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Home , Astemizole, Bamipine, Casopitant, Chlorcyclizine, Deptropine, Dimetindene

US 20100113431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0113431 A1 Gant et al. (43) Pub. Date: May 6, 2010

(54) N-METHYL PPERAZINE MODULATORS OF (52) U.S. Cl...... 514/226.2:544/396; 514/255.04 H1

(75) Inventors: Thomas G. Gant, Carlsbad, CA (57) ABSTRACT (US); Manouchehr M. Shahbaz, San Diego, CA (US) The present invention relates to new N-methyl Correspondence Address: modulators of H1 receptor activity, pharmaceutical composi GLOBAL PATENT GROUP - APX tions thereof, and methods of use thereof. 10411 Clayton Road, Suite 304 ST. LOUIS, MO 63131 (US) (73) Assignee: AUSPEX PHARMACEUTICALS, INC.,

Formula I Vista, CA (US) (21) Appl. No.: 12/611,973 (22) Filed: Nov. 4, 2009 Related U.S. Application Data (60) Provisional application No. 61/111,595, filed on Nov. 5, 2008. Publication Classification (51) Int. C. A6 IK 3/495 (2006.01) CO7D 24/04 (2006.01) A6 IK 3/54 (2006.01) A6IPI/00 (2006.01) US 2010/01 13431 A1 May 6, 2010

N-METHYL PPERAZINE MODULATORS OF , , epigastric distress, diarrhea, and dry mouth H1 RECEPTOR (Steffeket al., Teratology 1968, 1(4),399-406; and Herbert et al., J. Pharmacol. Exp. Ther: 1967, 155(3), 494-505). 0001. This application claims the benefit of priority of Deuterium Kinetic Isotope Effect U.S. provisional application No. 61/111,595, filed Nov. 5, 0005. In order to eliminate foreign substances such as 2008, the disclosure of which is hereby incorporated by ref therapeutic agents, the animal body expresses various erence as if written herein in its entirety. enzymes, such as the cytochrome Paso enzymes (CYPs), 0002 Disclosed herein are new N-methylpiperazine com esterases, proteases, reductases, dehydrogenases, and pounds, pharmaceutical compositions made thereof, and monoamine oxidases, to react with and convert these foreign methods to modulate H1 receptor activity in a subjectare also Substances to more polar intermediates or metabolites for provided for the treatment of disorders such as acute nausea renal . Such metabolic reactions frequently involve and Vomiting, delayed onset nausea and Vomiting, postopera the oxidation of a carbon-hydrogen (C H) bond to either a tive nausea and Vomiting, motion sickness, reac carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. tions, immune disorders, toxicity resulting from exposure to The resultant metabolites may be stable or unstable under anticholinesterases, , hay fever, con physiological conditions, and can have substantially different junctivitis, urticaria, human immunodeficiency virus (HIV), pharmacokinetic, pharmacodynamic, and acute and long tumor growth, and cancer. term toxicity profiles relative to the parent compounds. For 0003 (Alergicide, Chlorcycline, Chloro most drugs, such oxidations are generally rapid and ulti cycline, Compound 47-282, NSC 25246, Perazyl, Chlorcy mately lead to administration of multiple or high daily doses. clizine Hydrochloride. Histachlorazine, Chlorcyclizinium 0006. The relationship between the activation energy and , Di-Paralene, Di-Paralen; Trihistan, and CAS #82 the rate of reaction may be quantified by the Arrhenius equa 93-9), 1-(4-Chloro-phenyl)-phenyl-methyl-4-methyl-pip tion, k=Ae'. The Arrhenius equation states that, at a erazine, is a H1 . Chlorcyclizine is com given temperature, the rate of a chemical reaction depends monly prescribed for the treatment of acute nausea and exponentially on the activation energy (E). Vomiting, delayed onset nausea and Vomiting, postoperative 0007. The transition state in a reaction is a short lived state nausea and Vomiting, motion sickness, histamine reactions, along the reaction pathway during which the original bonds and immune disorders (Korttila et al., Acta Anaesth. Scand. have stretched to their limit. By definition, the activation 2007, 51 (8), 989-990; Kuntzman et al., J. Pharmacol. Exp. energy E for a reaction is the energy required to reach the Ther: 1965, 149(1), 29-35; and Castillo et al., J. Pharmacol. transition state of that reaction. Once the transition state is Exp. Ther: 1949, 96(4), 388-395). Chlorcyclizine has also reached, the molecules can either revert to the original reac shown promise in treating toxicity resulting from exposure to tants, or form new bonds giving rise to reaction products. A organophosphate anticholinesterases, as well as rhinitis, hay catalyst facilitates a reaction process by lowering the activa fever, conjunctivitis, urticaria, human immunodeficiency tion energy leading to a transition state. Enzymes are virus (HIV), tumor growth, and cancer (Welch et al., J. Phar examples of biological catalysts. macol. Exp. Ther: 1964, 143(2), 192-198). 