US 20100055072A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0055072 A1 Gant et al. (43) Pub. Date: Mar. 4, 2010

(54) 2-OXO-1,2-DIHYDRO-QUINOLINE Publication Classification MODULATORS OF IMMUNE FUNCTION (51) Int. Cl. A638/2 (2006.01) C07D 25/00 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A6II 3/47 (2006.01) (US); Manoucher M. Shahbaz, A 6LX 39/395 (2006.01) Escondido, CA (US) (52) U.S. Cl...... 424/85.6; 546/157: 514/312; 424/85.5; 424/85.7; 424/133.1 Correspondence Address: (57) ABSTRACT GLOBAL PATENT GROUP - APX The present invention relates to new 2-oxo-1,2-dihydro 10411 Clayton Road, Suite 304 quinoline modulators of immune function, pharmaceutical ST. LOUIS, MO 63131 (US) compositions thereof, and methods of use thereof.

(73) Assignee: AUSPEX Formula I PHARMACEUTICALS, INC., R R16 Vista, CA (US) R3 R R15 R4 R17 (21) Appl. No.: 12/552,663 Rs N O

(22) Filed: Sep. 2, 2009

C O Related U.S. Application Data (60) Provisional application No. 61/093.943, filed on Sep. 3, 2008. US 2010/0055072 A1 Mar. 4, 2010

2-OXO-1,2-DIHYDRO-QUINOLINE given temperature, the rate of a chemical reaction depends MODULATORS OF IMMUNE FUNCTION exponentially on the activation energy (E). 0007. The transition state in a reaction is a short lived state along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation 0001. This application claims the benefit of priority of energy E for a reaction is the energy required to reach the U.S. provisional application No. 61/093.943, filed Sep. 3, transition state of that reaction. Once the transition state is 2008, the disclosure of which is hereby incorporated by ref reached, the molecules can either revert to the original reac erence as if written herein in its entirety. tants, or form new bonds giving rise to reaction products. A 0002 Disclosed herein are new substituted 2-oxo-1,2-di catalyst facilitates a reaction process by lowering the activa hydro-quinoline compounds, pharmaceutical compositions tion energy leading to a transition state. Enzymes are made thereof, and methods to modulate immune function examples of biological catalysts. activity in a subject are also provided for, for the treatment of 0008 Carbon-hydrogen bond strength is directly propor disorders such as multiple Sclerosis and autoimmune disor tional to the absolute value of the ground-state vibrational ders. energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the 0003 Laquinimod (ABR 215062; SAIK-MS; ABR mass of one or both of the atoms making the bond increases. 215062; SAIKMS: CAS #248281-84-7), 5-chloro-4-hy Since deuterium (D) has twice the mass of protium ("H), a droxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic C-D bond is stronger than the corresponding C–H bond. If acid ethyl-phenyl-amide, is an immune function modulator. a C-H bond is broken during a rate-determining step in a Laquinimod is currently under investigation for the treatment chemical reaction (i.e. the step with the highest transition of multiple sclerosis (Burton et al., Curr. Neurol. & Neurosc. state energy), then Substituting a deuterium for that protium Reports 2007, 7(3), 223-30; Tuvesson et al., Xenobiotica will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The 2005, 35(3), 293-304; Cohen et al., Int. J. Clin. Pract. 2007, magnitude of the DKIE can be expressed as the ratio between 61 (11), 1922-30). Laquinimod has also shown promise in therates of a given reaction in which a C H bond is broken, treating autoimmune disorders (TuVesson et al., Xenobiotica and the same reaction where deuterium is substituted for 2005, 35(3), 293-304). protium. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more. Substitution of tritium for hydrogen results in yet a stronger bond than deu terium and gives numerically larger isotope effects. 0009 Deuterium (H or D) is a stable and non-radioactive isotope of hydrogen which has approximately twice the mass NY - of protium (H), the most common isotope of hydrogen. 21 N Deuterium oxide (DO or “heavy water) looks and tastes like HO, but has different physical properties. 0010 When pure DO is given to rodents, it is readily C OH O absorbed. The quantity of deuterium required to induce tox icity is extremely high. When about 0-15% of the body water Laquinimod has been replaced by DO, animals are healthy but are unable to gain weight as fast as the control (untreated) group. When 0004 Laquinimod is subject to extensive oxidative about 15-20% of the body water has been replaced with D.O. metabolism by cytochrome Paso enzymes, particularly by the animals become excitable. When about 20-25% of the CYP3A4 (Tuvesson et al., Drug Metab. & Disp. 2005, 33(6), body water has been replaced with DO, the animals become 866-72). Primary metabolites include those formed by quino so excitable that they go into frequent convulsions when line hydroxylation at various sites, quinoline demethylation, stimulated. Skin lesions, ulcers on the paws and muzzles, and aniline de-ethylation, and aniline hydroxylation at the para necrosis of the tails appear. The animals also become very aggressive. When about 30% of the body water has been position (Tuvesson et al., Xenobiotica 2005, 35(3), 293-304). replaced with DO, the animals refuse to eat and become comatose. Their body weight drops sharply and their meta Deuterium Kinetic Isotope Effect bolic rates drop far below normal, with death occurring at 0005. In order to eliminate foreign substances such as about 30 to about 35% replacement with D.O.The effects are therapeutic agents, the animal body expresses various reversible unless more than thirty percent of the previous enzymes, such as the cytochrome Paso enzymes (CYPs), body weight has been lost due to DO Studies have also esterases, proteases, reductases, dehydrogenases, and shown that the use of DO candelay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents. monoamine oxidases, to react with and convert these foreign 0011 Deuteration of pharmaceuticals to improve pharma Substances to more polar intermediates or metabolites for cokinetics (PK), pharmacodynamics (PD), and toxicity pro renal excretion. Such metabolic reactions frequently involve files has been demonstrated previously with some classes of the oxidation of a carbon-hydrogen (C-H) bond to either a drugs. For example, the DKIE was used to decrease the hepa carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. totoxicity of halothane, presumably by limiting the produc The resultant metabolites may be stable or unstable under tion of reactive species such as trifluoroacetylchloride. How physiological conditions, and can have Substantially different ever, this method may not be applicable to all drug classes. pharmacokinetic, pharmacodynamic, and acute and long For example, deuterium incorporation can lead to metabolic term toxicity profiles relative to the parent compounds. For Switching. Metabolic Switching occurs when Xenogens, most drugs, such oxidations are generally rapid and ulti sequestered by Phase I enzymes, bind transiently and re-bind mately lead to administration of multiple or high daily doses. in a variety of conformations prior to the chemical reaction 0006. The relationship between the activation energy and (e.g., oxidation). Metabolic switching is enabled by the rela the rate of reaction may be quantified by the Arrhenius equa tively vast size of binding pockets in many Phase I enzymes tion, k=Ae'. The Arrhenius equation states that, at a and the promiscuous nature of many metabolic reactions. US 2010/0055072 A1 Mar. 4, 2010

