 1193-1203, which is CYP2D6 (+/-)-Bufuralol hereby incorporated by reference in its entirety. CYP2E1 ChlorZoxazone CYP3A4 Testosterone I0129. From the foregoing description, one skilled in the art CYP4A "C-Lauric acid can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to Monoamine Oxidase A Inhibition and Oxidative Turnover adapt it to various usages and conditions. 0119 The procedure is carried out using the methods What is claimed is: described by Weyler et al., Journal of Biological Chemistry 1. A compound of structural Formula I 1985, 260, 13199-13207, which is hereby incorporated by reference in its entirety. Monoamine oxidase A activity is measured spectrophotometrically by monitoring the increase (I) in absorbance at 314 nm on oxidation of kynuramine with formation of 4-hydroxyquinoline. The measurements are car ried out, at 30°C., in 50 mM sodium phosphate buffer, pH 7.2. containing 0.2% Triton X-100 (monoamine oxidase assay buffer), plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total Volume. Monooamine Oxidase B Inhibition and Oxidative Turnover 0120. The procedure is carried out as described in Uebel hacket al., Pharmacopsychiatry 1998, 31(5), 187-192, which is hereby incorporated by reference in its entirety. Quantitation of Dronabinol in Hair Using LC-MS 0121 The procedure is carried out as described in Coulter et al., Drug Testing and Analysis 2009, 1 (5), 234-239, which is hereby incorporated by reference in its entirety. or a pharmaceutically acceptable salt thereof, wherein: R-Ro are independently selected from the group consist Analysis of Dronabinol and its Metabolites in Whole Blood ing of hydrogen and deuterium; by LC-MS at least one of R-Ro is deuterium; 0122) The procedure is carried out as described in Jag if R-Rs are deuterium, then at least one of Re-Ro is deu erdeo et al., Rapid Communications in Mass Spectrometry terium; 2009, 23(17), 2697-2705, which is hereby incorporated by if R7-Ro and Ras-Rao are deuterium, then at least one of reference in its entirety. R-R and R-o-R2 is deuterium; US 2010/0152283 A1 Jun. 17, 2010 34

if Ras-Rao are deuterium, then at least one of R-R is deuterium; -continued if R-R are deuterium, then at least one of Ro-R is deuterium; D if R-R are deuterium, then at least one of R-R and yH OH Ris-Ro is deuterium; D S if R12-Rs, R-R-7, and R2O-R2 are deuterium, then at D D O least one of R1a-Rs. Ris-Rio, and R22-Rao is deuterium; if R-R and Ro-R2 are deuterium, then at least one of O s R-R, R-Ro, and R-Ro is deuterium; if R-R. R. and Ro-R are deuterium, then at least one of R-R, R-Rs. R7-Ro, and R-Ro is deute rium; if R-R are deuterium, then at least one of R-R and Ra-Ro is deuterium; if R-R are deuterium, then at least one of Ra-Ro is deu terium; if R and Ro-R are deuterium, then at least one of R-Rs, R7-Ro, and R-Ro is deuterium; if R7-R are deuterium, then at least one of R-R and Ro-Ro is deuterium; if Rs-R are deuterium, then at least one of R-R-7 and R-Ro is deuterium; if Ro-R are deuterium, then at least one of R-Ro and R-Ro is deuterium; ifR-R. R. Rs, and Ro are deuterium, then at least one of Rs. R-7, Ro R, and R-Ro is deuterium; if R and Ra are deuterium, then at least one of R-R- and Rs-Ro is deuterium; and if R is deuterium, then at least one of R-R and Re-Ro. is deuterium.

2. The compound as recited in claim 1 wherein at least one of R-Ro independently has deuterium enrichment of no less than about 10%. 3. The compound as recited in claim 1 wherein at least one of R-Ro independently has deuterium enrichment of no less than about 50%. 4. The compound as recited in claim 1 wherein at least one of R-Ro independently has deuterium enrichment of no less than about 90%. 5. The compound as recited in claim 1 wherein at least one of R-Ro independently has deuterium enrichment of no less than about 98%. 6. The compound as recited in claim 1 wherein said com pound has a structural formula selected from the group con sisting of

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7. The compound as recited in claim 6 wherein each posi tion represented as D has deuterium enrichment of no less than about 10%. 8. The compound as recited in claim 6 wherein each posi tion represented as D has deuterium enrichment of no less than about 50%. 9. The compound as recited in claim 6 wherein each posi tion represented as D has deuterium enrichment of no less than about 90%. 10. The compound as recited in claim 6 wherein each position represented as Dhas deuterium enrichment of no less than about 98%. US 2010/0152283 A1 Jun. 17, 2010 55

11. The compound as recited in claim 6 wherein said com pound has a structural formula selected from the group con- -continued sisting of US 2010/0152283 A1 Jun. 17, 2010 56

13. The compound as recited in claim 11 wherein said -continued compound has the structural formula:

14. The compound as recited in claim 11 wherein said compound has the structural formula:

15. A pharmaceutical composition comprising a pharma ceutically acceptable carrier together with a compound of structural Formula I