0008 Carbon-hydrogen bond strength is directly propor tional to the absolute value of the ground-state vibrational energy of the bond. This vibrational energy depends on the mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. Since deuterium (D) has twice the mass of protium (H), a C-D bond is stronger than the corresponding C–H bond. If a C-H bond is broken during a rate-determining step in a () chemical reaction (i.e. the step with the highest transition state energy), then Substituting a deuterium for that protium will cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE). The magnitude of the DKIE can be expressed as the ratio between Chlorcyclizine the rates of a given reaction in which a C H bond is broken, and the same reaction where deuterium is substituted for protium. The DKIE can range from about 1 (no isotope effect) 0004 Chlorcyclizine is subject to hepatic metabolism. to very large numbers, such as 50 or more. Substitution of Chlorcyclizine is predominantly metabolized via N-dem tritium for hydrogen results in yet a stronger bond than deu ethylation at the piperazine nitrogen to form a desmethyl terium and gives numerically larger isotope effects metabolite. This desmethyl metabolite can be further metabo I0009 Deuterium (H or D) is a stable and non-radioactive lized, by oxidative ring opening of the pipererizine ring, to isotope of hydrogen which has approximately twice the mass form an metabolite. Both metabolites are of protium ("H), the most common isotope of hydrogen. not pharmacologically active. The relative contribution of Deuterium oxide (DO or "heavy water) looks and tastes like these metabolites to the the drug's toxicity profile has yet to be HO, but has different physical properties. determined (Gaertner et al., J. Pharmacol. Exp. Ther: 1973, I0010. When pure DO is given to rodents, it is readily 185(2), 195-201; and Kuntzman et al., J. Pharmacol. Exp. absorbed. The quantity of deuterium required to induce tox Ther: 1967, 155(2),337-344). Adverse effects associated with icity is extremely high. When about 0-15% of the body water chlorcyclizine administration include abortion or congenital has been replaced by DO, animals are healthy but are unable malformations such as a cleft palate in pregnant females, to gain weight as fast as the control (untreated) group. When US 2010/01 13431 A1 May 6, 2010

about 15-20% of the body water has been replaced with D.O. decrease the amount of a dose needed to achieve a desired the animals become excitable. When about 20-25% of the effect, (e) increase the formation of active metabolites, if any body water has been replaced with DO, the animals become are formed, (f) decrease the production of deleterious so excitable that they go into frequent convulsions when metabolites in specific tissues, and/or (g) create a more effec stimulated. Skin lesions, ulcers on the paws and muzzles, and tive drug and/or a safer drug for polypharmacy, whether the necrosis of the tails appear. The animals also become very polypharmacy be intentional or not. The deuteration aggressive. When about 30% of the body water has been approach has the strong potential to slow the metabolism of replaced with DO, the animals refuse to eat and become chlorcyclizine and attenuate interpatient variability. comatose. Their body weight drops sharply and their meta 0014 Novel compounds and pharmaceutical composi bolic rates drop far below normal, with death occurring at tions, certain of which have been found to modulate H1 about 30 to about 35% replacement with D.O.The effects are receptors have been discovered, together with methods of reversible unless more than thirty percent of the previous synthesizing and using the compounds, including methods body weight has been lost due to D.O. Studies have also for the treatment of H1 receptor-mediated disorders in a shown that the use of DO can delay the growth of cancer cells patient by administering the compounds as disclosed herein. and enhance the cytotoxicity of certain antineoplastic agents. 0015. In certain embodiments of the present invention, 0011 Deuteration of pharmaceuticals to improve pharma compounds have structural Formula I: cokinetics (PK), (PD), and toxicity pro files has been demonstrated previously with some classes of drugs. For example, the DKIE was used to decrease the hepa (I) totoxicity of , presumably by limiting the produc tion of reactive species such as trifluoroacetylchloride. How ever, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic Switching. Metabolic Switching occurs when Xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching is enabled by the rela tively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class. 