AU2015200975B2 - Substituted n-aryl pyridinones - Google Patents

Abstract

)sosed hereni are SubstitutddNaryl poifione iib U c inhb rs and/or co da en thereof, and methods of' use thereof

Description

AUSTRALIA PATENTS ACT 1990 REGULATION 3.2 Name of Applicant: AUSPEX PHARMACEUTICALS, NC. Actual Inventor/s; THOMAS G. CANT; and SEPEHR SARSHAR Address for Service: E. F. WELLINGTON & CO., Patent and Trade Mark Attorneys, 312 St. Kilda Road, Melbourne, Southbank, Victoria, 3006. invention Title: "SUBSTITUTED N-ARYL PYRIDIONES" Details of Associated Provisional Applications Nos: The following statement is a full description of this invention including the best method of performing it known to us. Next page is page IA CROSS-REFERENCE TO RELATED APPLICATIONS [00011 This application is a 'divisional application derived from Australian Patent Application No. 2008265595 (PCT/US2008/067732: WO 2008/57786) claiming priority of US Application No. 60/945136, the entire text of each of which is hereby incorporated herein by referencee FIElD j00021 The present invention is directed to substituted N-Atyl pyridinones, ph~armaceCutically acetbesalts and prodrugs thereof, the chemical synthesis there-of, and medical use of such compounds for the treatment and/or management of idiopathic pulmonary fibrosis, uterine fibroids, multiple scerosis, renal fibrosis diabetic kidney disease, endotoxin induced liver injury after partial hepatectony or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis, atrial fibrilation, neutropenia, scieroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia, rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues. BACKGROUND [00031 Pirfenidone (Deskar), 5-methyl-penyl1H-pyridin-2-one is an orally administered antifbrotic agent Pirfenidone is effective in rodent disease models, Pirfenidone inhibits DNA synthesis in leiomyoma cells and myometrial cells (Lee et al, Journal of Clinical Endocrinology and Metabolism 1998, 83(1), 219-23), Pirfenidone is currently undergoing Phase III enrollment for idiopathic pulmonary fibrosis (IPF N Virfenidone N e xt p)a ge , I s pa g c2.

I.A

[00041 While the chemical structure of pirfenidone is relatively simple, the metabolism is only partially understood, For example, the methyl group is thought to be susceptible to oxidation which would lead to a corresponding hydroxymethyl metabolite "Mi." MI is thought to be further oxidized to a carboxylic acid metabolite, "M2' (Wang et al, Biomedicad Chromatography 2006, 20, 1375- 1379), A third detected metabolite is believed to be a phase l product possibly originating from NI or M2 Pirfenidone has a very short half-life in humans and will likely be dosed at more than once per day, SUMMARY OF THE INVENTION 100051 Disclosed herein is a compound having structural Formula 1:

R

8

R

7 0 R Rg- q N R5 RIO R 1

R

4 R R 2 or a pharmaceutically acceptable salt, solvate, or piodrug thereof; wherein: R, R 2 . R-, R R 5 , R 6 , R, R,& R4. R, and Ri 1 are selected from the group consisting of hydrogen or deluteriun at least one Rj. R R, RI, ,. R1 R R ,K 9 , Rlj, and Ri is deuterium: and vien R, R,, R. R, and R 1 are deuterium, then at least one of R, , R R4 R5, and R 6 is deuterium. [00061 Further, disclosed herein are methods of modulating collagen infiltration into tissues and/or inhibiting fibrosis. [00071 Disclosed herein is a method for treating preventing, or ameliorating one or more symptom of a fibrotic-mediated disorder and/or a collagen-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound as disclosed herein. [00081 Further disclosed herein is a method wherein the fibrotic-mediated disorder and/or the collagen-mediated disorder is seocted from the group consisting of, but not limited to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, aillograft injury after organ transplantation, cystic fibrosis, atrial fibrilation, neutropenia, scleroderma, -2dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis spleen fibrosis caused by sickle-el anemia, rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues. 100091 Also disclosed herein are articles of manufacture and kits containing compounds as disclosed herein. By way of example only a kit or article of manufacture can include a container (such as a bottle) with a desired amount of at least one compound (or pharmaceutical composition of a compound) as disclosed herein. Further, such a kit or article of manufacture can further include instructions for using said compound (or pharmaceutical composition of a compound) disclosed herein, The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container. [00101 in another aspect is the use of a compound as disclosed herein in the manufacture of a medicament for treating a disorder in an animal in which fibrosis and/or collagen infiltration contribute to the pathology and/or symptomology of the disorder. In a further embodiment, said disorder is, but not liroted to, idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, alograft injury after organ transplantation, cystic fibrosis, atrial fibrillation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia, rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues, 100111 In another aspect are processes for preparing a compound as described herein as a fibrotic inhibitor and/or collagen infiltration modulator, or other phamaeutically acceptable derivatives such as prodrug derivatives, or individual isomers and mixture of isomers or enantiomers thereof 10012] In another aspect are processes for preparing a compound as disclosed herein as a fibrosis modulator and/or collagen infiltration modulator. 100131 Also disclosed herein are processes for formulating pharmaceutical compositions with a compound disclosed herein. 100141 In certain embodiments said pharmaceutical composition comprises one or more release-controlling excipients, [00151 In other embodiments said pharaceutical composition further comprises one or more non-release controlling excipients. 100161 In certain embodiments said pharmeaceutical composition is suitable for ora, parenteral, or intravenous infusion administration. 100171 In yet other embodiments said pharmaceutical composition comprises a tablet, or capsule. 100181 In certain embodiments the compounds as disclosed herein are adninistered in a dose of 0,5 milligram to 1000 miliram. [0*191 In yet further embodiments said pharmaceutical compositions further comprise another therapeutic agent. 100201 In yet other embodiments said therapeutic agent is selected from the gmup consisting of sepsis agents,anti-bacterials, anti-ungals antioagulants thrombolytics, steroidal drugs, non-steroidal anti-inflammatory drugs (NSMIDsI opioids, anesthetics cacium channel blockers, Beta-blockers, nitrates or nitrites, ACE inhibitors, statins, platelet aggregation inhibitors, adenosine, digitoxin, anti-arrhythmic agents, sympathomrnimetic drugs, endothelin converting enzyme (NCE) inhibitors, thromboxane enzyme antagonists, potassium channel. opener;, thmombin inhibitor;, growth factor inhibitors, platelet activating factor (PMf antagonists, anti-platelet agents, Factor Vila Inhibitors, Factor Xa Inhibitors, rein inhibitors, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, 11MG CoA reductase inhibitor;, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic agents, MTP Inhibitors, potassium channel activators, alpha-PDE5 agents, beta-PDE5 agents. diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme antagonists, aP2 inhibitors, potein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, cheniotherapeutic agents, imununosuppressants. anticancer agents, cytotoxic agents, antimetabolites, farnesyIprotein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stablizing agents, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors, eyclooxygenase~2 (COX-2) inhibitors, gold compounds, antalarmin, Z338 and platinum coordination complexes. [00211 In yet other embodiments said therapeutic agent is a steroidal drug. 100221 In further embodiments said steroidal drug is selected from the group consisting of aldosterone, beelometasone, betamethasone deoxycorticosterone acetate, fludrocortisone -.4acetate, hydrocortisone (cortisol), prednisolone, prednisone, methylprenisolone dexametasone, and triamcinolone. [0023) In yet other embodiments said therapeutic agent is a non-steroidal anti inflammatory agent 100241 In further embodiments said non-steroidal anti-inflammatory agent is selected from the group consisting of aceclofenac, acemetacin, amoxiprin. aspirin, azapropazone, benorilate, bronfenac, carprofen, celecoxib, choline magnesium salicylate, dielo fenac. diflunisaa. etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicamn, loxoprofen, lumiracoxib meclofenamic acid, mefenamic acid, mloxicam metamizoe methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, sal icyl salicylate, sulindac sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and olmetin. f0025 In other embodiments, a method for the treatment, prevention, o amelioration of one or more symptoms of a fibrotic-nediated disorder and/or collagen-rnediated disorder in a subject comprises administering a therapeutically effective amount of a compound as disclosed herein. 100261 In yet other embodiments said fibrotic-mediated disorder and/or said collagen mediated disorder is selected from the group consisting of idiopathic pulmonary fibrosis, uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-inducedliver injury after partial hepatectomy or hepatic ischemial alograft injury after organ transplantation, cystic fibrosis, atrial fibrilation, neutropenia, scleroderma, dermatomyositis, cirrhosis, diffise parenchymal lug diseasenediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia, and rheumatoid arthritis. 100271 In other embodiments said fibrotic-mediated disorder and/or said collagen mediated disorder can be lessened, alleviated, or prevented by modulating fibrosis. [00281 In further embodiments said fibrotic-mediated disorder and/or said collagen mediated disorder can be lessened, alleviated, or prevented by modulating collagen infiltration. (00291 In other embodiments said compound has at least one of the following properties: a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound; b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; c) decreased average plasma levels of at east one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and e) an improved clinical effect during the treatment in saidA subject per dosage unit thereof as compared to the non-isotopicaily enriched compound. [00301 In yet further embodiments said compound has at least two of the following properties: a) decreased inter-individual variation in plasma levels of said compound or a rnetabolite thereof as compared to the non-isotopically enriched compound; b) increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopicallv enriched compound; d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the nonisotopicaiy enriched compound; and e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopicadly enriched compound. 100311 In certain embodiments said compound has a decreased metabolism by at least one polymorphicaly-expressed cytochrome P,;, isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 100321 In other embodiments said cytohrme P 4 5 isoforn is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6, [00331 In yet further embodiments said compound i characterized by decreased inhibition of at least one cytochrome P 450 or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 100341 in certain embodiments said. cytochrome P 450 or monoamine oxidase isoforrn is selected from the group consisting of CYPIAI, CYPIA2, CYPIB, CYP2A6, CYP2AI3, CYP2B6, CYP2C8, CYP2C9, CIYPZC 18 CYP2C19, CYP2D6. CYPE1, CYP2GI, CYP2J2, CYP2RI, CYP2SI, (YP3A4, CYP3AS, CYP3A5PI, CYP3A5P2. CYP37 CYP4Alt -6- CYP4B, CYP4F2, CYP4F3, CYP4F8, CYP4F1 1 CYP4F12, CYP4X .1CYP4ZI, CYP5M, CYP7AI, CYP7B1, CYP8Ai. CYP8Bl. CYPIlAI, CYPIBL, CYP1iB2, CYPir CYP19, CYP2JCYP24, CYP26A I, CYP26B1, CYP27AI, CYP27BI, CYP39 YP46, CYP5I MAGA and MAOr, [00351 In other embodiments said method method affects the treatment of the disorder while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound. 100361 I yet further embodiments said diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ('SGPT"), aspartate aminotransferase ("AST," "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"). ammonia levels, bilirubin, gammaglutamyl transpeptidase ("GGTP," "y-GTP," "GGT"), leucine aninopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5'nucleotidase, and blood protein. INCORPORATION BY REFERENCE [00371 All publications and references cited herein, including those in the background section, arc expressly incorporated herein by reference in their entirety,. However, with respect to any similar or identical terms found in both the incorporated publications or references and those expressly put forth or defined in this document, then those terms definitions or meanings expressly put forth in this document shall control in all respects. DETAILED DESCRIPTION [00381 To facilitate understanding of the disclosure set forth herein, a number of terms are defined below, Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharnacology described herein are those well known and commonly employed in the art Unless defined otherwise all technical and scientific terms used herein generally have the same meaning ascommonly understood in the art to which this disclosure belongs, i the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise. -7- [0039] As used herein, the singular forms "a," "anand "the"may refer to plural articles unless specifically stated otherwise. [00401 The term. "subject" refers to an animal, incLuding but not limited to, a primate (e~g., human monkey, chimpanzee, gorilla, and the like), rodents(e g ratsmice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (eg, pig, miniature pig) equine, canine, feline, and the like. The termm "subject" and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human patient [0041 The terms treaty 4 " "treating," and "treatment are meant to include alleviating or abrogating a disorder; or alleviating or abrogating one or more of the symptoms associated with the disorder; and/or alleviating or eradicating the causes) of the disorder itself. [00421, The terms "prevent," "preventing," and "preventionrefer to a method of delaying or precluding the onset of a disorder; delaying or precluding its attendant symptoms; barring a subject from acquiring a disorder; and/or reducing a subject's risk. of acquiring a disorder [00431 The term "therapeutically effetive amount" refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder being treated, The temi "therapeutically effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue system animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician [00441 The tem "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a phanaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical fomulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation allergic response, immunogenecity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice ofParmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook ofPharmaceutcai Excipients, 5th Edition; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and -8 ~ Handbook oftharmaceudcai Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceusical Prefdrmulation and Formulation, Gibson Ed,, CRC Press LLC Boes Raton. FL, 2004). 100451 The term "deuterium enrichment" refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non enriched starting materials is about 0,0156%,. The deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectTOscopy. f00461 The term "is/arc deuterium," when used to describe a given position in a molecule such as RI, R 2 , R, R 4 Rs, R, RB. , Rg, R.,, Rw. and Rw or the symbol "D," when used to represent a given position. in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium, In an embodiment deuterium enrichment is of no less than about I1, in another no less than about 5% in another no less than about 10%, in another no less than about 20% in another no less than about 50% in another no less than about 70%, in anothernio less than about 80% in another no less than about 90%, or in another no less than about 98% of deuterium at the specified position, f00471 The term "isotopic enrichment" refers to the percentage of incorporation of a less prevalent isotope of an element at a given position in a molecule in the place of the more prevalent isotope of the element. [00481 The term "non-isotopically enriched" refers to a molecule in which the percentages of the various isotopes are substantially the same as the naturally occurring percentages 100491 The terms "substantially pure" and "substantially homogeneous" mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), nuclear m agnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, or biological and pharmacological 9.~ properties, such as enzymatic and biological activities, of the substance. In certain embodiments. "substantially pure" or "substantially homogeneous" refers to a collection of molecules, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%. at least about 98%, at least about 99%, or at least about 99:5% of the molecules are a single compound, including a racemic mixture or single steroisomer thereof, as determined by standard analytical methods [0050] The term "about" or "approximately" means an acceptable error for a particular valuehich depends in part on how the value is measured or determined. In certain embodiments, "about" can mean I or more standard deviations 00511 The terms "active ingredient" and "active substance" efer to a compound, which s administered, alone or in combination with o.ne or more pharmaceutical acceptable excipients and/or carriers, to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder, 100521 The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound, or a pharmaceutical composition thereof which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a disorder 100531 The term "disorder" as used herein is intended to be generally synonymous, and is used interchangeably with, the terms "disease" syndrome " and "condition" (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms. 100541 The term "release control ling excipient" refers to an excipient whose primary function is to modify the duration or place of release of the active substance from dosage form as compared with a conventional immediate release dosage form. 100551 The term "nonrelease controlling excipient" refers to an excipient whose primary fiction do not include modifying the duration or place of release o f the active substance from a dosage form as compared with a conventional immediate release dosage form. 100561 The term "protecting group" or "removable protecting group" refers to a group which, when bound to a functionality, such as the oxygen atom of a hydroxyl or carboxyl group. or the nitrogen atom of an amino group, prevents reactions from occurring at that functional group, and which can be removed by a conventional chemical or enzymatic step to reestablish - 10the functional group (Greene and Wuts, Protective Grmups in Organic Synthesis, 34 Ed., John Wiley & Sons, New York, NY, 1999), 100571 The term "fibrosis" refers to the development of excessive fibrous connective tissue within an organ or tissue, 100581 The term "collagen infiltration" refers to the entry of the connective tissue collagen into cells or into the extracellular matrix around cells. This occurs in organs and tissues naturally and under normal circumstances but can occur excessively and accompany or cause disease. 100591 The terms "fibrosis" and "collagen infiltration" are not necessarily synonymous but can, in certain contexts, be used interchangeably. 10060] The terms "collagen-mediated disorder" refers to a disorder that is characterized by abnormal or undesired collagenic infiltration, that when collagen infiltration activity is modified, leads to the desired responses depending on the route of administration and desired end result. A colagen-mediated disorder may be completely or partially mediated through the modulation of collagen infiltration, in particular, a collagen-mediated disorder is one in which modulation of collagen infiltration activity results in some effect on the underlying disorder, e.g, administering a collagen-infiltration modulator resuls in some improvement in at least some of the patients being treated. [00611 The terms "fibrotic-mediated disorder" refers to a disorder that is characterized by abnormal or undesired fibrotic activity, that when fibrosis activity is modified, leads to the desired responses depending on theroute of administration and desired end result. A Fibrosis mediated disorder may be completely or partial mediated through the modulation of fibrosis. In particular, a fibrosis-mediated disorder is one in which modulation of fibrosis activity results in some effect on the underlying disorder, e.g., administering a fibrosis modulator results in some improvement in at least some of the patients being treated. [00621 The terms "fibrosis modulator" or "modulating fibrosis" are meant to be interchangeable and refer to the ability of a compound disclosed herein to alter the occurrence and/or amount of fibrosis. A fibrosis modulator may increase the occurrence or level of fibrosis, may increase or decrease the occurrence and/or amount of fibrosis depending on the concentration of the compound exposed to the adrenergic receptor; or may decrease the occurrence and/or amount of fibrosis. Such activation or inhibitlon may be contingent on the -1l occurrence of a specific event, such as activation of a signal transduction pathway and/or may be manifest only in particular cell types. 10063] The terms "collagen-nfiitration modulator or "modulating collagen infiltration" are meant to be interchangeable and refer to the ability of a compound disclosed. herein to alter the occurrence and/or amount of collagen infiltration, A fibrosis modulator may increase the occurrence or level of collagen infiltration may increase or decrease the occurrence and/or amount of collagen infiltration depending on the concentration of the compound exposed to the adrenergic receptor, or may decrease the occurrence and/or amount of collagen infiltration. Such activation or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal. transduction pathway, and/or may be manifest only in particular cell types Deuteriun Kinetie Isotope Effect [00641 In an attempt to eliminate foreign substances, such as therapeutic agents. from its circulation system, the animal body expresses various enzymes, such as the cytochrome Pso enzymes or CYPs, esterases, proteases, reductases, dey drogenases and monoamine oxidases, to react with and convert these foreign sNubstances to rore polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical. compounds involve the oxidation of a caron-hydrogen (C-4) bond to either a carbon-oxygen (C-O) or carbon-carbon (C n-bond The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long-term toxicity profiles relative to the parent compounds. For most drugs, such. oxidations are generally rapid and ultimately lead to administration of multiple or high daily doses. [00651 The relationship between the activation energy and the rate of reaction may be quantified by the Arrhenius equation, k Ae where E,. is the actvation energy Tis temperature, R. is the molar gas constant k is the rate constant for the reaction 3 and A (the frequency factor) is a constant specific to each reaction that depends on the pobability that the molecules will collide with the correct orientation, The Arrhenius equation states that the fraction of molecules that have enough energy to overcome an energy barrier, that is, those with energy at least equal to the activation energy, depends exponentially on the ratio of the activation -12energy to thermal energy (RT), the average amount of thermal energy that molecules possess at a certain temperature. 10066] The transition state in a reaction is a short lived state (on the order of 0 -4ec) along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation energy E. for a reaction is the energy required to reach the transition state of that reaction. Reactions that involve multiple steps will necessarily have a number of transition states, and in these instances, the activation energy tor the reaction is equal to the energy difference between the reactants and the most unstable transition state. Once the transition state is reached, the molecules can either revert, thus reforrning the original reactants, or the new bonds form giving rise to the products. This dichotomy is possible because both pathways, forward and. reverse, result in the release of energy. A catalyst facilitates a reaction process by lowering the activation energy leading to a transition state. Enzymes are examples of biological catalysts that reduce the energy necessary to achieve a particular transition state. [0067] A carbon-hydrogen bond is by nature a covalent chemical bond. Such a bond forms when two atoms of similar electronegativity share some of their valence electrons, thereby creating a force that holds the atoms together. This force or bond strength can be quantified and is expressed in units of energy, and as such, covalent bonds between various atoms can be classified according to how much energy must be applied to the bond in order to break the bond or separate the two atoms. [00aS The bond strength is directly proportional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy, which is also known as the zero-point vibrational energy, depends on the mass of the atoms that form the bond. The absolute vaue of the zero-point vibrational energy increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) is two-ibid more massive than hydrogen (H), it follows that a C-D bond is stronger than the corresponding C-H bond. Compounds withD C-t bonds are frequently indefinitely stable in HzO, and have been widely used for isotopic studies. If a C-H bond is broken during a rate-determining step in a chemical reaction (ie. the step with the highest transition state energy), then substituting a deuterium. for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE) and can range from about I (no isotope effect) to very large numbers, such as 50 or more meaning that the reaction can be fi fty, or more, times slower - 13 when deuterium is substituted for hydrogen, High DKLE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small size of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. A deuterium is larger and statistically has a much lower probability of undergoing this phenomenon. Substitution of tritium for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. j0069 Discovered in 1932 by Urey, deuterium (D) is a stable and non-radioactive isotope of hydrogen. It was the first isotope to be separated from its element in pure form and is twice as massive as hydrogen, and makes up about 0,02% of the total mass of hydrogen (in this usage meaning all hydrogen isotopes) on earth. When two deuteriums bond with one oxygen, deuterium oxide (D20 or "heavy water") is formed. D00 looks and tastes like 1-120, but has different physical properties. It boils at 101.41 'C and freezes at 339 C., Its heat capacity, heat of fusion, heat of vaporization, and entropy are all higher than H20. It is also more viscous and is not as powerful a solvent as 1120. 10070) When. pure D20 is given to rodents, it is readily absorbed and reaches an equilibrium level that is usually about eighty percent of the concentration of what was consumed. The quantity of deuterium required to induce toxicity is extremely high. When 0% to as much as 15% of the body water has been replaced by D20, animals are healthy but are unable to gain weight as fast as the control (untreated) group. When about 15% to about 20% of the body water has been replaced with D20, the animals become excitable. When about 20% to about 25% of the body water has been replaced with D20, the animals are so excitable that they go into frequent convulsions when stimulated. Skin lesions, ulcers on the paws and muzzles, and necrosis of the tails appear. The animals also become very aggressive; males becoming almost unmanageable. When about 30%, of the body water has been replaced with D20, the animals refuse to eat and become comatose. Their body weight drops sharply and their metabolic rates drop far below normal, with death occurring at about 30 to about 35% replacement with D20. The effects are reversible unless more than thirty percent of the previous body weight has been lost due to D20 Studies have also shown that the use of DO can delay the growth of cancer cells and enhance the cytotoxicity of certain antineoplastic agents. - 14- 100711 Tritium (T) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Mixing tritium with a phosphor provides a continuous light source, a technique that is commonly used in wristwatches, compasses, rifle sights and exit signs. It was discovered by Rutherford, Oliphant and Harteck in 1934, and is produced naturally in the upper atmosphere when cosmic rays react with HT 2 molecules, Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T 2 0, a colorless and odorless liquid. Tritium decays slowly (half-life = 12.3 years) aid emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level, [00721 Deuteration of pharmaceuticals to improve pharmacokinetics (PK. pharmacodynamics (PD), and toxicity profiles, has been demonstrated previously with some classes of drugs. For example, DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching which may even give rise to an oxidative intermediate with a faster off-rate from an activating Phase I enzyme (e.g., cytochrome Pa., 3A4). The concept of metabolic switching asserts that xenogens, when sequestered by Phase I enzymes, may bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g, oxidation). This hypothesis is supported by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions, Metabolic switching can potentially 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 have not been heretofore sufficiently predictable a prior for any drug class. - 15- Deuterated Pyridinone Derivatives 100731 Pirfenidone is a substituted pyridinone-based fibrosis modulator and/or collagen infiltration modulator. The carbon-hydrogen bonds of pirfenidone contain a naturally occurring distribution of hydrogen isotopes, namely 1 H or protium (about 999844%), 2 H or deuterium (about (00156%), and 3 H or tritium (in the range between about 0.5 and 67 tritium atoms per 10 protium atoms). Increased levels of deuterium incorporation may produce a detectable Kinetic Isotope Effect (KIE) that could affect the pharmacokinetic, pharmacologic and/or toxicologic profiles of of such fibrosis modulators and/or collagein-nfiltration modulators in comparison with the compound having naturally occurring levels of deuterium [0074 Pirfenidone is likely metabolized in humans by oxidizing the methyl group. Other sites on the molecule may also undergo transformations leading to metabolites with as-yet unknown pharmacology/toxicology. Lirniting the production of these metabolites has the potential to decrease the danger of the administration of such drugs and may even allow increased dosage and concomitant increased efficacy, All of these transformations can occur through polymorphicalely-expressed enzymes, thus exacerbating the interpatient variability. Further, disorders, such as multiple sclerosis, are best treated when the subject is medicated around the clock for an extended period of time. For all of foregoing reasons, there is a strong likelihood that a longer half-ife medicine will diminish these problems with greater efficacy and cost savings [00751 Various deuteration patterns can be used to a) reduce or eliminate unwanted metabolites, b) increase the half-life of the parent drug, c) decrease the number of doses needed to achieve a desired effect, d) decrease the amount of a dose needed to achieve a desired effect, e) increase the formation of active metabolites, if any are formed, and/or f) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for polypharmacy, whether the polypharmacy be intentional or not. The deuteration approach has strong potential to slow the metabolism via various oxidative and racemization mechanisms. -16f0076j In one aspect, disclosed herein is a compound having structural Formula 1.