Metabolic switching can lead to different proportions of or a salt, Solvate, or prodrug thereof, wherein: known metabolites as well as altogether new metabolites. 0016 R-R, are independently selected from the group This new metabolic profile may impart more or less toxicity. consisting of hydrogen and deuterium; and Such pitfalls are non-obvious and are not predictable a priori 0017 at least one of R-R, is deuterium. for any drug class. 0018 Certain compounds disclosed herein may possess 0012 Laquinimod is an immune function modulator. The carbon-hydrogen bonds of laquinimod contain a naturally useful immune function modulating activity, and may be used occurring distribution of hydrogen isotopes, namely "H or in the treatment or prophylaxis of a disorder in which immune protium (about 99.984.4%), H or deuterium (about function plays an active role. Thus, certain embodiments also 0.0156%), and H or tritium (in the range between about 0.5 provide pharmaceutical compositions comprising one or and 67 tritium atoms per 1018 protium atoms). Increased more compounds disclosed herein together with a pharma levels of deuterium incorporation may produce a detectable ceutically acceptable carrier, as well as methods of making Deuterium Kinetic Isotope Effect (DKIE) that could effect and using the compounds and compositions. Certain embodi the pharmacokinetic, pharmacologic and/or toxicologic pro ments provide methods for modulating immune function. files of laquinimod in comparison with laquinimod having Other embodiments provide methods for treating a immune naturally occurring levels of deuterium. function-mediated disorder in a patient in need of such treat 0013 Based on discoveries made in our laboratory, as well ment, comprising administering to said patient a therapeuti as considering the literature, laquinimod is metabolized in cally effective amount of a compound or composition accord humans at the quinoline ring, the N-methyl group, the N-ethyl ing to the present invention. Also provided is the use of certain group, and the phenyl ring. The current approach has the compounds disclosed herein for use in the manufacture of a potential to prevent metabolism at these sites. Other sites on medicament for the prevention or treatment of a disorder the molecule may also undergo transformations leading to ameliorated by the modulation of immune function. metabolites with as-yet-unknown pharmacology/toxicology. 0019. The compounds as disclosed herein may also con Limiting the production of these metabolites has the potential tain less prevalent isotopes for other elements, including, but to decrease the danger of the administration of such drugs and not limited to, 'Cor'C for carbon, S, ''S, or ''S for sulfur, may even allow increased dosage and/or increased efficacy. 'N for nitrogen, and ''O or "O for oxygen. All of these transformations can occur through polymorphi 0020. In certain embodiments, the compound disclosed cally-expressed enzymes, exacerbating interpatient variabil herein may expose a patient to a maximum of about ity. Further, some disorders are best treated when the subject 0.000005% DO or about 0.00001% DHO, assuming that all is medicated around the clock or for an extended period of of the C-D bonds in the compound as disclosed herein are time. For all of the foregoing reasons, a medicine with a metabolized and released as DO or DHO. In certain embodi longer half-life may result in greater efficacy and cost sav ments, the levels of DO shown to cause toxicity in animals is ings. Various deuteration patterns can be used to (a) reduce or much greater than even the maximum limit of exposure eliminate unwanted metabolites, (b) increase the half-life of caused by administration of the deuterium enriched com the parent drug, (c) decrease the number of doses needed to pound as disclosed herein. Thus, in certain embodiments, the achieve a desired effect, (d) decrease the amount of a dose deuterium-enriched compound disclosed herein should not needed to achieve a desired effect, (e) increase the formation cause any additional toxicity due to the formation of DO or of active metabolites, if any are formed, (f) decrease the DHO upon drug metabolism. production of deleterious metabolites in specific tissues, and/ 0021. In certain embodiments, the deuterated compounds or (g) create a more effective drug and/or a safer drug for disclosed herein maintain the beneficial aspects of the corre polypharmacy, whether the polypharmacy be intentional or sponding non-isotopically enriched molecules while Substan not. The deuteration approach has the strong potential to slow tially increasing the maximum tolerated dose, decreasing tox the metabolism of laquinimod and attenuate interpatient vari ability. icity, increasing the half-life (T), lowering the maximum 0014 Novel compounds and pharmaceutical composi plasma concentration (C) of the minimum efficacious tions, certain of which have been found to modulate immune dose (MED), lowering the efficacious dose and thus decreas function have been discovered, together with methods of ing the non-mechanism-related toxicity, and/or lowering the synthesizing and using the compounds, including methods probability of drug-drug interactions. for the treatment of immune function-mediated disorders in a 0022 All publications and references cited herein are patient by administering the compounds. expressly incorporated herein by reference in their entirety. 0015. In certain embodiments of the present invention, However, with respect to any similar or identical terms found compounds have structural Formula I: in both the incorporated publications or references and those explicitly put forth or defined in this document, then those terms definitions or meanings explicitly put forth in this docu (I) ment shall control in all respects. R R16 0023. As used herein, the terms below have the meanings R3 R R15 indicated. R4 R17 0024. The singular forms “a,” “an and “the may refer to Rs N O plural articles unless specifically stated otherwise. 0025. The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting Such 21 N Rs a value as variable within a margin of error. When no particu lar margin of error, such as a standard deviation to a mean C O value given in a chart or table of data, is recited, the term “about’ should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. US 2010/0055072 A1 Mar. 4, 2010

0026. When ranges of values are disclosed, and the nota Solvents such as water, ethanol, and the like. In general, the tion “from n ... to n' or “n-n” is used, where n and n are Solvated forms are considered equivalent to the unsolvated the numbers, then unless otherwise specified, this notation is forms. intended to include the numbers themselves and the range 0032. The term “bond refers to a covalent linkage between them. This range may be integral or continuous between two atoms, or two moieties when the atoms joined by between and including the end values. the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise speci 0027. The term “deuterium enrichment” refers to the per fied. A dashed line between two atoms in a drawing of a centage of incorporation of deuterium at a given position in a molecule indicates that an additional bond may be present or molecule in the place of hydrogen. For example, deuterium absent at that position. enrichment of 1% at a given position means that 1% of mol 0033. The term “disorder as used herein is intended to be ecules in a given sample contain deuterium at the specified generally synonymous, and is used interchangeably with, the position. Because the naturally occurring distribution of deu terms “disease' and “condition' (as in medical condition), in terium is about 0.0156%, deuterium enrichment at any posi that all reflect an abnormal condition of the human or animal tion in a compound synthesized using non-enriched starting body or of one of its parts that impairs normal functioning, is materials is about 0.0156%. The deuterium enrichment can typically manifested by distinguishing signs and symptoms. be determined using conventional analytical methods known 0034. The terms “treat,” “treating,” and “treatment” are to one of ordinary skill in the art, including mass spectrometry meant to include alleviating or abrogating a disorder or one or and nuclear magnetic resonance spectroscopy. more of the symptoms associated with a disorder; or allevi 0028. The term “is/are deuterium, when used to describe ating or eradicating the cause(s) of the disorder itself. As used a given position in a molecule such as R-R7 or the symbol herein, reference to “treatment of a disorder is intended to “D. when used to represent a given position in a drawing of include prevention. The terms “prevent.” “preventing, and a molecular structure, means that the specified position is “prevention” refer to a method of delaying or precluding the onset of a disorder; and/or its attendant symptoms, barring a enriched with deuterium above the naturally occurring distri Subject from acquiring a disorder or reducing a subject's risk bution of deuterium. In one embodiment deuterium enrich of acquiring a disorder. ment is no less than about 1%, in another no less than about 0035. The term “therapeutically effective amount” refers 5%, in another no less than about 10%, in another no less than to the amount of a compound that, when administered, is about 20%, in another no less than about 50%, in another no sufficient to prevent development of, or alleviate to some less than about 70%, in another no less than about 80%, in extent, one or more of the symptoms of the disorder being another no less than about 90%, or in another no less than treated. The term “therapeutically effective amount” also about 98% of deuterium at the specified position. refers to the amount of a compound that is sufficient to elicit 0029. The term “isotopic enrichment” refers to the per the biological or medical response of a cell, tissue, system, centage of incorporation of a less prevalent isotope of an animal, or human that is being sought by a researcher, Veteri element at a given position in a molecule in the place of the narian, medical doctor, or clinician. more prevalent isotope of the element. 0036. The term “subject” refers to an animal, including, 0030 The term “non-isotopically enriched’ refers to a but not limited to, a primate (e.g., human, monkey, chimpan molecule in which the percentages of the various isotopes are Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, Substantially the same as the naturally occurring percentages. hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, 0031 Asymmetric centers exist in the compounds dis miniature pig), equine, canine, feline, and the like. The terms closed herein. These centers are designated by the symbols “subject' and “patient” are used interchangeably herein in “R” or “S” depending on the configuration of substituents reference, for example, to a mammalian Subject, such as a around the chiral carbon atom. It should be understood that human patient. the invention encompasses all Stereochemical isomeric 0037. The term “combination therapy’ means the admin forms, including diastereomeric, enantiomeric, and epimeric istration of two or more therapeutic agents to treat a thera forms, as well as D-isomers and L-isomers, and mixtures peutic disorder described in the present disclosure. Such thereof. Individual stereoisomers of compounds can be pre administration encompasses co-administration of these pared synthetically from commercially available starting therapeutic agents in a Substantially simultaneous manner, materials which contain chiral centers or by preparation of Such as in a single capsule having a fixed ratio of active mixtures of enantiomeric products followed by separation ingredients or in multiple, separate capsules for each active such as conversion to a mixture of diastereomers followed by ingredient. In addition, Such administration also encom separation or recrystallization, chromatographic techniques, passes use of each type of therapeutic agent in a sequential direct separation of enantiomers on chiral chromatographic manner. In either case, the treatment regimen will provide columns, or any other appropriate method known in the art. beneficial effects of the drug combination in treating the Starting compounds of particular stereochemistry are either disorders described herein. commercially available or can be made and resolved by tech 0038. The term “immune function” refers to the collection niques known in the art. Additionally, the compounds dis of mechanisms within an organism that protects against dis closed herein may exist as geometric isomers. The present ease. Such mechanisms include macrophages, T-lympho invention includes all cis, trans, syn, anti, entgegen (E), and cytes, and B-lymphocytes and their respective activities. Zusammen (Z) isomers as well as the appropriate mixtures 0039. The term “immune function-mediated disorder.” thereof. Additionally, compounds may exist as tautomers; all refers to a disorder that is characterized by abnormal immune tautomeric isomers are provided by this invention. Addition function. An immune function-mediated disorder may be ally, the compounds disclosed herein can exist in unsolvated completely or partially mediated by modulating the immune as well as Solvated forms with pharmaceutically acceptable function in a subject. In particular, an immune function-me US 2010/0055072 A1 Mar. 4, 2010

