US 2008.0312247A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0312247 A1 Gant et al. (43) Pub. Date: Dec. 18, 2008

(54) SUBSTITUTED PIPERAZINES Publication Classification (51) Int. Cl. (75) Inventors: Thomas G. Gant, Carlsbad, CA A63/495 (2006.01) (US); Sepehr Sarshar, Cardiff by A6IP 9/00 (2006.01) the Sea, CA (US) A6IP 9/10 (2006.01) C07D 24I/04 (2006.01) Correspondence Address: (52) U.S. Cl...... 514/252.12:544/400 GLOBAL PATENT GROUP - APX (57) ABSTRACT Ms. LaVern Hall Disclosed herein are substituted piperazine late Na" channel 10411 Clayton Road, Suite 304 modulators of Formula I, process of preparation thereof, ST. LOUIS, MO 63131 (US) pharmaceutical compositions thereof, and methods of use thereof. (73) Assignee: AUSPEX PHARMACEUTICALS, INC., Formula I Vista, CA (US) Rs R14 Ris R10 R R31 (21) Appl. No.: 12/138,169 R6 R4 R11 R 23. R24V > R9 N N R O R56 N (22) Filed: Jun. 12, 2008 R O 2K O R30 R 8 R2 R ". 20R,\ R. R. Related U.S. Application Data R. R3 19 R22 R4 R29 (60) Provisional application No. 60/943,731, filed on Jun. R28 13, 2007. US 2008/0312247 A1 Dec. 18, 2008

SUBSTITUTED PPERAZINES nal of Clinical Pharmacology 2005, 45,802-09; Chaitman et al, Journal of the Americal College of Cardiology 2004, 43(8), 1375-82; Opie, European Heart Journal 2003, 24, 0001. This application claims the benefit of priority of 1854-56: Anderson et al, Heart Disease 2001, 3, 263-69; U.S. provisional application No. 60/943,731, filed Jun. 13, Zacharowski etal, European Journal of Pharmacology 2001, 2007, the disclosure of which is hereby incorporated by ref 418, 105-10; McCormacket al. General Pharmacology 1998, erence as if written herein in its entirety. 30(5), 639-45). FIELD SUMMARY OF THE INVENTION 0002 The present invention is directed to substituted pip 0005 Disclosed herein is a compound having structural erazines, pharmaceutically acceptable salts and prodrugs Formula I: thereof, the chemical synthesis thereof, and medical use of Such compounds for the treatment and/or management of angina, intermittent claudication, ischemia, and/or any disor (I) der ameliorated by modulating late Na channels. Rs R14 Ris R10 R13 R R31 BACKGROUND R6 R4 | RIR 2 R16 R24V DN R9 N N N R O R6 Q 0003 R O 2K O R30 R 8 R2 R is R 20R,\ R. R. OH No R. R3 17 K-9 R22 R1 R29 N-- NH p-1 or a pharmaceutically acceptable salt, Solvate, or prodrug thereof, wherein: O -> 0006 R. R. R. R. R. R. R. R. R. R. R. R. R. R14. R1s. R 63 R17, R 83 R19. R20. R21. R22. R2s. R24. R2s. R26. Ranolazine R7, Rs. Ro Ro, R. R. and Rs are selected from the group consisting of hydrogen or deuterium; and 0004 Ranolazine (RanexaR), N-(2,6-dimethyl-phenyl)- 0007 at least one of R. R. R. R. Rs. Re, R7Rs, Ro Ro, 2-4-2-hydroxy-3-(2-methoxy-phenoxy)-propyl-piper R11, R12, R13, R14, R1s. R16, R17, Ris, R19, R20 R2, R22, R23. azin-1-yl)-acetamide, is indicated for treating chronic stable R24, R2s, R26, R27, R2s, R-29, Rao, Rs 1, R32, and Rss is deute angina. Ranolazine improves left ventricular diastolic func rium. tion in patients with ischemic heart disease (Hayashida W. et 0008 Further, disclosed herein are methods of modulating al., Cardiovasc Drugs. Ther 1994, 8,741-7). Ranolazine is a late Na" channels. selective inhibitor of late Na" channels (Pharmacotherapy 0009 Disclosed herein is a method for treating, prevent 2007, 27(12), 1659-1676). At therapeutic concentrations (up ing, or ameliorating one or more symptoms of a late Na" to 10 Limol/L), ranolazine selectively inhibits late sodium channel-mediated disorder in a subject, comprising adminis current (I) with an ICso of 5-21 umol/L. (Antzelevitch C, et tering a therapeutically effective amount of a compound as al., J. Cardiovasc Pharmacol Therapeut 2004, 9(suppl 1), disclosed herein. S65-83). At therapeutic plasma concentrations, ranolazine 0010 Further disclosed herein is a method wherein the does not significantly inhibit late I in healthy myocytes late Na" channel-mediated disorder is selected from the (nonischemic and/or nonfailing myocytes), but does signifi group consisting of, but not limited to, angina, intermittent cantly inhibit late I in ischemic or failing myocytes in claudication, ischemia, and/or any disorder ameliorated by which the current is amplified and problematic. By inhibiting modulating late Na" channels. late I, there is an overall reduction in intracellular Na". The 0011. Also disclosed herein are articles of manufacture reduction in intracellular Na" contributes to a reduction in the and kits containing compounds as disclosed herein. By way magnitude of ischemia-induced Ca" overload, and improves of example only a kit or article of manufacture can include a myocardial function as well as myocardial perfusion (Belar container (Such as a bottle) with a desired amount of at least dinelli L, et al., Eur Heart J2004, Suppl. 6, 13-7; Antzelevitch one compound (or pharmaceutical composition of a com C, et al. Circulation 2004, 110, 904-10; Wu L, et al., J Phar pound) as disclosed herein. Further, such a kit or article of macol Exp Ther 2004, 310, 599-605). Ranolazine produces manufacture can further include instructions for using said this anti-ischemic effect without significantly altering either compound (or pharmaceutical composition of a compound) heart rate, blood pressure, or increase the rate-pressure prod disclosed herein. The instructions can be attached to the con uct. Ranolazine at high doses is reported to shift ATP produc tainer, or can be included in a package (such as a box or a tion away from fatty acid oxidation and towards glucose plastic or foil bag) holding the container. oxidation, thereby reducing lactic acid production and tissue 0012. In another aspect is the use of a compound as dis acidosis (Tianetal, Journal of Chromatography B, 2007, 846, closed herein in the manufacture of a medicament for treating 346–50; McCormack, Biochemical Society Transactions a disorder in an animal in which late Na" channels contribute 2006, 34(2), 238-42; Jerling, Clinical Pharmacokinetics to the pathology and/or symptomology of the disorder. In a 2006, 45(5), 469-91; Jerling et al. Clinical Pharmacology & further embodiment, said disorder is, but not limited to, Therapeutics 2005, 78(3), 288-97: Abdallah et al. The Jour angina, intermittent claudication, and/or ischemia. US 2008/0312247 A1 Dec. 18, 2008

0013 In another aspectare processes for preparing a com 0025. In yet other embodiments said therapeutic agent is a pound as described herein as a late Na" channel modulator, or Beta-blocker. other pharmaceutically acceptable derivatives Such as pro 0026 Infurther embodiments said beta-blocker is selected drug derivatives, or individual isomers and mixture of iso from the group consisting of alprenolol, oXprenolol, pindolol. mers or enantiomers thereof. propranolol, timolol, Sotalol, nadolol, mepindolol, carteolol. 0014. In another aspectare processes for preparing a com tertatolol, bopindolol, bupranolol, penbutolol, cloranolol, pound as disclosed herein as a late Na" channel modulator. practolol, metoprolol, atenolol, acebutolol, betaxolol, bevan 0015. Also disclosed herein are processes for formulating tolol, bisoprolol, celiprolol, esmolol, epanolol, S-atenolol. pharmaceutical compositions with a compound disclosed nebivolol, tallinolol, labetalol, and carvedilol. herein. 0027. In yet other embodiments said therapeutic agent is a 0016. In certain embodiments said pharmaceutical com nitrate or nitrite. position comprises one or more release-controlling excipi 0028. In further embodiments said nitrate or nitrite is entS. selected from the group consisting of glyceryl trinitrate, isos 0017. In other embodiments said pharmaceutical compo orbide dinitrate, isosorbide mononitrate, pentaerythritol tet sition further comprises one or more non-release controlling ranitrate, methylpropylpropanediol dinitrate, propatylnitrate, excipients. troInitrate, eritrity1 tetranitrate, amyl nitrite, butyl nitrite, 0018. In certain embodiments said pharmaceutical com ethyl nitrite, methyl nitrite, isopropyl nitrite, isobutyl nitrite, position is Suitable for oral, parenteral, or intravenous infu and cyclohexyl nitrite. sion administration. 0029. In yet other embodiments said therapeutic agent is an ACE inhibitor. 0019. In yet other embodiments said pharmaceutical com 0030. In further embodiments said ACE inhibitor is position comprises a tablet, or capsule. selected from the group consisting of captopril, enalapril, 0020. In certain embodiments the compounds as disclosed lisinopril, perindopril, ramipril, quinapril, benazepril, cilaza herein are administered in a dose of 0.5 milligram to 1000 pril, fosinopril, trandolapril, spirapril, delapril, moexipril, milligram. temocapril. Zofenopril, and imidapril. 0021. In yet further embodiments said pharmaceutical 0031. In yet other embodiments said therapeutic agent is a compositions further comprise another therapeutic agent. statin. 0022. In yet other embodiments said therapeutic agent is 0032. In further embodiments said statin is selected from selected from the group consisting of calcium channel block the group consisting of atorvastatin, cerivastatin, fluvastatin, ers, beta-blockers, nitrates or nitrites, ACE inhibitors, statins, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, platelet aggregation inhibitors, adenosine, digitoxin, anti-ar and simvastatin. rhythmic agents, sympathomimetic drugs, steroidal drugs, 0033. In yet other embodiments said therapeutic agent is a non-steroidal anti-inflammatory drugs (NSAIDs), opioids, platelet aggregation inhibitor. anesthetics, sepsis agents, anti-bacterials, anti-fungals, anti 0034. In further embodiments said platelet aggregation coagulants, thrombolytics, endothelin converting enzyme inhibitor is selected from the group consisting of aspirin, (ECE) inhibitors, thromboxane enzyme antagonists, potas aloxiprin, ditazole, carbasalate calcium, cloricromen, dipy sium channel openers, thrombin inhibitors, growth factor ridamole, indobufen, picotamide, triflusal, clopidogrel, ticlo inhibitors, platelet activating factor (PAF) antagonists, anti pidine, praSugrel, beraprost, prostacyclin, iloprost, and tre platelet agents, Factor VIa Inhibitors, Factor Xa Inhibitors, prostinil. renin inhibitors, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, HMG CoA reductase inhibitors, 0035. In certain embodiments said platelet aggregation squalene synthetase inhibitors, fibrates, bile acid seques inhibitor is aspirin. trants, anti-atherosclerotic agents, MTP Inhibitors, potassium 0036. In other embodiments, a method for the treatment, channel activators, alpha-PDE5 agents, beta-PDE5 agents, prevention, or amelioration of one or more symptoms of a diuretics, anti-diabetic agents, PPAR-gamma agonists, min Na channel-mediated disorderina Subject comprises admin eralocorticoid enzyme antagonists, aP2 inhibitors, protein istering a therapeutically effective amount of a compound as tyrosine kinase inhibitors, antiinflammatories, antiprolifera disclosed herein. tives, chemotherapeutic agents, immunosuppressants, anti 0037. In yet other embodiments said Na channel-medi cancer agents, cytotoxic agents, antimetabolites, farnesyl ated disorder is selected from the group consisting of angina, protein transferase inhibitors, hormonal agents, microtubule intermittent claudication, and ischemia. disruptor agents, microtubule-stablizing agents, 0038. In other embodiments said Na channel-mediated topoisomerase inhibitors, prenyl-protein transferase inhibi disorder can be lessened, alleviated, or prevented by admin tors, cyclosporins, TNF-alpha inhibitors, cyclooxygenase-2 istering a Na" channel modulator. (COX-2) inhibitors, gold compounds, antalarmin, Z-338, and 0039. In other embodiments said compound has at least platinum coordination complexes. one of the following properties: 0023. In yet other embodiments said therapeutic agent is a 0040 a) decreased inter-individual variation in plasma calcium channel blocker. levels of said compound or a metabolite thereofas com 0024. In further embodiments said calcium channel pared to the non-isotopically enriched compound; blocker is selected from the group consisting of amlodipine, 0041 b) increased average plasma levels of said com felodipine, isradipine, nicardipine, nifedipine, nimodipine, pound per dosage unit thereofas compared to the non inhisoldipine, nitrendipine, lacidipine, nilvadipine, manid isotopically enriched compound; ipine, barnidipine, lercanidipine, cilnidipine, benidipine, 0.042 c) decreased average plasma levels of at least one mibefradil, Verapamil, gallopamil, diltiazem, fendiline, metabolite of said compound per dosage unit thereof as bepridil, lidoflazine, and perhexyline. compared to the non-isotopically enriched compound; US 2008/0312247 A1 Dec. 18, 2008

0043 d) increased average plasma levels of at least one cine aminopeptidase (“LAP), liver biopsy, liver ultrasonog metabolite of said compound per dosage unit thereof as raphy, liver nuclear Scan, 5'-nucleotidase, and blood protein. compared to the non-isotopically enriched compound; and INCORPORATION BY REFERENCE 0044 e) an improved clinical effect during the treat 0057 All publications and references cited herein, includ ment in said Subject perdosage unit thereofas compared ing those in the background section, are expressly incorpo to the non-isotopically enriched compound. rated herein by reference in their entirety. However, with 0045. In yet further embodiments said compound has at respect to any similar or identical terms found in both the least two of the following properties: incorporated publications or references and those expressly 0046) a) decreased inter-individual variation in plasma put forth or defined in this document, then those terms defi levels of said compound or a metabolite thereofas com nitions or meanings expressly put forth in this document shall pared to the non-isotopically enriched compound; control in all respects. 0047 b) increased average plasma levels of said com pound per dosage unit thereofas compared to the non DETAILED DESCRIPTION isotopically enriched compound; 0.058 To facilitate understanding of the disclosure set 0048 c) decreased average plasma levels of at least one forth herein, a number of terms are defined below. Generally, metabolite of said compound per dosage unit thereof as the nomenclature used herein and the laboratory procedures compared to the non-isotopically enriched compound; in organic chemistry, medicinal chemistry, and pharmacol 0049 d) increased average plasma levels of at least one ogy described herein are those well known and commonly metabolite of said compound per dosage unit thereof as employed in the art. Unless defined otherwise, all technical compared to the non-isotopically enriched compound; and Scientific terms used herein generally have the same and meaning as commonly understood in the art to which this 0050 e) an improved clinical effect during the treat disclosure belongs. In the event that there is a plurality of ment in said Subject perdosage unit thereofas compared definitions for a term used herein, those in this section prevail to the non-isotopically enriched compound. unless stated otherwise. 0051. In certain embodiments said compound has a 0059. As used herein, the singular forms “a,” “an,” and decreased metabolism by at least one polymorphically-ex “the may refer to plural articles unless specifically stated pressed cytochrome Paso isoform in said subject per dosage otherwise. unit thereof as compared to the non-isotopically enriched 0060. The term “subject” refers to an animal, including, compound. but not limited to, a primate (e.g., human monkey, chimpan Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, 0052. In other embodiments said cytochrome Paso isoform hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, is selected from the group consisting of CYP2C8, CYP2C9, miniature pig), equine, canine, feline, and the like. The terms CYP2C19, and CYP2D6. “subject' and “patient” are used interchangeably herein in 0053. In yet further embodiments said compound is char reference, for example, to a mammalian Subject, such as a acterized by decreased inhibition of at least one cytochrome human patient. Por monoamine oxidase isoform in said subject per dosage 0061. The terms “treat,” “treating,” and “treatment” are unit thereof as compared to the non-isotopically enriched meant to include alleviating or abrogating a disorder, or alle compound. viating or abrogating one or more of the symptoms associated 0054. In certain embodiments said cytochrome Paso or with the disorder, and/or alleviating or eradicating the cause monoamine oxidase isoform is selected from the group con (s) of the disorder itself. sisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, 0062. The terms “prevent.” “preventing, and “preven CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, tion” refer to a method of delaying or precluding the onset of CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, a disorder, delaying or precluding its attendant symptoms; CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, barring a subject from acquiring a disorder, and/or reducing a CYP3A5P2, CYP3A7, CYP4A11, CYP4B1 CYP4F2, Subject's risk of acquiring a disorder. CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, 0063. The term “therapeutically effective amount” refers CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1 to the amount of a compound that, when administered, is CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, sufficient to prevent development of, or alleviate to some CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, extent, one or more of the symptoms of the disorder being CYP27B1, CYP39, CYP46, CYP51, MAO and MAO. treated. The term “therapeutically effective amount” also 0055. In other embodiments said method method affects refers to the amount of a compound that is sufficient to elicit the treatment of the disorder while reducing or eliminating a the biological or medical response of a cell, tissue, system, deleterious change in a diagnostic hepatobiliary function end animal, or human that is being sought by a researcher, Veteri point, as compared to the corresponding non-isotopically narian, medical doctor, or clinician. enriched compound. 0064. The term “pharmaceutically acceptable carrier. s 0056. In yet further embodiments said diagnostic hepato “pharmaceutically acceptable excipient,” “physiologically biliary function endpoint is selected from the group consist acceptable carrier,” or “physiologically acceptable excipient’ ing of alanine aminotransferase (ALT), serum glutamic refers to a pharmaceutically-acceptable material, composi pyruvic transaminase (“SGPT), aspartate aminotransferase tion, or vehicle, such as a liquid or Solid filler, diluent, excipi (AST,”“SGOT), ALT/AST ratios, serumaldolase, alkaline ent, solvent, or encapsulating material. Each component must phosphatase (ALP), ammonia levels, bilirubin, gamma be “pharmaceutically acceptable' in the sense of being com glutamyl transpeptidase (“GGTP” “Y-GTP “GGT), leu patible with the other ingredients of a pharmaceutical formu US 2008/0312247 A1 Dec. 18, 2008