(I)

12. The compound as recited in claim 11 wherein said compound has the structural formula:

or a pharmaceutically acceptable salt thereof, wherein: R-Ro are independently selected from the group con sisting of hydrogen and deuterium; and at least one of R-Ro is deuterium. 16. A method of treatment of a cannabinoid receptor-me diated disorder comprising the administration, to a patient in need thereof, of a therapeutically effective amount of a com pound of structural Formula I US 2010/0152283 A1 Jun. 17, 2010 57

e. an improved clinical effect during the treatment in said Subject per dosage unit thereofas compared to the non (I) isotopically enriched compound. 23. The method as recited in claim 16, further resulting in at least two effects selected from the group consisting of a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereofas compared to the non-isotopically enriched compound; b. increased average plasma levels of said compound per dosage unit thereofas compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com pared to the non-isotopically enriched compound; d. increased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com or a pharmaceutically acceptable salt thereof, wherein: pared to the non-isotopically enriched compound; and R-Ro are independently selected from the group con e. an improved clinical effect during the treatment in said sisting of hydrogen and deuterium; and Subject per dosage unit thereofas compared to the non at least one of R-Ro is deuterium. isotopically enriched compound. 17. The method as recited inclaim 16 wherein said disorder 24. The method as recited in claim 16, wherein the method is chemotherapy-induced emesis, pain, neuropathic pain, affects a decreased metabolism of the compound per dosage multiple Sclerosis, spasticity, Alzheimer's disease, nausea; unit thereof by at least one polymorphically-expressed cyto Vomiting, affective disorders, anorexia nervosa, dementia, chrome Paso isoform in the subject, as compared to the cor major depressive disorder, cachexia, HIV wasting syndrome, responding non-isotopically enriched compound. Tourette's syndrome, and emesis. 25. The method as recited in claim 24, wherein the cyto 18. The method as recited in claim 16 further comprising chrome Paso isoform is selected from the group consisting of the administration of an additional therapeutic agent. CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 19. The method as recited in claim 18 wherein said addi 26. The method as recited claim 16, wherein said com tional therapeutic agent is selected from the group consisting pound is characterized by decreased inhibition of at least one cytochrome Paso or monoamine oxidase isoform in said Sub of anti-emetics and analgesics. ject per dosage unit thereofas compared to the non-isotopi 20. The method as recited in claim 19 wherein said anal cally enriched compound. gesic is selected from the group consisting of carbamazepine, gabapentin, , acetaminophen, acetylsalicyclic 27. The method as recited in claim 26, wherein said cyto acid, ibuprofen, and naproxen. chrome Paso or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, 21. The method as recited in claim 19 wherein said anti CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, emetic is selected from the group consisting of dolasetron, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. granisetron, ondansetron, tropisetron, and , CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, domperidone, droperidol, haloperidol, chlorpromazine, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, promethazine, prochlorperazine, metoclopramide, aliza CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4x pride, cyclizine, diphenhydramine, dimenhydrinate, mecliz 1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1 ine, promethazine, hydroxy Zine, dronabinol, midazolam, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, lorazepam, hyoscine, dexamethasone, aprepitant, casopitant, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, , and propofol. CYP27B1, CYP39, CYP46, CYP51, MAO, and MAO. 22. The method as recited in claim 16, further resulting in 28. The method as recited in claim 16, wherein the method at least one effect selected from the group consisting of: reduces a deleterious change in a diagnostic hepatobiliary a. decreased inter-individual variation in plasma levels of function endpoint, as compared to the corresponding non said compound or a metabolite thereofas compared to isotopically enriched compound. the non-isotopically enriched compound; 29. The method as recited in claim 28, wherein the diag b. increased average plasma levels of said compound per nostic hepatobiliary function endpoint is selected from the dosage unit thereofas compared to the non-isotopically group consisting of alanine aminotransferase (ALT), serum enriched compound; glutamic-pyruvic transaminase (“SGPT), aspartate ami c. decreased average plasma levels of at least one metabo notransferase (AST,” “SGOT), ALT/AST ratios, serum lite of said compound per dosage unit thereofas com aldolase, alkaline phosphatase (ALP), ammonia levels, pared to the non-isotopically enriched compound; bilirubin, gamma-glutamyl transpeptidase (“GGTP d. increased average plasma levels of at least one metabo “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver lite of said compound per dosage unit thereofas com biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti pared to the non-isotopically enriched compound; and dase, and blood protein. 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30. A compound, for use as a medicament, of structural by modulating cannabinoid receptor activity, wherein said Formula I compound has structural Formula I

(I) (I)

or a pharmaceutically acceptable salt thereof, wherein: or a pharmaceutically acceptable salt thereof, wherein: R-Ro are independently selected from the group con- R-Ro are independently selected from the group con sisting of hydrogen and deuterium; and sisting of hydrogen and deuterium; and at least one of R-Ro is deuterium. at least one of R-Ro is deuterium. 31. A compound for use in the manufacture of a medica ment for the prevention or treatment of a disorder ameliorated ck