R

8

R

7 0 R 6 RIO R 1 1

R

4 R

R

1 R 2 or a pharmaceuically acceptable salt, solvate, or prodrug thereof; wherein: R1, R 2 , R, Rj, Rs, R 6 , R,, RqR Ric and R 11 are selected from the group consisting of hydrogen and deuterium; and at least one of leR 1 , R. R , R, R RR -! Pa a,). Rici and R 1 I is deuterium; and when R. R, R9, Rio, and R; are deuterium, then at least one of Re 1 6 a RR . and R6 is deuterium, [00771 In another embodiment, at least one of R, R, R4, PR KR, R ,, R, R,, Ri, and

R

11 independently has deuterium enrichment of no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98% 100781 In yet another embodiment, at least one of R 1

R

2 , and R 3 is deuterium. f00791 In yet another embodiment, R. R and RK are deuterium. 100801 In yet another embodimentR is deuterium. 100811 In yet another embodiment, at least one of Rs and R, is deuterium, [00821 In yet another enibodiment. R and R( are deuterium 100831 In yet another embodiment Rs and Rs are deuterium; and at least one of R 1 , R. Ra R, RR R

,

) R 10 , and R, is deuterium j00841 In yet another embodiment, at least one of 7 , R, P Ri, and R 1 is deuterium. [0085] In yet another embodiment, R R'>, RR 0 and k 1 are deuterium. 100861 In yet another embodiment, R 7 R, and R are deuteriunm and at least one of R-, Ra 2 , R 3 , R 1 , R, 6 , RK 1 R, and R- 1 is deuteriumrn 100871 In yet another embodiment, at least one of R 1 , R. and R 3 is deuterium; and R4

K

5 , R& R, -R, R, Ro, and R are hydrogen. - 17 - 100881 In yet another embodiment, R1, R and R3 are deuteriun; and R 4 R, R 4 Rs R, R RQ 1,and RI are hydrogen. 100891 In yet another embodiment, R 4 is deuterium; and Rj. R 2 . R, R. R R, Ra, R>, RIc, and R are hydrogen. [00901 In vet another embodiment, at least one of Rs and R6 is deuterium; and R 1 , R 2

R

3

R

4 $ R, R, R 9 R and R are hydrogen. 10091 In yet another embodiment, R 5 and R. are deuterium.; and R1, R), R; 3 14, R:- R.s R, R. and R ware hydrogen. 100921 In yet another embodiment, at least one of R. R7 R , RP 5 and R.6 is deuterium; and R, RR and R. are hydrogen. 100931 In yet another embodiment, R1, RI, R, 4 Rs and R are deuterium; and R:, R-, R), R , and R are hydrogen, [00941 N yet another embodiment, at least one of R7, Rs. R R4 . and Ri is deuterium and 1 , R. R R5, and R 6 are hydrogen. 100951 In yet another embodiment, , R, P 9 Rio, and Rnj are deuteiun; and at least one of R, R.RRRtP and R.

4 is deremurnm [0096] In other embodiments, R is hydrogen. In yet other embodiments, P, is hydrogen In still other embodiments, R3 is hydrogen. In yet other embodiments. it is hydrogen. In some embodiments, Rs is hydrogen. In yet other embodiments, R4 is hydrogen. in still other emibodmnents, Ris hydrogen. In still other embodiments Rs is hydrogen in some embodiments R9 is hydrogen. In other embodiments, R.

3 is hydrogen. in yet other embodiments, R is hydrogen. 100971 In other embodiments, R, is deuterium. In yet other embodiments. R2 is deuterium. In still other embodiments, 1(3 is deuterium In yet other embodiments, P 4 is deuterium. in some embodiments, R5 is deuterium. In yet other embodiments, Rd s deuterium. In still other embodiments, R, is deuterium, In still other embodiments, K is deuteriuIn la some embodiments, R is deuterium. In other embodiments, Rc is deuterium. In yet other embodiments, R is deuteriumn.

100981 In yet another embhodiment, the compound of Formula I is selected fom the group consisting of: 0 D 0 D 0C, 0 0 CD c 00 0 CO, 0 00ol 00 00, 0 0 0 003 003 0 CD~0 0 003 00 00 C0 C30 0 0 0 on, o D GD or a pharmaceutically acceptable salt, solvate, or prodru there [00991 In another embodiment, at last one of the positions represented as, D independently hais deuteriuni enrichment of no less; than abut1 ,lss than about t -%no ls than about 1o%1 no less than about 20%. no Aess than about 5o, no Iess than about 70%, no les than about 80%, no less than about 90%, or no less than about 98%. 191001 In a further embodiment, said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (-+enantiomer and about 10% or less by weight of the naiomera mixture of about 90% or more by weightof the (-enantiomer and about 10% or less by weight of the (4enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of anv other diastereomer, 1001011 In certain embodiments the compound as disclosed herein contains about 60 or more by weight of the (+eantiomer of (he compound and about 40% or less by weight of (+) enantiomer of the compound, In certain emoie ts, th compound as disclose-d hereinl - 19contains about 70% or more by weight of the (-enantiorner of the compound and about 30% or less by weight of (+ enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 80% or more by weight of the (-)-enantiomer of the compound and about 20% or less by weight of (+)-enantiomer of the compound. In certain embodiments. the compound as disclosed herein contains about 90% or more by weight of the -enantiormer of the compound and about 10% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 95% or more by weight of the (~)-enantiorner of the compound and about 5% or less by weight of (iYenantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 99% or more by weight of the ( )-enantiomer of the compound and about .1% or less by weight of(+) enantiomer of the compound. [00102] In certain embodiments, the compound as disclosed hereU contains about 60% or more by weight of the (+)-enantiomer of the compound and about 40% or less by weight of ( enantioner of the compound. in certain embodiments, the compound as disclosed herein contains about 70% or more by weight of the (-)enantiorner of the compound and about 30% or less by weight of ()enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 80% or more by weight of the (+>enantiomer of the compound and about 20% or less by weight of (--enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 90% or more by weight of the (-)-enantiomer of the compound and about 10% or less by weight of the (--enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 95% or more by weight of the ()-enantiomer of the compound and about 5% or less by weight of (-)-enantiomer of the compound. In certain embodiments, the compound as disclosed herein contains about 99% or more by weight of the (+)enantioner of the compound and about 1% or less by weight of (enantiomer of the compound 1001031 The deuterated compound as disclosed herein may also contain less prevalent isotopes for other elements, including, but not limited to, 'C or "C for carbon, "N for nitrogen, and O ( or 18O for oxygen. 1001041 In one embodiment, the den terated compounds discIosed herein maintain tie beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, decreasing toxicity increasing the half-life ( 1 ) -20lowering the maximum plasma concentration (C,,.) of the minimum efficacious dose (MED), lowering the efficacious dose and thus decreasing the non-mechanism-related toxicity, and/or lowering the probability of drug-drug interactions. 10010s Isotopic hydrogen can be introduced into a compound of a compound disclosed herein as disclosed herein by synthetic techniques that employ deuterated reagems, whereby incorporation rates are pre-determined; and/or by exchange techniques, wherein incorporation rates are determined by equilibrium conditions, and may be highly variable depending on the reaction conditions. Synthetic techniques, where tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, may yield high tritium or deuterium abundance, but can be limited by the chemistry required In addition, the Molecule being labeled may be changed, depending upon the severity of tl synthetic reaction employed, Exchange techniques, on the other hand, may yield lower tritium or deutenum incorporation, often with the isotope being distributed over many sites on the molecule, but offer the advantage that they do not require separate synthetic steps and are less likely to disrupt the structure of the molecule being labeled. 1001061 The compounds as disclosed herein can be prepared by methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described in the Example section herein and routine modifications thereof, and/or procedures found in Esaki et al Tetrahedron 2006, 62, 10954-10961, Smith et al Organic Syntheses 2002, 76 - 516, U 3,94 1 and W02003/014087, and references cited therein and routine modifications thereof Compounds as disclosed herein can also be prepared as shown in any of the following schemes and routine modifications thereof 1001071 For example, certain compounds as disclosed herein can be prepared as shown in Schemes I and 2. Scheme I RRe R 0 R R2~ R? RI RR R2 t00108] Ainnopyridone I when treated with a base, such as potassium carbonate, and in -21 the presence of a copper containing reagent, such as copper powder, reacts with benzene 2 (wherein X is either Bromine or iodine) at an elevated temperature with or without solvent to afford N-aryl pyridinone 3 of Fonnula 1. 100109j Deuterium is incorporated into different positions synthetcally according to the synthetic procedures as shown in Scheme 1, by using appropriate deuterated intermediates, For example to introduce deuterium at positions RI, . R, R 4 , R.- aid R, 2-hydroxy-5picoline with the corresponding deuterium substitutions can be used To introduce deuterium at one or more positions selected from Ry. Rs R 9 R and R 11 , the appropriate halobenzene with the corresponding deuterium substitutions can be used. These deuterated intermediates are either commercially available, or are prepared by methods known to one of skill in the art or following procedures similar to those described in the Example section herein and routine modifications thereof [00110] Deuterium can also be incorporated to various positions having an exchangeable proton via proton-deuterium equilibrium exchange, Such protons may be replaced with deuteriuim selectively or nion-selectively through a pr-oton-deuterim exhnge methodl known in. the aft Scheme 2 0~ N, 0 N. JJ-B(OH)2 2