lation. It must also be suitable for use in contact with the tissue ing a racemic mixture or single stereoisomerthereof, as deter or organ of humans and animals without excessive toxicity, mined by standard analytical methods. irritation, allergic response, immunogenecity, or other prob (0070. The term “about” or “approximately” means an lems or complications, commensurate with a reasonable ben acceptable error for a particular value, which depends in part efit/risk ratio. See, Remington. The Science and Practice of on how the value is measured or determined. In certain Pharmacy, 21st Edition; Lippincott Williams & Wilkins: embodiments, “about can mean 1 or more standard devia Philadelphia, Pa., 2005, Handbook of Pharmaceutical tions. Excipients, 5th Edition; Rowe et al., Eds. The Pharmaceuti 0071. The terms “active ingredient' and “active sub cal Press and the American Pharmaceutical Association: stance' refer to a compound, which is administered, alone or in combination with one or more pharmaceutically accept 2005; and Handbook of Pharmaceutical Additives, 3rd Edi able excipients and/or carriers, to a subject for treating, pre tion; Ash and Ash Eds. Gower Publishing Company: 2007; venting, or ameliorating one or more symptoms of a disorder. Pharmaceutical Preformulation and Formulation, Gibson 0072 The terms “drug.” “therapeutic agent,” and “chemo Ed., CRC Press LLC: Boca Raton, Fla., 2004). therapeutic agent” refer to a compound, or a pharmaceutical 0065. The term “deuterium enrichment” refers to the per composition thereof, which is administered to a subject for centage of incorporation of deuterium at a given position in a treating, preventing, or ameliorating one or more symptoms molecule in the place of hydrogen. For example, deuterium of a disorder. enrichment of 1% at a given position means that 1% of mol 0073. The term “disorder as used herein is intended to be ecules in a given sample contain deuterium at the specified generally synonymous, and is used interchangeably with, the position. Because the naturally occurring distribution of deu terms “disease.” “sydrome' and “condition' (as in medical terium is about 0.0156%, deuterium enrichment at any posi condition), in that all reflect an abnormal condition of the tion in a compound synthesized using non-enriched starting body or of one of its parts that impairs normal functioning and materials is about 0.0156%. The deuterium enrichment can is typically manifested by distinguishing signs and Symp be determined using conventional analytical methods, such as tOmS. mass spectrometry and nuclear magnetic resonance spectros 0074 The term “release controlling excipient” refers to an copy. excipient whose primary function is to modify the duration or 0.066. The term “is/are deuterium, when used to describe place of release of the active Substance from a dosage form as a given position in a molecule Such as R. R. R. R. Rs. R. compared with a conventional immediate release dosage R7, Rs. Ro. Rio, R1, R12, R1s. R14, R1s. R16, R17, R1s. R19. form. R20 R2, R22, R23, R24 R2s, R26, R27, R2s, R29, Rao, Rs 1, R32, 0075. The term “nonrelease controlling excipient” refers and R or the symbol “D, when used to represent a given to an excipient whose primary function do not include modi position in a drawing of a molecular structure, means that the fying the duration or place of release of the active Substance specified position is enriched with deuterium above the natu from a dosage form as compared with a conventional imme rally occurring distribution of deuterium. In an embodiment diate release dosage form. deuterium enrichment is of no less than about 1%, in another 0076. The term “protecting group' or “removable protect no less than about 5%, in another no less than about 10%, in ing group' refers to a group which, when bound to a func another no less than about 20%, in another no less than about tionality, Such as the oxygen atom of a hydroxyl or carboxyl 50%, in another no less than about 70%, in another no less group, or the nitrogen atom of an amino group, prevents than about 80%, in another no less than about 90%, or in reactions from occurring at that functional group, and which another no less than about 98% of deuterium at the specified can be removed by a conventional chemical or enzymatic step position. to reestablish the functional group (Greene and Wuts, Protec 0067. The term “isotopic enrichment” refers to the per tive Groups in Organic Synthesis, 3" Ed., John Wiley & Sons, centage of incorporation of a less prevalent isotope of an New York, N.Y., 1999). element at a given position in a molecule in the place of the 0077. The term “late Na" channel-mediated disorder more prevalent isotope of the element. refers to a disorder that is characterized by abnormal or 0068. The term “non-isotopically enriched’ refers to a undesired late I, that, when the late Na" channel activity is molecule in which the percentages of the various isotopes are modified, leads to the desired responses depending on the Substantially the same as the naturally occurring percentages. route of administration and desired end result. A late Na" 0069. The terms “substantially pure' and “substantially channel-mediated disorder may be completely or partially homogeneous' mean Sufficiently homogeneous to appear mediated through modulating late Na channels. In particu free of readily detectable impurities as determined by stan lar, a late Na" channel-mediated disorder is one in which dard analytical methods, including, but not limited to, thin modulation of the late Na" channel activity results in some layer chromatography (TLC), gel electrophoresis, high per effect on the underlying disorder, e.g., modulating late Na" formance liquid chromatography (HPLC), nuclear magnetic channels results in some improvement in at least Some of the resonance (NMR), and mass spectrometry (MS); or suffi patients being treated. ciently pure such that further purification would not detect 0078. The term “late Na" channel modulator, as used ably alter the physical and chemical properties, or biological herein is intended to be generally synonymous, and is used and pharmacological properties. Such as enzymatic and bio interchangeably with “modulation of late Na" channels' or logical activities, of the Substance. In certain embodiments, “modulating late Na" channels.” and refers to the ability of a “substantially pure' or “substantially homogeneous” refers to compound disclosed herein to alter the function of late Na" a collection of molecules, wherein at least about 50%, at least channels. A modulator may activate the activity of a late Na" about 70%, at least about 80%, at least about 90%, at least channel, may activate or inhibit the activity of a late Na" about 95%, at least about 98%, at least about 99%, or at least channel depending on the concentration of the compound about 99.5% of the molecules are a single compound, includ exposed to the late Na channel, or may inhibit the activity of US 2008/0312247 A1 Dec. 18, 2008 a late Na channel. Such activation or inhibition may be energy required to reach the transition state of that reaction. contingent on the occurrence of a specific event. Such as Reactions that involve multiple steps will necessarily have a activation of a signal transduction pathway, and/or may be number of transition states, and in these instances, the acti manifest only in particular cell types, such as myocytes. The Vation energy for the reaction is equal to the energy difference term “late Na" channel modulator also refers to altering the between the reactants and the most unstable transition state. function of a late Na" channel by increasing or decreasing the Once the transition state is reached, the molecules can either probability that a complex forms between a late Na channel revert, thus reforming the original reactants, or the new bonds receptor and a late Na channel regulator, such as a protein form giving rise to the products. This dichotomy is possible kinase. A late Na" channel modulator may increase the prob ability that such a complex forms between the late Na" chan because both pathways, forward and reverse, result in the nel and the late Na" channel regulator, may increase or release of energy. A catalyst facilitates a reaction process by decrease the probability that a complex forms between the lowering the activation energy leading to a transition state. late Na" channel and the late Na" channel regulator depend Enzymes are examples of biological catalysts that reduce the ing on the concentration of the compound exposed to the late energy necessary to achieve a particular transition state. Na channel, and or may decrease the probability that a com I0083. A carbon-hydrogen bond is by nature a covalent plex forms between the late Na" channel and the late Na" chemical bond. Suchabond forms when two atoms of similar channel regulator. electronegativity share some of their valence electrons, 007.9 The term "iodinating reagent” refers to a reactive thereby creating a force that holds the atoms together. This chemical reagent used in iodination reactions, whereby force or bond strength can be quantified and is expressed in iodine is transferred to a substrate. Examples of iodinating units of energy, and as Such, covalent bonds between various agents include, but are not limited to, iodine monochloride, atoms can be classified according to how much energy must N-iodosuccinimide, 1-Iodobutane, 2-Iodo-1,1,1-trifluoroet be applied to the bond in order to break the bond or separate hane, ammonium iodide, calcium iodate, cuprous iodide, eth the two atoms. ylenediamine dihydriodide (EDDI), ferrous iodide, hydriodic I0084. The bond strength is directly proportional to the acid, iodic acid, iodine, iodobenzene diacetate, iodoethane, absolute value of the ground-state vibrational energy of the iodoform, iodotrimethylsilane, lithium iodide, methyl iodide, bond. This vibrational energy, which is also known as the potassium iodate, potassium iodide, sodium iodide, sodium Zero-point vibrational energy, depends on the mass of the metaperiodate, Sodium selenite, thymol iodide, and trimethyl atoms that form the bond. The absolute value of the Zero-point sulfoxonium iodide. vibrational energy increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) is Deuterium Kinetic Isotope Effect two-fold more massive than hydrogen (H), it follows that a 0080. In an attempt to eliminate foreign substances, such C-D bond is stronger than the corresponding C–H bond. as therapeutic agents, from its circulation system, the animal Compounds with C-D bonds are frequently indefinitely stable body expresses various enzymes, such as the cytochrome Paso in HO, and have been widely used for isotopic studies. If a enzymes or CYPs, esterases, proteases, reductases, dehydro C-H bond is broken during a rate-determining step in a genases, and monoamine oxidases, to react with and convert chemical reaction (i.e. the step with the highest transition these foreign substances to more polar intermediates or state energy), then Substituting a deuterium for that hydrogen metabolites for renal excretion. Some of the most common will cause a decrease in the reaction rate and the process will metabolic reactions of pharmaceutical compounds involve slow down. This phenomenon is known as the Deuterium the oxidation of a carbon-hydrogen (C-H) bond to either a Kinetic Isotope Effect (DKIE) and can range from about 1 (no carbon-oxygen (C-O) or carbon-carbon (C-C) JU-bond. isotope effect) to very large numbers, such as 50 or more, The resultant metabolites may be stable or unstable under meaning that the reaction can be fifty, or more, times slower physiological conditions, and can have Substantially different when deuterium is substituted for hydrogen. High DKIE val pharmacokinetic, pharmacodynamic, and acute and long ues may be due in part to a phenomenon known as tunneling, term toxicity profiles relative to the parent compounds. For which is a consequence of the uncertainty principle. Tunnel most drugs, such oxidations are generally rapid and ulti ing is ascribed to the Small size of a hydrogen atom, and mately lead to administration of multiple or high daily doses. occurs because transition states involving a proton can some 0081. The relationship between the activation energy and times form in the absence of the required activation energy. A the rate of reaction may be quantified by the Arrhenius equa deuterium is larger and statistically has a much lower prob tion, k=Ae', where E is the activation energy, T is ability of undergoing this phenomenon. Substitution of tri temperature, R is the molar gas constant, k is the rate constant tium for hydrogen results in yet a stronger bond than deute for the reaction, and A (the frequency factor) is a constant rium and gives numerically larger isotope effects. specific to each reaction that depends on the probability that I0085 Discovered in 1932 by Urey, deuterium (D) is a the molecules will collide with the correct orientation. The stable and non-radioactive isotope of hydrogen. It was the Arrhenius equation states that the fraction of molecules that first isotope to be separated from its element in pure form and have enough energy to overcome an energy barrier, that is, is twice as massive as hydrogen, and makes up about 0.02% of those with energy at least equal to the activation energy, the total mass of hydrogen (in this usage meaning all hydro depends exponentially on the ratio of the activation energy to gen isotopes) on earth. When two deuteriums bond with one thermal energy (RT), the average amount of thermal energy oxygen, deuterium oxide (DO or “heavy water) is formed. that molecules possess at a certain temperature. DO looks and tastes like HO, but has different physical 0082. The transition state in a reaction is a short lived state properties. It boils at 101.41° C. and freezes at 3.79° C. Its (on the order of 10' sec) along the reaction pathway during heat capacity, heat offusion, heat of vaporization, and entropy which the original bonds have stretched to their limit. By are all higher than H2O. It is also more viscous and is not as definition, the activation energy Eeges for a reaction is the powerful a solvent as H.O. US 2008/0312247 A1 Dec. 18, 2008

I0086. When pure DO is given to rodents, it is readily lazine contain a naturally occurring distribution of hydrogen absorbed and reaches an equilibrium level that is usually isotopes, namely H or protium (about 99.984.4%), H or about eighty percent of the concentration of what was con deuterium (about 0.0156%), and H or tritium (in the range Sumed. The quantity of deuterium required to induce toxicity between about 0.5 and 67 tritium atoms per 1018 protium is extremely high. When 0% to as much as 15% of the body atoms). Increased levels of deuterium incorporation may pro water has been replaced by DO, animals are healthy but are duce a detectable Kinetic Isotope Effect (KIE) that could unable to gain weight as fast as the control (untreated) group. affect the pharmacokinetic, pharmacologic and/or toxico When about 15% to about 20% of the body water has been logic profiles of late Na" channel modulators in comparison replaced with DO, the animals become excitable. When with the compound having naturally occurring levels of deu about 20% to about 25% of the body water has been replaced terium. with DO, the animals are so excitable that they go into 0090 Ranolazine is known to inhibit the polymorphic frequent convulsions when stimulated. Skinlesions, ulcers on CYP2D6 and CYP3A enzymes. Ranolzine, therefore, can the paws and muzzles, and necrosis of the tails appear. The cause drug-drug interactions that are not, a priori, predictable animals also become very aggressive; males becoming on a per patient basis. With a half-life of less than two hours, almost unmanageable. When about 30%, of the body water ranolazine must be taken frequently. Even extended-release has been replaced with DO, the animals refuse to eat and ranolazine formulations have to be taken twice daily. Further, become comatose. Their body weight drops sharply and their it is quite typical for disorders ameliorated by the compounds metabolic rates drop far below normal, with death occurring disclosed herein, Such as angina, intermittent claudication, at about 30 to about 35% replacement with DO. The effects and/orischemia, to produce chronic symptoms which are best are reversible unless more than thirty percent of the previous medicated around the clock. Additionally, it is quite typical body weight has been lost due to D.O. Studies have also for medicines to produce highly undesirable withdrawal shown that the use of DO can delay the growth of cancer cells effects upon discontinuation. and enhance the cytotoxicity of certain antineoplastic agents. 0091. The main metabolite of ranolazine in humans may 0087 Tritium (T) is a radioactive isotope of hydrogen, result from the oxidation of the methylene group adjacent to used in research, fusion reactors, neutron generators and the aryl oxygen. The resultant metabolite may further break radiopharmaceuticals. Mixing tritium with a phosphor pro down to the catecholora variant thereof, which can be further vides a continuous light source, a technique that is commonly transformed into a reactive ortho quinone. Ortho quinones used in wristwatches, compasses, rifle sights and exit signs. It may be expected to produce hepato- and other toxicities. was discovered by Rutherford, Oliphant and Harteck in 1934, Other positions of ranZolazine that are also susceptible to and is produced naturally in the upper atmosphere when enzymatic oxidation include the C-H bonds of the methyl cosmic rays react with H molecules. Tritium is a hydrogen enes alpha to the piperazinyl ring nitrogens as well as the atom that has 2 neutrons in the nucleus and has an atomic C-H bonds of the methoxy group. These transformations, weight close to 3. It occurs naturally in the environment in mediated by Paso enzymes or through other oxidative pro very low concentrations, most commonly found as TO, a cesses, can account for ranZoline's short half-life. These colorless and odorless liquid. Tritium decays slowly (half metabolites have as-yet-unknown pharmacology/toxicology. life=12.3 years) and emits a low energy beta particle that Limiting the production of such metabolites has the potential cannot penetrate the outer layer of human skin. Internal expo to decrease the danger of the administration of such drugs and Sure is the main hazard associated with this isotope, yet it may even allow increased dosage and concomitant increased must be ingested in large amounts to pose a significant health efficacy. risk. As compared with deuterium, a lesser amount of tritium 0092 Various deuteration patterns can be used to a) reduce must be consumed before it reaches a hazardous level. or eliminate unwanted metabolites, b) increase the half-life of 0088 Deuteration of pharmaceuticals to improve pharma the parent drug, c) decrease the number of doses needed to cokinetics (PK), pharmacodynamics (PD), and toxicity pro achieve a desired effect, d) decrease the amount of a dose files, has been demonstrated previously with some classes of needed to achieve a desired effect, e) increase the formation drugs. For example, DKIE was used to decrease the hepato ofactive metabolites, if any are formed, and/or f) decrease the toxicity of halothane by presumably limiting the production production of deleterious metabolites in specific tissues and/ of reactive species such as trifluoroacetylchloride. However, or create a more effective drug and/or a safer drug for polyp this method may not be applicable to all drug classes. For harmacy, whether the polypharmacy be intentional or not. example, deuterium incorporation can lead to metabolic The deuteration approach has strong potential to slow the Switching which may even give rise to an oxidative interme metabolism via various oxidative mechanisms and attenuate diate with a faster off-rate from an activating Phase I enzyme interpatient variatability. (e.g., cytochrome Paso 3A4). The concept of metabolic 0093. In one aspect, disclosed herein is a compound hav Switching asserts that Xenogens, when sequestered by Phase I ing structural Formula 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 (I) binding pockets in many Phase I enzymes and the promiscu ous 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 suffi ciently predictable a priori for any drug class. Deuterated Piperazine Derivatives 0089 Ranolazine is a substituted piperazine-based late Na channel modulator. The carbon-hydrogen bonds of rano US 2008/0312247 A1 Dec. 18, 2008

or a pharmaceutically acceptable salt, Solvate, or prodrug 13, R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s. thereof, wherein: 26, R27, R2s, R29. Rao Rs1, R32, and Ras are hydrogen. 0094. R. R. R. R. Rs. R. R-7, Rs. Ro, Rio, R, R2, R1s. I0120 In yet another embodiment, R. R. R. R. Rs, and R14 Ris, R16, R17, Ris, R19, R20 R2, R22, R23, R24. R2s, R26. are deuterium; and R-7, Rs. Ro, Rio, R1, R12, R1s. Rat Rs. R27, R2s, Rao, Rao, Rs 1, R-2, and Rs are selected from the 6. R17, Ris, R19, R20. R2, R22, R2s, R24. R2s, R26, R27, R2s. group consisting of hydrogen and deuterium; and 29, Rao Rs1, R32, and Rs are hydrogen. 0095 at least one of R. R. R. R. R. R. R. R. R. R. 0.121. In yet another embodiment, at least one of R7, Rs. R11, R12, R13, R14, R1s. RoR 17, R1s. R19, R20. R2, R22, R2s. and Ro is deuterium; and R, R2, R. R. Rs. R. Rio, R1, R12, R24. R2s, R26, R27. R2s, R29 Rao Rs1, R32, and Rss is deute R13, R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s. rium. R26, R27, R2s, R29, Rso Rs1, R32, and Ras are hydrogen. 0096. In another embodiment, at least one of R. R. R. I0122) In yet another embodiment, R. Rs, and R are deu R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, R1s. R16, R17, terium; and R, R2, Rs. R4 Rs. Rs. Rio, R1, R12, R1s. R14, R1s. R19, R20 R2, R22, R2s, R24. R2s, R26, R27, R2s, R29. Rao. R1s. R16, R17, Ris, R19, R20. R21, R22, R23, R24 R2s, R26, R27, R. R. and R independently has deuterium enrichment of R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. no less than about 1%, no less than about 5%, no less than I0123. In yet another embodiment, at least one of R. R. about 10%, no less than about 20%, no less than about 50%, R. R. Rs. R. R-7, Rs, and R is deuterium; and Ro, R. R. no less than about 70%, no less than about 80%, no less than Ris. R14, R1s. R16, R17, R1s. R19, R20. R2, R22, R23, R24. R2s. about 90%, or no less than about 98%. R26, R27, R2s, R29. Rso Rs1, R32, and Rss are hydrogen. 0097. In yet another embodiment, at least one of R. R. 0.124. In yet another embodiment, R. R. R. R. R. R. R. R. Rs, and R is deuterium. R-7, Rs, and Ro are deuterium; and Rio R, R2, R. R. 0098. In yet another embodiment, R. R. R. R. Rs, and R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27. Rare deuterium. R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. 0099. In yet another embodiment, at least one of R7, Rs. I0125. In yet another embodiment, Ro and R are deute and R is deuterium. rium; and R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, R1, R12, R1s. 0100. In yet another embodiment, R-7, Rs, and R are deu R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R2s, R2s, R26, R27. terium. R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. 0101. In yet another embodiment, at least one of R. R. I0126. In yet another embodiment, at least one of R and R. R. Rs. R. R-7, Rs, and Ro is deuterium. R is deuterium; and R. R. R. R. Rs. R. R7, Rs. R. Rio, 0102) In yet another embodiment, R. R. R. R. R. R. Ris. R14. R1s. R16. R17, R18, R19. R20. R21. R22. R2s. R24. R2s. R7, Rs, and Ro are deuterium. R26, R27, R2s, R29. Rso Rs1, R32, and Rss are hydrogen. 0103) In yet another embodiment, Ro and R are deute I0127. In yet another embodiment, R and R are deute rium. rium; and R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, Rs. R14, 0104. In yet another embodiment, at least one of R and Rs. R16. R17. R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. R is deuterium. R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. 0105. In yet another embodiment, R and R are deute I0128. In yet another embodiment, at least one of R. R. rium. Rs. R. R.17, Rs. Rio, and R2 is deuterium; and R, R2, Rs. 0106. In yet another embodiment, at least one of R. R. R4: Rs. Rs. R7, Rs. Ro, Rio, R1, R12, R2, R22, R2s, R24. R2s. Rs. R16, R17, Ris, R19, and R20 is deuterium. R26, R27, R2s, R29. Rso Rs1, R32, and Rss are hydrogen. 0107. In yet another embodiment, R. R. R. R. R7. 0129. In yet another embodiment, R. R. R. R. R7. Rs. Rio, and Rao are deuterium. Rs. Rio, and Ro are deuterium; and R. R. R. R. Rs. R. 0108. In yet another embodiment, at least one of R and R7, Rs. Ro. Rio, R1, R12, R2, R22, R2s, R24. R2s, R26, R27. R, is deuterium. R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. 0109. In yet another embodiment, R and R are deute I0130. In yet another embodiment, at least one of R and rium. R, is deuterium; and R. R. R. R. Rs. Rs. R-7, Rs. Ro, Rio, R11, R12, R13, R14, R1s. R16, R17, Ris, R19, R20 R23, R24. R2s. 0110. In yet another embodiment, R is deuterium. R26, R27, R2s, R29, Rso Rs1, R32, and Ras are hydrogen. 0111. In yet another embodiment, at least one of Rs and I0131. In yet another embodiment, R and R are deute R is deuterium. rium; and R, R2, R. R. Rs. R. R7, Rs. Ro, Rio, R1, R12, 0112 In yet another embodiment, Ras and R2 are deute Ris. R14, R1s. R16, R17, R1s. R19, R20. R23, R24. R2s, R26, R27. rium. R2s, Rao, Rao, Rs 1, R32, and Ras are hydrogen. 0113. In yet another embodiment, at least one of R. R. 0.132. In yet another embodiment, R is deuterium; and R2s, R2s, and R2 is deuterium. R1, R2, R. R. Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, 0114. In yet another embodiment, R. R. R. Ras, and R1s. R16, R17, Ris, R19, R20. R21, R22, R24. R2s, R26, R27, R2s. Rare deuterium. R29. Rao Rs1, R32, and Ras are hydrogen. 0115. In yet another embodiment, at least one of R-7, Rs. I0133. In yet another embodiment, at least one of Rs and R29, and Rao is deuterium. R is deuterium; and R. R. R. R. Rs. R. R7, Rs. Ro, Rio, 0116. In yet another embodiment, R-7, Rs. Ro, and Rio R11, R12, R1s. R14, R1s. R16, R17, Ris, R19, R20. R21, R22, R2s. are deuterium. R24, R27, R2s, R29, Rso Rs1, R32, and Ras are hydrogen. 0117. In yet another embodiment, at least one of R. R. 0.134. In yet another embodiment, Ras and R2 are deute and R is deuterium. rium; and R, R2, R. R. Rs. R. R7, Rs. Ro, Rio, R1, R12, 0118. In yet another embodiment, R, R2, and Rs are Ris. R14, R1s. R16, R17, R1s. R19, R20. R2, R22, R23, R24. R27. deuterium. R2s, R29. Rao, Rs 1, R32, and Ras are hydrogen. 0119. In yet another embodiment, at least one of R. R. I0135) In yet another embodiment, at least one of R. R. R. R. Rs, and R is deuterium; and R-7, Rs. Ro, Rio, R1, R12, R2, R2s and R2 is deuterium; and R, R2, R. R. Rs. R. R-7, US 2008/0312247 A1 Dec. 18, 2008