diated disorder is one in which modulation of immune func composition thereof, which is administered to a subject for tion results in Some effect on the underlying disorder e.g., treating, preventing, or ameliorating one or more symptoms administration of a immune function modulator results in of a disorder. Some improvement in at least some of the patients being 0045. The term “release controlling excipient” refers to an treated. excipient whose primary function is to modify the duration or 0040. The term “immune function modulator.” refers to place of release of the active Substance from a dosage form as the ability of a compound disclosed herein to alter immune compared with a conventional immediate release dosage function activity. An immune function modulator may stimu form. late immune function activity, may activate or inhibit immune 0046. The term “nonrelease controlling excipient” refers function activity depending on the concentration of the com to an excipient whose primary function do not include modi pound exposed to the Subject, or may inhibitimmune function fying the duration or place of release of the active Substance activity. Such activation or inhibition may be contingent on from a dosage form as compared with a conventional imme the occurrence of a specific event, such as activation of a diate release dosage form. signal transduction pathway, and/or may be manifest only in 0047. The term “prodrug” refers to a compound functional derivative of the compound as disclosed herein and is readily particular cell types. For example, compounds disclosed convertible into the parent compound in vivo. Prodrugs are herein may modulate immune function by inhibiting the infil often useful because, in Some situations, they may be easier to tration of both CD4 T-cells and macrophages into central administer than the parent compound. They may, for instance, nervous tissues and changing the T-lymphocyte population in be bioavailable by oral administration whereas the parent favour of cells expressing Th2/Th3 cytokines interleukin compound is not. The prodrug may also have enhanced solu (IL)-4, IL-10 and transforming growth factor-beta. In some bility in pharmaceutical compositions over the parent com embodiments, modulation of the immune function may be pound. A prodrug may be converted into the parent drug by assessed using the method described in Karussis et al., Ann. various mechanisms, including enzymatic processes and Neurol. 1993, (34), 654-660; Yang, et al., Journal of Neuroim metabolic hydrolysis. See Harper, Progress in Drug Research munology 2004, 156(1-2), 3-9: Brunmarket al., J. Neuroim 1962, 4, 221–294; Morozowich et al. in “Design of Biophar munol. 2002, 130, 163-172; and Jonsson et al., J. Med Chem. maceutical Properties through Prodrugs and Analogs. Roche 2004, 47, 2075-88. Ed., APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers 0041. The term “therapeutically acceptable” refers to in Drug in Drug Design, Theory and Application. Roche Ed., those compounds (or salts, prodrugs, tautomers, Zwitterionic APHA Acad. Pharm. Sci. 1987: "Design of Prodrugs.” Bund forms, etc.) which are suitable for use in contact with the gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, tissues of patients without excessive toxicity, irritation, aller 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997,27, 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; 0042. 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 excipient’ 39, 183-209: Browne, Clin. Neuropharmacol. 1997, 20, 1-12; refers to a pharmaceutically-acceptable material, composi Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, tion, or vehicle, such as a liquid or Solid filler, diluent, excipi Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. ent, solvent, or encapsulating material. Each component must Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug be “pharmaceutically acceptable' in the sense of being com Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods patible with the other ingredients of a pharmaceutical formu Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. lation. It must also be suitable for use in contact with the tissue 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. or organ of humans and animals without excessive toxicity, Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. irritation, allergic response, immunogenecity, or other prob Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. lems or complications, commensurate with a reasonable ben Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and efit/risk ratio. See, Remington. The Science and Practice of Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs Philadelphia, Pa., 2005; Handbook of Pharmaceutical 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, Excipients, 5th Edition; Rowe et al., Eds. The Pharmaceuti 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 cal 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). 0048. The compounds disclosed herein can exist as thera 0043. The terms “active ingredient,” “active compound.” peutically acceptable salts. The term “therapeutically accept and “active Substance' refer to a compound, which is admin able salt, as used herein, represents salts or Zwitterionic istered, alone or in combination with one or more pharma forms of the compounds disclosed herein which are therapeu ceutically acceptable excipients or carriers, to a Subject for tically acceptable as defined herein. The salts can be prepared treating, preventing, or ameliorating one or more symptoms during the final isolation and purification of the compounds or of a disorder. separately by reacting the appropriate compound with a Suit 0044) The terms “drug.” “therapeutic agent,” and “chemo able acid or base. Therapeutically acceptable salts include therapeutic agent” refer to a compound, or a pharmaceutical acid and basic addition salts. For a more complete discussion US 2010/0055072 A1 Mar. 4, 2010

of the preparation and selection of salts, refer to “Handbook a modified release dosage form, including delayed-, of Pharmaceutical Salts, Properties, and Use.” Stah and Wer extended-, prolonged-, Sustained-, pulsatile-, controlled muth, Ed. (Wiley-VCH and VHCA, Zurich, 2002) and Berge accelerated- and fast-, targeted-, programmed-release, and et al., J. Pharm. Sci. 1977, 66, 1-19. Suitable acids for use in gastric retention dosage forms. These dosage forms can be the preparation of pharmaceutically acceptable salts include, prepared according to conventional methods and techniques but are not limited to, acetic acid, 2,2-dichloroacetic acid, known to those skilled in the art (see, Remington. The Science acylated amino acids, adipic acid, alginic acid, ascorbic acid, and Practice of Pharmacy, supra; Modified-Release Drug L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-aceta Deliver Technology, Rathbone et al., Eds. Drugs and the midobenzoic acid, boric acid, (+)-camphoric acid, camphor Pharmaceutical Science, Marcel Dekker, Inc.: New York, Sulfonic acid, (+)-(1S)-camphor-10-Sulfonic acid, capric N.Y., 2002; Vol. 126). acid, caproic acid, caprylic acid, cinnamic acid, citric acid, 0051. The compositions include those suitable for oral, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric parenteral (including Subcutaneous, intradermal, intramuscu acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hy lar, intravenous, intraarticular, and intramedullary), intraperi droxy-ethanesulfonic acid, formic acid, fumaric acid, galac toneal, transmucosal, transdermal, rectal and topical (includ taric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, ing dermal, buccal, Sublingual and intraocular) D-glucuronic acid, L-glutamic acid, C.-OXO-glutaric acid, gly administration although the most Suitable route may depend colic acid, hippuric acid, hydrobromic acid, hydrochloric upon for example the condition and disorder of the recipient. acid, hydroiodic acid, (+)-L-lactic acid, (+)-DL-lactic acid, The compositions may conveniently be presented in unit dos lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, age form and may be prepared by any of the methods well malonic acid, (+)-DL-mandelic acid, methanesulfonic acid, known in the art of pharmacy. Typically, these methods naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic include the step of bringing into association a compound of acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, the Subject invention or a pharmaceutically salt, prodrug, or oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, solvate thereof (“active ingredient') with the carrier which perchloric acid, phosphoric acid, L-pyroglutamic acid, sac constitutes one or more accessory ingredients. In general, the charic acid, Salicylic acid, 4-amino-salicylic acid, sebacic compositions are prepared by uniformly and intimately acid, Stearic acid, Succinic acid, Sulfuric acid, tannic acid, bringing into association the active ingredient with liquid (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, carriers or finely divided solid carriers or both and then, if undecylenic acid, and Valeric acid. necessary, shaping the product into the desired formulation. 0049 Suitable bases for use in the preparation of pharma 0052 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, 0053 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 0050. 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 The pharmaceutical compositions may also be formulated as organic solvents or solvent mixtures. Dyestuffs or pigments US 2010/0055072 A1 Mar. 4, 2010