CO

2 Me 6 O~~~0 N NN " OH Or 1001111 6-Hydroxynicotinic acid (4) reacts with thionyl chloride and methanol to give methyl-6~oxo- I,6-dihydropyridine-3-carboxylate (5), which is coupled with phenylboronic acid in the presence of copper(i) acetate monohydrate, pyridine and molecular sieves in dickloromethane to give methyl-6-oxo-I -phenyl I &dihydropyridine-3- catboxylate (6), Compound 6 is hydrolyzed with lithium hydroxide monohydrate in tetrahydrofuiran water to -22give 6-oxo-4 phenyl I6-dihydropyrdine-3carboxylic acid 7, Acid 7 reacts with isobutyl chlorofornate in the presence of N-methylmorpholine in tetrahydrofuran to give a mixed anhydride which is reduced with sodium borodeuteride in tetrahydrofuran to give d'5 (hydroxynmethyl)- -phenylpyridine2(R)mone (8); Compoumd 8 is converted to d 2 -5 broromethyl- -phenyMHl- It1pyridin-2-one (9) by reacting with phosphorus tribromide in dichlorometbae. (Bromide 9 is reduced with lithium aluminum deuteride to give d 3 -5-(methyl) I -phenylpyridine-2(I H)-one (10) of Formula (I) tool 121 It is to be understood that the compounds disclosed herein may contain one or more chiral centers, chiral axes, and/or chiral planes, as described in "Stereochemistry of Carbon Compounds" Eiel and Wilen, John Wiley & Sons, New York. 1994, pp. 1 19-11 (90. Such chiral centers, chiral axes, and chiral planes may be of either the (R) or (S) configuration, or may be a mixture thereof [00113J Another method for characterizing a composition containing a compound having at least one chiral center is by the effect of the composition on a beam of polarized light When a beam of plane polarized light is passed through a solution of a chiral compound, the plane of polarization of the light that emerges is rotated relative to the original plane. This phenomenon is known as optical activity, and compounds that rotate the plane of polarized light are said to be optically active, One enantiomer of a compound will rotate the beam of polarized light in one direction, and the other enantiomer will rotate the beam of light in the opposite direction The enantiomer that rotates the polarized light in the clockwise direction is the (i enantiomer, and the enantiomer thatrotates the polarized light in the omterclockwise direction is the (-) cnantiomer. Included within the scope of the compositions described herein are compositions containing between 0 and 100% of the (+-) and/or (-) enantiomer of compounds disclosed herein 1001141 Where a compound as disclosed herein contains an alkenyl or alkenylene group. the compound may exist as one or niixtureof geometric cish man (or ZiE isomers. Where structure isomers are intercouvertible via a low energy barrier, tie compound disclosed herein may exist as a single tautomer or a mixture of tautomers. This can take the fon of proton tautomerism in the compound disclosed herein that contains for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. -23 joo115l The compounds disclosed herein may be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stercoisomeric mixtures, such as a mixture of enantiomers, a racemic mixture, or a diastereomeric mixture. As such, one of skill in the art will recognize that administration of a compound in its (R) fon is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S form. Conventional techniques for the preparation/isolation of individual enanfiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral chromatography, recrysta lization. resolution, diasteeomeric sal formation, or derivatization into diastereomeric adducts followed by separation. [001161 When the compound disclosed herein contains an acidic or basic moiety, it may also disclosed as a pharnaceutically acceptable salt (See, Berge et atl,1. Pharm Sci. 1977, 66, 1 19; and "Handbook of Phamiaceutical Salts, Properties, and Use," Stah and Wermiuth, Ed.; Wiley-CH and VH-CA, Zurich, 2002), [001171 Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amno acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoi acid, 4 acetamidobenzoic acid, boric acid, (lj-camphoric acid, camphorsulfonic acid, -(1S)-camphor 10-sulfonic acid, capric acid, caproic acid, caprylic acid 4 cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-I,2-disulfonic acid, ethanesuifonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fitnaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluonic acid, D-glucuronic acid, L-glutarnic acid, c-oxo-glutaric acid glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid., (+)-L-lactic acid, (:tf)-L).-lactic acid, lactobionic acid, laurie acid, maleic acid, (+)L-malic acid, rmalonice acid, (+-DL-andelic acid, methanesulfonic acid, naphthalene2-sulfonic acid, naphthalenedisulfonic acid, I-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, painoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylie acid, Sebaic acid, steadc acid, sucoinic acid, sulfuric acid, tanic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid. 1001181 Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, - 24potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as prinmry, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-argiine benethamine, benzathinc, choline, deanol, diethanolamindiethylamine. dimethylamine, dipropylami ne, diisopropylamine 2(diethylamino)ethanoehanolamine, ethylanine, ethylenedianine, isopropylamine, N-methyl-glucamine, hydrabamine, I H-imidazole, L-lysine, norpholine, 4-(2-hydmxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine pyrrolidine ( pyridine, quinulidine; quinoline, isoquinoline. secondary aminess, triethanolamine, trimethylainine, triethylamine, N-methyl-D-glucamnine, 2 amino-2(hydroxymethy ) ,3-propancdiol, and tromethamine. [00119} The compound as disclosed herein may also be designed as a prodrug, which is a functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound., They may, for instance, be bioavailable by oral administration whereas the parent compound is not' The prodoug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962. 4, 221-294;_Morozowich et at in "Design of Biopharmaccutical Properties through Prodrugs and Analogs) Roche Ed, APHA Acad. Phami Sci. 1977 "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et alt Curr, Pharm Design 1999, 5 265-287; Pauletti e at, Adi Drug Delivery Re 1997, 2 235-256; Mizen et al., hal m Riotech. 1998, 11, 345-365; Gaignault et alPracl . Med. hem, 1996, 671-696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et at, Ed., Marcell Dekker, 185-218, 2000; Balant et aL, Ewar J Drug Metab Pharmacokinm, 1990, 15, 143-53; Balimane and Sinko, A dv. Drug Delivery Rev. 1999, 39, 183 209; Browne, Clin Neuropharmaco; 1997, 20, 1-12; Bundgaard, Arch Pharm. Chem, 1979,186, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv Drug Delivery Rev 1992, 8, 1-38; Fleisher et al, Adv. Drug Delivery Rev, 1996, 19,115-130; Fleisher et at, Methods EnzvmoL 1985, 112, 36048 I; Farquhar et at J Pharn Sci. 1983, 72,324-325; Freeman et at,, Chew. Soc.. CheIc. Comin. 1991,875-877; Fiis and Bundgaard, Eurl J Pharm. ei. 1996, 4, 49-59; Gangwar et al., Des. iBiopharm, Prop. Prodigs Analogs, 1977, 409 -25 - 421; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Ad. Drug Delivry Rev. 1996, 19, 241-273; Stella et at., Drugs 19859, 455-73; Tan ct al, Adv. Drug Delivery Rev, 1999, 39, 117-151; Taylor, Adv Drug Deively Rev 1996, 19, 131~148; Vlentino and Borchardt, Drug Discovery Today 199 148-55; Wiebeand KnausAdv Drug Delivery Rev 1999, 39, 63-80; Waler et aB, BJ Clin. Pharmac. 1989, 2c 497-507. Pharmaceutical Composition [001201 Disclosed herein are pharmaceutical compositions comprising a compound as disclosed herein, or a pharmaceutically acceptable salt sovate, or prodrug thereof as an active ingredient, combined with a pharmaceuticaly acceptable vehicle, carrier. diluent, or excipient, or a mixture thereof; in combination with one or more pharmaceutically acceptable excipients or carriers, 100121 Disclosed herein are pharmaceutical compositions in modified release dosage forms, which comprise a compound as disclosed herein, or a pharmaceutically acceptable sat solvate, or prodrug thereof; and one or more release controlling recipients or carriers as described herein. Suitable modified release dosage vehicles include, but are not limited to hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof The pharmaceutical compositions may also comprise non-release controlling recipients or carriers. 1001221 Further disclosed herein are pharmaceutical compositions in enteric coated dosage forms, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt solvate, or prodrug thereof; and one or more release controlling recipients or carriers for use in an enteric coated dosage form, The pharmaceutical compositions may also comprise non-release controlling excipients or carriers. 1001231 Further disclosed herein are pharmaceutical compositions in effervescent dosage forms, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more release controlling recipients or carriers for use in an effervescent dosage form The pharmaceutical compositions may also comprise non-release controlling excipients or carriers. [00124j Additionally disclosed are pharmaceutical composiions in a dosage form that has an instant releasing component and at least one delayed releasing component, and is capable of giving a discontinuous release of the compound in the form of at least two consecutive pulses separated in time from 0.1 up to 24 hours, The pharmaceuttical compositions comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more release controlling and non-release controlling excipients or careers, such as those excipients or carriers suitable for a disruptable semipermeabe membrane and as swellable substances 1001251 Disclosed herein also are pharmaceutical compositions in a dosage form for oral administration to a subject, which comprise a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; and one or more pharmaceutically acceptable recipients or carriers, enclosed in an intermediate reactve layer comprising a gastric juice-resistant polymeric layered material partially neutralized with alkali and having cation exchange capacity and a gastric juice-resistant outer layer, 1001261 Disclosed herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about I to about 500 mg, about 2 to about 100 mg, about I mg, about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg about 200 tgn about 250 mg, about 300 mog, about 350 mig, about 400 nig about 450 mg, about 500 mg of one or more compounds as disclosed herein in the form of fil-coated immediate-release tablets for oral administration, The pharmaceutical compositions further comprise hypromellos, hydroxypropyl cellulose, croscarmellose sodiummagnesium separate, microcrystalline cellulose, povidone, pregelatinized starch, propylene glycoi, silicon dioxide. sorbic acid, sorbitan motiooleatestearic acid talc, titanium dioxide, and vanillin. f001271 Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg about I to about 500 mg, about 2 to about 250 mg, about 1 ing, about 10 mg, about 25 mg, about 50 mg, about 75 mng, about 100 mig. about 150 mg, about 200 mg about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg. about 500 Ing of one or more compounds as disclosed herein in the form of film-coated immediate-release tablets for oral administration. The pharmaceutical compositions further comprise hypromellose, hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate. microcrystalline cellulose, povidone, propylene glycolsorbic acid, sorbitan mnonooleae, titanium dioxide, and vanillin. 100128] Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about I to about 500 tog, about 2 to about 250 mg, about I mwg, about 10 mg, about 25 - 27 mg, about 50 mag, about 75 mg, about 100 rmg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mag, about 400 mg, about 450 rmg, about 500 mg of one or more compounds as disclosed herein in the form of film-coated extended-release tablets for oral administration. The pharmaceuticalcompositions further Comprise cellulosic polymers, lactose monohydrate, magnesium stearate, propylene glycol1, sorbie acid, sorbitan monooleate, tale, titanium dioxide. and vanillin. [001291 Provided herein are pharmaceutical compositions that comprise about 0.1 to about 1000 mg, about I to about 500 mg, about 2 to about 250 mg, about I ng, about 10 mg, about 25 mg, about 50 mgabout 75 mg, about 100 mg, about 150 mug, about 200 mg, about 250 mg, about 300 mg, about 350 rug, about 400 mg, about 450 mg, about 500 rmg of one or more compounds as disclosed herein in the form of granules for oral. suspension. The pharmaceutical compositions further comprise carbomer, castor oil, citric acid hypromellose phthalate, maltodextrin, potassium sorbate, povidone, silicon dioxide, sucrose, xanthan gum, titanium dioxide and fruit punch flavor. [001301 The pharmaceuical compositions disclosed herein may be disclosed in unit dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is know in the art. Each unit-dose contains a predetermined quantity of the active ingredients) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampouls, syringes, and individually packaged tabets and capsules Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated utit-dosage form, Examples of ultiple-dosage fbrms include vials, bottes of tablets or capsules or bottles of pints or gallons. 1001311 The compound as disclosed herein may be administered alone, or in combination with one or more other compounds disclosed herein, one or more other active ingredients. The pharmaceutical compositions that comprise a compound disclosed herein may be formulated in various dosage fbrms for oral, parenteral, and topical administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, -28programmed-release, and gastric retention dosage forms These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see Remingtonm The Science and Practicx of Pharmacy, supra; Modfled. Release Drag Deliver Technology Rathbone et al, Eds., Drugs and the Pharmaceutical Science, Martel Dekker Inc±: New York, NY, 2002; Vol. 126). _01321 The pharmaceutical compositions disclosed herein may be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. I is further understood that for any particular individualspecific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering orsupervising the administration of the formulations 1001331 In the case wherein the patient's condition does not improve, upon the doctor' discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, inchding throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. 00f134 In the case wherein the patient's status does improve, upon the doctors discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (iTe, a "drug holiday"). [001351 Once improvement of the patient' conditions has occurred, a maintenance dose s administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. A. Oral Administration [001361 The pharmaceutical compositions disclosed herein may be lbrmulated in solid, semisolid, or liquid dosage forms for oral administration. As used herein, oral a dmiiistation. also include buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets pilots, medicated chewing gum, granules, bulk powders effervescent or non-effervescent powders or -29 granulessolutions, emulsionssuspensions solutions wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or recipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents' lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents. 1001371 Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e g.. STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethyleellulose methylcellulose, polyvinylpyrrolidone (PVP), Veeguniarch arabogalactan, powdered tragacanth, aud guar gum; celluloses, such as ethyl cellulose, cellulose aceate, carboxyrethyl cellulose calcium, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (IEC) hydroxypropylceliulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses; such as ANICEL-PH- 101, AVICEL-PH- 103, AVICEL RC-58 1, AVICEL-PH -105 (FMC Co, Marcus ook, PA); and mixtures thereof Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kao inannitol, silidi acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof: The binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions disclosed herein. 