Rs. R9. Rio. R11, R12. Ris. R14. R1s. R16. R17, R1s. R19. R20. ments, R is deuterium. In yet other embodiments, R2s is R24, R27, R2s, R29, Rso Rs1, R32, and Ras are hydrogen. deuterium. In yet other embodiments, R is deuterium. In yet 0136. In yet another embodiment, R. R. R. R.2s and other embodiments, R, is deuterium. In yet other embodi Rare deuterium; and R. R. R. R. Rs. R. R7, Rs. R. Rio, ments, Rs is deuterium. In yet other embodiments, Rao is R11, R12, R1s. R14, R1s. R16, R17, Ris, R19, R20. R24. R27, R2s. R29. Rao, Rs 1, R32, and Ras are hydrogen. deuterium. In yet other embodiments, Ro is deuterium. In yet I0137 In yet another embodiment, at least one of R, Rs. other embodiments, R is deuterium. In yet other embodi R29, and Rao is deuterium; and R, R2, Rs. R. Rs. R. R-7, Rs. ments, R is deuterium. In yet other embodiments, R is Ro. Rio R ls R12, Rs. R14. Rs. R16. R17. R1s. R19. R20. R21. deuterium. R22, R2s, R24, R2s, R26, R31, R32, and Ras are hydrogen. 0143. In yet another embodiment, the compound of For 0138. In yet another embodiment, R-7, Ras, Ro, and Rio mula I is selected from the group consisting of are deuterium; and R. R. R. R. Rs. R. R-7, Rs. Ro Ro, R11, R12, R1s. R14, R1s. R16, R17, Ris, R19, R20. R21, R22, R2s. R2, R2s, R26, R3, R32, and Ras are hydrogen. 0.139. In yet another embodiment, at least one of R. R. and Rs is deuterium; and R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio R11, R12, Rs. R14. Rs. R16. R17. R1s. R19. R20. R21. R22. R2s, R24. R2s, R26, R27, R2s, R29, and Rao are hydrogen. 0140. In yet another embodiment, R, R2, and Rs are deuterium; and R, R2, R. R. Rs. R. R-7, Rs. Ro, Rio, R. R12, R13, R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. ser) R2s, R2, R27, R2s, Rao, and Rao are hydrogen. 0141. In other embodiments, R is hydrogen. In yet other embodiments, R is hydrogen. In still other embodiments, R. is hydrogen. In yet other embodiments, R is hydrogen. In Some embodiments, Rs is hydrogen. In yet other embodi ments, R is hydrogen. In still other embodiments, R, is hydrogen. In still other embodiments, Rs is hydrogen. In some embodiments, R is hydrogen. In other embodiments, cer) Rishydrogen. In yet other embodiments, R is hydrogen. In still other embodiments, R is hydrogen. In yet other embodiments, R is hydrogen. In other embodiments, R is hydrogen. In certain embodiments, Ris is hydrogen. In other embodiments, R is hydrogen. In yet other embodiments, R is hydrogen. In some embodiments, Ris is hydrogen. In other embodiments, R is hydrogen. In yet other embodi ments, Ro is hydrogen. In yet other embodiments, R is ser) hydrogen. In yet other embodiments, R is hydrogen. In yet other embodiments, R is hydrogen. In yet other embodi ments, R is hydrogen. In yet other embodiments, R2s is hydrogen. In yet other embodiments, R is hydrogen. In yet other embodiments, R-7 is hydrogen. In yet other embodi ments, R2s is hydrogen. In yet other embodiments, Ro is hydrogen. In yet other embodiments, Ro is hydrogen. In yet other embodiments, R is hydrogen. In yet other embodi ments, R is hydrogen. In yet other embodiments, R is hydrogen. 0142. In other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In still other embodiments, R. is deuterium. In yet other embodiments, R is deuterium. In some embodiments. Rs is deuterium. In yet other embodi ments, R is deuterium. In still other embodiments, R, is deuterium. In still other embodiments, R is deuterium. In Some embodiments, Ro is deuterium. In other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In still other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In other embodiments, R is deuterium. In certain embodiments. Rs is deuterium. In other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In some embodiments, Ris is deuterium. In other embodiments, R is deuterium. In yet other embodi ments, Ro is deuterium. In yet other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In yet other embodiments, R is deuterium. In yet other embodi US 2008/0312247 A1 Dec. 18, 2008

-continued -continued

DC OH No OH DCN, CD3 N-- N O D NH -1 r: ^{ D D O O D CD3 D D D

OH No OH DCN, N O H NH -p-1 CD3 N-X

ill--1-X.O c O D CD OH No D OH No N-i- O N CD 's 1 D O DC OH No OH No N O NH | p-1 CD3 N-in 's D-1 D O I O N D3CN CD OH DC* no

O CD3 O OH No DC OH No H D-1. N-k H D Nr. - D D N D O D r N O D CD OH No OH No US 2008/0312247 A1 Dec. 18, 2008 10

-continued -continued

OH No OH No CD3 N-in- N O D NH 11 D D NH D r: ^{ D D O O D CD D D D DC OH No 3- N OH O CD3 N O N - O D - N - I-16 D NH I-1 D N D D

r: D CD O O D D D DC OH No

CD O DC OH 3 No OH No

D-1JN D O CD3 NH 1 Sk r D D r D D O O CD DC n DC OH O OH No

US 2008/0312247 A1 Dec. 18, 2008 12

-continued -continued OH No N CD3 N O OH O C r D D --- if Y if Y CD." O OH PCS,

US 2008/0312247 A1 Dec. 18, 2008 14

-continued -continued

OH No OH No

D NH 1 D D N-in N D D N O O CD3 D D D OH No DC OH No CD3 D D N-in D NH y D-11 N-X D X. Np1 Y1. r N D D O O CD D D DC DC OH * no OH No CD3 D D N O D D N-in N D NH D-1. D X. D-1 D r N D D O O CD D D OH No

CD3 H D D - N-in D N D N O D CD3 D OH No

D D N O

N D D

O OH No

CD3 D D N O

ND1 D D D

O CD3 DC OH No

US 2008/0312247 A1 Dec. 18, 2008 17

-continued -continued DC OH No DC OH No D NH p-1 D D CD3 NH D D p1- XD N D D D D N D D O D O D CD3 D DC D OH No

OH No D NH 1 D N D D D D

H O N y-axxp-1 D D CD N D D D D D O or a pharmaceutically acceptable salt, Solvate, or prodrug OH No thereof. CD3 0144. In another embodiment, at least one of the positions NH D t-ixxp-1 D represented as D independently has deuterium enrichment of N D D D D 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%, O no less than about 70%, no less than about 80%, no less than CD3 about 90%, or no less than about 98%. DC 0145. In a further embodiment, said compound is substan OH No tially a single enantiomer, a mixture of about 90% or more by weight of the (-)-enantiomerandabout 10% or less by weight H of the (+)-enantiomer, a mixture of about 90% or more by N D t-ixxp-1 D weight of the (+)-enantiomerandabout 10% or less by weight N D D D D of the (-)-enantiomer, Substantially an individual diastere O omer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of DC any other diastereomer. OH No 0146 In certain embodiments, the compound as disclosed CD3 herein contains about 60% or more by weight of the (-)- H enantiomer of the compound and about 40% or less by weight N D t-ixxp-1 D of (+)-enantiomer of the compound. In certain embodiments, N D D D D the compound as disclosed herein contains about 70% or O more by weight of the (-)-enantiomer of the compound and CD about 30% or less by weight of (+)-enantiomer of the com pound. In certain embodiments, the compound as disclosed OH No herein contains about 80% or more by weight of the (-)- D D N O 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 XC-9 xx r more by weight of the (-)-enantiomer of the compound and O about 10% or less by weight of the (+)-enantiomer of the compound. In certain embodiments, the compound as dis closed herein contains about 95% or more by weight of the (-)-enantiomer of the compound and about 5% or less by OH No weight of (+)-enantiomer of the compound. In certain CD3 D D N O 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 XC-9 xx r) of the compound. O 0.147. In certain embodiments, the compound as disclosed CD herein contains about 60% or more by weight of the (+)- enantiomer of the compound and about 40% or less by weight of (-)-enantiomer of the compound. In certain embodiments, US 2008/0312247 A1 Dec. 18, 2008 18 the compound as disclosed herein contains about 70% or decreasing the non-mechanism-related toxicity, and/or low more by weight of the (+)-enantiomer of the compound and ering the probability of drug-drug interactions. about 30% or less by weight of (-)-enantiomer of the com 0150. Isotopic hydrogen can be introduced into a com pound of a compound disclosed herein as disclosed herein by pound. In certain embodiments, the compound as disclosed synthetic techniques that employ deuterated reagents, herein contains about 80% or more by weight of the (+)- whereby incorporation rates are pre-determined; and/or by enantiomer of the compound and about 20% or less by weight exchange techniques, wherein incorporation rates are deter of (-)-enantiomer of the compound. In certain embodiments, mined by equilibrium conditions, and may be highly variable the compound as disclosed herein contains about 90% or depending on the reaction conditions. Synthetic techniques, more by weight of the (+)-enantiomer of the compound and where tritium or deuterium is directly and specifically about 10% or less by weight of the (-)-enantiomer of the inserted by tritiated or deuterated reagents of known isotopic compound. In certain embodiments, the compound as dis content, may yield high tritium or deuterium abundance, but closed herein contains about 95% or more by weight of the can be limited by the chemistry required. In addition, the (+)-enantiomer of the compound and about 5% or less by molecule being labeled may be changed, depending upon the severity of the synthetic reaction employed. Exchange tech weight of (-)-enantiomer of the compound. In certain niques, on the other hand, may yield lower tritium or deute embodiments, the compound as disclosed herein contains rium incorporation, often with the isotope being distributed about 99% or more by weight of the (+)-enantiomer of the over many sites on the molecule, but offer the advantage that compound and about 1% or less by weight of (-)-enantiomer they do not require separate synthetic steps and are less likely of the compound. to disrupt the structure of the molecule being labeled. 0148. The deuterated compound as disclosed herein may 0151. The compounds as disclosed herein can be prepared also contain less prevalent isotopes for other elements, by methods known to one of skill in the art and routine including, but not limited to, C or ''C for carbon, 'N for modifications thereof, and/or following procedures similar to nitrogen, and ''O or 'O for oxygen. those described in the Example section herein and routine 0149. In one embodiment, the deuterated compounds dis modifications thereof, and/or procedures found in U.S. Pat. closed herein maintain the beneficial aspects of the corre No. 4,567,264 and WO2006/008753, and references cited sponding non-isotopically enriched molecules while Substan therein and routine modifications thereof. Compounds as dis tially increasing the maximum tolerated dose, decreasing closed herein can also be prepared as shown in any of the toxicity, increasing the half-life (T), lowering the maxi following schemes and routine modifications thereof. mum plasma concentration (C) of the minimum effica 0152 For example, certain compounds as disclosed herein cious dose (MED), lowering the efficacious dose and thus can be prepared as shown in Scheme 1.

Scheme 1 R26 O, R22 R 31 R32 R R25 R21 y4 R. R6 5 R4 C R23 O 2 9, R R 30 R NH o R16 H R20 9 2 ------N R11 R12 R5 R15 R19 R R R22 R3. R R29 C 33 R32 25 26 R14 N R17 C. Rs R 2 R31 R27 is R13 H R18 O R R3 O 3 4 6 7 R30 HO R29 R7 R28 1 R3 R32 R15 R14 R >{ R16 R13 R6 5 R4 R11 R-12 O R33 HO Rs C H R30 O N NH R9 N -- O R26 R25 R22 R21 R R39 R27 R20 R18 Rs R19 R17 R2 R28 US 2008/0312247 A1 Dec. 18, 2008 19

-continued R31 R32 R15 R14 -X As R16 R13 Rs O R33 C. R. R12 R11 R10 R4 R6 R30 X^X- N Ro R39 R25 R22 R21 2 . OR R19 R17 R Rs R28 2 R3 R

0153 Methoxyphenol 1 reacts with epichlorohydrin 2 in York, 1994, pp. 1119-1190. Such chiral centers, chiral axes, the presence of a base. Such as Sodium hydroxide, and in an and chiral planes may be of either the (R) or (S) configuration, appropriate solvent, such as water and dioxane or mixture or may be a mixture thereof. thereof, at an elevated temperature to afford oxirane 3, which 0157 Another method for characterizing a composition reacts with piperazine 4 in an appropriate solvent, such as containing a compound having at least one chiral center is by methanol, to give amino alcohol 5. Acid chloride 6 reacts with the effect of the composition on a beam of polarized light. aniline 7 in the presence of a base, such as triethylamine, and When a beam of plane polarized light is passed through a in an appropriate solvent. Such as dichloromethane, to give Solution of a chiral compound, the plane of polarization of the amide 8, which reacts with compound 5 in the presence of an light that emerges is rotated relative to the original plane. This appropriate catalyst, Such as sodium iodide or potassium phenomenon is known as optical activity, and compounds that iodide, a base, such as potassium carbonate, in an appropriate rotate the plane of polarized light are said to be optically solvent, such as dimethylformamide, to afford piperazine 9 of active. One enantiomer of a compound will rotate the beam of Formula I. polarized light in one direction, and the other enantiomer will rotate the beam of light in the opposite direction. The enan 0154 Deuterium can be incorporated to different posi tiomer that rotates the polarized light in the clockwise direc tions synthetically, according to the synthetic procedures as tion is the (+) enantiomer, and the enantiomer that rotates the shown in Scheme 1, by using appropriate deuterated interme polarized light in the counterclockwise direction is the (-) diates. For example, to introduce deuterium at one or more enantiomer. Included within the scope of the compositions positions selected from R. R. R. R. R. R. R. Rs, and Ro, described herein are compositions containing between 0 and 2,6-dimethylaniline with the corresponding deuterium sub 100% of the (+) and/or (-) enantiomer of compounds dis stitutions can be used. To introduce deuterium at one or more closed herein. positions selected from R and R2, chloroacetyl chloride 0158 Where a compound as disclosed herein contains an with the corresponding deuterium Substitutions can be used. alkenyl or alkenylene group, the compound may exist as one To introduce deuterium at one or more positions of R. R. or mixture of geometric cis/trans (or Z/E) isomers. Where Rs. R. R.17, Rs. Rio, and Rao, piperazine with the corre structural isomers are interconvertible via a low energy bar sponding deuterium Substitutions can be used. To introduce rier, the compound disclosed herein may exist as a single deuterium at one or more positions of R2, R22, R2, R2s, and tautomer or a mixture of tautomers. This can take the form of R epichlorohydrin with the corresponding deuterium Sub proton tautomerism in the compound disclosed herein that stitutions can be used. To introduce deuterium at one or more contains for example, an imino, keto, or Oxime group; or positions of R27, R2s, Rao, Rao, Rs. R-2, and Rs. 2-methoX so-called Valence tautomerism in the compound that contain yphenol with the corresponding deuterium Substitutions can an aromatic moiety. It follows that a single compound may be used. These deuterated intermediates are either commer exhibit more than one type of isomerism. cially available, or can be prepared by methods known to one 0159. The compounds disclosed herein may be enantio of skill in the art or following procedures similar to those merically pure. Such as a single enantiomer or a single dias described in the Example section herein and routine modifi tereomer, or be stereoisomeric mixtures, such as a mixture of cations thereof. enantiomers, a racemic mixture, or a diastereomeric mixture. As such, one of skill in the art will recognize that administra 0155 Deuterium can also be incorporated to various posi tion of a compound in its (R) form is equivalent, for com tions having an exchangeable proton, such as the amine and pounds that undergo epimerization in Vivo, to administration hydroxyl protons, via proton-deuterium equilibrium of the compound in its (S) form. Conventional techniques for exchange. To introduce deuterium at Ro and R, these pro the preparation/isolation of individual enantiomers include tons may be replaced with deuterium selectively or non chiral synthesis from a Suitable optically pure precursor or selectively through a proton-deuterium exchange method resolution of the racemate using, for example, chiral chroma known in the art. tography, recrystallization, resolution, diastereomeric salt 0156. It is to be understood that the compounds disclosed formation, or derivatization into diastereomeric adducts fol herein may contain one or more chiral centers, chiral axes, lowed by separation. and/or chiral planes, as described in "Stereochemistry of Car 0160. When the compound disclosed herein contains an bon Compounds' Eliel and Wilen, John Wiley & Sons, New acidic or basic moiety, it may also disclosed as a pharmaceu US 2008/0312247 A1 Dec. 18, 2008 20 tically acceptable salt (See, Berge et al., J. Pharm. Sci. 1977, gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, 66, 1-19; and “Handbook of Pharmaceutical Salts, Properties, 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997,27, and Use.” Stah and Wermuth, Ed.; Wiley-VCH and VHCA, 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; Zurich, 2002). Gaignault et al., Pract. Med. Chem. 1996, 671-696; 0161 Suitable acids for use in the preparation of pharma Asgharnejad in “Transport Processes in Pharmaceutical Sys ceutically acceptable salts include, but are not limited to, tems. Amidon et al., Ed., Marcell Dekker, 185-218, 2000; acetic acid, 2,2-dichloroacetic acid, acylated amino acids, Balant et al., Eur: J. Drug Metab. Pharmacokinet. 1990, 15, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, ben 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, Zenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 39, 183-209: Browne, Clin. Neuropharmacol. 1997, 20, 1-12; boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, (1S)-camphor-10-Sulfonic acid, capric acid, caproic acid, Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclo Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug hexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disul Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods fonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. acid, formic acid, fumaric acid, galactaric acid, gentisic acid, 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. glucoheptonic acid, D-gluconic acid, D-glucuronic acid, Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. L-glutamic acid, C-OXO-glutaric acid, glycolic acid, hippuric Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and (+)-L-lactic acid, (t)-DL-lactic acid, lactobionic acid, lauric Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. acid, maleic acid, (-)-L-malic acid, malonic acid, (+)-DL Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naph 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 thoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, 148; Valentino and Borchardt, Drug Discovery Today 1997.2, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phos 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, phoric acid, L-pyroglutamic acid, Saccharic acid, salicylic 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, acid, 4-amino-salicylic acid, sebacic acid, Stearic acid, suc 497-507. cinic acid, Sulfuric acid, tannic acid, (+)-L-tartaric acid, thio cyanic acid, p-toluenesulfonic acid, undecylenic acid, and Pharmaceutical Composition Valeric acid. 0164 Disclosed herein are pharmaceutical compositions 0162 Suitable bases for use in the preparation of pharma comprising a compound as disclosed herein, or a pharmaceu ceutically acceptable salts, including, but not limited to, inor tically acceptable salt, Solvate, or prodrug thereof, as an active ganic bases, such as magnesium hydroxide, calcium hydrox ingredient, combined with a pharmaceutically acceptable ide, potassium hydroxide, Zinc hydroxide, or sodium vehicle, carrier, diluent, or excipient, or a mixture thereof; in hydroxide; and organic bases, such as primary, secondary, combination with one or more pharmaceutically acceptable tertiary, and quaternary, aliphatic and aromatic amines, excipients or carriers. including L-arginine, benethamine, benzathine, choline, 0.165 Disclosed herein are pharmaceutical compositions deanol, diethanolamine, diethylamine, dimethylamine, in modified release dosage forms, which comprise a com dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, pound as disclosed herein, or a pharmaceutically acceptable ethanolamine, ethylamine, ethylenediamine, isopropy salt, Solvate, or prodrug thereof, and one or more release lamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, controlling excipients or carriers as described herein. Suitable L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, modified release dosage vehicles include, but are not limited methylamine, piperidine, piperazine, propylamine, pyrroli to, hydrophilic or hydrophobic matrix devices, water-soluble dine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, separating layer coatings, enteric coatings, osmotic devices, quinoline, isoquinoline, secondary amines, triethanolamine, multiparticulate devices, and combinations thereof. The phar trimethylamine, triethylamine, N-methyl-D-glucamine, maceutical compositions may also comprise non-release con 2-amino-2-(hydroxymethyl)-1,3-propanediol. and trolling excipients or carriers. tromethamine. 0166 Further disclosed herein are pharmaceutical compo 0163 The compound as disclosed herein may also be sitions in enteric coated dosage forms, which comprise a designed as a prodrug, which is a functional derivative of the compound as disclosed herein, or a pharmaceutically accept compound as disclosed herein and is readily convertible into able salt, Solvate, or prodrug thereof, and one or more release the parent compound in vivo. Prodrugs are often useful controlling excipients or carriers for use in an enteric coated because, in Some situations, they may be easier to administer dosage form. The pharmaceutical compositions may also than the parent compound. They may, for instance, be bio comprise non-release controlling excipients or carriers. available by oral administration whereas the parent com 0.167 Further disclosed herein are pharmaceutical compo pound is not. The prodrug may also have enhanced solubility sitions in effervescent dosage forms, which comprise a com in pharmaceutical compositions over the parent compound. A pound as disclosed herein, or a pharmaceutically acceptable prodrug may be converted into the parent drug by various salt, Solvate, or prodrug thereof, and one or more release mechanisms, including enzymatic processes and metabolic controlling excipients or carriers for use in an effervescent hydrolysis. See Harper, Progress in Drug Research 1962, 4, dosage form. The pharmaceutical compositions may also 221-294; Morozowich etal. in “Design of Biopharmaceutical comprise non-release controlling excipients or carriers. Properties through Prodrugs and Analogs. Roche Ed., 0168 Additionally disclosed are pharmaceutical compo APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers in sitions in a dosage form that has an instant releasing compo Drug in Drug Design, Theory and Application. Roche Ed., nent and at least one delayed releasing component, and is APHA Acad. Pharm. Sci. 1987: “Design of Prodrugs.” Bund capable of giving a discontinuous release of the compound in US 2008/0312247 A1 Dec. 18, 2008