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. 0061 For administration by inhalation, compounds may 0054 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. 0062 Preferred unit dosage formulations are those con 0055 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 0063 Compounds may be administered orally or via ers, bacteriostats and solutes which render the formulation injection at a dose of from 0.1 to 500 mg/kg per day. The dose isotonic with the blood of the intended recipient; and aqueous range for adult humans is generally from 5 mg to 2 g/day. and non-aqueous sterile Suspensions which may include Sus Tablets or other forms of presentation provided in discrete pending agents and thickening agents. Suitable lipophilic units may conveniently contain an amount of one or more Solvents or vehicles include fatty oils such as sesame oil, or compounds which is effective at Such dosage or as a multiple synthetic fatty acid esters, such as ethyl oleate or triglycer of the same, for instance, units containing 5 mg to 500 mg. ides, or liposomes. Aqueous injection suspensions may con usually around 10 mg to 200 mg. tain Substances which increase the Viscosity of the Suspen 0064. The amount of active ingredient that may be com Sion, such as Sodium carboxymethyl cellulose, Sorbitol, or bined with the carrier materials to produce a single dosage dextran. Optionally, the Suspension may also contain Suitable form will vary depending upon the host treated and the par stabilizers or agents which increase the solubility of the com ticular mode of administration. pounds to allow for the preparation of highly concentrated 0065. The compounds can be administered in various Solutions. modes, e.g. orally, topically, or by injection. The precise 0056. In addition to the formulations described previously, amount of compound administered to a patient will be the the compounds may also be formulated as a depot prepara responsibility of the attendant physician. The specific dose tion. Such long acting formulations may be administered by level for any particular patient will depend upon a variety of implantation (for example Subcutaneously or intramuscu factors including the activity of the specific compound larly) or by intramuscular injection. Thus, for example, the employed, the age, body weight, general health, sex, diets, compounds may be formulated with Suitable polymeric or time of administration, route of administration, rate of excre hydrophobic materials (for example as an emulsion in an tion, drug combination, the precise disorder being treated, acceptable oil) or ion exchange resins, or as sparingly soluble and the severity of the disorder being treated. Also, the route derivatives, for example, as a sparingly soluble salt. of administration may vary depending on the disorder and its 0057 Forbuccal or sublingual administration, the compo severity. sitions may take the form of tablets, lozenges, pastilles, or 0066. In the case wherein the patient's condition does not gels formulated in conventional manner. Such compositions improve, upon the doctor's discretion the administration of may comprise the active ingredient in a flavored basis such as the compounds may be administered chronically, that is, for Sucrose and acacia or tragacanth. an extended period of time, including throughout the duration 0058. The compounds may also be formulated in rectal of the patient's life in order to ameliorate or otherwise control compositions such as Suppositories or retention enemas, e.g., or limit the symptoms of the patient’s disorder. containing conventional Suppository bases such as cocoa but 0067. In the case wherein the patient's status does ter, polyethylene glycol, or other glycerides. improve, upon the doctor's discretion the administration of 0059 Certain compounds disclosed herein may be admin the compounds may be given continuously or temporarily istered topically, that is by non-systemic administration. This Suspended for a certain length of time (i.e., a "drug holiday'). includes the application of a compound disclosed herein 0068. Once improvement of the patient's conditions has externally to the epidermis or the buccal cavity and the instil occurred, a maintenance dose is administered if necessary. lation of Sucha compound into the ear, eye and nose, such that Subsequently, the dosage or the frequency of administration, the compound does not significantly enter the blood stream. or both, can be reduced, as a function of the symptoms, to a In contrast, Systemic administration refers to oral, intrave level at which the improved disorder is retained. Patients can, nous, intraperitoneal and intramuscular administration. however, require intermittent treatment on a long-term basis 0060 Formulations suitable for topical administration upon any recurrence of symptoms. include liquid or semi-liquid preparations Suitable for pen 0069 Disclosed herein are methods of treating an immune etration through the skin to the site of inflammation Such as function-mediated disorder comprising administering to a US 2010/0055072 A1 Mar. 4, 2010