1001381 Suitable diluents include, but arc not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulosekaolin mnannitolsodium chloride, dry starch, and powdered sugar, Certain diluents, such as mannifol, lactose, sorbitol, sucrose, and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that pcrmiit disintegration in the mouth by chewing Such compressed tablets can be used as chewable tablets. 1001391 Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge;cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, Such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; - 30polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre gelatinized starch; clays; aligns; and mixtures thereof The amount of disintegrant in the pharmaceutical compositions disclosed herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art. The phannaceutical compositions disclosed herein may contain from about 0.5 to about 15% or from about I to about 5% by weight of a disintegrant 1001401 Suitable lubricants include, hut are not limited to, calciun stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunower oilsesame oil, olive oil, com oil, and soybean oil; zinc starate; ethyl late ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIY 200 (WK Grace Co., Baltimore, MD) and CAB-O-SJL® (Cabot Co, of Boston, MA); and mixtures thereof The pharmaceutical compositions disclosed herein may contain about 0.1 to about 5% by weight of a lubricant [001411 Suitable glidants include colloidal silicon dioxide, CAB-O-SiC (Cabot Co..of Boston, MA), and asbestos-free talc. Coloring agents include any of the appmved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof A color lake is the combination by adsorption of a water solubledye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Flavoring agents include natural flavors extracted from plants, such as fruits and synthetic blends of compounds which produce a pleasant tastesensation such as peppermint and methyl salicylate. Sweetening agents include sucrose, lactose, mannitol, symps glycerin, and artificial sweetener, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, acacia, tragacanth bentonite, and surfactants, such as polyoxycthylcne sorbitan monooleato (TWEEN* 20), polyoxyethyiene sorbitan mnonooleate 80 (TWEEl< 80), and triethanolamine oleate Suspending and dispersing agents include sodium carboxymethylcellulose pectin, tragacanth. eegunt acacia, sodium carbonethyleellulose, hidroxypropyl methyicelldose and polyvinylpyrolidone. Preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol, Wetting agents include propylene glycol monostearate, sorhifan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Solvents include glycerii, sorbitol ethyl alcohol, and syrup, Examples of non-aqueous liquids utilized in -3.1 emulsions include mineral oil and cottonseed oil. Organic acids include citric and tartaric acid Sources of carbon dioxide include sodium bicarbonate and sodium carbonate [001421 It should be understood that many carriers and excipients may serv several functins, even within the same formulation. [00143J The phannaceutical compositions disclosed herein may be formulated as compressed tablets, tablet triturates, chewable lozengesapidly dissolving tablets, mhiple compressed tabletsor enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach, Enteric-coatngs include. but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and celhilose acetate phthalates Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up olectionable tastes or odors and in protecting the tablets from oxidation, Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material. Film coatings include butare not limited to, hydroxy0thviceldose sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate, Film coating imparts the same general characteristics as sugar coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets [001441 The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms alone or in combination with one or more carriers or excipients described herein, including bindersdisintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the foration of chewable tablets and lozenges. 1001451 The pharmaceutical compositions disclosed herein may be formulated as soft or hard capsules, which can be made from gelatin, methylceliulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections one shpping over the other, thus completely enclosing the active ingredient The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, - 32-e including methyl- and propyl-parabens, and sorbic acid, The liquid, semisolid, and solid dosage forms disclosed herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient, 1001461 The pharmaceutical compositions disclosed herein may be formulated in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may include a pharmaceutically acceptable non-aqueous liquids or solvent, emulsifying agent. and preservative. Suspensions may include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde (the term "lower" means an alkyl having between I and 6 carbon atoms), e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions, Syrups are concentrated aqueous solutions of a sugar., for example, sucrose, and may also contain a preservative, For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, eg., water, to be measured conveniently for administration. 1001471 Other useful liquidand semisolid dosage forms include, but are not limUted to, those containing the active ingredients) disclosed herein, and a dialkylated mono- or poly alkylene glycolincluding, 1L2-dimethoxymethtane, diglyme, triglyme, tetraglyme. polyethylene glycol-350-dimethyl ether, polyethylene glycol-5$0-dimethyl ether, polyethylene glycol- 50 dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further comprise one or more antioxidants, such as butylaied hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxyco umarins, ethanoiamine, lecithin cephalin ascorbic acid, malic acid, sorbitol. phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbama tes -33 - 001481 The pharmaceutical compositions disclosed herein for oral administration may be also formulated in the forms of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms can be prepared as described in US, Pat No. 6,350,458. [001491 The pharmaceutical compositions disclosed herein may be formulated as non effervescent or efferescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and recipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide. 001501 Coloring and flavoring agents can be used in all of the above dosage forms. fool 511 The pharmaceutical compositions disclosed herein may be formulated as immediate or modified release dosage fomis, including delayed-, sustained, pulsed-, controlled targeted, and programmed-release forms. [001521 The pharmaceutical compositions disclosed herein may be co-formulated with other active ingredients which do not impair the desired therapeutic action, or with substances that supplement the desired action, such as drotrecgin-a, and hydrocortisone, B. Parenteral Administration 1001531 The pharmaceutical compositions disclosed herein may be administered parenterally by injection, infusion, or implantation, for local or systemicadmnistration Parenteral administrations used herein, include int ntraarterial, ntraperitoneal, intrathecal, intraventricularintraurethral, intrasternal intracranial, intramuscular intrasynovial, and subcutaneous administration. [001541 The pharmaceutical compositions disclosed herein may be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, enuisions, nicelles, liposomes, rnicrospheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection, Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (see, Remington. The Science and Practice of Pharmacy, supra). 1001551 The pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not - 34limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers. solubility enhancers, isotonic agents buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agent, pH adjusting agents, and inert gases, 1001561 Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline(PBS),odium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, pepperminti oil, oil, sesame oil, soybean oil hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil, Water-amiscible vehicles include, but are not limited to, ethanol, I,3-butanedio, liquid polyethylene glycol (e.g, polyethylene glycol 300 and polyethylene glycol. 400), propylene glycol, glycerin, Nmethyl2 dimethylacetamide, and dimethylsulfoxide. [001571 Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutianol, methyl and propyl p hydroxybenzates.s thimerosal, benzalkonium chloride, benzethoniurn chloride methyl- and propyl-parbens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite Suitable local anesthetics include,but are not limited to, procaine hydrochloride, Suitable suspending and dispersing agents are those as described herein, iMhiding sodium carboxymethyleelluose, hydroxypropyl methyl Ilulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, including polyoxyethylene sorbitan nonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable sequestering or cheating agents include, but are not limited to EDTA, Suitable pH adjusting agents include but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid, Suitable complexing agents include, but are not limited to, cyclodextrins, including t-cyclodextrin, p-eyclodextrin, hydroxypropyl- - 35 cyclodextnn, suffobutylether-p-cyclodextrn, and sifobutylether 7-f-cyclodex tin (CAPTISOL, CyDex, Lenexa, KS 100158 The pharmaceutical compositions disclosed herein may be formulated for single or multiple dosage administration, The single dosage formulations are packaged in an ampule, a vial, or a syringe. The multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations, All parenteral formulations must be sterile. as known and practiced in the art. 1001591 In one embodiment, the pharmaceutical compositions are formulated as ready-to use sterile solutions. In another embodiment, the pharmaceutical compositions are formulated as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use. In yet another embodiment, the pharmaceutical compositions are formulated as ready-to-use sterile suspensions. In yet another embodiment, the pharmaceutical compositions are formulated as sterile dry insoluble products to be reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical compositions are formulated as ready-to-use sterile emulsions. [001601 The pharmaceutical compositions disclosed herein may be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms. 1001611 The pharmaceutical compositions may be formulated as a suspension, solid, semi solid, or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions disclosed herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the phamiaceutical compositions diffuse through. )001621 Suitable inner matrixes include polymethyhnethacrylate polybutylmethacrylate plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthal ate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, poyethylene, ethylene-vinylacetate copolymers silicone rubbrs, polydimethisi loxanes, silicone carbonate copolymers, hydrophilic polymers. such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol, and cross-linked partially hydrolyzed polyvinyl acetate. ~36 - [001631 Suitable outer polymeric membranes include polyethylen, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethyleeivinyichloride vinylchioride copolymrers with vinyl acetate. vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanoi copolymer. C, Topical Administration 1001641 The phannaceutical compositions disposed herein may be administered topically to the skin, orifices or mucosa The topical administration, as used herein, include (iitra)dermal, conjuctival, intracomeal, intraocular, ophthalmic, auricular, transdennal, nasal. vaginal, uretheral, respiratory, and rectal administration 100165] The phannaceutical compositions disclosed herein may be fonmulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions suspensions creams, gels, hydrogels ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, dermal patches. The topical formnulation of the pharmaceutical compositions disclosed herein may also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof 190166] Pharmaceutically acceptable carriers and recipients suitable foruse in the topical formulations disclosed herein include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganismsstabilizers, solubility enhancers, isotonic agents. buffering agets antioxidants, local anesthetics suspending and dispersing agents, wetting or emulsifying agentS, complexing agents, sequestering or chelating agents, penetration enhances, cryopretectants, lyoprotectants thickening agents, and inert gases, 1001671 The pharmaceutical compositions may also be administered topically by electroporation, iontophoresis phonophoresis sonophosisis and microneedle or needle-free injection, such as POWDERJECTrM (Chiron Corp., Emeryville., CA), and BJOJECTM (Bioiect Medical Technologies Inc, Tualatin, OR). - 37 - 1001681 The pharmaceutical compostions disclosed herein may be formulated in the forms of ointments, creams, and gels. Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including such as lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles such as hydrophilic petrolatum hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (WIO) emulsions or oil-in-water (O/W) emulsions. including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: he Science and Practice of'Pharmacy. suprat These vehicles are emollient but generally require addition of antioxidants and presenatives. 