the form of at least two consecutive pulses separated in time patient being treated, and may be determined empirically from 0.1 up to 24 hours. The pharmaceutical compositions using known testing protocols or by extrapolation from in comprise a compound as disclosed herein, or a pharmaceuti vivo or in vitro test or diagnostic data. It is further understood cally acceptable salt, Solvate, or prodrug thereof, and one or that for any particular individual, specific dosage regimens more release controlling and non-release controlling excipi should be adjusted over time according to the individual need ents or carriers, such as those excipients or carriers suitable and the professional judgment of the person administering or for a disruptable semi-permeable membrane and as swellable Supervising the administration of the formulations. Substances. 0169 Disclosed herein also are pharmaceutical composi 0.174. In the case wherein the patient's condition does not tions in a dosage form for oral administration to a subject, improve, upon the doctor's discretion the administration of which comprise a compound as disclosed herein, or a phar the compounds may be administered chronically, that is, for maceutically acceptable salt, Solvate, or prodrug thereof, and an extended period of time, including throughout the duration one or more pharmaceutically acceptable excipients or carri of the patient's life in order to ameliorate or otherwise control ers, enclosed in an intermediate reactive layer comprising a or limit the symptoms of the patient's disease or condition. gastric juice-resistant polymeric layered material partially 0.175. In the case wherein the patient's status does neutralized with alkali and having cation exchange capacity improve, upon the doctor's discretion the administration of and a gastric juice-resistant outer layer. the compounds may be given continuously or temporarily 0170 Disclosed herein are pharmaceutical compositions Suspended for a certain length of time (i.e., a "drug holiday'). that comprise about 0.1 to about 1000 mg, about 1 to about 0176 Once improvement of the patient's conditions has 500 mg, about 2 to about 100 mg, about 1 mg, about 2 mg, occurred, a maintenance dose is administered if necessary. about 3 mg, about 5 mg, about 10 mg, about 20 mg, about 30 Subsequently, the dosage or the frequency of administration, mg, about 40 mg, about 50 mg, about 100 mg, about 500 mg of one or more compounds as disclosed herein in the form of or both, can be reduced, as a function of the symptoms, to a extended-release tablet, and contains the following inactive level at which the improved disease, disorder or condition is ingredients: dibasic calcium phosphate (anhydrous), hydrox retained. Patients can, however, require intermittent treat ypropyl methylcellulose (hypromellose), lactose monohy ment on a long-term basis upon any recurrence of symptoms. drate, magnesium Stearate, titanium dioxide and triacetin. 0171 The pharmaceutical compositions disclosed herein A. Oral Administration may be disclosed in unit-dosage forms or multiple-dosage 0177. The pharmaceutical compositions disclosed herein forms. Unit-dosage forms, as used herein, refer to physically may beformulated in Solid, semisolid, or liquid dosage forms discrete units Suitable for administration to human and animal for oral administration. As used herein, oral administration Subjects and packaged individually as is known in the art. also include buccal, lingual, and Sublingual administration. Each unit-dose contains a predetermined quantity of the Suitable oral dosage forms include, but are not limited to, active ingredient(s) sufficient to produce the desired thera tablets, capsules, pills, troches, lozenges, pastilles, cachets, peutic effect, in association with the required pharmaceutical pellets, medicated chewing gum, granules, bulk powders, carriers or excipients. Examples of unit-dosage forms include effervescent or non-effervescent powders or granules, solu ampouls, Syringes, and individually packaged tablets and tions, emulsions, Suspensions, Solutions, wafers, sprinkles, capsules. Unit-dosage forms may be administered in frac elixirs, and syrups. In addition to the active ingredient(s), the tions or multiples thereof. A multiple-dosage form is a plu pharmaceutical compositions may contain one or more phar rality of identical unit-dosage forms packaged in a single maceutically acceptable carriers or excipients, including, but container to be administered in segregated unit-dosage form. not limited to, binders, fillers, diluents, disintegrants, wetting Examples of multiple-dosage forms include vials, bottles of agents, lubricants, glidants, coloring agents, dye-migration tablets or capsules, or bottles of pints or gallons. inhibitors, Sweetening agents, and flavoring agents. 0172. The compound as disclosed herein may be admin 0.178 Binders or granulators impart cohesiveness to a tab istered alone, or in combination with one or more other com let to ensure the tablet remaining intact after compression. pounds disclosed herein, one or more otheractive ingredients. Suitable binders or granulators include, but are not limited to, The pharmaceutical compositions that comprise a compound starches, such as corn Starch, potato starch, and pre-gelati disclosed herein may be formulated in various dosage forms nized starch (e.g., STARCH 1500); gelatin: sugars, such as for oral, parenteral, and topical administration. The pharma Sucrose, glucose, dextrose, molasses, and lactose; natural and ceutical compositions may also be formulated as a modified Synthetic gums, such as acacia, alginic acid, alginates, extract release dosage form, including delayed-, extended-, pro of Irish moss, Panwar gum, ghatti gum, mucilage of isabgol longed-, Sustained-, pulsatile-, controlled-, accelerated- and husks, carboxymethylcellulose, methylcellulose, polyvi fast-, targeted-, programmed-release, and gastric retention nylpyrrolidone (PVP), Veegum, larch arabogalactan, pow dosage forms. These dosage forms can be prepared according dered tragacanth, and guar gum, celluloses, such as ethyl to conventional methods and techniques known to those cellulose, cellulose acetate, carboxymethyl cellulose cal skilled in the art (see, Remington. The Science and Practice of cium, Sodium carboxymethyl cellulose, methyl cellulose, Pharmacy, supra; Modified-Release Drug Deliver Technol hydroxyethylcellulose (HEC), hydroxypropylcellulose ogy, Rathbone et al., Eds. Drugs and the Pharmaceutical (HPC), hydroxypropyl methylcellulose (HPMC); microcrys Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. talline celluloses, such as AVICEL-PH-101, AVICEL-PH 126). 103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Mar 0173 The pharmaceutical compositions disclosed herein cus Hook, Pa.); and mixtures thereof. Suitable fillers include, may be administered at once, or multiple times at intervals of but are not limited to, talc, calcium carbonate, microcrystal time. It is understood that the precise dosage and duration of line cellulose, powdered cellulose, dextrates, kaolin, manni treatment may vary with the age, weight, and condition of the tol, silicic acid, Sorbitol, Starch, pre-gelatinized starch, and US 2008/0312247 A1 Dec. 18, 2008 22 mixtures thereof. The binder or filler may be present from col monostearate, Sorbitan monooleate, diethylene glycol about 50 to about 99% by weight in the pharmaceutical com monolaurate, and polyoxyethylene lauryl ether. Solvents positions disclosed herein. include glycerin, Sorbitol, ethyl alcohol, and syrup. Examples 0179 Suitable diluents include, but are not limited to, of non-aqueous liquids utilized in emulsions include mineral dicalcium phosphate, calcium sulfate, lactose, Sorbitol, oil and cottonseed oil. Organic acids include citric and tartaric Sucrose, inositol, cellulose, kaolin, mannitol, Sodium chlo acid. Sources of carbon dioxide include sodium bicarbonate ride, dry starch, and powdered Sugar. Certain diluents, such as and sodium carbonate. mannitol, lactose, Sorbitol. Sucrose, and inositol, when 0183. It should be understood that many carriers and present in Sufficient quantity, can impart properties to some excipients may serve several functions, even within the same compressed tablets that permit disintegration in the mouth by formulation. chewing. Such compressed tablets can be used as chewable 0.184 The pharmaceutical compositions disclosed herein tablets. may be formulated as compressed tablets, tablet triturates, 0180 Suitable disintegrants include, but are not limited to, chewable lozenges, rapidly dissolving tablets, multiple com agar, bentonite; celluloses. Such as methylcellulose and car pressed tablets, or enteric-coating tablets, Sugar-coated, or boxymethylcellulose; wood products; natural sponge; cation film-coated tablets. Enteric-coated tablets are compressed exchange resins; alginic acid: gums, such as guar gum and tablets coated with substances that resist the action of stom Veegum HV. citrus pulp, cross-linked celluloses, such as ach acid but dissolve or disintegrate in the intestine, thus croScarmellose; cross-linked polymers, such as crospovi protecting the active ingredients from the acidic environment done; cross-linked Starches; calcium carbonate; microcrys of the stomach. Enteric-coatings include, but are not limited talline cellulose, Such as sodium starch glycolate; polacrilin to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammo potassium; Starches, such as corn starch, potato starch, tapi niated shellac, and cellulose acetate phthalates. Sugar-coated oca starch, and pre-gelatinized starch; clays; aligns; and mix tablets are compressed tablets Surrounded by a Sugar coating, tures thereof. The amount of disintegrant in the pharmaceu which may be beneficial in covering up objectionable tastes tical compositions disclosed herein varies upon the type of or odors and in protecting the tablets from oxidation. Film formulation, and is readily discernible to those of ordinary coated tablets are compressed tablets that are covered with a skill in the art. The pharmaceutical compositions disclosed thin layer or film of a water-soluble material. Film coatings herein may contain from about 0.5 to about 15% or from include, but are not limited to, hydroxyethylcellulose, sodium about 1 to about 5% by weight of a disintegrant. carboxymethylcellulose, polyethylene glycol 4000, and cel 0181 Suitable lubricants include, but are not limited to, lulose acetate phthalate. Film coating imparts the same gen calcium Stearate; magnesium Stearate; mineral oil; light min eral characteristics as Sugar coating. Multiple compressed eral oil; glycerin; Sorbitol; mannitol; glycols, such as glycerol tablets are compressed tablets made by more than one com behenate and polyethylene glycol (PEG); stearic acid; pression cycle, including layered tablets, and press-coated or Sodium lauryl Sulfate; talc, hydrogenated vegetable oil, dry-coated tablets. including peanut oil, cottonseed oil, Sunflower oil, Sesame oil, 0185. The tablet dosage forms may be prepared from the olive oil, corn oil, and soybean oil; Zinc Stearate; ethyl oleate; active ingredient in powdered, crystalline, or granular forms, ethyl laureate; agar, starch, lycopodium; silica or silica gels, alone or in combination with one or more carriers or excipi such as AEROSIL(R) 200 (W.R. Grace Co., Baltimore, Md.) ents described herein, including binders, disintegrants, con and CAB-O-SILR) (Cabot Co. of Boston, Mass.); and mix trolled-release polymers, lubricants, diluents, and/or colo tures thereof. The pharmaceutical compositions disclosed rants. Flavoring and Sweetening agents are especially useful herein may contain about 0.1 to about 5% by weight of a in the formation of chewable tablets and lozenges. lubricant. 0186 The pharmaceutical compositions disclosed herein 0182 Suitable glidants include colloidal silicon dioxide, may be formulated as Soft or hard capsules, which can be CAB-O-SILR) (Cabot Co. of Boston, Mass.), and asbestos made from gelatin, methylcellulose, starch, or calcium algi free talc. Coloring agents include any of the approved, certi nate. The hard gelatin capsule, also known as the dry-filled fied, water soluble FD&C dyes, and water insoluble FD&C capsule (DFC), consists of two sections, one slipping over the dyes Suspended on alumina hydrate, and color lakes and other, thus completely enclosing the active ingredient. The mixtures thereof. A color lake is the combination by adsorp soft elastic capsule (SEC) is a soft, globular shell, such as a tion of a water-soluble dye to a hydrous oxide of a heavy gelatin shell, which is plasticized by the addition of glycerin, metal, resulting in an insoluble form of the dye. Flavoring Sorbitol, or a similar polyol. The Soft gelatin shells may con agents include natural flavors extracted from plants, such as tain a preservative to prevent the growth of microorganisms. fruits, and synthetic blends of compounds which produce a Suitable preservatives are those as described herein, includ pleasant taste sensation, Such as peppermint and methyl sali ing methyl- and propyl-parabens, and Sorbic acid. The liquid, cylate. Sweetening agents include Sucrose, lactose, mannitol, semisolid, and Solid dosage forms disclosed herein may be syrups, glycerin, and artificial Sweeteners, such as saccharin encapsulated in a capsule. Suitable liquid and semisolid dos and aspartame. Suitable emulsifying agents include gelatin, age forms include solutions and Suspensions in propylene acacia, tragacanth, bentonite, and Surfactants, such as poly carbonate, vegetable oils, or triglycerides. Capsules contain oxyethylene sorbitan monooleate (TWEENR 20), polyoxy ing Such solutions can be prepared as described in U.S. Pat. ethylene sorbitan monooleate 80 (TWEENR 80), and trietha Nos. 4.328,245; 4,409.239; and 4.410,545. The capsules may nolamine oleate. Suspending and dispersing agents include also be coated as known by those of skill in the art in order to Sodium carboxymethylcellulose, pectin, tragacanth, Veegum, modify or Sustain dissolution of the active ingredient. acacia, Sodium carbomethylcellulose, hydroxypropyl meth 0187. The pharmaceutical compositions disclosed herein ylcellulose, and polyvinylpyrolidone. Preservatives include may be formulated in liquid and semisolid dosage forms, glycerin, methyl and propylparaben, benzoic add, sodium including emulsions, Solutions, Suspensions, elixirs, and Syr benzoate and alcohol. Wetting agents include propylene gly ups. An emulsion is a two-phase system, in which one liquid US 2008/0312247 A1 Dec. 18, 2008

is dispersed in the form of Small globules throughout another administration, as used herein, include intravenous, intraar liquid, which can be oil-in-water or water-in-oil. Emulsions terial, intraperitoneal, intrathecal, intraventricular, intraure may include a pharmaceutically acceptable non-aqueous liq thral, intrasternal, intracranial, intramuscular, intrasynovial, uids or solvent, emulsifying agent, and preservative. Suspen and Subcutaneous administration. sions may include a pharmaceutically acceptable Suspending 0.195 The pharmaceutical compositions disclosed herein agent and preservative. Aqueous alcoholic solutions may may be formulated in any dosage forms that are suitable for include a pharmaceutically acceptable acetal. Such as a parenteral administration, including solutions, Suspensions, di(lower alkyl)acetal of a lower alkyl aldehyde (the term emulsions, micelles, liposomes, microspheres, nanoSystems, “lower” means an alkyl having between 1 and 6 carbon and Solid forms Suitable for Solutions or Suspensions in liquid atoms), e.g., acetaldehyde diethyl acetal; and a water-mis prior to injection. Such dosage forms can be prepared accord cible solvent having one or more hydroxyl groups, such as ing to conventional methods known to those skilled in the art propylene glycol and ethanol. Elixirs are clear, Sweetened, of pharmaceutical Science (see, Remington. The Science and and hydroalcoholic Solutions. Syrups are concentrated aque Practice of Pharmacy, Supra). ous solutions of a Sugar, for example, Sucrose, and may also 0196. The pharmaceutical compositions intended for contain a preservative. For a liquid dosage form, for example, parenteral administration may include one or more pharma a solution in a polyethylene glycol may be diluted with a ceutically acceptable carriers and excipients, including, but Sufficient quantity of a pharmaceutically acceptable liquid not limited to, aqueous vehicles, water-miscible vehicles, carrier, e.g., water, to be measured conveniently for adminis non-aqueous vehicles, antimicrobial agents or preservatives tration. against the growth of microorganisms, stabilizers, Solubility 0188 Other useful liquid and semisolid dosage forms enhancers, isotonic agents, buffering agents, antioxidants, include, but are not limited to, those containing the active local anesthetics, Suspending and dispersing agents, wetting ingredient(s) disclosed herein, and a dialkylated mono- or or emulsifying agents, complexing agents, sequestering or poly-alkylene glycol, including, 1,2-dimethoxymethane, dig chelating agents, cryoprotectants, lyoprotectants, thickening lyme, triglyme, tetraglyme, polyethylene glycol-350-dim agents, pH adjusting agents, and inert gases. ethyl ether, polyethylene glycol-550-dimethyl ether, polyeth 0.197 Suitable aqueous vehicles include, but are not lim ylene glycol-750-dimethyl ether, wherein 350, 550, and 750 ited to, water, Saline, physiological Saline or phosphate buff refer to the approximate average molecular weight of the ered saline (PBS), sodium chloride injection, Ringers injec polyethylene glycol. These formulations may further com tion, isotonic dextrose injection, sterile water injection, prise one or more antioxidants, such as butylated hydroxy dextrose and lactated Ringers injection. Non-aqueous toluene (BHT), butylated hydroxyanisole (BHA), propyl gal vehicles include, but are not limited to, fixed oils of vegetable late, vitamin E, hydroquinone, hydroxycoumarins, origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, peppermint oil, Safflower oil, Sesame oil, soybean oil, hydro sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, genated vegetable oils, hydrogenated Soybean oil, and thiodipropionic acid and its esters, and dithiocarbamates. medium-chain triglycerides of coconut oil, and palm seed oil. 0189 The pharmaceutical compositions disclosed herein Water-miscible vehicles include, but are not limited to, etha for oral administration may be also formulated in the forms of nol. 1,3-butanediol, liquid polyethylene glycol (e.g., polyeth liposomes, micelles, microspheres, or nanosystems. Micellar ylene glycol 300 and polyethylene glycol 400), propylene dosage forms can be prepared as described in U.S. Pat. No. glycol, glycerin, N-methyl-2-pyrrolidone, dimethylaceta 6,350,458. 0190. The pharmaceutical compositions disclosed herein mide, and dimethylsulfoxide. may be formulated as non-effervescent or effervescent, gran 0198 Suitable antimicrobial agents or preservatives ules and powders, to be reconstituted into a liquid dosage include, but are not limited to, phenols, cresols, mercurials, form. Pharmaceutically acceptable carriers and excipients benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxy used in the non-effervescent granules or powders may include benzates, thimerosal, benzalkonium chloride, benzethonium diluents, Sweeteners, and wetting agents. Pharmaceutically chloride, methyl- and propyl-parabens, and Sorbic acid. Suit acceptable carriers and excipients used in the effervescent able isotonic agents include, but are not limited to, Sodium granules or powders may include organic acids and a source chloride, glycerin, and dextrose. Suitable buffering agents of carbon dioxide. include, but are not limited to, phosphate and citrate. Suitable 0191 Coloring and flavoring agents can be used in all of antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, the above dosage forms. but are not limited to, procaine hydrochloride. Suitable sus 0.192 The pharmaceutical compositions disclosed herein pending and dispersing agents are those as described herein, may be formulated as immediate or modified release dosage including sodium carboxymethylcellulose, hydroxypropyl forms, including delayed-, Sustained, pulsed-, controlled, tar methylcellulose, and polyvinylpyrrolidone. Suitable emulsi geted-, and programmed-release forms. fying agents include those described herein, including poly 0193 The pharmaceutical compositions disclosed herein oxyethylene Sorbitan monolaurate, polyoxyethylene Sorbitan may be co-formulated with other active ingredients which do monooleate 80, and triethanolamine oleate. Suitable seques not impair the desired therapeutic action, or with Substances tering or chelating agents include, but are not limited to that Supplement the desired action, Such as drotrecogin-C. EDTA. Suitable pH adjusting agents include, but are not and hydrocortisone. limited to, Sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are B. Parenteral Administration not limited to, cyclodextrins, including C-cyclodextrin, B-cy 0194 The pharmaceutical compositions disclosed herein clodextrin, hydroxypropyl-f-cyclodextrin, sulfobutylether may be administered parenterally by injection, infusion, or B-cyclodextrin, and sulfobutylether 7-B-cyclodextrin (CAP implantation, for local or systemic administration. Parenteral TISOL(R), CyDex, Lenexa, Kans.). US 2008/0312247 A1 Dec. 18, 2008 24

0199 The pharmaceutical compositions disclosed herein pensions, tinctures, pastes, foams, films, aerosols, irrigations, may be formulated for single or multiple dosage administra sprays, Suppositories, bandages, dermal patches. The topical tion. The single dosage formulations are packaged in an formulation of the pharmaceutical compositions disclosed ampule, a vial, or a syringe. The multiple dosage parenteral herein may also comprise liposomes, micelles, microspheres, formulations must contain an antimicrobial agent at bacterio nanosystems, and mixtures thereof. static or fungistatic concentrations. All parenteral formula 0207 Pharmaceutically acceptable carriers and excipients tions must be sterile, as known and practiced in the art. suitable for use in the topical formulations disclosed herein 0200. In one embodiment, the pharmaceutical composi include, but are not limited to, aqueous vehicles, water-mis tions are formulated as ready-to-use sterile solutions. In cible vehicles, non-aqueous vehicles, antimicrobial agents or another embodiment, the pharmaceutical compositions are preservatives against the growth of microorganisms, stabiliz formulated as sterile dry soluble products, including lyo ers, solubility enhancers, isotonic agents, buffering agents, philized powders and hypodermic tablets, to be reconstituted antioxidants, local anesthetics, Suspending and dispersing with a vehicle prior to use. In yet another embodiment, the agents, wetting or emulsifying agents, complexing agents, pharmaceutical compositions are formulated as ready-to-use sequestering or chelating agents, penetration enhancers, sterile Suspensions. In yet another embodiment, the pharma cryopretectants, lyoprotectants, thickening agents, and inert ceutical compositions are formulated as Sterile dry insoluble gases. products to be reconstituted with a vehicle prior to use. In still 0208. The pharmaceutical compositions may also be another embodiment, the pharmaceutical compositions are administered topically by electroporation, iontophoresis, formulated as ready-to-use sterile emulsions. phonophoresis, Sonophoresis and microneedle or needle-free 0201 The pharmaceutical compositions disclosed herein injection, such as POWDERJECTTM (Chiron Corp., may be formulated as immediate or modified release dosage Emeryville, Calif.), and BIOJECTTM (Bioject Medical Tech forms, including delayed-, Sustained, pulsed-, controlled, tar nologies Inc., Tualatin, Oreg.). geted-, and programmed-release forms. 0209. The pharmaceutical compositions disclosed herein 0202 The pharmaceutical compositions may be formu may be formulated in the forms of ointments, creams, and lated as a Suspension, Solid, semi-solid, or thixotropic liquid, gels. Suitable ointment vehicles include oleaginous or hydro for administration as an implanted depot. In one embodiment, carbon vehicles, including Such as lard, benzoinated lard, the pharmaceutical compositions disclosed herein are dis olive oil, cottonseed oil, and other oils, white petrolatum; persed in a solidinner matrix, which is Surrounded by an outer emulsifiable or absorption vehicles, such as hydrophilic pet polymeric membrane that is insoluble in body fluids but rolatum, hydroxystearin sulfate, and anhydrous lanolin; allows the active ingredient in the pharmaceutical composi water-removable vehicles, such as hydrophilic ointment; tions diffuse through. water-soluble ointment vehicles, including polyethylene gly 0203 Suitable inner matrixes include polymethyl cols of varying molecular weight; emulsion vehicles, either methacrylate, polybutylmethacrylate, plasticized or unplasti water-in-oil (W/O) emulsions or oil-in-water (O/W) emul cized polyvinylchloride, plasticized nylon, plasticized poly sions, including cetyl alcohol, glyceryl monostearate, lano ethyleneterephthalate, natural rubber, polyisoprene, lin, and Stearic acid (see, Remington. The Science and Prac polyisobutylene, polybutadiene, polyethylene, ethylene-vi tice of Pharmacy, supra). These vehicles are emollient but nylacetate copolymers, silicone rubbers, polydimethylsilox generally require addition of antioxidants and preservatives. anes, silicone carbonate copolymers, hydrophilic polymers, 0210 Suitable cream base can be oil-in-water or water-in Such as hydrogels of esters of acrylic and methacrylic acid, oil. Cream vehicles may be water-washable, and contain an collagen, cross-linked polyvinylalcohol, and cross-linked oil phase, an emulsifier, and an aqueous phase. The oil phase partially hydrolyzed polyvinyl acetate. is also called the “internal' phase, which is generally com 0204 Suitable outer polymeric membranes include poly prised of petrolatum and a fatty alcohol Such as cetyl or ethylene, polypropylene, ethylene/propylene copolymers, Stearyl alcohol. The aqueous phase usually, although not nec ethylene/ethyl acrylate copolymers, ethylene/vinylacetate essarily, exceeds the oil phase in Volume, and generally con copolymers, silicone rubbers, polydimethyl siloxanes, neo tains a humectant. The emulsifier in a cream formulation may prene rubber, chlorinated polyethylene, polyvinylchloride, be a nonionic, anionic, cationic, or amphoteric Surfactant. vinylchloride copolymers with vinyl acetate, vinylidene chlo 0211 Gels are semisolid, Suspension-type systems. ride, ethylene and propylene, ionomer polyethylene tereph Single-phase gels contain organic macromolecules distrib thalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl uted substantially uniformly throughout the liquid carrier. alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ter Suitable gelling agents include crosslinked acrylic acid poly polymer, and ethylene/vinyloxyethanol copolymer. mers, such as carbomers, carboxypolyalkylenes, Carbopol R; hydrophilic polymers, such as polyethylene oxides, polyoxy C. Topical Administration ethylene-polyoxypropylene copolymers, and polyvinylalco 0205 The pharmaceutical compositions disclosed herein hol; cellulosic polymers, such as hydroxypropyl cellulose, may be administered topically to the skin, orifices, or mucosa. hydroxyethyl cellulose, hydroxypropyl methylcellulose, The topical administration, as used herein, include (intra) hydroxypropyl methylcellulose phthalate, and methylcellu dermal, conjuctival, intracorneal, intraocular, ophthalmic, lose; gums, such as tragacanth and Xanthan gum, Sodium auricular, transdermal, nasal, vaginal, uretheral, respiratory, alginate; and gelatin. In order to prepare a uniform gel, dis and rectal administration. persing agents such as alcohol or glycerin can be added, or the 0206. The pharmaceutical compositions disclosed herein gelling agent can be dispersed by trituration, mechanical mix may be formulated in any dosage forms that are suitable for ing, and/or stirring. topical administration for local or systemic effect, including 0212. The pharmaceutical compositions disclosed herein emulsions, Solutions, Suspensions, creams, gels, hydrogels, may be administered rectally, urethrally, vaginally, or ointments, dusting powders, dressings, elixirs, lotions, Sus perivaginally in the forms of Suppositories, pessaries, bou US 2008/0312247 A1 Dec. 18, 2008