Subject having or Suspected to have such a disorder, a thera CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, peutically effective amount of a compound as disclosed CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and herein or a pharmaceutically acceptable salt, Solvate, or pro CYP51. drug thereof. 0075 Examples of monoamine oxidase isoforms in a 0070 Immune function-mediated disorders, include, but mammalian Subject include, but are not limited to, MAO are not limited to, multiple Sclerosis and autoimmune disor and MAO. ders, and/or any disorder which can lessened, alleviated, or 0076. The inhibition of the cytochrome Paso isoform is prevented by administering a immune function modulator. measured by the method of Ko et al., British Journal of 0071. In certain embodiments, a method of treating a Clinical Pharmacology, 2000, 49,343-351. The inhibition of immune function-mediated disorder comprises administer the MAO isoform is measured by the method of Weyler et ing to the Subject a therapeutically effective amount of a al., J. Biol. Chem. 1985, 260, 13199-13207. The inhibition of compound of as disclosed herein, or a pharmaceutically the MAO isoform is measured by the method of Uebelhack acceptable salt, Solvate, or prodrug thereof, so as to affect: (1) et al. Pharmacopsychiatry, 1998, 31, 187-192. decreased inter-individual variation in plasma levels of the 0077. Examples of polymorphically-expressed cyto compound or a metabolite thereof, (2) increased average chrome Paso isoforms in a mammalian Subject include, but are plasma levels of the compound or decreased average plasma not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. levels of at least one metabolite of the compound per dosage 0078. The metabolic activities of liver microsomes, cyto unit; (3) decreased inhibition of, and/or metabolism by at chrome Paso isoforms, and monoamine oxidase isoforms are least one cytochrome Paso or monoamine oxidase isoform in measured by the methods described herein. the Subject; (4) decreased metabolism via at least one poly 0079. Examples of improved disorder-control and/or dis morphically-expressed cytochrome Paso isoform in the Sub order-eradication endpoints, or improved clinical effects ject; (5) at least one statistically-significantly improved dis include, but are not limited to, cumulative number of active order-control and/or disorder-eradication endpoint; (6) an lesions seen at week 24, cumulative and active number of improved clinical effect during the treatment of the disorder, active and gadolinium-enhancing lesions on MRI every 8 (7) prevention of recurrence, or delay of decline or appear weeks, relapse rate, multiple Sclerosis functional composite, ance, of abnormal alimentary or hepatic parameters as the short form 36 quality of life assessment (Burton et al., Curr: primary clinical benefit, or (8) reduction or elimination of Neurol. & Neurosc. Reports 2007, 7(3), 223-30). deleterious changes in any diagnostic hepatobiliary function 0080 Examples of diagnostic hepatobiliary function end endpoints, as compared to the corresponding non-isotopi points include, but are not limited to, alanine aminotrans cally enriched compound. ferase (ALT), serum glutamic-pyruvic transaminase (“SGPT), aspartate aminotransferase (“AST' or “SGOT), 0072. In certain embodiments, inter-individual variation ALT/AST ratios, serum aldolase, alkaline phosphatase in plasma levels of the compounds as disclosed herein, or (ALP), ammonia levels, bilirubin, gamma-glutamyl metabolites thereof, is decreased; average plasma levels of transpeptidase (“GGTP” “Y-GTP or “GGT), leucine ami the compound as disclosed herein are increased; average nopeptidase (“LAP), liver biopsy, liver ultrasonography, plasma levels of a metabolite of the compound as disclosed liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa herein are decreased; inhibition of a cytochrome Paso or tobiliary endpoints are compared to the stated normal levels monoamine oxidase isoform by a compound as disclosed as given in “Diagnostic and Laboratory Test Reference', 4' herein is decreased; or metabolism of the compound as dis edition, Mosby, 1999. These assays are run by accredited closed herein by at least one polymorphically-expressed laboratories according to standard protocol. cytochrome Paso isoform is decreased; by greater than about I0081 Besides being useful for human treatment, certain 5%, greater than about 10%, greater than about 20%, greater compounds and formulations disclosed herein may also be than about 30%, greater than about 40%, or by greater than useful for veterinary treatment of companion animals, exotic about 50% as compared to the corresponding non-isotopi animals and farm animals, including mammals, rodents, and cally enriched compound. the like. More preferred animals include horses, dogs, and 0073 Plasma levels of the compound as disclosed herein, Cats. or metabolites thereof, may be measured using the methods described by Li et al. Rapid Communications in Mass Spec Combination Therapy trometry 2005, 19, 1943-1950; Sennbro, et al., Rapid Com munications in Mass Spectrometry 2006, 20022), 3313-3318; I0082. The compounds disclosed herein may also be com Edman, et al., Journal of Chromatography, B: Analytical bined or used in combination with other agents useful in the Technologies in the Biomedical and Life Sciences 2003, 785 treatment of immune function-mediated disorders. Or, by (2); and any references cited therein and modifications made way of example only, the therapeutic effectiveness of one of thereof. the compounds described herein may be enhanced by admin 0074 Examples of cytochrome Paso isoforms in a mam istration of an adjuvant (i.e., by itself the adjuvant may only malian subject include, but are not limited to, CYP1A1, have minimal therapeutic benefit, but in combination with CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, another therapeutic agent, the overall therapeutic benefit to CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, the patient is enhanced). CYP2E1, CYP2G1 CYP2J2, CYP2R1, CYP2S1, CYP3A4, I0083. Such other agents, adjuvants, or drugs, may be CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein. When a compound as disclosed herein is used contemporaneously with one or more other drugs, a US 2010/0055072 A1 Mar. 4, 2010 pharmaceutical composition containing such other drugs in tissue plasminogen activator (tPA), recombinant tRA, strep addition to the compound disclosed herein may be utilized, tokinase, urokinase, prourokinase, and anisoylated plasmino but is not required. gen streptokinase activator complex (APSAC); anti-diabetic 0084. In certain embodiments, the compounds disclosed agents, such as biguanides (e.g. metformin), glucosidase herein can be combined with one or more immunomodula inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repa tors, Steroidal drugs or cyclosporins. glinide), Sulfonylureas (e.g., glimepiride, glyburide, and glip 0085. In certain embodiments, the compounds provided izide), thioZolidinediones (e.g. troglitaZone, rosiglitaZone herein can be combined with one or more immunomodulators and pioglitaZone), and PPAR-gamma agonists; mineralocor known in the art, including, but not limited to, filgrastim, ticoid receptor antagonists, such as Spironolactone and molgramoStim, Sargramos tim, lenograstim, ancestim, peg eplerenone; growth hormone secretagogues; aP2 inhibitors; filgrastim, interferon gamma, interferon alpha-2a, interferon phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., alpha-2b, interferon alpha-n1, interferon beta-1a, interferon cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil. beta-1b, interferon alphacon-1, peginterferon alpha-2b. Vardenafil); protein tyrosine kinase inhibitors; antiinflamma tories; antiproliferatives, such as methotrexate, FK506 (tac peginterferon alpha-2a, interferon omega, aldesleukin, rolimus, Prograf), mycophenolate mofetil: chemotherapeutic oprelvekin, lentinan, roquinimex, BCG vaccine, pegade agents; immunosuppressants; anticancer agents and cyto mase, pidotimod, Poly I:C, Poly ICLC, thymopentin, immu toxic agents (e.g., alkylating agents, such as nitrogen mus nocyanin, tasonermin, melanoma vaccine, glatirameracetate, tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria histamine dihydrochloride, mi?amurtide, plerixafor, Zenes); antimetabolites, such as folate antagonists, purine muromonab-CD3, antilymphocyte immunoglobulin (horse), analogues, and pyrridine analogues; antibiotics, such as antithymocyte immunoglobulin (rabbit), mycophenolic acid, anthracyclines, bleomycins, mitomycin, dactinomycin, and Sirolimus, leflunomide, alefacept, everolimus, gusperimus, plicamycin; enzymes, such as L-asparaginase; farnesyl-pro efalizumab, abetimus, natalizumab, abatacept, eculizumab, tein transferase inhibitors; hormonal agents, such as gluco etanercept, infliximab, afelimomab, adalimumab, certoli corticoids (e.g., cortisone), estrogens/antiestrogens, andro Zumab pegol, daclizumab, basiliximab, anakinra, gens/antiandrogens, progestins, and luteinizing hormone ciclosporin, tacrolimus, azathioprine, thalidomide, methotr releasing hormone anatagonists, and octreotide acetate; exate, and lenalidomide. microtubule-disruptor agents, such as ecteinascidins; micro I0086. The compounds disclosed herein can also be admin tubule-stabilizing agents, such as pacitaxel, docetaxel, and istered in combination with other classes of compounds, epothilones A-F; plant-derived products. Such as Vinca alka including, but not limited to, norepinephrine reuptake inhibi loids, epipodophyllotoxins, and taxanes; and topoisomerase tors (NRIs) such as atomoxetine; dopamine reuptake inhibi inhibitors; prenyl-protein transferase inhibitors; and tors (DARIs). Such as methylphenidate; serotonin-norepi cyclosporins; steroids. Such as prednisone and dexametha nephrine reuptake inhibitors (SNRIs), such as milnacipran; Sone; cytotoxic drugs, such as azathiprine and cyclophospha sedatives. Such as diazepham; norepinephrine-dopamine mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti reuptake inhibitor (NDRIs), such as bupropion; serotonin bodies or soluble TNF receptor, such as etanercept, norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) Such as Venlafaxine; monoamine oxidase inhibitors, such as inhibitors, such as celecoxib and rofecoxib; and miscella Selegiline; hypothalamic phospholipids; endothelin convert neous agents such as, hydroxyurea, procarbazine, mitotane, ing enzyme (ECE) inhibitors, such as phosphoramidon; opio hexamethylmelamine, gold compounds, platinum coordina ids. Such as tramadol; thromboxane receptor antagonists, tion complexes, such as cisplatin, satraplatin, and carbopl Such as ifetroban; potassium channel openers; thrombin atin. inhibitors, such as hirudin; hypothalamic phospholipids; I0087 Thus, in another aspect, certain embodiments pro growth factor inhibitors, such as modulators of PDGF activ vide methods for treating immune function-mediated disor ity; platelet activating factor (PAF) antagonists; anti-platelet ders in a human or animal Subject in need of Such treatment agents, such as GPIb/IIIa blockers (e.g., abdximab, eptifi comprising administering to said subject an amount of a batide, and tirofiban), P2Y (AC) antagonists (e.g., clopi compound disclosed herein effective to reduce or prevent said dogrel, ticlopidine and CS-747), and aspirin; anticoagulants, disorder in the subject, in combination with at least one addi Such as warfarin; low molecular weight heparins, such as tional agent for the treatment of said disorder that is known in enoxaparin; Factor VIa Inhibitors and Factor Xa Inhibitors: the art. In a related aspect, certain embodiments provide renin inhibitors; neutral endopeptidase (NEP) inhibitors: therapeutic compositions comprising at least one compound vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibi disclosed herein in combination with one or more additional tors, such as pravastatin, lovastatin, atorvastatin, simvastatin, agents for the treatment of immune function-mediated disor NK-104 (a.k.a. itavastatin, niSvastatin, or nisbastatin), and ders. 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 I0088 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, ide, flumethiazide, hydroflumethiazide, bendroflumethiaz and may be highly variable depending on the reaction condi ide, methylchlorothiazide, trichloromethiazide, polythiazide, tions. Synthetic techniques, where tritium or deuterium is benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, directly and specifically inserted by tritiated or deuterated furosenilde, musolimine, bumetanide, triamterene, reagents of known isotopic content, may yield high tritium or amiloride, and spironolactone; thrombolytic agents, such as deuterium abundance, but can be limited by the chemistry US 2010/0055072 A1 Mar. 4, 2010

required. Exchange techniques, on the other hand, may yield entirety, and references cited therein and routine modifica lower tritium or deuterium incorporation, often with the iso tions thereof. Compounds as disclosed herein can also be tope being distributed over many sites on the molecule. prepared as shown in any of the following schemes and rou 0089. The compounds as disclosed herein can be prepared tine modifications thereof. by methods known to one of skill in the art and routine 0090 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 in the Example section herein and routine optionally substituted with deuterium.