0012 Chlorcyclizine is a H1 receptor competitive antago nist. The carbon-hydrogen bonds of chlorcyclizine contain a or a salt, Solvate, or thereof, wherein: naturally occurring distribution of hydrogenisotopes, namely 0016 R-R are independently selected from the group "H or protium (about 99.984.4%), H or deuterium (about consisting of hydrogen and deuterium; and 0.0156%), and H or tritium (in the range between about 0.5 0017 at least one of R-R is deuterium. and 67 tritium atoms per 10' protium atoms). Increased 0018 Certain compounds disclosed herein may possess levels of deuterium incorporation may produce a detectable useful H1 receptor modulating activity, and may be used in Deuterium Kinetic Isotope Effect (DKIE) that could effect the treatment or prophylaxis of a disorder in which H1 recep the pharmacokinetic, pharmacologic and/or toxicologic pro tors play an active role. Thus, certain embodiments also pro files of chlorcyclizine in comparison with chlorcyclizine hav vide pharmaceutical compositions comprising one or more ing naturally occurring levels of deuterium. compounds disclosed herein together with a pharmaceuti 0013 Based on discoveries made in our laboratory, as well cally acceptable carrier, as well as methods of making and as considering the literature, chlorcyclizine is metabolized in using the compounds and compositions. Certain embodi humans at the piperazine methyl and methylene groups. The ments provide methods for modulating H1 receptors. Other current approach has the potential to prevent metabolism at embodiments provide methods for treating a H1 receptor these sites. Other sites on the molecule may also undergo mediated disorder in a patient in need of Such treatment, transformations leading to metabolites with as-yet-unknown comprising administering to said patient a therapeutically pharmacology/toxicology. Limiting the production of these effective amount of a compound or composition according to metabolites has the potential to decrease the danger of the the present invention. Also provided is the use of certain administration of Such drugs and may even allow increased compounds disclosed herein for use in the manufacture of a dosage and/or increased efficacy. All of these transformations medicament for the prevention or treatment of a disorder can occur through polymorphically-expressed enzymes, ameliorated by the modulation of H1 receptors. exacerbating interpatient variability. Further, some disorders 0019. The compounds as disclosed herein may also con are best treated when the subject is medicated around the tain less prevalent isotopes for other elements, including, but clock or for an extended period of time. For all of the forego not limited to, 'Cor'C for carbon, S.S, or S for sulfur, ing reasons, a medicine with a longer half-life may result in 'N for nitrogen, and ''O or "O for oxygen. greater efficacy and cost savings. Various deuteration patterns 0020. In certain embodiments, the compound disclosed can be used to (a) reduce or eliminate unwanted metabolites, herein may expose a patient to a maximum of about (b) increase the half-life of the parent drug, (c) decrease the 0.000005% DO or about 0.00001% DHO, assuming that all number of doses needed to achieve a desired effect, (d) of the C-D bonds in the compound as disclosed herein are US 2010/01 13431 A1 May 6, 2010

metabolized and released as DO or DHO. In certain embodi less than about 70%, in another no less than about 80%, in ments, the levels of DO shown to cause toxicity in animals is another no less than about 90%, or in another no less than much greater than even the maximum limit of exposure about 98% of deuterium at the specified position. caused by administration of the deuterium enriched com (0029. The term “isotopic enrichment” refers to the per pound as disclosed herein. Thus, in certain embodiments, the centage of incorporation of a less prevalent isotope of an deuterium-enriched compound disclosed herein should not element at a given position in a molecule in the place of the cause any additional toxicity due to the formation of DO or more prevalent isotope of the element. DHO upon . 0030 The term “non-isotopically enriched’ refers to a 0021. In certain embodiments, the deuterated compounds molecule in which the percentages of the various isotopes are disclosed herein maintain the beneficial aspects of the corre Substantially the same as the naturally occurring percentages. sponding non-isotopically enriched molecules while Substan 0031 Asymmetric centers exist in the compounds dis tially increasing the maximum tolerated dose, decreasingtox closed herein. These centers are designated by the symbols icity, increasing the half-life (T), lowering the maximum “R” or “S”, depending on the configuration of substituents plasma concentration (C) of the minimum efficacious around the chiral carbon atom. It should be understood that dose (MED), lowering the efficacious dose and thus decreas the invention encompasses all Stereochemical isomeric ing the non-mechanism-related toxicity, and/or lowering the forms, including diastereomeric, enantiomeric, and epimeric probability of drug-drug interactions. forms, as well as D-isomers and L-isomers, and mixtures 0022 All publications and references cited herein are thereof. Individual stereoisomers of compounds can be pre expressly incorporated herein by reference in their entirety. pared synthetically from commercially available starting However, with respect to any similar or identical terms found materials which contain chiral centers or by preparation of in both the incorporated publications or references and those mixtures of enantiomeric products followed by separation explicitly put forth or defined in this document, then those such as conversion