gies, poultices or cataplasm, pastes, powders, dressings, modifier, such as 1-leucine, mannitol, or magnesium Stearate. creams, plasters, contraceptives, ointments, solutions, emul The lactose may be anhydrous or in the form of the monohy Sions, Suspensions, tampons, gels, foams, sprays, or enemas. drate. Other suitable excipients or carriers include dextran, These dosage forms can be manufactured using conventional glucose, maltose, Sorbitol. Xylitol, fructose. Sucrose, and tre processes as described in Remington. The Science and Prac halose. The pharmaceutical compositions disclosed herein tice of Pharmacy, Supra. for inhaled/intranasal administration may further comprise a 0213 Rectal, urethral, and vaginal suppositories are solid suitable flavor, such as menthol and levomenthol, or sweet bodies for insertion into body orifices, which are solid at eners, such as saccharin or saccharin Sodium. ordinary temperatures but melt or soften at body temperature 0219. The pharmaceutical compositions disclosed herein to release the active ingredient(s) inside the orifices. Pharma for topical administration may beformulated to be immediate ceutically acceptable carriers utilized in rectal and vaginal release or modified release, including delayed-, Sustained Suppositories include bases or vehicles, such as stiffening pulsed-, controlled-, targeted, and programmed release. agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical D. Modified Release compositions disclosed herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite. Suitable 0220. The pharmaceutical compositions disclosed herein vehicles include, but are not limited to, cocoa butter (theo may be formulated as a modified release dosage form. As broma oil), glycerin-gelatin, carbowax (polyoxyethylene gly used herein, the term “modified release' refers to a dosage col), spermaceti, paraffin, white and yellow wax, and appro form in which the rate or place of release of the active ingre priate mixtures of mono-, di- and triglycerides offatty acids, dient(s) is different from that of an immediate dosage form hydrogels, such as polyvinyl alcohol, hydroxyethyl meth when administered by the same route. Modified release dos acrylate, polyacrylic acid; glycerinated gelatin. Combina age forms include delayed-, extended-, prolonged-, Sus tions of the various vehicles may be used. Rectal and vaginal tained-, pulsatile-, controlled-, accelerated- and fast-, tar Suppositories may be prepared by the compressed method or geted-, programmed-release, and gastric retention dosage molding. The typical weight of a rectal and vaginal Supposi forms. The pharmaceutical compositions in modified release tory is about 2 to about 3 g. dosage forms can be prepared using a variety of modified 0214. The pharmaceutical compositions disclosed herein release devices and methods known to those skilled in the art, may be administered ophthalmically in the forms of solu including, but not limited to, matrix controlled release tions, suspensions, ointments, emulsions, gel-forming solu devices, osmotic controlled release devices, multiparticulate tions, powders for Solutions, gels, ocular inserts, and controlled release devices, ion-exchange resins, enteric coat implants. ings, multilayered coatings, microspheres, liposomes, and 0215. The pharmaceutical compositions disclosed herein combinations thereof. The release rate of the active ingredient may be administered intranasally or by inhalation to the res (s) can also be modified by varying the particle sizes and piratory tract. The pharmaceutical compositions may be for polymorphorism of the active ingredient(s). mulated in the form of an aerosol or solution for delivery 0221 Examples of modified release include, but are not using a pressurized container, pump, spray, atomizer, Such as limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916, an atomizer using electrohydrodynamics to produce a fine 899; 3,536,809;3,598,123; 4,008,719:5,674,533; 5,059,595; mist, or nebulizer, alone or in combination with a suitable 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; propellant. Such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3- 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; heptafluoropropane. The pharmaceutical compositions may 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; also be formulated as a dry powder for insufflation, alone or in 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; combination with an inert carrier Such as lactose orphospho 6,376.461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500. lipids; and nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, including chitosan or cyclo 1. Matrix Controlled Release Devices dextrin. 0222. The pharmaceutical compositions disclosed herein 0216 Solutions or suspensions for use in a pressurized in a modified release dosage form may be fabricated using a container, pump, spray, atomizer, or nebulizer may beformu matrix controlled release device known to those skilled in the lated to contain ethanol, aqueous ethanol, or a Suitable alter art (see, Takada et al in “Encyclopedia of Controlled Drug native agent for dispersing, Solubilizing, or extending release Delivery.” Vol. 2, Mathiowitz ed., Wiley, 1999). of the active ingredient disclosed herein, a propellant as Sol 0223) In one embodiment, the pharmaceutical composi vent; and/or a surfactant, such as Sorbitan trioleate, oleic acid, tions disclosed herein in a modified release dosage form is or an oligolactic acid. formulated using an erodible matrix device, which is water 0217. The pharmaceutical compositions disclosed herein swellable, erodible, or soluble polymers, including synthetic may be micronized to a size suitable for delivery by inhala polymers, and naturally occurring polymers and derivatives, tion, such as about 50 micrometers or less, or about 10 Such as polysaccharides and proteins. micrometers or less. Particles of such sizes may be prepared 0224 Materials useful in forming an erodible matrix using a comminuting method known to those skilled in the art, include, but are not limited to, chitin, chitosan, dextran, and Such as spiral jet milling, fluid bed jet milling, Supercritical pullulan, gum agar, gum arabic, gum karaya, locust bean fluid processing to form nanoparticles, high pressure homog gum, gum tragacanth, carrageenans, gum ghatti, guar gum, enization, or spray drying. Xanthan gum, and Scleroglucan: Starches, such as dextrin and 0218 Capsules, blisters and cartridges for use in an inhaler maltodextrin; hydrophilic colloids, such aspectin; phosphati or insufflator may be formulated to contain a powder mix of des, such as lecithin; alginates; propylene glycol alginate; the pharmaceutical compositions disclosed herein; a suitable gelatin; collagen; and cellulosics, such as ethyl cellulose powder base. Such as lactose or starch; and a performance (EC), methylethyl cellulose (MEC), carboxymethyl cellulose US 2008/0312247 A1 Dec. 18, 2008 26

(CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypro water to the core from an aqueous environment of use so as to pyl cellulose (HPC), cellulose acetate (CA), cellulose propi cause drug release by extrusion through the delivery port(s). onate (CP), cellulose butyrate (CB), cellulose acetate butyrate 0229. In addition to the active ingredient(s), the core of the (CAB), CAP, CAT, hydroxypropyl methyl cellulose osmotic device optionally includes an osmotic agent, which (HPMC), HPMCP HPMCAS, hydroxypropyl methyl cellu creates a driving force for transport of water from the envi lose acetate trimelitate (HPMCAT), and ethylhydroxyethyl ronment of use into the core of the device. One class of cellulose (EHEC); polyvinyl pyrrolidone; polyvinyl alcohol: osmotic agents water-swellable hydrophilic polymers, which polyvinyl acetate; glycerol fatty acid esters; polyacrylamide; are also referred to as “osmopolymers' and “hydrogels.” polyacrylic acid; copolymers of ethacrylic acid or meth including, but not limited to, hydrophilic vinyl and acrylic acrylic acid (EUDRAGITR), Rohm America, Inc., Piscat polymers, polysaccharides such as calcium alginate, polyeth away, N.J.), poly(2-hydroxyethyl-methacrylate); polylac ylene oxide (PEO), polyethylene glycol (PEG), polypropy tides; copolymers of L-glutamic acid and ethyl-L-glutamate; lene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly degradable lactic acid-glycolic acid copolymers; poly-D-(-)- (acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone 3-hydroxybutyric acid; and other acrylic acid derivatives, (PVP), crosslinked PVP polyvinyl alcohol (PVA), PVA/PVP Such as homopolymers and copolymers ofbutylmethacrylate, copolymers, PVA/PVP copolymers with hydrophobic mono methylmethacrylate, ethylmethacrylate, ethylacrylate, mers such as methyl methacrylate and vinyl acetate, hydro (2-dimethylaminoethyl)methacrylate, and (trimethylamino philic polyurethanes containing large PEO blocks, sodium ethyl)methacrylate chloride. croScarmellose, carrageenan, hydroxyethyl cellulose (HEC), 0225. In further embodiments, the pharmaceutical com hydroxypropyl cellulose (HPC), hydroxypropyl methyl cel positions are formulated with a non-erodible matrix device. lulose (HPMC), carboxymethyl cellulose (CMC) and car The active ingredient(s) is dissolved or dispersed in an inert boxyethyl, cellulose (CEC), sodium alginate, polycarbophil, matrix and is released primarily by diffusion through the inert gelatin, Xanthan gum, and Sodium starch glycolate. matrix once administered. Materials Suitable for use as a 0230. The other class of osmotic agents are osmogens, non-erodible matrix device included, but are not limited to, which are capable of imbibing water to affect an osmotic insoluble plastics. Such as polyethylene, polypropylene, pressure gradient across the barrier of the Surrounding coat polyisoprene, polyisobutylene, polybutadiene, polymethyl ing. Suitable osmogens include, but are not limited to, inor methacrylate, polybutylmethacrylate, chlorinated polyethyl ganic salts, such as magnesium sulfate, magnesium chloride, ene, polyvinylchloride, methyl acrylate-methyl methacrylate calcium chloride, sodium chloride, lithium chloride, potas copolymers, ethylene-vinylacetate copolymers, ethylene? sium sulfate, potassium phosphates, sodium carbonate, propylene copolymers, ethylene/ethyl acrylate copolymers, Sodium sulfite, lithium sulfate, potassium chloride, and vinylchloride copolymers with vinyl acetate, vinylidene chlo Sodium sulfate; Sugars, such as dextrose, fructose, glucose, ride, ethylene and propylene, ionomer polyethylene tereph inositol, lactose, maltose, mannitol, raffinose, Sorbitol, thalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl Sucrose, trehalose, and Xylitol; organic acids, such as ascorbic alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol ter acid, benzoic acid, fumaric acid, citric acid, maleic acid, polymer, and ethylene/vinyloxyethanol copolymer, polyvi sebacic acid, Sorbic acid, adipic acid, edetic acid, glutamic nyl chloride, plasticized nylon, plasticized polyethylene acid, p-toluenesulfonic acid, Succinic acid, and tartaric acid; terephthalate, natural rubber, silicone rubbers, urea; and mixtures thereof. polydimethylsiloxanes, silicone carbonate copolymers; 0231 Osmotic agents of different dissolution rates may be hydrophilic polymers, such as ethyl cellulose, cellulose employed to influence how rapidly the active ingredient(s) is acetate, crospovidone, and cross-linked partially hydrolyzed initially delivered from the dosage form. For example, amor polyvinyl acetate; and fatty compounds, such as carnauba phous Sugars, such as Mannogeme EZ (SPI Pharma, Lewes, wax, microcrystalline wax, and triglycerides. Del.) can be used to provide faster delivery during the first 0226. In a matrix controlled release system, the desired couple of hours to promptly produce the desired therapeutic release kinetics can be controlled, for example, via the poly effect, and gradually and continually release of the remaining mer type employed, the polymer viscosity, the particle sizes amount to maintain the desired level of therapeutic or pro of the polymer and/or the active ingredient(s), the ratio of the phylactic effect over an extended period of time. In this case, active ingredient(s) versus the polymer, and other excipients the active ingredient(s) is released at Such a rate to replace the or carriers in the compositions. amount of the active ingredient metabolized and excreted. 0227. The pharmaceutical compositions disclosed herein 0232. The core may also include a wide variety of other in a modified release dosage form may be prepared by meth excipients and carriers as described herein to enhance the ods known to those skilled in the art, including direct com performance of the dosage form or to promote stability or pression, dry or wet granulation followed by compression, processing. melt-granulation followed by compression. 0233. Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, 2. Osmotic Controlled Release Devices polyamides, polyesters, and cellulosic derivatives that are 0228. The pharmaceutical compositions disclosed herein water-permeable and water-insoluble at physiologically rel in a modified release dosage form may be fabricated using an evant pHs, or are susceptible to being rendered water-in osmotic controlled release device, including one-chamber soluble by chemical alteration, Such as crosslinking. system, two-chamber system, asymmetric membrane tech Examples of suitable polymers useful informing the coating, nology (AMT), and extruding core system (ECS). In general, include plasticized, unplasticized, and reinforced cellulose Such devices have at least two components: (a) the core which acetate (CA), cellulose diacetate, cellulose triacetate, CA contains the active ingredient(s) and (b) a semipermeable propionate, cellulose nitrate, cellulose acetate butyrate membrane with at least one delivery port, which encapsulates (CAB), CAethyl carbamate, CAP, CA methylcarbamate, CA the core. The semipermeable membrane controls the influx of succinate, cellulose acetate trimellitate (CAT), CA dimethy US 2008/0312247 A1 Dec. 18, 2008 27 laminoacetate, CA ethyl carbonate, CA chloroacetate, CA that coats a core comprising the active ingredient(s), a ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA hydroxylethyl cellulose, and other pharmaceutically accept p-toluene Sulfonate, agar acetate, amylose triacetate, beta able excipients or carriers. glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxlated ethylene 3. Multiparticulate Controlled Release Devices vinylacetate, EC, PEG, PPG, PEG/PPG copolymers, PVP. 0241 The pharmaceutical compositions disclosed herein HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, in a modified release dosage form may be fabricated a mul HPMCAT, poly(acrylic) acids and esters and poly-(meth tiparticulate controlled release device, which comprises a acrylic) acids and esters and copolymers thereof, starch, dex multiplicity of particles, granules, or pellets, ranging from tran, dextrin, chitosan, collagen, gelatin, polyalkenes, poly about 10 um to about 3 mm, about 50 um to about 2.5 mm, or ethers, polysulfones, polyetherSulfones, polystyrenes, from about 100 um to about 1 mm in diameter. Such multi polyvinyl halides, polyvinyl esters and ethers, natural waxes, particulates may be made by the processes know to those and synthetic waxes. skilled in the art, including wet- and dry-granulation, extru 0234 Semipermeable membrane may also be a hydropho sion/spheronization, roller-compaction, melt-congealing, bic microporous membrane, wherein the pores are Substan and by spray-coating seed cores. See, for example, Multipar tially filled with a gas and are not wetted by the aqueous ticulate Oral Drug Delivery; Marcel Dekker: 1994; and Phar medium but are permeable to water vapor, as disclosed in U.S. maceutical Pelletization Technology; Marcel Dekker: 1989. Pat. No. 5,798,119. Such hydrophobic but water-vapor per 0242 Other excipients or carriers as described herein may meable membrane are typically composed of hydrophobic be blended with the pharmaceutical compositions to aid in polymers such as polyalkenes, polyethylene, polypropylene, processing and forming the multiparticulates. The resulting polytetrafluoroethylene, polyacrylic acid derivatives, poly particles may themselves constitute the multiparticulate ethers, polysulfones, polyetherSulfones, polystyrenes, poly device or may be coated by various film-forming materials, vinyl halides, polyvinylidene fluoride, polyvinyl esters and Such as enteric polymers, water-swellable, and water-soluble ethers, natural waxes, and synthetic waxes. polymers. The multiparticulates can be further processed as a 0235. The delivery port(s) on the semipermeable mem capsule or a tablet. brane may be formed post-coating by mechanical or laser drilling. Delivery port(s) may also be formed in situ by ero 4. Targeted Delivery sion of a plug of water-soluble material or by rupture of a 0243 The pharmaceutical compositions disclosed herein thinner portion of the membrane over an indentation in the may also be formulated to be targeted to a particular tissue, core. In addition, delivery ports may be formed during coat receptor, or other area of the body of the subject to be treated, ing process, as in the case of asymmetric membrane coatings including liposome-, resealed erythrocyte-, and antibody of the type disclosed in U.S. Pat. Nos. 5,612,059 and 5,698, based delivery systems. Examples include, but are not limited 220. to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359; 6,253, 0236. The total amount of the active ingredient(s) released 872: 6,139,865; 6,131.570; 6,120,751; 6,071,495; 6,060,082: and the release rate can substantially by modulated via the 6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; thickness and porosity of the semipermeable membrane, the 5,900,252; 5,840,674; 5,759,542; and 5,709,874. composition of the core, and the number, size, and position of the delivery ports. Methods of Use 0237. The pharmaceutical compositions in an osmotic 0244 Disclosed are methods for treating, preventing, or controlled-release dosage form may further comprise addi ameliorating one or more symptoms of a late Na" channel tional conventional excipients or carriers as described herein mediated-disorder comprising administering to a Subject hav to promote performance or processing of the formulation. ing or being Suspected to have Such a disorder, a therapeuti 0238. The osmotic controlled-release dosage forms can be cally effective amount of a compound as disclosed herein, or prepared according to conventional methods and techniques a pharmaceutically acceptable salt, Solvate, or prodrug known to those skilled in the art (see, Remington. The Science thereof. and Practice of Pharmacy, Supra; Santus and Baker, J. Con 0245. In one embodiment is a method for the treatment, trolled Release 1995, 35, 1-21; Verma et al., Drug Develop prevention, or amelioration of one or more symptoms of, but ment and Industrial Pharmacy 2000, 26, 695-708; Verma et not limited to, angina, intermittent claudication, ischemia, al., J. Controlled Release 2002, 79, 7-27). and/or any disorder ameliorated by modulating late Na" chan 0239. In certain embodiments, the pharmaceutical com nels, the method comprising administering a therapeutically positions disclosed herein are formulated as AMT controlled effective amount of a compound as disclosed herein, or a release dosage form, which comprises an asymmetric pharmaceutically acceptable salt, Solvate, or prodrug thereof. osmotic membrane that coats a core comprising the active “Symptoms of angina, include, but are not limited to, tight ingredient(s) and other pharmaceutically acceptable excipi ness in the chest, shortness of breath, pain, nausea, fatigue, ents or carriers. See, U.S. Pat. No. 5,612,059 and WO 2002/ Sweating, and light headedness. “Symptoms of intermittent 17918. The AMT controlled-release dosage forms can be claudication, include, but are not limited to, cyanosis, atro prepared according to conventional methods and techniques phic changes, for e.g. loss of hair or shiny skin, decreased known to those skilled in the art, including direct compres body temperature, decreased pulse, increase in pallor, and Sion, dry granulation, wet granulation, and a dip-coating pain. method. 0246 Disclosed herein are methods for treating a subject, 0240. In certain embodiments, the pharmaceutical com including a human, having or suspected of having a late Na" positions disclosed herein are formulated as ESC controlled channel mediated-disorder or for preventing Such disorder in release dosage form, which comprises an osmotic membrane a subject prone to the disorder; comprising administering to US 2008/0312247 A1 Dec. 18, 2008 28 the Subject a therapeutically effective amount of a compound 0254 Examples of monoamine oxidase isoforms in a as disclosed herein, or a pharmaceutically acceptable salt, mammalian Subject include, but are not limited to, MAO Solvate, or prodrug thereof. So as to affect decreased inter and MAO. individual variation in plasma levels of the compound or a 0255. In certain embodiments, the decrease in inhibition metabolite thereof, during the treatment of the disorder as of the cytochrome Paso or monoamine oxidase isoform by a compared to the corresponding non-isotopically enriched compound as disclosed herein is greater than about 5%, compound. greater than about 10%, greater than about 20%, greater than 0247. In certain embodiments, the inter-individual varia about 30%, greater than about 40%, or greater than about 50% tion in plasma levels of the compounds as disclosed herein, or as compared to the corresponding non-isotopically enriched metabolites thereof, is decreased by greater than about 5%, compounds. greater than about 10%, greater than about 20%, greater than 0256 The inhibition of the cytochrome Paso isoform is about 30%, greater than about 40%, or by greater than about measured by the method of Ko et al. (British Journal of 50% as compared to the corresponding non-isotopically Clinical Pharmacology, 2000, 49, 343-351). The inhibition enriched compound. of the MAO isoform is measured by the method of Weyleret 0248 Disclosed herein are methods for treating a subject, al. (J. Biol. Chem. 1985,260, 13199-13207). The inhibition of including a human, having or Suspected of having a late Na" the MAO isoform is measured by the method of Uebelhack channel mediated-disorder or for preventing such disorder in et al. (Pharmacopsychiatry, 1998, 31, 187-192). a Subject prone to the disorder; comprising administering to 0257 Disclosed herein are methods for treating a subject, the Subject a therapeutically effective amount of a compound including a human, having or Suspected of having a late Na" as disclosed herein, or a pharmaceutically acceptable salt, channel mediated-disorder or for preventing Such disorder in Solvate, or prodrug thereof, so as to affect increased average a subject prone to the disorder; comprising administering to plasma levels of the compound or decreased average plasma the Subject a therapeutically effective amount of a compound levels of at least one metabolite of the compound per dosage as disclosed herein, or a pharmaceutically acceptable salt, unit as compared to the corresponding non-isotopically Solvate, or prodrug thereof. So as to affect a decreased enriched compound. metabolism via at least one polymorphically-expressed cyto 0249. In certain embodiments, the average plasma levels chrome Paso isoform in the subject during the treatment of the of the compound as disclosed herein are increased by greater disorder as compared to the corresponding non-isotopically than about 5%, greater than about 10%, greater than about enriched compound. 20%, greater than about 30%, greater than about 40%, or (0258 Examples of polymorphically-expressed cyto greater than about 50% as compared to the corresponding chrome Paso isoforms in a mammalian Subject include, but are non-isotopically enriched compounds. not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 0250 In certain embodiments, the average plasma levels 0259. In certain embodiments, the decrease in metabolism of a metabolite of the compound as disclosed herein are of the compound as disclosed herein by at least one polymor decreased by greater than about 5%, greater than about 10%, phically-expressed cytochrome Paso isoforms cytochrome greater than about 20%, greater than about 30%, greater than Pisoform is greater than about 5%, greater than about 10%, about 40%, or greater than about 50% as compared to the greater than about 20%, greater than about 30%, greater than corresponding non-isotopically enriched compounds about 40%, or greater than about 50% as compared to the 0251 Plasma levels of the compound as disclosed herein, corresponding non-isotopically enriched compound. or metabolites thereof, are measured using the methods 0260 The metabolic activities of the cytochrome Paso iso described by Li et al. (Rapid Communications in Mass Spec forms are measured by the method described in Example 11. trometry 2005, 19, 1943-1950). The metabolic activities of the monoamine oxidase isoforms 0252) Disclosed herein are methods for treating a subject, are measured by the methods described in Examples 12, and including a human, having or suspected of having a late Na" 13. channel mediated-disorder or for preventing such disorder in 0261 Disclosed herein are methods for treating a subject, a Subject prone to the disorder; comprising administering to including a human, having or suspected of having a late Na" the Subject a therapeutically effective amount of a compound channel mediated-disorder or for preventing Such disorder in as disclosed herein, or a pharmaceutically acceptable salt, a subject prone to the disorder; comprising administering to Solvate, or prodrug thereof. So as to affect a decreased inhi the Subject a therapeutically effective amount of a compound bition of, and/or metabolism by at least one cytochrome Paso as disclosed herein, or a pharmaceutically acceptable salt, or monoamine oxidase isoform in the Subject during the treat Solvate, or prodrug thereof. So as to affect at least one statis ment of the disorder as compared to the corresponding non tically-significantly improved disorder-control and/or disor isotopically enriched compound. der-eradication endpoint, as compared to the corresponding 0253 Examples of cytochrome Paso isoforms in a mam non-isotopically enriched compound. malian subject include, but are not limited to, CYP1A1, 0262 Examples of improved disorder-control and/or dis CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, order-eradication endpoints include, but are not limited to, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, statistically-significant improvement in exercise treadmill CYP2E1, CYP2G1 CYP2J2, CYP2R1, CYP2S1, CYP3A4, time (duration increase), reduction in toxicological adverse CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, events including but not limited to, hepatotoxicity, as com CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, pared to the corresponding non-isotopically enriched com CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, pound. CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, 0263. Disclosed herein are methods for treating a subject, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, including a human, having or suspected of having a late Na" CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and channel mediated-disorder or for preventing Such disorder in CYP51. a subject prone to the disorder; comprising administering to US 2008/0312247 A1 Dec. 18, 2008 29 the Subject a therapeutically effective amount of a compound patient requires, the dose can, by way of alternative, be as disclosed herein, or a pharmaceutically acceptable salt, administered as a continuous infusion. Solvate, or prodrug thereof. So as to affect an improved clini 0269. In certain embodiments, an appropriate dosage level cal effect as compared to the corresponding non-isotopically is about 0.01 to about 100 mg per kg patient body weight per enriched compound. Examples of improved disorder-control day (mg/kg per day), about 0.01 to about 50 mg/kg per day, and/or disorder-eradication endpoints include, but are not about 0.01 to about 25 mg/kg per day, or about 0.05 to about limited to, statistically-significant improvement in exercise 10 mg/kg per day, which may be administered in single or treadmill time (duration increase), reduction intoxicological multiple doses. A suitable dosage level may be about 0.01 to adverse events including but not limited to, hepatotoxicity, as about 100 mg/kg per day, about 0.05 to about 50 mg/kg per compared to the corresponding non-isotopically enriched day, or about 0.1 to about 10 mg/kg per day. Within this range compound. the dosage may be about 0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, or about 10 to about 50 mg/kg per 0264 Disclosed herein are methods for treating a subject, day. including a human, having or suspected of having a late Na" channel mediated-disorder or for preventing such disorder in Combination Therapy a Subject prone to the disorder; comprising administering to the Subject a therapeutically effective amount of a compound 0270. The compounds disclosed herein may also be com as disclosed herein, or a pharmaceutically acceptable salt, bined or used in combination with other agents useful in the Solvate, or prodrug thereof, so as to affect prevention of treatment, prevention, or amelioration of one or more symp recurrence, or delay of decline or appearance, of abnormal toms of a late Na" channel mediated-disorder. Or, by way of alimentary or hepatic parameters as the primary clinical ben example only, the therapeutic effectiveness of one of the efit, as compared to the corresponding non-isotopically compounds described herein may be enhanced by adminis enriched compound. tration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with 0265 Disclosed herein are methods for treating a subject, another therapeutic agent, the overall therapeutic benefit to including a human, having or Suspected of having a late Na" the patient is enhanced). channel mediated-disorder or for preventing such disorder in 0271 Such other agents, adjuvants, or drugs, may be a Subject prone to the disorder; comprising administering to administered, by a route and in an amount commonly used the Subject a therapeutically effective amount of a compound therefor, simultaneously or sequentially with a compound as as disclosed herein, or a pharmaceutically acceptable salt, disclosed herein. When a compound as disclosed herein dis Solvate, or prodrug thereof. So as to allow the treatment the closed herein is used contemporaneously with one or more late Na" channel mediated-disorder while reducing or elimi other drugs, a pharmaceutical composition containing Such nating deleterious changes in any diagnostic hepatobiliary other drugs in addition to the compound disclosed herein may function endpoints as compared to the corresponding non be utilized, but is not required. Accordingly, the pharmaceu isotopically enriched compound. tical compositions disclosed herein include those that also 0266 Examples of diagnostic hepatobiliary function end contain one or more other active ingredients or therapeutic points include, but are not limited to, alanine aminotrans agents, in addition to the compound disclosed herein. ferase (ALT), serum glutamic-pyruvic transaminase 0272. In certain embodiments, the compounds disclosed (“SGPT), aspartate aminotransferase (AST or “SGOT), herein can be combined with one or more calcium channel ALT/AST ratios, serum aldolase, alkaline phosphatase blockers known in the art, including, but not limited to, amlo (ALP), ammonia levels, bilirubin, gamma-glutamyl dipine, felodipine, isradipine, nicardipine, nifedipine, nimo transpeptidase (“GGTP”“D-GTP or “GGT), leucine ami dipine, inhisoldipine, nitrendipine, lacidipine, nilvadipine, nopeptidase (“LAP), liver biopsy, liver ultrasonography, manidipine, barnidipine, lercanidipine, cilnidipine, benid liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa ipine, mibefradil, Verapamil, gallopamil, diltiazem, fendiline, tobiliary endpoints are compared to the stated normal levels bepridil, lidoflazine, and perhexyline. as given in “Diagnostic and Laboratory Test Reference', 4' 0273. In certain embodiments, the compounds disclosed edition, Mosby, 1999. These assays are run by accredited herein can be combined with one or more Beta-blockers laboratories according to standard protocol. known in the art, including, but not limited to, alprenolol. 0267 Depending on the disorder to be treated and the oXprenolol, pindolol, propranolol, timolol, Sotalol, nadolol. Subject's condition, the compound as disclosed herein dis mepindolol, carteolol, tertatolol, bopindolol, bupranolol, closed herein may be administered by oral, parenteral (e.g., penbutolol, cloranolol, practolol, metoprolol, atenolol, ace intramuscular, intraperitoneal, intravenous, ICV, intraciste butolol, betaxolol, bevantolol, bisoprolol, celiprolol, mal injection or infusion, Subcutaneous injection, or esmolol, epanolol, S-atenolol, nebivolol, talinolol, labetalol, implant), inhalation, nasal, vaginal, rectal, Sublingual, or and carvedilol. topical (e.g., transdermal or local) routes of administration, 0274. In certain embodiments, the compounds disclosed and may be formulated, alone or together, in Suitable dosage herein can be combined with one or more nitrates or nitrites unit with pharmaceutically acceptable carriers, adjuvants and known in the art, including, but not limited to, glyceryl trini vehicles appropriate for each route of administration. trate, isosorbide dinitrate, isosorbide mononitrate, pen 0268. The dose may be in the form of one, two, three, four, taerythritol tetranitrate, methylpropylpropanediol dinitrate, five, six, or more Sub-doses that are administered at appro propatylnitrate, troInitrate, eritrityl tetranitrate, amyl nitrite, priate intervals per day. The dose or sub-doses can be admin butyl nitrite, ethyl nitrite, methyl nitrite, isopropyl nitrite, istered in the form of dosage units containing from about 0.1 isobutyl nitrite, and cyclohexyl nitrite. to about 1000 milligrams, from about 0.1 to about 500 milli 0275. In certain embodiments, the compounds disclosed grams, or from 0.5 about to about 100 milligrams active herein can be combined with one or more HMG-CoA reduc ingredient(s) per dosage unit, and if the condition of the tase inhibitors (statins) known in the art, including, but not US 2008/0312247 A1 Dec. 18, 2008 30 limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, liferatives, such as methotrexate, FK506 (tacrolimus, Pro mevastatin, pitavastatin, pravastatin, rosuvastatin, and simv graf), mycophenolate mofetil: chemotherapeutic agents; astatin. immunosuppressants; anticancer agents and cytotoxic agents 0276. In certain embodiments, the compounds disclosed (e.g., alkylating agents. Such as nitrogen mustards, alkyl Sul herein can be combined with one or more angiotensin-con fonates, nitrosoureas, ethylenimines, and triaZenes); antime verting enzyme inhibitors (ACE inhibitors) known in the art, tabolites, such as folate antagonists, purine analogues, and including, but not limited to, captopril, enalapril, lisinopril, pyrridine analogues; antibiotics, such as anthracyclines, bleo perindopril, ramipril, quinapril, benazepril, cilaZapril, fosi mycins, mitomycin, dactinomycin, and plicamycin; nopril, trandolapril, spirapril, delapril, moexipril, temocapril, enzymes, such as L-asparaginase; farnesyl-protein trans Zofenopril, and imidapril. ferase inhibitors; hormonal agents, such as glucocorticoids 0277. In certain embodiments, the compounds disclosed (e.g., cortisone), estrogens/antiestrogens, androgens/antian herein can be combined with one or more plateletaggregation drogens, progestins, and luteinizing hormone-releasing hor inhibitors known in the art, including, but not limited to mone anatagonists, and octreotide acetate; microtubule-dis aspirin, aloxiprin, ditazole, carbasalate calcium, cloricromen, ruptor agents, such as ecteinascidins; microtubule-stablizing dipyridamole, indobufen, picotamide, triflusal, clopidogrel, agents, such as pacitaxel, docetaxel, and epothilones A-F. ticlopidine, prasugrel, beraprost, prostacyclin, iloprost, and plant-derived products, such as Vinca alkaloids, epipodophyl treprostinil. lotoxins, and taxanes; and topoisomerase inhibitors; prenyl protein transferase inhibitors; and cyclosporins; steroids, 0278. The compounds disclosed herein can also be admin Such as prednisone and dexamethasone; cytotoxic drugs, such istered in combination with other classes of compounds, as azathiprine and cyclophosphamide; TNF-alpha inhibitors, including, but not limited to, adenosine, digitoxin, anti-ar such as tenidap; anti-TNF antibodies or soluble TNF receptor, rhythmic agents, sympathomimetic drugs, steroidal drugs, Such as etanercept, rapamycin, and leflunimide; and non-steroidal anti-inflammatory drugs (NSAIDs), opioids, cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and anesthetics, sepsis agents, anti-bacterials, anti-fungals, anti rofecoxib; and miscellaneous agents such as, hydroxyurea, coagulants, thrombolytics, endothelin converting enzyme procarbazine, mitotane, hexamethylmelamine, gold com (ECE) inhibitors, such as phosphoramidon; thromboxane pounds, platinum coordination complexes, such as cisplatin, receptor antagonists, such as ifetroban; potassium channel satraplatin, and carboplatin. openers; thrombin inhibitors, such as hiruding growth factor inhibitors, such as modulators of PDGF activity; platelet acti Kits/Articles of Manufacture vating factor (PAF) antagonists; anti-platelet agents, such as GPIb/IIIa blockers (e.g., abdximab, eptifibatide, and 0279 For use in the therapeutic applications described tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopi herein, kits and articles of manufacture are also described dine and CS-747), and aspirin; anticoagulants, such as war herein. Such kits can comprise a carrier, package, or container farin; low molecular weight heparins, such as enoxaparin; that is compartmentalized to receive one or more containers Factor VIa Inhibitors and Factor Xa Inhibitors; renin inhibi Such as vials, tubes, and the like, each of the container(s) tors; neutral endopeptidase (NEP) inhibitors; vasopepsidase comprising one of the separate elements to be used in a inhibitors (dual NEP-ACE inhibitors), such as omapatrilat method described herein. Suitable containers include, for and gemopatrilat; HMG CoA reductase inhibitors, such as example, bottles, vials, Syringes, and test tubes. The contain pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 ers can be formed from a variety of materials such as glass or (a.k.a. itavastatin, nis vastatin, or nisbastatin), and ZD-4522 plastic. (also known as rosuvastatin, or atavastatin or visastatin); 0280 For example, the container(s) can comprise one or squalene synthetase inhibitors; fibrates; bile acid seques more compounds described herein, optionally in a composi trants. Such as questran; niacin; anti-atherosclerotic agents, tion or in combination with another agent as disclosed herein. such as ACAT inhibitors; MTP Inhibitors; calcium channel The container(s) optionally have a sterile access port (for blockers, such as amlodipine besylate; potassium channel example the container can be an intravenous solution bag or a activators; alpha-adrenergic agents: diuretics, such as chlo vial having a stopper pierceable by a hypodermic injection rothlazide, hydrochlorothiazide, flumethiazide, hydroflume needle). Such kits optionally comprise a compound with an thiazide, bendroflumethiazide, methylchlorothiazide, identifying description or label or instructions relating to its trichloromethiazide, polythiazide, benzothlazide, ethacrynic use in the methods described herein. acid, tricrynafen, chlorthalidone, furosenilde, musolimine, 0281 Akit will typically comprise one or more additional bumetanide, triamterene, amiloride, and Spironolactone; containers, each with one or more of various materials (such thrombolytic agents, such as tissue plasminogen activator as reagents, optionally in concentrated form, and/or devices) (tPA), recombinant tEPA, Streptokinase, urokinase, prouroki desirable from a commercial and user standpoint for use of a nase, and anisoylated plasminogen Streptokinase activator compound described herein. Non-limiting examples of Such complex (APSAC); anti-diabetic agents, such as biguanides materials include, but are not limited to, buffers, diluents, (e.g. metformin), glucosidase inhibitors (e.g., acarbose), filters, needles, syringes; carrier, package, container, vial and/ insulins, meglitinides (e.g., repaglinide), Sulfonylureas (e.g., or tube labels listing contents and/or instructions for use, and glimepiride, glyburide, and glipizide), thioZolidinediones package inserts with instructions for use. A set of instructions (e.g. troglitaZone, rosiglitaZone and pioglitaZone), and will also typically be included. PPAR-gamma agonists; mineralocorticoid receptor antago 0282. A label can be on or associated with the container. A nists, such as Spironolactone and eplerenone; growth hor label can be on a container when letters, numbers or other mone secretagogues; aP2 inhibitors; phosphodiesterase characters forming the label are attached, molded or etched inhibitors, such as PDE III inhibitors (e.g., cilostazol) and into the container itself, a label can be associated with a PDE V inhibitors (e.g., sildenafil, tadalafil. Vardenafil); pro container when it is present within a receptacle or carrier that tein tyrosine kinase inhibitors; antiinflammatories; antipro also holds the container, e.g., as a package insert. A label can US 2008/0312247 A1 Dec. 18, 2008

be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate -continued directions for use of the contents, such as in the methods 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 ordi nary skill in the art. 0283. The invention is further illustrated by the following examples:

EXAMPLE1 0286 2-(2-Methoxy-phenoxymethyl)-oxirane: Epichlo rohydrin (8.4g, 91.3 mmol) was slowly added to a solution of N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- 2-methoxyphenol (8 g. 64.4 mmol) dissolved in water (6 mL) methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta and dioxane (20 mL) containing Sodium hydroxide (2.9 g, mide 72.5 mmol). The resulting mixture was heated at reflux for about 3 hours. Following standard extractive workup with 0284 ether, the crude product was purified by flash column chro matography on silica gel (4x20 cm, petroleum ether/ethyl acetate=5/1 elution) to afford the title product (4.95 g, 43%). "H NMR (300 MHz, CDC1) & 6.99-6.89 (m, 4H), 4.24 (dd. 1H, J–8.4, 3.6 Hz), 4.05 (dd. 1H, J–9.6, 5.4 Hz), 3.88 (s.3H), r^ OH o1 3.43-3.38 (m. 1H), 2.90 (t, 1H, J=4.5 Hz), 2.76-2.74 (m, 1H): O N--- LC-MS: m/z =195 (MH)".

Step 3

Step 1.

NH2 O ^- -- O He -- --- esusC

H N ra O C-- 0287 1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-propan 0285 2-Chloro-N-(2,6-dimethyl-phenyl)-acetamide: At 2-ol: At 0-5°C. 2-(2-methoxy-phenoxymethyl)-oxirane (2g, about 0°C., Chloroacetyl chloride (3.2 mL, 40.6 mmol) was 11 mmol) was slowly added, over a period of about 60 min slowly added to a solution of 2,6-dimethylaniline (4.9 mL, 40 utes, to a solution of anhydrous piperazine (3.93 g, 46 mmol) mmol) and triethylamine (6.5 mL) in dichloromethane (50 in methanol (10 mL). The reaction mixture was maintained at mL). The mixture was maintained at about 0°C. for about 14 0-5° C. for an additional 12 hours. Dilution with water and hours, and then washed with 1N hydrochloric acid (60 mL). The organic phase was concentrated in vacuo, and hexane standard extractive workup afforded the title product which (100 mL) was added to precipitate the title product (6.21 g, was used directly in next reaction without further purification. 78%). H NMR (300 MHz, CDC1,) & 7.82 (br. s. 1H), 7.15 "H NMR (300 MHz, CDC1) & 6.98-6.89 (m, 4H), 4.17-4.13 7.09 (m, 3H), 4.27 (s. 2H), 2.25 (s, 6H), 2.90, 2.63-2.46 (m, (m. 1H), 4.03 (d. 2H, J=5.7 Hz), 3.86 (s.3H), 2.90 (br. s, 4H), 6H), LC-MS: m/z =198 (MH)". 2.63-2.46 (m, 6H); LC-MS: m/z 267 (MH)".

Step 2 Step 4 No HO- Cl su-A -- US 2008/0312247 A1 Dec. 18, 2008 32

(5 mL, 78.6 mmol). The mixture was maintained at about 41° -continued C. for about 16 hours, and then filtered. The filtrate was evaporated, and the resulting residue was purified by flash column chromatography on silica gel (6x20 cm, petroleum ether?ethyl acetate=8/1 elution) to afford the title product r He (10.4g, 82%). "H NMR (300 MHz, CDC1) & 6.96-6.87 (m, 4H), 5.62 (br. s. 1H).