C O

R4 C O Rs NH2 R4 R6 O 2 Ho OH -- -N R6 R Rs N O

C O R-)- R4 R 1.3 R 1 R3 R 3

R R17 C o1 O R6 N N Rs Rs N OR; R4 R R R O R2

7 modifications thereof, and/or procedures found in Wenner 0091 Compound 1 is reacted with an appropriate chloro berget al., Org. Proc. Res. & Dev. 2007, 11(4), 674-80; Wang formate or phosgene equivalent, such as isopropyl carbon et al., Bioorganic & Medicinal Chemistry Letters 2007, ochloridate, in the presence of an appropriate dehydrating 17(10), 2817-2822; Jansson et al., J. Org. Chem. 2006, 71(4), agent, Such as acetylchloride, in an appropriate solvent. Such 1658-67: Joensson et al., J. Med. Chem. 2004, 47(8), 2075 as 1,4-dioxane, at an elevated temperature to give compound 88: US 2007/088050; US 2005/215586: US 2005/192315; 2. Compound 2 is reacted with compound 3 in the presence of US 2004/034227; WO 2005/74899, WO 2003106424; and an appropriate base, such as sodium hydride, in an appropri WO 1999/55678, which are hereby incorporated in their ate solvent, such as dimethylformamide, under an inert atmo US 2010/0055072 A1 Mar. 4, 2010

sphere. Such as nitrogen, to give compound 4. Compound 4 is one portion, and the solution was maintained at about 50° C. reacted with an appropriate malonate derivative. Such as for about 30 minutes. The resulting solids were collected by diethyl malonate, in the presence of an appropriate base. Such filtration and purified by silica gel chromatography (ethyl as Sodium hydride, in an appropriate solvent, Such as dimeth acetate/petroleum ether 10:1) to afford the title product as a ylformamide, at an elevated temperature, to give compound gray white solid (17.6 g., yield: 76%). 5. Compound 5 is reacted with compound 6 in an appropriate Solvent. Such as n-heptane, at an elevated temperature, to give Step 2 compound 7 of Formula I. 0092 Deuterium can be incorporated to different posi 0098 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 C O positions of Ra-R compound 1 with the corresponding deu terium substitutions can be used. To introduce deuterium at O In one or more positions of R-Rs, compound 3 with the corre sponding deuterium Substitutions can be used. To introduce N O " - deuterium at one or more positions of Rs-R7, compound 6 H with the corresponding deuterium Substitutions can be used. C O 0093 Deuterium can be incorporated to various positions having an exchangeable proton, Such as the hydroxyl O—H. O via proton-deuterium equilibrium exchange. For example, to introduce deuterium at R-7, this proton may be replaced with deuterium selectively or non-selectively through a proton deuterium exchange method known in the art. s 0094. The invention is further illustrated by the following examples. All IUPAC names were generated using Cam 0099 5-Chloro-1-methyl-1H-benzod1.3oxazine-2,4- bridgeSoft's ChemDraw 10.0. dione: Under an atmosphere of nitrogen, 5-chloro-1H-benzo d1.3oxazine-2,4-dione (10 g, 50.61 mmol. 1.00 equiv) EXAMPLE1 was dissolved in N,N-dimethylformamide (100 ml) at about Sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1-me 5° C. Sodium hydride (2.8 g. 121.5 mmol. 2.4 equiv) and thyl-2-oxo-1,2-dihydroquinolin-4-olate methyl iodide (5.7 ml, 2 equiv) were then added, and the resulting mixture was stirred at ambient temperature for 0095 about 16 hours. The mixture was purged with nitrogen for about 1 hour to give the title product as a yellow solid, which was used directly in the next step without any purification. "Na C O O Step 3 01.00

Clto N C O

O

Step 1 - O 0.096 \ O O O C O C O ov NH2 OH C 's C OH O

0097. 5-Chloro-1H-benzod 133oxazine-2,4-dione: Under an atmosphere of nitrogen, isopropyl carbonochlori C date (50 ml. 4.50 equiv) was added dropwise to a suspension so N of 2-amino-6-chlorobenzoic acid (20 g, 116.56 mmol. 1.00 equiv) in 1,4-dioxane (150 ml). The resulting solution was maintained at about 90° C. for 30 minutes, and then cooled to 0101 Ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-di about 50° C. Acetylchloride (50 ml, 6.00 equiv) was added in hydroquinoline-3-carboxylate: Sodium hydride (1.9 g, 79.17 US 2010/0055072 A1 Mar. 4, 2010

mmol. 1.60 equiv) was added in several portions to the mix ture of 5-chloro-1-methyl-1H-benzod1.3oxazine-2,4-di -continued one in N,N-dimethylformamide from Step 2. Diethyl mal "Na onate (7.7 g, 48.07 mmol. 1.00 equiv) was then added C O O dropwise to the stirred mixture over a period of about 30 minutes. The resulting solution was stirred at about 85°C. for about 1 hour, water (800 ml) was added, and the pH of the solution was adjusted to 2 with a solution of hydrochloric acid C N (5 mol/L). The resulting crude product was collected by fil tration and then re-crystallized in ethanol to give the title product as a light yellow solid (2.5g, yield: 18%. 2 steps). 0105 Sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1- methyl-2-oxo-1,2-dihydroquinolin-4-olate: The pH value of Step 4 a solution of 5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo 01.02 N-phenyl-1,2-dihydroquinoline-3-carboxamide (170 mg. 0.48 mmol. 1.00 equiv) in ethanol (5 ml) was adjusted to 9-10 with a solution of 5M sodium hydroxide. The mixture then C OH O was stirred for about 30 min at ambient temperature. The resulting solids were collected by filtration and washed with ethanol to give the title compound as a white Solid (70 mg. N O yield: 39%). H NMR (300 MHz, DMSO) 8: 6.84-7.31 (m, 8H), 3.68 (q, 2H), 3.34 (s.3H), 1.02 (t,3H). LC-MS: m/z–357 O ls (M-Na2H)" EXAMPLE 2 Sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1-d- 1n O methyl-2-oxo-1,2-dihydroquinolin-4-olate H 0106 C OH O

N N "Na C O O

to N N N

0103 5-Chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N- so N phenyl-1,2-dihydroquinoline-3-carboxamide: N-ethylbenze CD namine (430 mg, 3.55 mmol. 2.00 equiv) was added dropwise to ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydro quinoline-3-carboxylate (500 mg, 1.78 mmol. 1.00 equiv) Step 1 dissolved in heptane (10 ml). The resulting mixture was 01.07 heated about 100° C. and the volatiles were removed by distillation over a period of about 7 hours. After cooling to ambient temperature, the resulting crystals were collected by C O filtration, washed with heptane, and purified by silica gel chromatography (ethyl acetate/petroleum ether 1:3) to afford O n the title product as a white solid (0.38 g, yield: 60%). -N -- CD3 Her N O Step 5 H 0104 C O

O

C OH O Ho N N s CD

N O N 0.108 d-Ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2- dihydroquinoline-3-carboxylate: The procedure of Example 1, Step 2 was followed, but substituting d-methyl iodide for US 2010/0055072 A1 Mar. 4, 2010 12 methyl iodide. The resulting product, ayellow solid, was used 0112 d-5-Chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo directly in the next step without any purification. N-phenyl-1,2-dihydroquinoline-3-carboxamide: The proce dure of Example 1, Step 4 was followed, but substituting Step 3 d-ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydro quinoline-3-carboxylate for ethyl 5-chloro-4-hydroxy-1-me 0109 thyl-2-oxo-1,2-dihydroquinoline-3-carboxylate. The title product was isolated as a white solid (1.0 g, yield: 79%). C O Step 5

O 0113 C OH O - O CD \ O N O N O O C. CD3 "Na ov C -O O C OH O C.to NN C to N CD CD3 0114 Sodium 5-chloro-3-(ethyl(phenyl)carbamoyl)-1- d-methyl-2-oxo-1,2-dihydroquinolin-4-olate: The proce dure of Example 1, Step 5 was followed, but substituting 0110 d-Ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2- d-5-chloro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl dihydroquinoline-3-carboxylate: The procedure of Example 1,2-dihydroquinoline-3-carboxamide for 5-chloro-N-ethyl 1, Step 3 was followed, but substituting di-ethyl 5-chloro-4- 4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxy 3-carboxamide. The title product was isolated as a white solid late for ethyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihy (0.17g, yield: 80%). H NMR (300 MHz, DMSO) 8: 6.83-7. droquinoline-3-carboxylate. The title product was isolated as 32 (m, 8H), 3.68 (q, 2H), 1.03 (t, 3H). LC-MS: m/z 360 a yellow solid (5.8 g., yield: 57%. 2 steps). (M-Na'iH)". Step 4 EXAMPLE 3 0111 Sodium 5-chloro-3-(dis-ethyl(phenyl)carbamoyl)-1- methyl-2-oxo-1,2-dihydroquinolin-4-olate C OH O 0115