to a mixture of diastereomers followed by terms definitions or meanings explicitly put forthin this docu separation or recrystallization, chromatographic techniques, ment shall control in all respects. direct separation of enantiomers on chiral chromatographic 0023. As used herein, the terms below have the meanings columns, or any other appropriate method known in the art. indicated. Starting compounds of particular Stereochemistry are either 0024. The singular forms “a”, “an', and “the may refer to commercially available or can be made and resolved by tech plural articles unless specifically stated otherwise. niques known in the art. Additionally, the compounds dis 0025. The term “about’, as used herein, is intended to closed herein may exist as geometric isomers. The present qualify the numerical values which it modifies, denoting Such invention includes all cis, trans, syn, anti, entgegen (E), and a value as variable within a margin of error. When no particu Zusammen (Z) isomers as well as the appropriate mixtures lar margin of error, such as a standard deviation to a mean thereof. Additionally, compounds may exist as tautomers; all value given in a chart or table of data, is recited, the term tautomeric isomers are provided by this invention. Addition “about’ should be understood to mean that range which ally, the compounds disclosed herein can exist in unsolvated would encompass the recited value and the range which as well as Solvated forms with pharmaceutically acceptable would be included by rounding up or down to that figure as Solvents such as water, ethanol, and the like. In general, the well, taking into account significant figures. Solvated forms are considered equivalent to the unsolvated 0026. When ranges of values are disclosed, and the nota forms. tion “from n ... to n' or “n-n' is used, where n and n are 0032. The term “bond refers to a covalent linkage the numbers, then unless otherwise specified, this notation is between two atoms, or two moieties when the atoms joined by intended to include the numbers themselves and the range the bond are considered to be part of larger substructure. A between them. This range may be integral or continuous bond may be single, double, or triple unless otherwise speci between and including the end values. fied. A dashed line between two atoms in a drawing of a 0027. The term “deuterium enrichment” refers to the per molecule indicates that an additional bond may be present or centage of incorporation of deuterium at a given position in a absent at that position. molecule in the place of hydrogen. For example, deuterium 0033. The term “disorder as used herein is intended to be enrichment of 1% at a given position means that 1% of mol generally synonymous, and is used interchangeably with, the ecules in a given sample contain deuterium at the specified terms “disease”, “syndrome', and “condition' (as in medical position. Because the naturally occurring distribution of deu condition), in that all reflect an abnormal condition of the terium is about 0.0156%, deuterium enrichment at any posi human or animal body or of one of its parts that impairs tion in a compound synthesized using non-enriched starting normal functioning, is typically manifested by distinguishing materials is about 0.0156%. The deuterium enrichment can signs and Symptoms. be determined using conventional analytical methods known 0034. The terms “treat”, “treating, and “treatment” are to one of ordinary skill in the art, including mass spectrometry meant to include alleviating or abrogating a disorder or one or and nuclear magnetic resonance spectroscopy. more of the symptoms associated with a disorder; or allevi 0028. The term “is/are deuterium', when used to describe ating or eradicating the cause(s) of the disorder itself. As used a given position in a molecule such as R-R or the symbol herein, reference to “treatment'of a disorder is intended to “D’, when used to represent a given position in a drawing of include prevention. The terms “prevent”, “preventing, and a molecular structure, means that the specified position is “prevention” refer to a method of delaying or precluding the enriched with deuterium above the naturally occurring distri onset of a disorder; and/or its attendant symptoms, barring a bution of deuterium. In one embodiment deuterium enrich Subject from acquiring a disorder or reducing a subject's risk ment is no less than about 1%, in another no less than about of acquiring a disorder. 