Step 2 DC No Crous HO 0288 N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- -- He methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: A clu-A mixture of 1-(2-methoxy-phenoxy)-3-piperazin-1-yl-pro pan-2-ol (2 g, 7.52 mmol), 2-chloro-N-(2,6-dimethyl-phe nyl)-acetamide (1.84 g., 9.34 mmol), anhydrous potassium CD carbonate (2 g, 14.5 mmol) and sodium iodide (74 mg. 0.5 O o1 mmol) in dimethylformamide (5 mL) was maintained at 30-35°C. for about 18 hours. The mixture was quenched with water and standard extractive work up afforded a crude resi due which was purified by flash column chromatography on ^- silica gel (2x16 cm, dichloromethane/methanol/triethy lamine=100/2/1 elution) to afford the title compound (1.1 g, 34%). "H NMR (300 MHz, CDC1) & 7.11 (s.3H), 6.98-6.90 0291 d-2-(2-Methoxy-phenoxymethyl)-oxirane: The (m, 4H), 4.19 (br. s. 1H), 4.05 (d. 2H, J=5.4 Hz), 3.87 (s.3H), title product was made by following the procedure set forth in 3.30-324 (m, 2H), 2.76-2.63 (m. 10H), 2.25 (s, 6H); LC-MS: Example 1, step 2, but substituting d-2-methoxyphenol for m/Z-428 (MH); HPLC: 99% (Purity). 2-methoxyphenol. (1.8g, 24%). H NMR (300 MHz, CDC1) 8 6.99-6.88 (m, 4H), 4.24 (dd. 1H, J–8.4, 3.6 Hz), 4.05 (dd. EXAMPLE 2 1H, J=9.6, 5.4 Hz), 3.43-3.38 (m. 1H), 2.90 (t, 1H, J=4.8 Hz), da-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- 2.76-2.74 (m. 1H); LC-MS: m/z =184 (MH)". methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta mide 0289 Step 3

CD r N-N-N-OH - 'i Al-S -- O Her

1. CD

Step 1. DC C-- OH * no HO - HO 0292 d-1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-pro pan-2-ol: The title product was made by following the proce dure set forth in Example 1, step 3, but substituting d-2-(2- methoxy-phenoxymethyl)-oxirane for 2-(2-methoxy phenoxymethyl)-oxirane. (2.3 g, 87%). "H NMR (300 MHz, 0290 d-2-methoxyphenol: Pyrocatechol (11 g, 100 CDC1) & 6.97-6.87(m, 4H), 5.30 (S. 1H), 4.16-4.10 (m. 1H), mmol) and potassium carbonate (13.2 g, 78.6 mmol) were 4.03 (d. 2H, J=5.1 Hz), 2.94 (br. s, 4H), 2.64-2.44 (m, 7H): mixed with anhydrous acetone (50 mL) and d-methyl iodide LC-MS: m/z 270 (MH)". US 2008/0312247 A1 Dec. 18, 2008

mg), sodium formate (20 mg) and deuterium oxide (40 mL) was heated at about 80° C. for about 48 hours. The mixture Step 4 was cooled to ambient temperature, extracted with dichlo romethane (3x50 mL), and the solvent removed by evapora tion to afford the title product (1.2g, 30%). "H NMR (300 MHz, CDC1) & 6.96 (s. 2H), 5.31 (s, 1H); LC-MS: m/z =129 (MH)".

Step 2 CD3

-> NH2 O -- -3- Crs C C D CD3 CD3 H N ra O D CD 0293 d-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: 0296) d-2-Chloro-N-(2,6-dimethyl-phenyl)-acetamide: The title product was made by following the procedure set The title product was made by following the procedure set forth in Example 1, step 4, but substituting d-1-(2-methoxy forth in Example 1, step 1, but Substituting d7-2,6-dimethy phenoxy)-3-piperazin-1-yl-propan-2-ol for 1-(2-methoxy laniline for 2,6-dimethylaniline. (2.38g, 70%). 'HNMR (300 phenoxy)-3-piperazin-1-yl-propan-2-ol. (420 mg, 29%). "H MHz, CDC1) & 7.85 (br. s. 1H), 7.10 (s, 3H), 4.26 (s. 2H): NMR (300 MHz, CDC1) & 8.65 (s, 1H), 7.11 (s.3H), 6.98 LC-MS: m/z-205 (MH)". 6.90 (m, 4H), 4.19 (br. s. 1H), 4.05 (d. 2H, J=4.8 Hz), 3.25 3.23 (m, 2H), 2.77-2.61 (m, 10H), 2.29 (s, 6H); LC-MS: m/z-431 (MH); HPLC: 98% (Purity). Step 3

EXAMPLE 3 HN dy-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta mide

0294 H N CD3 ra O D CD3 ^^ OH o1 CD3 O N-N-N- D CD r^ OH o1 D CD O N- N--

Step 1. 0297 d-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- CD3 (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: NH2 NH2 The title product was made by following the procedure set forth in Example 1, step 4, but substituting di-2-chloro-N-(2, 6-dimethylphenyl)-acetamide for 2-chloro-N-(2,6-dimeth ylphenyl)-acetamide. (198 mg, 21%). H NMR (300 MHz, D CD3 CDC1) & 8.64 (br. s. 1H), 7.09 (s. 2H), 6.98-6.90 (m, 4H), 4.17 (br. s. 1H), 4.05 (d. 2H, J=5.1 Hz), 3.87 (s.3H), 3.22 (s, 0295 d7-2,6-dimethylaniline: A mixture of 2,6-dimethy 2H), 2.76-2.60 (m, 10H); LC-MS: m/z-435 (MH)"; HPLC: laniline (4 mL, 32.5 mmol), 10% palladium on carbon (150 99% (Purity). US 2008/0312247 A1 Dec. 18, 2008 34

EXAMPLE 4 ds-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- Step 3 methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta 1. mide in- HO D O 0298 N- O -- D D D D

H N

r --- O

H N o1 ^^ HO D O N-XXX O D D D D

0301 ds-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- (2-methoxy-phenoxy)-propylpiperazin-1-yl)-acetamide: The title product was made by following the procedure set forth in Example 1, step 4, but substituting d-1-(2-methoxy phenoxy)-3-piperazin-1-yl-propan-2-ol for 1-(2-methoxy phenoxy)-3-piperazin-1-yl-propan-2-ol. (618 mg, 26%). "H NMR (300 MHz, CDC1) & 8.62 (br. s. 1H), 7.10 (s, 3H), 6.97-6.89 (m, 4H), 3.86 (s, 3H), 3.22 (s. 2H), 2.76-2.61 (m, 8H), 2.28 (s, 6H); LC-MS: m/z-433 (MH)"; HPLC: 97% (Purity). 0299 d-2-(2-Methoxy-phenoxymethyl)-oxirane: The title product was made by following the procedure set forth in EXAMPLE 5 Example 1, step 2, but substituting di-epichlorohydrin for epichlorohydrin. (1 g, 26%). "H NMR (300 MHz, CDC1) & dN-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- 6.96-6.89 (m, 4H), 3.88 (s.3H); LC-MS: m/z208 (M+Na)". methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta mide 0302)

D D H N D

D ^k D OH o1 > x.S () O D N-luo 1. D D "O ^ O D D D D

Step 1. 0300 d-1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-pro pan-2-ol: The title product was made by following the proce dure set forth in Example 1, step 3, but substituting di-2-(2- methoxy-phenoxymethyl)-oxirane for 2-(2-methoxy phenoxymethyl)-oxirane. (1.5g, 99%). "H NMR (300 MHz, CDC1) & 6.96-6.88 (m, 4H), 3.86 (s, 3H), 2.92 (br. s, 4H), 2.64-2.46 (m, 5H); LC-MS: m/z 272 (MH)". US 2008/0312247 A1 Dec. 18, 2008 35

EXAMPLE 6 -continued d-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta mide D D 0305 He D N D CD3 D D PD CD 1.D HO D -'s O N O

D. D. D. D. D D

Step 1. DC No D D 0303 d-1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-pro D HO pan-2-ol: The title product was made by following the proce C O dure set forth in Example 1, step 3, but Substituting dis-pip -- s erazine for piperazine. (1.1 g, 72%). H NMR (300 MHz, D D CDC1) & 6.98-6.89 (m, 4H), 5.24 (s, 1H), 4.16-4.11 (m, 1H), CD 4.03 (d. 2H, J=5.1 Hz), 3.85 (s.3H), 2.78 (br. s. 2H), 2.56-2.52 O D o1 D (m. 2H); LC-MS: m/z =275 (MH)". O

D -ex. D Step 2 D D 0306 ds-2-(2-Methoxy-phenoxymethyl)-oxirane: The D title product was made by following the procedure set forth in HN OH 1 Example 4. Step 1, but Substituting d2-lethoxypheng for D D 2-methoxyphenol. (1.48 g., 37%). "H NMR (300 MHz, N O -- CDC1) & 6.99-6.89 (m, 4H); LC-MS: m/z 211 (M+Na)". D

D D Step 2 CD O D o1 3 H D N O rC D -- O D

D D D H D N D D N OH o1 D He D D D D O N O N D D H D D D D D D CD HN HO D D 0304 dis-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- N O (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: D The title product was made by following the procedure set D. D. D. D. D D forth in Example 1, step 4, but Substituting ds-1-(2-methoxy phenoxy)-3-piperazin-1-yl-propan-2-ol for 1-(2-methoxy phenoxy)-3-piperazin-1-yl-propan-2-ol. (508 mg, 29%). "H 0307 de-1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-pro pan-2-ol: The title product was made by following the proce NMR (300 MHz, CDC1) & 8.60 (br. s. 1H), 7.10 (s, 3H), dure set forth in Example 5, step 1, but Substituting dis-2-(2- 6.97-6.89 (m, 4H), 4.20(brs, 1H), 4.05-4.04 (m, 2H), 3.86 (s, methoxy-phenoxymethyl)-oxirane for 2-(2-methoxy 3H), 2.86 (br. s. 2H), 2.23 (s, 6H); LC-MS: m/z. 436 (MH)"; phenoxymethyl)-oxirane. (1.0 g, 61%). "H NMR (300 MHz, HPLC: 99% (Purity). CDC1) & 6.97-6.87 (n, 4H); LC-MS: m/z =283 (MH)". US 2008/0312247 A1 Dec. 18, 2008 36

-continued Step 3 CD3 H D D N D CD Sr. --- HN HO D o1 O D N O D CD3 D -- CD3

CD3 D. D. D. D. D D r^ OH O1 CD3 H D CD3 O N-N-N- N 1. He O D CD3 0310 do-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- CD3 D D H D (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: N D Y CD3 The title product was made by following the procedure set 1.D HO D O forth in Example 2, step 4, but substituting d7-2-chloro-N-(2, O N O 6-dimethylphenyl)-acetamide for 2-chloro-N-(2,6-dimeth D CD D ylphenyl)-acetamide. (680 mg. 66%). H NMR (300 MHz, D. D. D. D. D D CDC1) & 8.61 (s, 1H), 7.09 (s. 2H), 6.97-6.88 (m, 4H), 4.19-4.15 (m, 1H), 4.04 (d. 2H, J=5.1 Hz), 3.22 (s. 2H), 2.77-2.63 (m, 10H); LC-MS: m/z =438 (MH)"; HPLC: 99% 0308 d-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- (Purity). (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: The title product was made by following the procedure set EXAMPLE 8 forth in Example 3, step 3, but substituting de-1-(2-methoxy dis-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- phenoxy)-3-piperazin-1-yl-propan-2-ol for 1-(2-methoxy methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta phenoxy)-3-piperazin-1-yl-propan-2-ol. (410 mg, 26%). "H mide NMR (300 MHz, CDC1) & 8.65 (br. s. 1H), 7.10 (s. 2H), 6.95-6.90 (m, 4H), 3.44 (brs, 1H), 3.22 (s. 2H); LC-MS: 0311 m/Z-451 (MH)"; HPLC: 97% (Purity). CD3 EXAMPLE 7 1 CD 3 do-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3-(2- r^ D OH O methoxy-phenoxy)-propyl-piperazin-1-yl)-aceta O N- O mide D CD3 D D D D 0309

Step 1.

1 CD3 O D O

Step 1.

0312 ds-2-(2-Methoxy-phenoxymethyl)-oxirane: The title product was made by following the procedure set forth in Example 2, step 3, but Substituting dis-2-(2-methoxy-phe US 2008/0312247 A1 Dec. 18, 2008 37 noxymethyl)-oxirane for d-2-(2-methoxy-phenoxymethyl)- oxirane. (540 mg, 100%). H NMR (300 MHz, CDC1) & 6.97-6.87 (im, 4H), 2.90-2.42 (m, 8H); LC-MS: m/Z 275 Step 1. (MH)". OCD3

HO D D O D + D He D D D di D

D DCO D O D

p/. D D D D D D CD3 H 0315 d-2-(2-Methoxy-phenoxymethyl)-oxirane: The N procedure of Step 1 is carried out using the methods described ra He in U.S. Pat. No. 4,567.264 and references cited therein. A O large excess of ds-epichlorohydrin (84 g) is slowly added to D CD d7-2-methoxyphenol (80 g. C/D 96 NIsotopes, Pointe-Claire Quebec) dissolved in about 60 ml of water and about 200 ml of dioxane containing Sodium hydroxide (29 g). The mixture is maintained at reflux for about 3 hours, and then diluted with CD3 ether, washed with two portions of water, and dried using Y CD 3 anhydrous magnesium sulfate. The dried extract is evapo ^ N ~ D OH O rated and then distilled to give the title product. O N- N O D CD3 D D D D Step 2 D3CO D 0313 dis-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- O D (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: The title product was made by following the procedure set I/. D -- forth in Example 3, step 3, but substituting dis-1-(2-methoxy D D D D phenoxy)-3-piperazin-1-yl-propan-2-ol for 1-(2-methoxy D phenoxy)-3-piperazin-1-yl-propan-2-ol. (480 mg, 55%). "H D H D NMR (300 MHz, CDC1) & 8.61 (brs, 1H), 7.10 (s. 2H), N 6.97-6.89 (m, 4H), 3.23 (s. 2H), 2.78-2.23 (m, 8H); LC-MS: D D -- m/z-443 (MH); HPLC: 100% (Purity). D D N D H D EXAMPLE 9 0314 dis-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide

OCD,

D D D D D. D. D. D. D D D 0316 do-1-(2-Methoxy-phenoxy)-3-piperazin-1-yl-pro D CD3 pan-2-ol: The procedure of Step 2 is carried out using the O D N O D methods described in WO2006/008753 and references cited N D D O OCD, therein. At 0-5°C., d-2-(2-methoxy-phenoxymethyl)-ox D A D D irane (107 g) is slowly added (over a period of 60 minutes) to CD3 D D D D D anhydrous dis-piperazine (210 g, Sigma-Aldrich, St. Louis, Mo. 63103) dissolved in methanol (500 mL). The mixture is maintained for about 2 hours at 0-5°C., and then diluted with US 2008/0312247 A1 Dec. 18, 2008 38 water, filtered, and extracted with dichloromethane. Acetic acid (65 g) and water (400 mL) are added, and the aqueous -continued layer is then separated, and basified with ammonium hydrox- D ide (100 mL). Standard extractive workup with dichlo romethane affords the title product. D D. D. D. D. D D D D D CD3 O D AX N XX. O D lu D D OH OCD, Step 3 D N D CD3 D D CD D ND C 0318 dis-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- -- C1 -> (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide (do-Ranolazine): The procedure of Step 4 is carried out using the methods described in WO2006/008753 and references D CD O cited therein. A mixture of do-1-(2-methoxy-phenoxy)-3- piperazin-1-yl-propan-2-ol (97 g), dg-2-chloro-N-(2,6-dim D ethyl-phenyl)-acetamide (89 gms), anhydrous potassium car bonate (120 g), and Sodium iodide (3.6 g) in dimethylformamide (260 mL) is maintained at 30-35°C. for CD3 about 18 hours. The reaction mixture is quenched with water D (1600 mL) and extracted with dichloromethane. The com C bined organic layers are washed with dilute hydrochloric acid. The acidic aqueous layer is basified with ammonia, O extracted with dichloromethane, and the solvent is removed D CD3 in vacuo to give the title product. D 0317 d-2-Chloro-N-(2,6-dimethyl-phenyl)-acetamide: The procedure of Step 3 is carried out using the methods described in U.S. Pat. No. 4,567,264 and references cited D D therein. Chloroacetylchloride (89.6 g. 800 mmoles) is slowly D D. D. D. D D D added to a cold solution of di-2,6-dimethylaniline (793 D CD D He mmol. C/D/N Isotopes, Pointe-Claire Quebec) and triethy- O D lamine (96 g. 130 mL) dissolved in dichloromethane (1000 -N-N D OH OCD, mL). The mixture is maintained at ambient temperature for D N about 4 hours, washed with dilute hydrochloric acid, and CD D D concentrated in vacuo. Hexane is then added to precipitate the D title product.

D D CD O A-XXXX, D Step 4 N D D O OCD D N M 3 D D D

D. D. D. D. D D 0319 d-N-(2,6-Dimethyl-phenyl)-2-4-2-hydroxy-3- (2-methoxy-phenoxy)-propyl-piperazin-1-yl)-acetamide: D N O D At ambient temperature, do-N-(2,6-Dimethyl-phenyl)-2-4- 2-hydroxy-3-(2-methoxy-phenoxy)-propyl-piperazin-1- HN D D OH OCD, yl)-acetamide dissolved in d-methanol (0.5 ml) is added D dropwise to a 0.1M solution of sodium carbonate in deute D D rium oxide (pH=11.4). Under continuous stirring, the solu tion is maintained at ambient temperature for about 4 days. Standard extractive workup with dichloromethane affords the CD3 title compound. D EXAMPLE 10 r In Vitro Liver Microsomal Stability Assay 0320 Liver microsomal stability assays were conducted with 0.2 mg per mL liver microsome protein in a NADPH generating system (2% sodium bicarbonate, 2.2 mM D NADPH, 25.6 mM glucose 6-phosphate, and 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCl). US 2008/0312247 A1 Dec. 18, 2008 39

The test compounds were solubulized in 20% acetonitrile water. The test compound solution was then added to the -continued -assay mixture (final assay concentration 1 M) and the mix ture was incubated at about 37°C. The final concentration of Cytochrome P4so Standard acetonitrile in the assay should be <1%. Aliquots (50 L) were CYP2C8 Paclitaxel collected at times 0, 15, 30, 45, and 60 min, and diluted with CYP2C9 Diclofenac ice cold acetonitrile (200 uL) (to quench the reactions). The CYP2C19 'C-(S)-mephenytoin CYP2D6 (+/-)-Bufuralol aliquots were centrifuged at about 12,000 RPM for about 10 CYP2E1 ChlorZoxazone minto precipitate the proteins. The Supernatants were then CYP3A4 Testosterone collected and transferred to micro centrifuge tubes for CYP4A 'C-Lauric acid LC/MS/MS analysis of degradation half-lives. It has thus been found that the compounds as disclosed herein, according to the present invention which have been tested in this assay, EXAMPLE 12 showed an increase of 6% or more in the degradation half-life, Monoamine Oxidase A Inhibition and Oxidative as compared to the non-isotopically enriched drug. For Turnover example, the degradation half-lives of Examples 2-6, were 0322 The procedure is carried out using the methods increased by 6 to 40% respectively, as compared to non described by Weyler, Journal of Biological Chemistry 1985, 260, 13199-13207. Monoamine oxidase A activity is mea isotopically enriched ranoZaline. Sured spectrophotometrically by monitoring the increase in absorbance at 314 nm on oxidation of kynuramine with for EXAMPLE 11 mation of 4-hydroxyquinoline. The measurements are carried out, at 30°C., in 50 mMNaP, buffer, pH 7.2, containing 0.2% In Vitro Metabolism. Using Human Cytochrome Ps Triton X-100 (monoamine oxidase assay buffer), plus 1 mM Enzymes kynuramine, and the desired amount of enzyme in 1 mL total 0321) The cytochrome Paso enzymes are expressed from Volume. the corresponding human cDNA using a baculovirus expres EXAMPLE 13 sion system (BD Biosciences, San Jose, Calif.). A 0.25 mil Monoamine Oxidase B Inhibition and Oxidative liliter reaction mixture containing 0.8 milligrams per millili Turnover ter protein, 1.3 millimolar NADP", 3.3 millimolar glucose 0323. The procedure is carried out using the methods 6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, described by Uebelhack, Pharmacopsychiatry 1998, 31, 187 3.3 millimolar magnesium chloride and 0.2 millimolar of a 192. compound of Formula 1, the corresponding non-isotopically EXAMPLE 1.4 enriched compound or standard or control in 100 millimolar Glucose Oxidation in Normoxic, Ischemic, and Rep potassium phosphate (pH 7.4) is incubated at 37° C. for 20 erfused Ischemic Rat Hearts min. After incubation, the reaction is stopped by the addition 0324. The procedure is carried out using the methods of an appropriate solvent (e.g., acetonitrile, 20% trichloro described by McCormacket al. Circulation 1996,93(1), 135 acetic acid, 94% acetonitrile/6% glacial acetic acid, 70% 142 and references cited therein. perchloric acid, 94% acetonitrile/6% glacial acetic acid) and 0325 The examples set forth above are disclosed to give centrifuged (10,000 g) for 3 min. The supernatant is analyzed those of ordinary skill in the art with a complete disclosure by HPLC/MS/MS. and description of how to make and use the claimed embodi ments, and are not intended to limit the scope of what is disclosed herein. All publications, patents, and patent appli cations cited in this specification are incorporated herein by Cytochrome P4so Standard reference as if each Such publication, patent or patent appli CYP1A2 Phenacetin cation were specifically and individually indicated to be CYP2A6 Coumarin incorporated herein by reference. CYP2B6 'C-(S)-mephenytoin What is claimed is: 1. A compound having structural Formula I