1001 69J Suitable cream base can be oil-in-water or water-rn-oil. Crearn vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the Intemal" Phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyi alcohol The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant, 1001701 Gels are semisolid, suspension-typo systems Single-phase gels contain organic macromoleciles distributed substantially uniformly throughout the liquid carrier, Suitable gelling agents include crosslinled acrylic acid polymers, such as carborners, carboxypolyalkylenes Carbopol@; hydrophilic polymiers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinyialcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydryl cell cellilose,hydroxypropyl methylcellulose, hydroxypropyl methylcellulose ph thalate, and methylcellulose; guns, such as tragacanth and xanthan gum; sodium alginate; and gelatin, In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by triuration, mechanical mixing, and/or stirring, 1001711 The pharmaceutical compositions disclosed herein may be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams,phaters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foamsspraysor enenas These dosage fors can be - 38a manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra, f001721 Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices, Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehiclessuch as stiffening agets; which produce a melting point in the proximity of body temperature; when formulated with the pharmaceutical compositions disclosed herein: and antioxidants as described herein, including bisuifite and sodium metabisuffite, Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethyene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and trIglycerides of fatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; glycerinated gelatin. Combinations of the various vehicles may be used. Rectal and vaginal suppositories may be prepared by the compressed method or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g. 1001731 The pharmaceutical compositions disclosed herein may be administered ophthal-mically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular insert, and implants. [00141 The pharmaceutical compositions disclosed herein may be administered intranasally or by inhalation to the respiratory tract, The pharmaceutical compositions may be formulated in the form of an aerosol or solution for delivery using a pressurized container, pump spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist or nebulizer, alone or in combination with a suitablepropellant such as 1 I,2-tetratluoroethane or L1,1,2.33,3 -heptafinomopropane, The pharmaceutical compositions may also be formulated as a dry powder for insuflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclodextrin, 100171 Solutions or suspensions for use in a pressurized container, pump. spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersingsolubilizing, or extending release of the active ingredient -39disclosed herein, a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid [001761 The pharmaceutical compositions disclosed herein may be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less, Particles of such sizes may be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid procession to form nanoparticles, high pressure homogenization, or spray drying 1001771 Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the pharmaceutical compositions disclosed herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as I-leucine, manitol. or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate. Other suitable recipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose, The pharmaceutical compositions disclosed herein for inhaled/intranasal administration may further comprise a suitable flavor, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium. [001781 The pharmaceutical compositions disclosed herein for topical administration may be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled- targeted, and programmed release. D. Modified Release [001791 The pharmaceuical compositions disclosed herein may be formulated as a modified release dosage form. As used herein, the term "modified release' refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsati-e controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms, The pharmaceutical compositions in. modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multi layered coatings, microspheres, -40 liposomes, and combinations thereof, The release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredientss. [001801 Examples of modified release include, but are not limited to, those described in U.S. Pat, Nos.: 3,845,770; 3,916,899; 3,536.809; 3,598,123; 4,008,7 19; 5,674,533; 5,05595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 61 13,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500, 1. Matrix Controlled Release Devices [00181] The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated using a matrix controlled release device known to those skilled in the art (ee Takada et al in "Encyclopedia of Controlled Drug Delivery," Vol. 2, Mathiowitz ed Wiley, 1999). 1001821 In one embodiment, the phamaceutical compositions disclosed herein in a modified release dosage form is formulated using an erodible matrix device, which is water sweilable, erodible, or soluble polymers, including synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins. 1001831 Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya locust bean gum, gum tragacanth, carrageenans, gum ghati, guar gum, xanthan gum, and seieroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin;collagen; and cellulosics, such as ethylI cellulose (EG), methylethyl cellulose (MEC), carboxymethy I cellulose (CMGCME hydroxyethy cellulose (HEC), hydroxypropyl cellulose (H-PC),cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB) CAP, CAT, hydroxypropyl methyl. cellulose (JPMC), HPMCP HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyihydroxy ethylellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acid or methacrylic acid (EUDRAGC,' Rohn America, Inc. Piscataway, NJ); poly(2-hydroxyethyl-methacryIate);polylactides; copolymers of L-glutamic 41 acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-)-3 hydroxybutyric acid; and other acrylic acid derivatives, such as homopolymers and copolymers of butylmethacrylate, methy lmethacrylate, ethylmethacrvlate, ethylacrylate, (2 dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylate chloride, 100184J In further embodiments, the pharmaceutical compositions are formulated with a non-erodible matrix device. The active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered. Materials suitable for use as a non-erodible matrix device included, but are not limited to, insoluble plastics, such as polyethylene, polypmpylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetate copolymers, ethyleneipropylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethyieneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxancs, silicone carbonate copolymers; hydrophilic polymers, such as ethyl. cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystal line wax, and triglycerides, 10918ss In a matrix controlled release system, the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredientss, the ratio ofhhe active ingredient(s) versus the polymer, and other recipients or carriers in the compositions. [001861 The pharmaceutical compositions disclosed herein in a modified release dosage form may be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, melt-granulation followed by compression. -42- 2. Osmotic Controlled Release Devices 1001871 The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated using an osmotic controlled release device, including one-chamber system, two-chamber system asymmetric membrae technology (AMT), and extruding core system (ECS). in general, such devices have at least two components:(a) the core which contains the active ingredients) and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core The semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s). 1001881 In addition to the active ingredientss, the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device. One class of osmotic agents water-swellable hydrophilic polymers, which are also referred to as "osmopolymers" and "hydrogels) including, but not limited to, hydrophilic vinyl and acrylic polymers, polysacchades such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl metbacrylate), poly(acrylic) acid, poly~methacrylic) acid' polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA). PVA/PVP copolymners, PVAJPVP copolymers with hydrophobic monomers such as methylmethacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmeiose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (IIPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophiIgelatin, xanthan gum, and sodium starch glycolate 100189] The other class of osmotic agents are osmogens, which are capable of imbibing water to affect an osmotic pressure gadient across the barrier of the surrounding coating Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloridesodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulflte, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylito;organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid sebaci acid sorbic acid adipic acid, edetic acid, glutamic acidp-tolunesdfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof -43 - [00:1901 Osmotic agents of diffeent dissolution rates may be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form, For example, amorphous sugars, such as Mannogeme EZ (SP harm, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted. 100191] The core may also include a wide variety of other recipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing 1001921 Materials useful in forming the semipermeable membrane include various grades of acrylics vinyls, ethers. polyamides, polyesters, and cellulosic derivatives that are water permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking. Examples of suitable polymers useful in forming the coating, include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate celldose triacetate, CA propionate, celulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, celulose acetate trinellitate (CAT), CA dimethyaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate. CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxiated ethylene-vinylacetate, EC, PEG, PPG, PEG/IPPG copolymers, PVP, HEC, :P1C, CMC, CNEC, HPMC, HPMCP. HPMCAS. HPMCAT. poly(acrylic) acids and esters and pol y-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersuflfones, polystyrenes; polyvinyl halides, polyvinyl esters and ethers natural waxes, and svntheti.c waxes. [00193 Semipermeable membrane may also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in S Pat No. -,798 119. Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as -44polyalkenes, polyethylene, polypropylene, polytetrafhaomethylene, polyacrylic acid derivatives. polyethers, polysulfones, polyethersulfbnes, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes [00194j The delivery ports) on the semipermeable membrane may be formed post-coating by mechanical or laser drilling, Deliery port(s) may also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports may be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.'S Pat. Nos. 5,612,059 and 5,6984220 [001951 The total amount of the active ingredients) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number,size, and position of th delivery ports. [001961 The pharmaceutical compositions in aw osmotic controlled-release dosage form may further comprise additional conventional recipients or carriers as described herein to promote performance or processing of the formulation. [001971 The osmotic controledrelee dosage forms can be prepared according to conventional methods and techniques known to tose skilled in the art (see, Remington: The Science and Pracice of Pharmacy supra; Santus and Baker,I Controlled Release 1995, 35, 1 21;Verma et a l, Drag Development andhlduswrial Pharmacy 2000, 26, 695-708; Verma et al. .iControlled We/ease 2002, 79, 727). 1001981 in certain embodiments. the pharmiaceutical compositions disclosed herein are formulated as AMT controlled-elease dosage form, which comprises an asymnmetric osmotic membrane that coats a core comprising the active ingrediet(s)and other pharmaceuticals acceptable excipients or carriers. See, US Pat No 5,612,059 and WO 20021 7918. The AMT eontrolledrelease dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method. [001991 In certain embodiments, the pharmaceuical compositions disclosed herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredientss, a hydroxylethyl cellulose, and other pharmaceutically acceptable recipients or carriers -45 - 3. Multiparticulate Controlled Release Devices (002001 The pharmaceutical compositions disclosed herein in a modified release dosage form may be fabricated a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 pm to about 3 mm, about 50 pm to about 2.5 mm, or from about 100 gm to about I mm in diameter. Such multiparticulates may be made by the processes know to those skilled in the art, including wet-and dry granulationextusion/spheronizationroller-compactionimcit-congealingand by spray-coating seed cores See, for examplekhdtipartiadate Oral Drug Dehvery; Marcel Dekker: 1994; and Pharmnaceutical Pelletization Technology; M arcel D~ekker: 199 1002011 Other recipients or carriers as described herein may be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates The resulting particles may themselves constitte the multiparticulate device or may be coated by various filmd-orming materialssuch as enteric polymers, water-swellable, and water-soluble polymers, The mutiparticulates can be further processed as a capsule or a tablet. 4. Targeted Delivery [00202J The pharmaceutical compositions disclosed herein may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythirocyte-, and antibody-based delivery systems. Examples include, but are not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082: 6,048,736; 6,039,975; 6,004,534; 5,985307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874. Methods of Use f002031 Disclosed are methods for treating, preventing, or ameliorating one or more symptoms of a fibrotic-mediated disorder and/or a collagen-mediated disorder comprising administering to a subject having or being suspected to have such a disorder, a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof [00204j In one embodiment is a method for the treatment, prevention, or amelioration of one or more symptoms of a fibrotic-mediated disorder and/or a collagen-mediated disorder, A -46 fibrotic-mediated disorder and/or a collagen-mediated disorder include, but are not limited to, idiopathic pulmonary fibrosis, uterine fThroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after partial hepatectomy or hepatic ischemia, allograft injury after organ transplantation, cystic fibrosis atrial fibrilation, neutropenia, scleroderma. dermatomyositis, cirrhosis, diffuse parenchymal lung disease, mediastinal fibrosis. tuberculosis spleen fibrosis caused by sickle-cell anemia, rheumatoid arthritis, and/or any disorder ameliorated by modulating fibrosis and/or collagen infiltration into tissues. 1002051 Disclosed herein are methods for treating a subject, including a human. having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subject prone to the disorder comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect decreased inter individual variation in plasma levels of the compound or a metabolite thereof during the treatment of the disorder as compared to the corresponding non-isotopically enriched compound. 1002061 In certain embodiments, the inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof, is decreased by greater than about 5% greater than about 10%, greater than about 20%, greater than about 30% greater than about 40%, or by greater than about 50% as compared to the corresponding non-isotopically enriched compound. 1002071 Disclosed herein are methods for treating a subject, including a human; having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect increased average plasma levels of the compound or decreased average plasma levels of at least one metabolite of the compound per dosage unit as compared to the corresponding non-isotopically enriched compound, 1002081 In certain embodiments, the average plasma levels of the compound as disclosed herein are increased by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50% as compared to the corresponding non-isotopically enriched compounds. -47f002091 In certain embodiments, the average plasma levels of a metabolite of the compound as disclosed herein are decreased by greater than about 5%, greater than about 10% greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50% as compared to the corresponding non-isotopically enriched compounds [002101 Plasma levels of the compound as disclosed herein, or metabolites thereof, are measured using the methods described by Li et A. (Rapid Cmmunicatuons in Mass Specrormery 2005, 19, 1943-1950), [00211 Disclosed herein are methods [or treating a subject, including a human, having or suspected of having a fibrotic-mediated disorder and/or a colagen-ediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect a decreased inhibition of, and/or metabolism by at least one cytochrome P 4 3 0 or monoamine oxidase isoforri in the subject during the treatment of the disorder as compared to the corresponding non isotopically enriched compound 1002121 Examples of cytochrome P4so isoforms in a mammalian subject include, but are not limited to, CYPlAI, CYPIA2, CYPIBI, CYP2A6, CYP2A13 CYP2B6, CYP2C8. CYP2C9, CYP2CI8, CYP2C 19, CYP2D6, CYP2El, CYP2G 1, CYP2J2, CYP2Ri CYP2SI, CYP3A4, CYP3A5, CYPA5P1, CY P3A5P2, CYP3A7, CYP4AI I, CYP4Bi, CYP4F2, CYP4F3, CYP4F8, CYP4FI I, CYP4F12, CYP4XI, CYP4ZI, CYP5AI CYP7Ai, CYP7Bi, CYP8Al, CYP8B1, CYPI1AI, CYPi1B, CYP i IB2, CYP17, CYPI9 CYP2I. CYP24, CYP26A.1, CYP26BI CYP27A ICYP27BI. CYP39, CYP46. and CYP51. 1002131 Examples of monoamine oxidase isoforms in a mammalian subject include, but are not listed to, MACA, and MAOr [002141 In certain embodiments, the decrease in inhibition of the cytochrome P 4