N O

O ls CD3

D

D 1. D C OH O Step 1 0116 C N O N CD US 2010/0055072 A1 Mar. 4, 2010

-continued -continued D H D N D > - - -k, - D D

Ork I0121 N-ds-Ethylbenzenamine: Over a period of 1 hour 0117 tert-butyl phenylcarbamate: Aniline (2.3 g, 25 and maintaining the temperature at around 25°C., hydrochlo mmol. 1 equiv) was dissolved in tetrahydrofuran (25 ml) at ric gas was introduced to ds-ethyl-phenyl-carbamic acid tert about 5°C. A solution of di-tert-butyl dicarbonate (6.0g, 27.5 butyl ester dissolved in ethyl acetate (5 ml). The pH of the mmol) in tetrahydrofuran (10 ml) was added to the solution, solution was then adjusted to 6-7 with a sodium hydroxide and the resulting mixture was heated at reflux for about 2 solution (10 mol/L). Standard extractive workup with ethyl hours. The solvent was removed in vacuo and the resulting acetate gave the title product as yellow oil (0.33 g, yield: residue was dissolved in ethyl acetate (50 ml). The resulting 93%). solution was washed with a 1M citric acid solution (2x50 ml) and brine (1x50 ml). The organic phase was dried over Step 4 Sodium sulfate and evaporated in vacuo to give the title prod uct as a white solid (4.3 g, yield: 83%). 0122) Step 2 C OH O 0118 N 1N --

O

Ork -- y Y.D P. Cr

0119 ds-Ethyl-phenyl-carbamic acid tert-butyl ester: D Potassium 2-methylpropan-2-olate (790 mg, 7.05 mmol. 2.50 equiv) and ds-iodoethane (500 mg, 3.11 mmol. 1.10 equiv) D were added to tert-butyl phenylcarbamate (540 mg, 2.80 D mmol. 1.00 equiv) dissolved in N,N-dimethylformamide (100 mL). The resulting mixture was stirred at about 55° C. for about 16 hours, and then deuterium oxide was added (10 (0123 5-Chloro-N-di-ethyl-4-hydroxy-1-methyl-2-oxo ml). The pH of the mixture was then adjusted to about 6-7 N-phenyl-1,2-dihydroquinoline-3-carboxamide: The proce with 1N hydrochloric acid. Standard extractive workup with dure of Example 1, Step 4 was followed, but substituting ethyl acetate gave the title product as a crude residue, which N-ds-ethylbenzenamine for N-ethylbenzenamine. The title was used in the next step without further purification. product was isolated as a white solid (0.4g, yield: 58%). Step 3 Step 5 0120 0.124 US 2010/0055072 A1 Mar. 4, 2010 14

-continued -continued C OH O C OH O

N N

D D N O N O D D D D D CD3 D I0128 5-chloro-N-dis-ethyl-4-hydroxy-1-methyl-2-oxo I0125 Sodium 5-chloro-3-(ds-ethyl(phenyl)carbamoyl)- N-phenyl-1,2-dihydroquinoline-3-carboxamide: The proce 1-methyl-2-oxo-1,2-dihydroquinolin-4-olate: The procedure dure of Example 2, Step 4 was followed, but substituting of Example 1, Step 5 was followed, but substituting 5-chloro N-di-ethylbenzenamine for N-ethylbenzenamine. The title N— dis-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-1,2-di product was isolated as a white Solid. hydroquinoline-3-carboxamide for 5-chloro-N-ethyl-4-hy droxy-1-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-3- Step 2 carboxamide. The title product was isolated as a white solid (90 mg, yield: 40.5%). H NMR (300 MHz, DMSO) 8: 0129 6.84-7.32 (m, 8H), 3.34 (s, 3H) LC-MS: m/z. 362 (M-Na+ 2H)". C OH O

EXAMPLE 4 N N

Sodium 5-chloro-3-(ds-ethyl(phenyl)carbamoyl)-1- D D d-methyl-2-oxo-1,2-dihydroquinolin-4-olate N O D D CD D

0126 "Na O

C "Na O D

N N D CD D D D N O D D 0.130 Sodium 5-chloro-3-(dis-ethyl(phenyl)carbamoyl)- CD D 1-d-methyl-2-oxo-1,2-dihydroquinolin-4-olate: The proce dure of Example 2, Step 5 was followed, but substituting N-ds-ethylbenzenamine for N-ethylbenzenamine. The title Step 1 product was isolated as a white solid (0.1 g, yield: 70%). "H NMR (300 MHz, DMSO) 8: 6.83-7.31 (m, 8H). LC-MS: O127 m/z–365 (M-Na2H)". I0131 The following compounds can generally be made using the methods described above. It is expected that these C OH O compounds when made will have activity similar to those described in the examples above. N 1N -- D O D D D, CD3 C O1 O D N N D D H D D N D N O D -- D D CD3 OX D CD

US 2010/0055072 A1 Mar. 4, 2010 16

-continued -continued

D, D C OH O O C OH O N N

N D N O D D N O cs: D D

D C OH O O

C OH O N N c N O ls

C OH O O O D N N CD D D O C OH O O D D, P N N D CD

N O D

D

I0132 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. C OH O Biological Activity Assays D N N In Vitro Liver Microsomal Stability Assay 0.133 Liver microsomal stability assays are conducted at 2 D O N mg per mL liver microsome protein with an NADPH-gener D CD 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 C OH O O centration 5 microgram per mL) and incubated at 37°C. Final D concentration of acetonitrile in the assay should be <1%. N N Aliquots (50 uL) are taken out at times 0, 30, 60.90, and 120 minutes, and diluted with ice cold acetonitrile (200 uL) to D N O stop the reactions. Samples are centrifuged at 12,000 RPM D for 10 minutes to precipitate proteins. Supernatants are trans D ferred to microcentrifuge tubes and stored for LC/MS/MS D CD3 analysis of the degradation half-life of the test compounds. It has thus been found that certain deuterium-enriched com US 2010/0055072 A1 Mar. 4, 2010

pounds disclosed herein that have been tested in this assay gies in the Biomedical and Life Sciences 2003,785(2), which showed an increased degradation half-life as compared to the is hereby incorporated by reference in its entirety. non-isotopically enriched drug. In certain embodiments, the increase in degradation half-life is at least 5%; at least 10%; at Determining Laquinimod in Human Plasma by Liquid Chro least 15%; at least 20%; at least 30%; at least 40%; at least matography/Tandem Mass Spectrometry 50%; at least 60%; at least 70%; at least 80%; at least 90%; or 0.139. The procedure is carried out as described in Senn at least 100%. bro, et al., Rapid Communications in Mass Spectrometry In Vitro Metabolism Using Human Cytochrome Paso 2006, 20022), 3313-3318, which is hereby incorporated by Enzymes reference in its entirety. 0134. The cytochrome Paso enzymes are expressed from Measuring Laquinimod’s Effect on Th1/Th2 Balance and the corresponding human cDNA using a baculovirus expres Th3 Cytokine and TGF-B Cytokine Production in Lewis Rats. sion system (BD Biosciences, San Jose, Calif.). A 0.25 mil liliter reaction mixture containing 0.8 milligrams per millili 0140. The procedure is carried out as described in Yang, et ter protein, 1.3 millimolar NADP", 3.3 millimolar glucose al., Journal of Neuroimmunology 2004, 156(1-2), 3-9, which 6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, is hereby incorporated by reference in its entirety. 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically Experimental Autoimmune Encephalomyelitis Model enriched compound or standard or control in 100 millimolar 0.141. The procedure is carried out as described in Karus potassium phosphate (pH 7.4) is incubated at 37° C. for 20 sis et al., Ann. Neurol. 1993, 34, 654-660, which is hereby min. After incubation, the reaction is stopped by the addition incorporated by reference in its entirety. of an appropriate solvent (e.g., acetonitrile, 20% trichloro 0142. From the foregoing description, one skilled in the art acetic acid, 94% acetonitrile/6% glacial acetic acid, 70% can ascertain the essential characteristics of this invention, perchloric acid, 94% acetonitrile/6% glacial acetic acid) and and without departing from the spirit and scope thereof, can centrifuged (10,000 g) for 3 min. The supernatant is analyzed make various changes and modifications of the invention to by HPLC/MS/MS. adapt it to various usages and conditions. What is claimed is: 1. A compound of structural Formula I Cytochrome P4so Standard CYP1A2 Phenacetin CYP2A6 Coumarin (I) CYP2B6 'C-(S)-mephenytoin R R16 CYP2C8 Paclitaxel R3 R R15 CYP2C9 Diclofenac R4 CYP2C19 'C-(S)-mephenytoin R17 CYP2D6 (+/-)-Bufuralol Rs N O CYP2E1 ChlorZoxazone R14 CYP3A4 Testosterone CYP4A 'C-Lauric acid 2 N. Rs R13 R6 Ro C On O R Monoamine Oxidase A Inhibition and Oxidative Turnover R1 R10 0135 The procedure is carried out using the methods R11 described by Weyler, Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by reference or a salt thereof, wherein: in its entirety. Monoamine oxidase A activity is measured R-R, are independently selected from the group consist spectrophotometrically by monitoring the increase in absor ing of hydrogen and deuterium; and bance at 314 nm on oxidation of kynuramine with formation at least one of R-R, is deuterium. of 4-hydroxyquinoline. The measurements are carried out, at 2. The compound as recited in claim 1 wherein at least one 30°C., in 50 mM sodium phosphate buffer, pH 7.2, contain of R-R-7 independently has deuterium enrichment of no less ing 0.2% Triton X-100 (monoamine oxidase assay buffer), than about 10%. plus 1 mM kynuramine, and the desired amount of enzyme in 3. The compound as recited in claim 1 wherein at least one 1 mL total volume. of R-R-7 independently has deuterium enrichment of no less than about 50%. Monoamine Oxidase B Inhibition and Oxidative Turnover 4. The compound as recited in claim 1 wherein at least one 0136. The procedure is carried out as described in Uebel of R-R, independently has deuterium enrichment of no less hack, Pharmacopsychiatry 1998, 31(5), 187-192, which is than about 90%. hereby incorporated by reference in its entirety. 5. The compound as recited in claim 1 wherein at least one 0.137 Determining Laquinimod in Plasma by Coupled of R-R, independently has deuterium enrichment of no less Column Liquid Chromatography with Ultraviolet Absor than about 98%. bance Detection 6. The compound as recited in claim 1 wherein said com 0.138. The procedure is carried out as described in Edman, pound has a structural formula selected from the group con et al., Journal of Chromatography, B: Analytical Technolo sisting of:

US 2010/0055072 A1 Mar. 4, 2010 19

-continued -continued D D D, D C OH O O C OH O N N

N N D D N O D N O D D CD

D CD D C OH O O N N

D N O D D D C OH O O l

D

D D, C OH O C OH O O N N

N O C.N O N D D CD3 D CD C OH O O N N

D N O N O D D D CD3 CD D CD D

D C OH O O C OH O O N N N N

D N O to N D D CD CD D C OH O , and N N D C OH O O N N N O D

D CD3 US 2010/0055072 A1 Mar. 4, 2010 20

8. The compound as recited in claim 7 wherein each posi -continued tion represented as D has deuterium enrichment of no less than about 10%. C OH O 9. The compound as recited in claim 7 wherein each posi tion represented as D has deuterium enrichment of no less N N than about 50%. 10. The compound as recited in claim 7 wherein each N O position represented as Dhas deuterium enrichment of no less D than about 90%. 11. The compound as recited in claim 7 wherein each D position represented as Dhas deuterium enrichment of no less than about 98%. 12. The compound as recited in claim 7 wherein said com 7. The compound as recited in claim 1 wherein said com pound has the structural formula: pound has a structural formula selected from the group con sisting of

C OH O C OH O O N N N OD CD3 N O CD D CD3 D CD3 13. The compound as recited in claim 7 wherein said com pound has the structural formula: C OH O O N N C OH O

N O N N D CD D N OD"> CD3 C OH O O N N 14. The compound as recited in claim 7 wherein said com to N pound has the structural formula: CD C OH O C OH O , and N N C.N O N N O D CD3

D CD 15. A pharmaceutical composition comprising a com pound as recited in claim 1 together with a pharmaceutically C OH O O acceptable carrier. N N 16. A method of treatment of a immune function-mediated disorder comprising the administration of a therapeutically effective amount of a compound as recited in claim 1 to a N O patient in need thereof. D 17. The method as recited in claim 16 wherein said disorder D is multiple Sclerosis and autoimmune disorders. 18. The method as recited in claim 16 further comprising the administration of an additional therapeutic agent. US 2010/0055072 A1 Mar. 4, 2010

19. The method as recited in claim 18 wherein said addi d. increased average plasma levels of at least one metabo tional therapeutic agent is selected from the group consisting lite of said compound per dosage unit thereofas com of immunomodulators and cyclosporins. pared to the non-isotopically enriched compound; and 20. The method as recited in claim 19 wherein said immu e. an improved clinical effect during the treatment in said nomodulator is selected from the group consisting of Subject per dosage unit thereofas compared to the non filgrastim, molgramostim, sargramostim, lenograstim, ances isotopically enriched compound. 23. The method as recited in claim 16, wherein the method tim, pegfilgrastim, interferon gamma, interferon alpha-2a, effects a decreased metabolism of the compound per dosage interferon alpha-2b, interferon alpha-n1, interferon beta-1a, unit thereof by at least one polymorphically-expressed cyto interferon beta-1b, interferon alphacon-1, peginterferon chrome Paso isoform in the Subject, as compared to the cor alpha-2b, peginterferon alpha-2a, interferon omega, responding non-isotopically enriched compound. aldesleukin, oprelvekin, lentinan, roquinimex, BCG vaccine, 24. The method as recited in claim 23, wherein the cyto pegademase, pidotimod, Poly I:C, Poly ICLC, thymopentin, chrome Paso isoform is selected from the group consisting of immunocyanin, tasonermin, melanoma vaccine, glatiramer CYP2C8, CYP2C9, CYP2C19, and CYP2D6. acetate, histamine dihydrochloride, mi?amurtide, plerixafor, 25. The method as recited claim 16, wherein said com muromonab-CD3, antilymphocyte immunoglobulin (horse), pound is characterized by decreased inhibition of at least one antithymocyte immunoglobulin (rabbit), mycophenolic acid, cytochrome Paso or monoamine oxidase isoform in said Sub Sirolimus, leflunomide, alefacept, everolimus, gusperimus, ject per dosage unit thereofas compared to the non-isotopi efalizumab, abetimus, natalizumab, abatacept, eculizumab, cally enriched compound. etanercept, infliximab, afelimomab, adalimumab, certoli 26. The method as recited in claim 25, wherein said cyto Zumab pegol, daclizumab, basiliximab, anakinra, chrome Paso or monoamine oxidase isoform is selected from ciclosporin, tacrolimus, azathioprine, thalidomide, methotr the group consisting of CYP1A1, CYP1A2, CYP1B1, exate, and lenalidomide. CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. 21. The method as recited in claim 16, further resulting in CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, at least one effect selected from the group consisting of: CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, a. decreased inter-individual variation in plasma levels of CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, said compound or a metabolite thereofas compared to CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, the non-isotopically enriched compound; CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, b. increased average plasma levels of said compound per CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, dosage unit thereofas compared to the non-isotopically CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO, and enriched compound; MAO. c. decreased average plasma levels of at least one metabo 27. The method as recited in claim 16, wherein the method lite of said compound per dosage unit thereofas com reduces a deleterious change in a diagnostic hepatobiliary pared to the non-isotopically enriched compound; function endpoint, as compared to the corresponding non d. increased average plasma levels of at least one metabo isotopically enriched compound. lite of said compound per dosage unit thereofas com 28. The method as recited in claim 27, wherein the diag pared to the non-isotopically enriched compound; and nostic hepatobiliary function endpoint is selected from the e. an improved clinical effect during the treatment in said group consisting of alanine aminotransferase (ALT), serum Subject per dosage unit thereofas compared to the non glutamic-pyruvic transaminase (“SGPT), aspartate ami isotopically enriched compound. notransferase (AST,” “SGOT), ALT/AST ratios, serum aldolase, alkaline phosphatase (ALP), ammonia levels, 22. The method as recited in claim 16, further resulting in bilirubin, gamma-glutamyl transpeptidase (“GGTP at least two effects selected from the group consisting of “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver a. decreased inter-individual variation in plasma levels of biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti said compound or a metabolite thereofas compared to dase, and blood protein. the non-isotopically enriched compound; 29. A compound as recited in claim 1 for use as a medica b. increased average plasma levels of said compound per ment. dosage unit thereofas compared to the non-isotopically 30. A compound as recited in claim 1 for use in the manu enriched compound; facture of a medicament for the prevention or treatment of a c. decreased average plasma levels of at least one metabo disorder ameliorated by the modulation of immune function. lite of said compound per dosage unit thereofas com pared to the non-isotopically enriched compound; c c c c c