(I) US 2008/0312247 A1 Dec. 18, 2008 40 or a pharmaceutically acceptable salt, Solvate, or prodrug 10. The compound as recited in claim 1, wherein the com thereof, wherein: pound is selected from the group consisting of: R. R2. Rs. R4, Rs. R. R7. Rs. Ro. Rio R ls R12, Rs. R14. R1s. R16. R17, R 8s R19. R20. R21. R22. R2s. R24. R2s. R26. R27, R2s, R29. Rao, Rs1, R32, and Rss are independently Selected from the group consisting of hydrogen and deu terium; and at least one of R. R. R. R. Rs. R. R-7, Rs. R. Rio R. R12. Ris. R14. R1s. R 63 R17, R 8s R19. R20. R21. R22. R2s. R24. R2s, R26, R27, R2s, R29. Rao Rs1, R32, and Rss is deuterium. ser) 2. The compound as recited in claim 1, wherein said com pound 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 (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (-)-enantiomer, Substantially an indi vidual diastereomer, or a mixture of about 90% or more by stro weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 3. The compound as recited in claim 1, wherein at least one of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, R1s. R16, R17, Ris, R19, R20. R21, R22, R23, R24 R2s, R26, R27, R2s, Rao, Rao, Rs 1, R32, and Rs independently has deuterium enrichment of no less than about 98%. ser) 4. The compound as recited in claim 1, wherein at least one of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27. R2s, Rao, Rao, Rs 1, R32, and Rs independently has deuterium enrichment of no less than about 90%. 5. The compound as recited in claim 1, wherein at least one of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, OH No R1s. R16, R17, Ris, R19, R20. R21, R22, R23, R24 R2s, R26, R27, Rs. Ro Ro, R. R. and R independently has deuterium CD3 N-- D NH Ip-1 enrichment of no less than about 50%. r N 6. The compound as recited in claim 1, wherein at least one O of R, R2. Rs. R4, Rs. R. R7. Rs. Ro, Rio R11, R12, Rs. R14. D CD3 Rs. R16. R17. R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. D R2s, Rao, Rao, Rs 1, R32, and Rs independently has deuterium DC enrichment of no less than about 20%. OH No 7. The compound as recited in claim 1, wherein at least one N-- of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, D NH 11 R1s. R16, R17, Ris, R19, R20. R2, R22, R23, R24. R2s, R26, R27. ^ N Rs. Ro Ro, R. R. and R independently has deuterium O enrichment of no less than about 10%. D 8. The compound as recited in claim 1, wherein at least one D DC of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, OH No R1s. R16. R17, R1s. R19. R20. R21. R22. R2s. R24. R2s. R26. R27. Rs. Ro Ro, R. R. and R independently has deuterium CD3 N-- enrichment of no less than about 5%. D NH Ip-1 9. The compound as recited in claim 1, wherein at least one ^ N of R, R2, Rs. R4 Rs. Rs. R-7, Rs. Ro, Rio, R1, R12, R1s. R14, O R1s. R16, R17, Ris, R19, R20. R21, R22, R23, R24 R2s, R26, R27, D CD3 R2s, Rao, Rao, Rs 1, R32, and Rs independently has deuterium D enrichment of no less than about 1%. US 2008/0312247 A1 Dec. 18, 2008 41

-continued -continued

OH No OH Dicn. N-> CD3 N-k N^{- D D r D Nr. D D r O O D CD D

N D CD3 O r O D3CN OH O N OH O N O D-1 CD3 N O

n- R - ND-11 O O D3C CD

US 2008/0312247 A1 Dec. 18, 2008 43

-continued -continued

D 3 C OH No

D tax r) re-C D OH OH No N O D CD3 N O ^{I-1 D D D D D NH p-1- N D D O D O D CD3 D D OH No OH PCS, CD3 N O D 1 D NH p1-X- --- YY (Y N D D O D CD3 D O D DC D OH No DC OH No N O D D1 CD3 H N O ^{ D D D D D N N|21 D D O D O D CD D DC D OH No OH No CD3 N O D D1 NH p-1N O ^{ D D D D N D D D D O D CD O D OH No OH No

CD3 NH D1 > x. NH D1 AlX r D D D D r D D O O CD DC OH No

N O

C O axxi) rt- x - r

US 2008/0312247 A1 Dec. 18, 2008 45

-continued -continued

OH No OH PCS,

D D |N-- CD3 H D D |N--

O X- r D I I O X- r) D CD3 D OH No CD3 D D N-- OH No r N p-1 H y-is-Xp-1 CD3 O C O X. D D DC OH * no OH No

H D D N-- CD3 D D O N - p-1 D D O O DC CD OH * no 3 DC OH No CD3 D D N O | 1 "Vy" N-Sk" O N XC D D CD O OH No D3CN OH O D D N O H D-1.| N-- CD3 D D N O D N N H

D O D CD

OH N O OH N O

CD3 H D D N-- H D D N-Sk D N

O X-1 r) ill-X-XO D CD3 D D D OH DC No OH No D D N-- CD3 D D N O H H -1 D N D N N N D D

O O D D CD D D

US 2008/0312247 A1 Dec. 18, 2008 49

-continued -continued

DC OH OH No

D D N O H NH Ip-1 D D N t-1 D N D D D D N D D D D O O D CD

OH or a pharmaceutically acceptable salt, Solvate, or prodrug CD3 D D N O thereof. H I N N I-1 D DD D D 11. The compound as recited in claim 10, wherein said compound is Substantially a single enantiomer, a mixture of O about 90% or more by weight of the (-)-enantiomerand about CD 10% or less by weight of the (+)-enantiomer, a mixture of DC about 90% or more by weight of the (+)-enantiomerand about OH 10% or less by weight of the (-)-enantiomer, substantially an D D N O individual diastereomer, or a mixture of about 90% or more NH II-1 D by weight of an individual diastereomer and about 10% or N D D D D less by weight of any other diastereomer. O 12. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of DC at least 98%. OH 13. The compound as recited in claim 10, wherein each of CD3 D said positions represented as Dhave deuterium enrichment of at least 90%. 14. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of at least 50%. OH N 15. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of at least 20%. D D D D D D 16. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of at least 10%. D 17. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of at least 5%. 18. The compound as recited in claim 10, wherein each of said positions represented as Dhave deuterium enrichment of D at least 1%. 19. The compound as recited in claim 1, wherein the com pound is selected from the group consisting of:

DC OH * no CD N O D D N ND1 Dxx D D D r rrn OH o1 CD O N-N-N- US 2008/0312247 A1 Dec. 18, 2008 50

or a pharmaceutically acceptable salt, Solvate, or prodrug -continued thereof. CD3 20. The compound as recited in claim 19, wherein said compound is Substantially a single enantiomer, a mixture of N CD3 about 90% or more by weight of the (-)-enantiomerand about r^ OH o1 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomerand about CD3 N-N-N- 10% or less by weight of the (-)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or D D less by weight of any other diastereomer. N D CD 3 21. The compound as recited in claim 19, wherein each of 1. D OH o1 said positions represented as Dhave deuterium enrichment of O D N-- at least 98%. D 22. The compound as recited in claim 19, wherein each of D D said positions represented as Dhave deuterium enrichment of at least 90%. CD3 D D 23. The compound as recited in claim 19, wherein each of N D CD said positions represented as Dhave deuterium enrichment of 3 at least 50%. 1. D OH o1 24. The compound as recited in claim 19, wherein each of said positions represented as Dhave deuterium enrichment of CD3 O D N-- D at least 20%. D D 25. The compound as recited in claim 19, wherein each of said positions represented as Dhave deuterium enrichment of CD3 D D at least 10%. N PD 1. CD 3 26. The compound as recited in claim 19, wherein each of 1. D OH O said positions represented as Dhave deuterium enrichment of O D N O at least 5%. CD D 27. The compound as recited in claim 19, wherein each of D. D. D. D. D D said positions represented as Dhave deuterium enrichment of at least 1%. 28. A pharmaceutical composition comprising the com N CD3 pound as recited in claim 1 and one or more pharmaceutically acceptable carriers. r^ OH o1 29. A pharmaceutical composition as recited in claim 28, O N----- D further comprising one or more release-controlling excipi entS. 30. The pharmaceutical composition as recited in claim 28, D D further comprising one or more non-release controlling N D excipients. 31. The pharmaceutical composition as recited in claim 28, r D OH 1 wherein the composition is suitable for oral, parenteral, or O D N-- intravenous infusion administration. D 32. The pharmaceutical composition as recited in claim 31, D D wherein the oral dosage form is a tablet or capsule. 33. The pharmaceutical composition as recited in claim 31, CD3 D D wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram. 34. The pharmaceutical composition as recited in claim 28, further comprising another therapeutic agent. 35. The pharmaceutical composition as recited in claim 34, wherein the therapeutic agent is selected from the group consisting of calcium channel blockers, beta-blockers, nitrates or nitrites, ACE inhibitors, statins, platelet aggrega tion inhibitors, adenosine, digitoxin, anti-arrhythmic agents, sympathomimetic drugs, steroidal drugs, non-steroidal anti inflammatory drugs (NSAIDs), opioids, anesthetics, sepsis agents, anti-bacterials, anti-fungals, anti-coagulants, throm bolytics, endothelin converting enzyme (ECE) inhibitors, D D D D thromboxane enzyme antagonists, potassium channel open ers, thrombin inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists, anti-platelet agents, Fac tor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors, US 2008/0312247 A1 Dec. 18, 2008 neutral endopeptidase (NEP) inhibitors, vasopepsidase group consisting of aspirin, aloXiprin, ditazole, carbasalate inhibitors, HMG CoA reductase inhibitors, squalene syn calcium, cloricromen, dipyridamole, indobufen, picotamide, thetase inhibitors, fibrates, bile acid sequestrants, anti-athero triflusal, clopidogrel, ticlopidine, praSugrel, beraprost, pros Sclerotic agents, MTP Inhibitors, potassium channel activa tacyclin, iloprost, and treprostinil. tors, alpha-PDE5 agents, beta-PDL5 agents, diuretics, anti diabetic agents, PPAR-gamma agonists, mineralocorticoid 48. The pharmaceutical composition as recited in claim 47. enzyme antagonists, aP2 inhibitors, protein tyrosine kinase wherein the platelet aggregation inhibitor is aspirin. inhibitors, antiinflammatories, antiproliferatives, chemo 49. A method for the treatment, prevention, or amelioration therapeutic agents, immunosuppressants, anticancer agents, of one or more symptoms of a late Nachannel-mediated cytotoxic agents, antimetabolites, farnesyl-protein trans disorder, in a subject, comprising administering a therapeu ferase inhibitors, hormonal agents, microtubule-disruptor tically effective amount of a compound as recited in claim 1. agents, microtubule-stablizing agents, topoisomerase inhibi 50. The method as recited in claim 49, wherein the late tors, prenyl-protein transferase inhibitors, cyclosporins, Nachannel-mediated disorder is selected from the group TNF-alpha inhibitors, cyclooxygenase-2 (COX-2) inhibitors, consisting of angina, intermittent claudication, and ischemia. gold compounds, antalarmin, Z-338 and platinum coordina tion complexes. 51. The method as recited in claim 49, wherein the late 36. The pharmaceutical composition as recited in claim 35, Nachannel-mediated disorder can be lessened, alleviated, or wherein the therapeutic agent is a calcium channel blocker. prevented by administering a late Nachannel modulator. 37. The pharmaceutical composition as recited in claim 36, 52. The method as recited in claim 49, wherein said com wherein the calcium channel blocker is selected from the pound has at least one of the following properties: group consisting of amlodipine, felodipine, isradipine, nica a) decreased inter-individual variation in plasma levels of rdipine, nifedipine, nimodipine, inhisoldipine, nitrendipine, said compound or a metabolite thereofas compared to lacidipine, nilvadipine, manidipine, barnidipine, lercanid the non-isotopically enriched compound; ipine, cilnidipine, benidipine, mibefradil, Verapamil, gallo b) increased average plasma levels of said compound per pamil, diltiazem, fendiline, bepridil, lidoflazine, and perhex dosage unit thereofas compared to the non-isotopically iline. enriched compound; 38. The pharmaceutical composition as recited in claim 35, c) decreased average plasma levels of at least one metabo wherein the therapeutic agent is a beta-blocker. lite of said compound per dosage unit thereofas com 39. The pharmaceutical composition as recited in claim38, pared to the non-isotopically enriched compound; wherein the beta-blocker is selected from the group consist ing of alprenolol, Oxprenolol, pindolol, propranolol, timolol. d) increased average plasma levels of at least one metabo Sotalol, nadolol, mepindolol, carteolol, tertatolol, bopindolol. lite of said compound per dosage unit thereofas com bupranolol, penbutolol, cloranolol, practolol, metoprolol. pared to the non-isotopically enriched compound; and atenolol, acebutolol, betaxolol, bevantolol, bisoprolol, celip e) an improved clinical effect during the treatment in said rolol, esmolol, epanolol, S-atenolol, nebivolol, talinolol, labe Subject per dosage unit thereofas compared to the non talol, and carvedilol. isotopically enriched compound. 40. The pharmaceutical composition as recited in claim 35, 53. The method as recited in claim 49, wherein said com wherein the therapeutic agent is a nitrate or nitrite. pound has at least two of the following properties: 41. The pharmaceutical composition as recited in claim 40, a) decreased inter-individual variation in plasma levels of wherein the nitrate or nitrite is selected from the group con said compound or a metabolite thereofas compared to sisting of glyceryl trinitrate, isosorbide dinitrate, isosorbide the non-isotopically enriched compound; mononitrate, pentaerythritol tetranitrate, methylpropylpro b) increased average plasma levels of said compound per panediol dinitrate, propatylnitrate, trolnitrate, eritrityltetrani dosage unit thereofas compared to the non-isotopically trate, amyl nitrite, butyl nitrite, ethyl nitrite, methyl nitrite, enriched compound; isopropyl nitrite, isobutyl nitrite, and cyclohexyl nitrite. c) decreased average plasma levels of at least one metabo 42. The pharmaceutical composition as recited in claim 35, lite of said compound per dosage unit thereofas com wherein the therapeutic agent is an ACE inhibitor. pared to the non-isotopically enriched compound; 43. The pharmaceutical composition as recited in claim 42, d) increased average plasma levels of at least one metabo wherein the ACE inhibitor is selected from the group consist ing of captopril, enalapril, lisinopril, perindopril, ramipril, lite of said compound per dosage unit thereofas com quinapril, benazepril, cilaZapril, fosinopril, trandolapril, spi pared to the non-isotopically enriched compound; and rapril, delapril, moexipril, temocapril. Zofenopril, and imi e) an improved clinical effect during the treatment in said dapril. Subject per dosage unit thereofas compared to the non 44. The pharmaceutical composition as recited in claim 35, isotopically enriched compound. wherein the therapeutic agent is a statin. 54. The method as recited in claim 49, wherein the method 45. The pharmaceutical composition as recited in claim 44. affects a decreased metabolism of the compound per dosage wherein the statin is selected from the group consisting of unit thereof by at least one polymorphically-expressed cyto atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, chrome P450 isoform in the subject, as compared to the pitavastatin, pravastatin, rosuvastatin, and simvastatin. corresponding non-isotopically enriched compound. 46. The pharmaceutical composition as recited in claim 35, 55. The method as recited in claim 54, wherein the cyto wherein the therapeutic agent is a platelet aggregation inhibi chrome Paso isoform is selected from the group consisting of tOr. CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 47. The pharmaceutical composition as recited in claim 46, 56. The method as recited in claim 49, wherein said com wherein the platelet aggregation inhibitor is selected from the pound is characterized by decreased inhibition of at least one US 2008/0312247 A1 Dec. 18, 2008 52 cytochrome Paso or monoamine oxidase isoform in said Sub 63. A compound of Formula B: ject per dosage unit thereofas compared to the non-isotopi cally enriched compound. Formula B 57. The method as recited in claim 56, wherein said cyto chrome Paso or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, H CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, Ne CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. R3 CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, R2b YN CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO and or a pharmaceutically acceptable salt thereof wherein: MAO. each of R', R', and R is independently selected from 58. The method as recited in claim 49, wherein the method —CH, —CDH2, —CDH, and —CDs.; affects the treatment of the disease while reducing or elimi R is selected from -CH , CDH , and CD : nating a deleterious change in a diagnostic hepatobiliary R" is C(R) CROH C(R) , wherein each Rs is independently selected from D and H; and function endpoint, as compared to the corresponding non at least one R contains a deuterium atom. isotopically enriched compound. 64. The compound of claim 60, wherein, 59. The method as recited in claim 58, wherein the diag each of R', R', and R’ is independently selected from nostic hepatobiliary function endpoint is selected from the —CH, and –CDs; and R is selected from —CH2—, group consisting of alanine aminotransferase (ALT), serum and - CD -. 65. The compound of claim 60, wherein R' is CP, glutamic-pyruvic transaminase (“SGPT), aspartate ami 66. The compound of claim 60, wherein R* and Rare notransferase (AST,” “SGOT), ALT/AST ratios, serum simultaneously —CD or —CH. aldolase, alkaline phosphatase (ALP), ammonia levels, 67. The compound of claim 66, wherein R* and Rare bilirubin, gamma-glutamyl transpeptidase (“GGTP simultaneously —CD. “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver 68. The compound of claim 60, wherein R is CD, . biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti 69. The compound of claim 60, wherein R is CD dase, and blood protein. CROH C(R) or C(R) CROH CD . 60. A compound of Formula A: 70. The compound of claim 69, wherein R is CD CROH CD, . 71. The compound of claim 70, wherein R is CD Formula A CDOH CD-. 72. The compound according to claim 60, wherein the R2a compound is selected from any one of the compounds in the H table below: N O NY Y la Ylb Y2a R R1 R2b YN Y2b o1 Compound each Y R' R2a R2b R3 R4 Y4a N O 100 H CD, CH, CH, CD, CHCH(OH)CH, N41 101 H CH, CD, CD, CD, CH-CH(OH)CH, y4b 102 H CD, CH, CH, CH, CDCD(OH)CD, 103 H CH, CD, CD, CH, CDCD(OH)CD, 104 H CH, CH, CH, CD, CDCD(OH)CD, 105 H CD, CH, CH, CD, CDCD(OH)CD, 106 H CH, CD, CD, CD, CDCD(OH)CD, or a pharmaceutically acceptable salt thereof wherein: 107 H CD, CD, CD, CD, CDCD(OH)CD each of R', R', and R is independently selected from —CH, —CDH2, —CDH, and —CDs.; or a pharmaceutically acceptable salt thereof. R is selected from —CH2—, —CDH , and CD : 73. The compound according to claim 60, wherein the R is C(R) CROH C(R) , wherein each R is compound is selected from any one of the compounds in the independently selected from D and H: table below: each Y is independently selected from H and D; and when each Y is H, at least one R comprises a deuterium 108 H CD, CD, CD, CH, CHCH(OH)CH, atOm. 109 H CD, CH, CH, CH, CH-CH(OH)CH 61. The compound of claim 60, wherein each Y is the same. 110 D CD, CD, CD, CD, CDCD(OH)CD, 62. The compound of claim 61, wherein each Y is deute rium. or a pharmaceutically acceptable salt thereof. US 2008/0312247 A1 Dec. 18, 2008

74. The compound according to claim 60, wherein any 81. A method of treating a disease or condition selected atom not designated as deuterium is present at its natural from: ischemia; chronic angina; unstable angina; arrhyth isotopic abundance. mias; congestive heart failure; myocardial infarction; diabe 75. A pyrogen-free composition comprising an effective tes; other pathological effects of acute increases in free fatty amount of a compound of claim 60; and an acceptable carrier. acid flux; inflammatory diseases; proliferative diseases; and 76. The composition according to claim 75, wherein the wounds, in a Subject in need thereof comprising the step of composition is formulated for pharmaceutical use; and the administering to the Subject a composition of claim 71. carrier is a pharmaceutically acceptable carrier. 77. The composition according to claim 76, further com 82. The method of claim 81, wherein the disease or condi prising a second therapeutic agent useful in treating a subject tion is selected from chronic angina and unstable angina. Suffering from or Susceptible to a disease or condition 83. The method of claim 81 comprising the further step of selected from ischemia; angina; left ventricular remodeling co-administering to the Subject in need thereof one or more after heart failure; arrhythmias; congestive heart failure; second therapeutic agents selected from a calcium channel myocardial infarction; diabetes; obesity; high serum choles blocker; a beta-blocker; a nitrate; a remodeling agent; pyri terol; viral infections; endothelial dysfunction; pathological doxal-5'-phosphate; a sterol absorption inhibitor; a sodium effects of acute increases in free fatty acid flux; inflammatory hydrogen exchanger type-1 inhibitor, an aldosterone antago diseases; proliferative diseases; and wounds. nist; an HMG CoA reductase inhibitor; an adenosine A-3 78. The composition according to claim 77, wherein the receptor agonist; an HMG CoA reductase inhibitor; a sterol second therapeutic agent is selected from a calcium channel absorption inhibitor; a cholesterol ester transfer protein blocker; a beta-blocker, a nitrate; a remodeling agent; a sterol (CETP) inhibitor; a UCP inhibitor; a Fas inhibitor; a quino absorption inhibitor, a sodium-hydrogen exchanger type-1 line or a derivative or an intermediate thereof, and a chemo inhibitor; an HMG CoA reductase inhibitor, a UCP inhibitor; therapeutic agent. a Fas inhibitor, an adenosine A-3 receptor agonist; an aldos 84. The method according to claim 83, wherein the disease terone antagonist; and a quinoline or a derivative or an inter or disorder is a cardiovascular disease and the second thera mediate thereof. peutic agent is selected from a beta blocker, a calcium channel 79. The composition according to claim 78, wherein the blocker and a nitrate. second therapeutic agent is selected from a beta blocker, a 85. The method according to claim 84, wherein the second calcium channel blocker or a nitrate. therapeutic agent is selected from amlodipine, atenolol and 80. The composition according to claim 79, wherein the nitroglycerine. second therapeutic agent is amlodipine, atenolol, or nitro glycerine.