%

0 or monoamine oxidase isoform by a compound as disclosed herein is greater than about 5%, greater than about 10%, than abohan about 20% greater than about 30%, greater than about. 40%, or greater than about 50% as compared to the corresponding non-isotopically enriched compounds. [OO215] The inhibition of the cytochrome P 4 5, isoform is measured by the method of Ko et al. (British Journai f Clinical Pharmacology, 2000, 49, 343-35 1v The inhibition ofthe MAO\ isoform is measured by the method of Weyler et at (J Bil Chem 1985, 260, 13199-13207), -48 - The inhibition of the MAO isoform is measured by the method of Uebelhack et aL (Pharmnacopsychiaty 1998, 31, 187- 192), [092161 Disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrotic-amediated disorder and/or a colagen-mediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, soivate. or prodrug thereof so as to affect a decreased metabolism via at least one polymorphically-expressed cytochrome P4eq isoform in the subject during the treatment of the disorder as compared to the corresponding non-isotopi cally enriched compound. [002171 Examples of polymorphically-expressed cytochrome P 45 isoforms in a mammalian subject includebut are not limited to, CYP2C8, CYP2C9. CYP2CI 9, and(CYP2D6 [00218] In certain embodiments, the decrease in metabolism of the compound as disclosed herein by at least one polymorphicaliy-expressed cytochrome P 4 50 isoforms cytochrome P isoform is greater than about 5%, greater than about 10% greater than about 20%, greater than about 30%, greater than about 40% or greater than about 50% as compared to the corresponding non-isotopically enriched compound. 100219] The metabolic activities of the cytochrome P 45 , isoforms are measured by the method. described in Example 5. The metabolic activities of the monoamine oxidase isoforms are measured by the methods described in Examples 6 and 7, [002201 Disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect at least one statistically-significantly improved disorder-control and/or disorder-eradication endpoint, as compared to the corresponding non-isotopically enriched compound. [002211 Examples of improved disorder-control and/or disorder-eradication endpoints include, but are not limited to, statistically-significant improvement in pupil dilation, nasal decongestion, migraine diminution, bronchial vasodilation, improvement of pain indices for anginal attacks, reduction in frequency and/or duration of anginal attacks, normalization of blood -49 pressure in hypotensive patients prevention of ischerni events including ischemic heart disease and intermittent claudication, and/or diminution of toxicity including but not limited to, hepatotoxicity or other toxicity, or a deease in aberrant liver enzyme levels as measured by standard lboratory protocols, as compared to the corresponding non-isotopically enriched compound when given under the same dosing protocol including the same number of doses per day and the same quantity of dmg per dose. 1002221 Disclosed herein are methods for treating a subject including a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to, the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof so as to affect an improved clinical effect as compared to the corresponding nonisotopicaily enriched compound Examples of improved disorder-control andor disorder-eradication endpoints include, but are not limited to, statistically-significant improvement in pupil dilation, nasal decongestion, migraine diminution bronchial vasodilation, improvement of pain indices for anginal attacks, reduction in frequency and/or duration of anginal attacks, normalization of blood pressure in hypotensive patients, prevention of ischenic events including ischemic heart disease and intermiitent claudication and/or diminution of toxicity including but not limited to, hepatotoxicity or other toxicity, or a decrease in aberrant liver enzyme levels as measured by standard laboratory protocols, as compared to the corresponding non.-isotopically enriched compound 1002231 Disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subect prone to the disorder comprising administering to the subject a therapeutically effective amount of a. compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to affect prevention of recurrence, or delay of decline or appearance, of abnormal alimentary or hepatic parameters as the primary clinical benefit, as compared to the corresponding non-isotopically enriched compound. 1002241 Disclosed herein are methods for treating a subject, including a human, having or suspected of having a fibrotic-mediated disorder and/or a collagen-mediated disorder or for preventing such disorder in a subject prone to the disorder; comprising administering to the subject a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt, solvate, or prodrug thereof; so as to allow the treatment the late Na channel mediated-disorder while reducing or eliminating deleterious changes in any diagnostic hepatobiliary function endpoints as compared to the corresponding non-isotopically enriched compound. 1002251 Examples of diagnostic hepatobiliary fUmtion endpoints include, but are not limited to alamne aminotransferase ("ALT"), serum ghitamic-pyruvic transaminase ("SGPT" aspartate aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"),,ammonia levels, bilirubin, gamma- glmtamiyl transpeptidase ("GGTP) W GTP" or "GOT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5r'-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference" edition, Mosby, 1999. These assays are run by accredited laboratories according to standard protocol. 1002261 Depending on the disorder to be treated and the subject's condition, the compound as disclosed herein disclosed herein may be administered by oral, parenteral (e g, intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion. subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g. transdernal or local) routes of administration, and may be formulated, alone or together in suitable dosage unit With pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration 100227 The dose may be in the form of one, two three, four, five, six, or more sub-doses that are administered at appropriate interals per day The dose or sub-doses can be administered in the form of dosage units containing from about 0.1 to about 1000 milligrams, from about 0. 1 to about 500 milligrams, or from 0.5 about to about 100 milligrams active ingredients) per dosage unit and if the condition of the patient requires, the dose can, by way of alternative, be administered as a continuous infusion. 1002281 In certain embodiments, an appropriate dosage level is about 0.01 to about 100 mg per kg patient body weight per day (mg/kg per day), about 0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, or about 0.05 to about 10 mg/kg per day, which may be administered in single or multiple doses. A suitable dosage level may be about 0.01 to about 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about 0.1 to about 10 mg/kg per day. -51 - Within this range the dosage may be about 0.01 to about 0J, about 01 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per day, Combination Tberapv f00229] The compounds disclosed herein may also be combined or used in combination with other agents useful in the treatment, prevention, or amelioration of one or more symptoms of a fibrotic-mediated disorder and/or a collagen-mediated disorder. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent. the overall therapeutic benefit to the patient is enhanced) 1002361 Such other agents, adjuvants; or drugs,, may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentialy with a compound as disclosed herein. When a compound as disclosed herein disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such odier drugs in addition to the compound disclosed herein may be utilized, but is not required, Accordingly, the pharmaceutical compositions disclosed herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to the compound disclosed herein. [002311 In some embodiments the Compounds provided herein can be combined with one or more therapeutic agents for sepsis treatment, including, but not limited to, drotrecogint or a biosimilar equivalent of activated protein C. 1002321 In certain embodiments, the compounds provided herein can be combined with one or more steroidal drugs, including, but not limited to, alosterone, beclometasone betamethasone, deoxycorticosterone acetate, fludrocortisone acetate. hydrocortisone (cortisol prednisolone. prednisone, methyiprenisolone dexamethasone and triamcinolone, f0023!] In other embodiments, the compounds provided herein can be combined with one or more antibacterial agents, including, but not limited to, amikaci amoxiillin ampicillin, arsphenamine, azithronycin, aztreonam, aziocillin, bacihracin, carbenicillin, cefac or, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cfepime, cefixime cefoperazone cefotaxime, cefoxitin cefpodoxirne, cefprozil, ceftazidime, ceflibuten, ceflidzoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin clindamycin, cloxaciin, - 52colistin, dalfopristan, demeclocycline, dicloxacillin, dirithromycin. doxycycline, erythromycin, enafloxacin, ertepenem, ethambutol, flucloxacillin fosfomyci n, furazolldone, gatifloxacin, geldana lycin, gentamicin, herbimicin, imipenemtisoniazide kanamicinevofloxacht linezolid, lomefloxacin, oracarbef, mafenide, moxifloxacin meropenem, metronidazole, melocilin, minocycline, m upirozin, nafeillin, neomycin, netilmicin, nitrofurantoin, norfioxacin, ofloxacin. oxytetracycline, penicillin, piperacillin; platensimycin, polymixin B, prontocil, pyrazinaTmide, quinupristine, rifampin, roxithromycin, spectinomycin, streptomycin, sufacetamide, sulfamethizole, sulfamethoxazole, teicoplanin, teithromyin, tetracycline, ticarcillin, tobramycin, trimethopri in, troleandomycin, trovafloxacin, and vancomycin.. 1042341 In some enmbodiments, the compounds provided herein can be combined with one or more antifungal agents, including, but not limited to, amorolfine, amphotericin B, anidulaflungin, bifonazole, butenafime, butoconazole, caspofungin, ciclopirox. clotrimazole econazole, fenticonazole, filipin, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxyConazole, ravuConazole, posaconazole, rimocidin, sertaconazole, suleonazole, terbinafine, terconazole, tioconazole, and voriconazole. [002351 In other embodiments, the compounds provided herein can be combined with one or more anticoagulants, including, but not i miied to, acenocoumarol, argatroban, bivalirudin, lepirudin, fondaparinux, heparin phenindione, warfarin. and ximalanatran. 1002361 In certain embodiments, the compounds provided herein can be combined with one or more thrombolytics, but not. limitedJ to, ansrpae eeit-PA (aiteplase activasetj streptokinase, tenecteplase, and urokinase. 1002371 IN certain embod-iments,. the compounds provided herein can be combined with one or more non-steroidal anti-inflammatory agents including, but not Limited to, aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, difluisal, etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen ketorolac, lonoxicam, loxoprofen, lunmiracoxib, meclofenamic acid, mefenarnic acid, meloxicam, metamizol en.ethyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone parecoxib, phenylbutazone, piroxicam. salicyl saicylate sulindac, sul fi naprazone , suprofen, tenoxicam, tiaprofenic acid, and tolmetin. - 53- {00238 In some embodiments, the compounds provided herein can be combined wirone or more antiplatelet agents, including, but not limited to, abeiximna, cilostazol, clopidogrel, dipyridamole, ticlopidine, and tirofibin 1002391 The compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, anti-arrhythmic agents, such as propranolol; sympathomimetic drugs, such as norepinephrine; opioids. such as tramadol, anesthetics, such as ketamine; calcium channel blockers, such as diltiazem; Beta-blockers, such as atenolol; nitrates or nitrites, such. as glyceryl trinitrate; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxane receptor antagonists, such as ifetroban potassium channel openers; thrombin inhibitors, such as hirudin; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAP) antagonists; anti-platelet agents such as GPUIib/IIa blockers (e.g, abdximab, eptifibatide and tirofiban), P2Y(AC) antagonists (eg., clopidogrel, tielopidine and CS-747) and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factr Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors, neutral endopeptidase (NEP) inhibitors vasopepsidase inhibitors (dual NEP) ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (ak a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran niacin; anti atherosclerotic agents, such as ACAT inhibitors; MITP Inhibitors; calcium channel blockers,,such as amlodipine besylate; potassium channel activators; alpha-adrenergic agents; diuretics, such as chlorothiazide, hydrochioroihiazide, flumethiazi de, hydroiurnethiazide, bendrofhimethiazide, methylchiorothiazide trichioromethiazide, polythiazidc benzothlazide, ethacrynic acid; tricrMynafen, chlorthalidone, finosenilde, musolimine, bumetanide, triarnterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (PA), recombinant tPA, steptokinase okikinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g mettormis), gI ucosidase inhibitors (eg, acarbose), insulins, meglitinides (eg., repaglinide). sulfonyiureas (e.g., glimepiride, glyburide, and glipizide) thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone\ and PPAR.-gamma agonists; maineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; -54phosphodiesterase inhibitors such as PDE Ill inhibitors g cilostazol) and PDE V inhibitors (e.g., sildena1, tadalafits vardenafil); protein tyrosine kinase inhibitors; antiinflamrmatories; antiproliferatives, such as methotrexate, FK506 (tacrollrmus, Prografl, mycophenolate mofetil; chemotherapeutic agents; immunosuppressants; anticancer agents and cytotoxic agents (e.g., alkylating agents, such as nitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, and triazenes); antinetabolites, such as folate antagonists, purine analogues, and pyrridine analogues antibiotics, such as anthracyclines bleomycins. mitomycin, dactinomycin, and plicanycin enzymes, such as L-asparaginase; famesyl-protein transferase inhibitors; horoial agents, such as glucocorticoids (e.g, cortisone), estrogens/andiestrogen androgens/antiendrogens, progestns and luteinizing hormone-releasing hormone anatagonists, and octreotide acetate; microtubule disruptor agents, such as ecteinascidins mnicrotubulestabliing agents, such as pacitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids. epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, sueh as cisplatin satraplatin, and carboplatin Kits/Articles of Manufacture 100240 For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein, Such kits can comprise a carrier, package or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the containers) comprising one of the separate elements to be used in a method described herein. Suitable containers include> for example boles, vials syringes, and test tubes The containers can be formed from a variety of materials such a glass or plastic. t0*2411 For example, the container(s) can comprise one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intraenous solution baghavina stop b n intaveou souin g or a vial hvna stopper pierceabie by a hypodermic. in~jectio needle) 55 , Such kits optionally comprise a compound with an identifying description or label or instructions relating to its use in thec methods described here-int. 1002421 A kit will typically comprise one or more additional containers each with one or more of various mnaterials (such as reagents, o-ptionally, in concentrated form, and/bor devices) desirable from a commercial and user standpoint fo iuse of a compound described herein. Non limiting examples of such materials include, but are not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included. 1002431 A label can be on or associated with the container. label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself- a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, eg, as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the Tnethods described herein These other therapeutic agents may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art, [002441 The invention is further illustrated by the following examples; EXAMPLE I 5-Methyi-i~phenylpyridin2(1 11)one NN HO"~ [002451 5tkt1Jph'vytf~ A finely pulverized mixture of 2-hydroxy 5-methylpyridine (0,500 g. 4.58 mmol) anhydrous potassium carbonate (0,693 g, 6.41 nunol), 56 copper powder (0,006 g, 0.09 mmoi) and iodobenzene (1.68 g, 8.26 mmwnol) was heated at 180 190 *C for 7 hours, The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%), mp. 105-107 *C; 'H NMR (400 MHz, DMS0-d) 8 2.50 (s. 31H). 6A3 (d, J = 9.3 Hz, i H), 7.36-7,53 (n, 7H); IR (KBr) v 3045, 1675, 1611, 1531, 1270 cmI; MS 186 (M + 1) EXAMPLE 2 dr-5(Methyl4 1 -phenylpyridine-2(i10-one CD' 0 N H H Q<N O N 00 2 L1CO 2 Me [002461 Methyl-6-oxo-1,6-dihydropyridine-3~carboxylate Thionyl chloride (6.3 mL, 86.33 mmol) was added dropwise to a solution of 6-bydroxynicotinic acid (10,0 g, 7194 mnmol) in methanol at 0'C, The mixture was heated to reflux for 6 hours, the solvent was removed and standard extractive work up provided the title compound as a brown solid (7.5 g, 68%). m.p, 166-172 "C; 'H NMR (400 MHz, DM4SO-) 6 377 (s1 31). 6.37 (dJ 9,3 Hz, 1 H), 7.79 (dd 1 -2.7, 9,5 Hz, I H), 8.04 (d, J = 2.4 Hz, 1I); IR (KIr) 1 3050, 2965, 1712, 1651, 1433, 1300, 1106 cm.; MS 154 (MA 1) S te 2 HN 0, N. / \B(OH)2

CO

2 Me O N

MCO

2 Me t102471 Methyl-6-oxo-I-phenvI.-I 6-dihydrorvridine-3-carboxylate Methyl-6-oxo-1,6 dihydropyridine-3-carboxylate (6,0 g, 39.22 mmolt), phenybonmic acid (5.74 g, 47,06 mmol),. copper(i) acetate monohydrate (11.76 g, 58.82 rumol) pyridine (6.2 mL, 78.43 mmol) and molecular sieves (4k, 6.0 g) in dichloromethane (100 mL) was stirred at ambient temperature for 12 hours and filtered, Standard extractive work up provided a orde residue which was purified by Silica gel column chromatography (100-200 mesh)(1-2% methanol in chloroform) to give the title compound as a brown solid (5.0 g, 56%). m.p. 100-105 "C; H NMR (400 MHz, CDCI) 6 3.86 (s, 3H), 6.63 (d, J= 9.5 Hz, 111), 7.36-7.55 (n, 5F), 7.91 (dd J 2.5, 9.9 Hz, 1H), 8.23 (d, J= 2.5 Hz, IH); JR (KBr a 3058, 2924, 2854, 1721, 1675, 1540, 1446, 1313, 1271, 1103 cml; MS 230 (M 1), 0 N CMe ...CO2H 1002481 6-Oxo- 1:-phenyl -L6-dihydropvridine-3-carbox vie acid: Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-1-phenyl-1 ,6 dihydropyridine-3-carboxyte (1.0 g, 4.37 mmol}, tetrahydrofuran (9 ml,) and water (6 niL)at 0 TThe mixture was sirred for I hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipiate was filtered to give the title compound as a brown solid (0.740 g, 79%). rnmp. 256-263 C' +H NMR (400 MHz DMSOd) 6)653 (d J= 9A Hz, l11), 740-7.49 (m, 5Hf), 7.87 (dd J = 2-5, 9.8 Hz -58 - 1H)1 8.23 (d,J 2.5 Hfz, IT", JR (KBr) o 3446, 1708, 16451 1577, 1263,1228 cOf MS 214 (M Stp4 O N ON O HC

CO

2 H D D 1002491 dr5-Hydroxvmethv -l+2henvlnvridine 2Qh/oneisobutyl chlorofomnate (0.45 ml 3.49 mmol) was added to a solution of 6-oxo I-p1heny-i .6-dihydropyridine-3-carboxylic acid (0.500 g,2-32 mmoi) and N-methylmorphoiine (0.38 ml, 349 mmolin tetrahydrofuran (10 niL) at -5 'C, The mixture was stirred for 3 hours at the same temperature, diluted with tetrahydrofuran and filtered over a pad of Celite under argon. The fitrate containing the rnixed anhydride was added dropwise to a suspension of sodium borodeuteride (0-117 g, 2,79 mmol) in tetrahydrofuran at -10 *C. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours, after which D2O (1 mi) was added. Standard extractive work up gave a crude residue which was purified by preparative HPLC to give the tile compound as a white sold (0,290 g 61%), mp. 115-120 ;H NMR (400 MHz, CDCI 3 ) 6,2.05 (br, 1114).66 (d, J 9. Iz, 111), 7.25-7.51 (m, 71); IR (KBr) o 3337, 1665, 1586. 1535 1257 cnt; M S 204 (M + 1). K. ~ Br0 N 1002501 d -(Methyl)-1henv r idine- 1-one Phosphorus tribromide (0.07 mIL, 0738 mmcl) was added dropwise to a solution of d 2 -5-(hydroxymethyl)phenylpyridine -59- 2(IH)~one (0,300 g, 1.47 mol) in dichiloromethane at 10 C and the mixture was stirred for 30 minutes, Dicbloromethane and excess phosphorus tribromide were flushed out by a stream of argon and the residue was dissolved in tetrahydrofuran, This solution of the bromide was added dropwise to a suspension of lithium aluminum deuteride (0.092 g, 2.2 mmol) in tetrahydrofuran at -78 *C and the mixture was stirred for I hour. D0 was added, and standard extractive work up gave a crude residue which was purified by preparative UPLC to give the title compound as a pale brown solid (0 070 g 25%). m.p 103-107 "C; -H MR (400 MHz, DMSO-de) 6.42 (d, J 9.2 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) u 3045, 2925, 1673, 1607, 1488, 1272 c I MS 189 (M + 1) EXAMP LE 3 d 1 -5-Methyl-.1-phenyl- I H-pyridin-2-one D 0 0 0 DC D D 0 Step 1 T CL 3 H (002511 d 6 5-methv1pyridin 2-yamine The procedure is carried out using the methods described by by Esaki et al TCtrahedron 2006, 62, 10954-10961. Step2 0 1 0 00252J d5-Methyl H-vrndin-one The procedure is carried out using the methods described by Smith et al Organic Syntheses 2002. 78, 51-56, but substituting d-sulfuric acid in deuterium oxide for sulfuric acid in water, and substituting d 6 -methylpyridin-2-ylamine for 5 methyl-pyridin-2-ylamine. -60 - + DC D 0 1002531 d 1 S-Methvl1-henylI-I-nvridin-2-one The procedure is carried out using the methods described in WO2003/01l4087 wherein the Ulhnaan coupling is run substituting d-5 methyl- I1H-pyridin-2-one for 5-methyl-I Fpyridin-2-one and also substituting d 5 -bromobenzene (commercially available from multiple sources) for bromobenzene EXAMPLE 4 In vitro Liver Microsomal Stability Assay 1002541 Liver microsomal stability assays were conducted with 0.2 mg per mL liver miterosomie protein in a NADPH-generating system. (2% sodium bicarbonate, 212 mM NADPH, 25,6 mM glucose 6-phosphate, and 6 units per mL glucose 6-phosphate dehydrogenase and ,3 mM MgCi 2 ). The test compounds were solubulized in 20% acetonitrile-w.aer The test compound soltion was then added to the assay mixture (fiat assay concentration I pIVI) and the mixture was incubated at about 37 *. The final concentration of acetonitrile in the assay should be <%. Aliquots (504d) were collected at times 0, 15, 30, 45, 60. 90 and 120 mn, and diluted with ice cold acetonitrile (200 L) (to quench the reactions), The aliquots were centrifuged at about 12,000 RPM for about 10 mnn to precipitate the proteins. The supernatants were then collected and transferred to micro centrifuge tubes for /MS/MS analysis of degradation half lives,.It can be predicted that the compounds as disclosed herein, when tested in. this assay, will demonstrate an increase of at least. 5% or more in the degradation half-life, as compared to the non-isotopieally enriched drug. For example the degradation halflives of any of the deuterated compounds as described in the Examplesection should show improvement in degradation half lives between 5-600% respectively, as compared to non-isotopicaly enriched pirfenidone, -61- EXAMPLE 5 In vitro metabolism usina human ctochrome Po enzymes [002551 The cytochrome P 4 enzymes are expressed from the corresponding human cDNA using a baculovirus expression system (BD Biosciences, San Jose, CA) A 0.25 milliliter reaction mixture containing 0.8 milligrams per unililiter protein, 13 millimolar NADP', 3.3 millimolar glucose-6-phosphate, 0A UimL glucose4-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula 1, the corresponding non~ isotopically enriched compound or standard or control in 100 miflimolar potassium phosphate (pH 7.4) is incubated at 37 C for 20 min; After incubation, te reaction is stopped by the addition of an appropriate solvent (e~g, acetonitrile, 20% trichloroacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchlorie acid, 94% acetonitrie/6% glacial acetic acid) and centrifuged (10,000 g) for 3 min. The supenatant is analyzed by HPLC;MS/MS Cytochrome Ps Standard CYP I A2 Phenacetin CYP2A6 Coumnarin CYP2B6 [ "C]-S)mephenytoin CYP2C8 Pachitaxel CYP2C9 Dictofenac CYP2c19 S])-ephenvto CYP2D6 BI(+/-)BufaraiIl CYP2EI Chlorzoxazone CYP3A4 esteone CYP4 A ['I CLauric acid -62-~ Monamie O idseA, ihibition and Oxidatiye Turnover 1002561 The procedure is carried ou using the methods described by Weyler Journal of Biological Chenisity 1985 260, 13199-l320 Mmoane oxidase A activity is measured spectrophotometrically by monitoring the increase in absorbnc e At 314 nos on oxidation of kynuramie with formation of 4-hydroxyquinohine. The measurements are cared out, at30 C in 50mM NaPi buffer, pH 7.2, containing 0.2% Triton X- 100 monoaminee oxidase assay buffer), phil I mm. kyRuramine, and the desired amount of enzyme in I moL total volume, EXAMPLE 7 Monoamine Oxidase Inhib on andOidative Tumnove 100257j The procedure is carried out using the methods described by Uebelhack, Pharmacopsychiatvy 1998, 31 187-192. EXAMPLE 8 Dytphi (mdx MouseuscFibrosis Asa 1002581 The procedures are carried out using the methods described by Gosselin et aL, Muscle & Nerve 2007, 35(2), 208-216, [002591 The examples set forth above are provided to give those of ordinary skill in the art with a disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein All publications, patents, and patent applications cited herein are incorporated by reference as if each such publication, patent, or patent application were specifically and individually indicated to be incorporated herein by reference, 1002160] A reeec eento a paten-t documt r otherT matterT whichis givn a prior arW. o taken as an admission that that document or prior art was part of common genel knowledge at the priority date ot any of the claims.' 100261 With reference to the use of the wordie foregoing descrion and/or in the following chlims unless the context reque otherwise, hose Wo are usedohe basis and earunderstanding that they are to be nte-tre n desripionand/,or the foloiclaims.

Claims (16)

1. An inhalable pharmacetical composition comprising a pharmaceutically acceptable carrier together with a compound having the structural formula: D wherein each of said positions represented as D has deuterium enrichment of at least 10%.

2. The composition as recited in Claim 1, wherein each of said positions represented as D has deuterium enrichment of at least 50%. 3 The composition as recited in Claim wherein each of said positions presented as D has deuterium enrichment of at least 90%.

4. The composition as recited in Claim 1, whierein each of said positions represented as D has deuterium enrichment of at least 98%

5. The composition as recited in any one of Claims I to 4,herein said composition is forn-nlatd as an solution or suspension.

6. The composition as recited in Claim 5, wherein said solution or suspension comprises ethanol, water, or mixtures thereof

7. The composition as recited in Claim 5 or 6. wherein said solution or suspension comprise a urfactant selected from the group consisting ofsorbitan trioleate. oleic acid, and an oligolactic acid -64 - S. The composition as recited in any one of Claims 5 to 7, wherein said solution or suspension is administered to a subject using a device selected from the group consisting of a pressurized container, a pump, a sprayer, an atomizer, and a nebulizer.

9. The composition as recited in any one of claims Claim I to 7, wherein said composition is formulated as an aerosol. 10, A compound having the structural kwmiula: Ofl D D 11 The compound as recited in Claim 10, wherein each of said positions represented as D has deuterium enrichment of at least 98%. 12 The compound as recited in Claim 10, wherein each of said positions represented as D has deuterium nrcmn Of at least 90)%. 13 The compound as recited in Claim 10, wh erein each of said positions represented as iD has deuterium enrichment of at least 50%.

14. The compound as recited in Claim 10, wherein each of said positions represented as D has deuteriunm enrichnent of least 10%, 15 A pharmaceutical composiion comprising a compound as recited in any one of Claim 10 to 14 together with a pharmaceutically acceptable carrier. 16 A method for the treatmentt, prevention, or amelioration of one or more syniptos of a fibroric-tmedi tated disorder, a cot lagen-ined-iAed disorder, or aftbrotic-mediated -65- and collagennediated disorder, comprising the administration a compound as recited in any one of Claims 10 to 14. or a composition as recited in Claim 15.

17. The method as recited in Claim 1 6. wherein the fibroic-meditated disorder, the collagen-mediated disorder or the fibroticimediated and the collagen-mediated disorder is selected from the group consisting of idiopathic pulonary fibrosis. uterine fibroids, multiple sclerosis, renal fibrosis, diabetic kidney disease, endotoxin-induced liver injury after pai-tial hepatectomy or hepatic ischemia. allograft injury atr organ transplantation, cystic fibrosi s, atri al fibrilarion-, neutropenia scleroderma deriatomyositis, cinosis, diffuse parenchymal lung disease mediastinal fibrosis, tuberculosis, spleen fibrosis caused by sickle-cell anemia, and rheumatoid arthritis.

18. The method as recited in Claim 17 wherein the fibrotic-meditated disorder is idiopathic pulmonary fibrosis

19. The method as recited in Claim 16, wherein said compound has at least one of the following properties: a) decreased inter-individual varaton in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound; b) increased average plasma levels of said compound per dosage uni thereof as compared to the non-isotopicaily enriched compound; c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as cotnparea to the non-isotopically enriched compound; d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched. conpou nd; and e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the nofn-isotopically enriched comniound. -66-

20. The method as recited in Clain 16, wherein said compound has at least two of the following properties: a) decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopicdally enriched compOUnd b) increased average plasma levels of said compound per dosage unit thereof as compared to the non~tsotopically enriched compound; c) decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the nonisotopically enriched compound; d) increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the nonisotopically enriched compound; and e) an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopicafly enriched compound.

21. The method as recited in Claim 16, wherein the method affects a decreased metabolism of the compound per dosage unit thereof by at least one poiyorpic'l iexprsse cyochomeP450 iso tbrm in the subject as compared to the corresponding non-isotopicaly enriched compound 22 The method as recited in Claim 21, wherein the cyochromelo isofo is selected from. thegroup consisting of CYP2C9, and CYP2D6. ]

23. The method as recited in Claim 16. wherein said compound is characterized by decreased inhibition of at least one cytochrome P, or monoanine o idase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.

24. The method as recited inClaim 23, wherein said cytochrome P or monoaninc oxidase isoforn is selected from the group consisting of CYPIAl, CYPIA2 CNI131, CYP2A6, W WI CYP2B6 CYP2CS, CY.P2N CYP2CI& (YP2CI9 2CP2 6, CY2EI. YP2G CI Y 232., ('YP2RI CYP2SI CYPIA4, -67- CYP3A5 CYP3A5PI, CYP3ASP2, CYP3A7, CYP4AII, CYP4II CYP4F2, CYP4F3 CYP4F8. CYP4FI I, CYP4FI2. CYP4X1 CYP4ZI, CYP5A 1, CYPTAI, CYP7B. CYP8AJ, CYP8B, CiP1IAL CYPI1BI CYPIB2, CYPl. CYPI9, CYP21. CYP24; CYP26AI, CYP26B1, CYP27AJ, CYP27B1, CYP39, CYP46, CYPS 1 MAOA and MAda. 25 The method as recited in Claim 16, wherein the method affects the treatment of the disease while reducing or eliminating a deleterious change in a diagnrostic hepatobiliary function endpoint, as compared to the corresponding non-isotopicaly ermched compound..

26. The method as recited in Claim 25, wherein the diagnostic hepatobiiary function endpoint is selected from the group consisting of alanine aminotrnsferase ("ALT") serilglutamlic-pyruvic transaminase C'SGPT"), alz'aeai-~t~sew ("AST," "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, ilirubinammag am transpeptidase CuGTP," TP " T")Jeucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonographv, liver nuc].e.ar sean. W ncloidsadbood protein. I3Ai~-68-