5%, in another no less than about 10%, in another no less than 0035. The term “therapeutically effective amount” refers about 20%, in another no less than about 50%, in another no to the amount of a compound that, when administered, is US 2010/01 13431 A1 May 6, 2010 sufficient to prevent development of, or alleviate to some activity of a H1 receptor, may activate or inhibit the activity of extent, one or more of the symptoms of the disorder being a H1 receptor depending on the concentration of the com treated. The term “therapeutically effective amount” also pound exposed to the H1 receptor, or may inhibit the activity refers to the amount of a compound that is sufficient to elicit of a H1 receptor. Such activation or inhibition may be con the biological or medical response of a cell, tissue, system, tingent on the occurrence of a specific event, such as activa animal, or human that is being sought by a researcher, Veteri tion of a signal transduction pathway, and/or may be manifest narian, medical doctor, or clinician. only in particular cell types. The term “H1 receptor modula 0036. The term “subject” refers to an animal, including, tor, also refers to altering the function of a H1 receptor by but not limited to, a primate (e.g., human, monkey, chimpan increasing or decreasing the probability that a complex forms Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, between a H1 receptor and a natural binding partner. A H1 hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, may increase the probability that Such a miniature pig), equine, canine, feline, and the like. The terms complex forms between the H1 receptor and the natural bind “subject' and “patient” are used interchangeably herein in ing partner, may increase or decrease the probability that a reference, for example, to a mammalian Subject, such as a complex forms between the H1 receptor and the natural bind human patient. ing partner depending on the concentration of the compound 0037. The term “combination therapy’ means the admin exposed to the H1 receptor, and or may decrease the prob istration of two or more therapeutic agents to treat a thera ability that a complex forms between the H1 receptor and the peutic disorder described in the present disclosure. Such administration encompasses co-administration of these natural binding partner. In some embodiments, modulation of therapeutic agents in a Substantially simultaneous manner, the H1 receptor may be assessed using the method described Such as in a single capsule having a fixed ratio of active in Castillo et al., J. Pharmacol. Exp. Ther: 1949, 96(4), 388 ingredients or in multiple, separate capsules for each active 395. ingredient. In addition, Such administration also encom 0041. The term “therapeutically acceptable” refers to passes use of each type of therapeutic agent in a sequential those compounds (or salts, , tautomers, Zwitterionic manner. In either case, the treatment regimen will provide forms, etc.) which are suitable for use in contact with the beneficial effects of the drug combination in treating the tissues of patients without excessive toxicity, irritation, aller disorders described herein. gic response, immunogenecity, are commensurate with a rea 0038. The term “H1 receptor refers to a class of G-protein sonable benefit/risk ratio, and are effective for their intended coupled receptors for which histamine is the endogenous SC. . There are four known histamine receptors: H1, H2, 0042. The term “modulation of H1 receptor activity” or H3, and H4. Histamine H1 receptors are metabotropic G-pro “modulate H1 receptor activity” refers to altering the function tein-coupled receptors expressed throughout the body, spe of H1 receptors by administering an H1 receptor modulator. cifically in Smooth muscles, on vascular endothelial cells, in 0043. The term “pharmaceutically acceptable carrier, the heart, and in the central nervous system. The H1 receptor “pharmaceutically acceptable excipient”, “physiologically is linked to an intracellular G-protein (Gd) which activates acceptable carrier, or “physiologically acceptable excipi phospholipase C and the phosphatidylinositol (PIP2) signal ent” refers to a pharmaceutically-acceptable material, com ling pathway. The production of prostaglandin E2 synthase position, or vehicle, such as a liquid or Solid filler, diluent, induces the release of histamine from neurons, consequen excipient, Solvent, or encapsulating material. Each compo tially causing systemic vasodilation along with increased cell nent must be “pharmaceutically acceptable' in the sense of permeability due to the its action on H1 receptors. Histamine being compatible with the other ingredients of a pharmaceu H1 receptors are activated by endogenous histamine, which is tical formulation. It must also be suitable for use in contact released by neurons which have their cell bodies in the with the tissue or organ of humans and animals without exces tuberomamillary nucleus of the hypothalamus. The histamin sive toxicity, irritation, allergic response, immunogenecity, or ergic neurons of the tuberomammillary nucleus become other problems or complications, commensurate with a rea active during the wake cycle. In the cortex, activation of H1 sonable benefit/risk ratio. See, Remington. The Science and receptors leads to inhibition of cell membrane potassium Practice of Pharmacy, 21st Edition; Lippincott Williams & channels. This depolarizes the neurons and increases the Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceu resistance of the neuronal cell membrane, bringing the cell tical Excipients, 5th Edition; Rowe et al., Eds. The Pharma closer to its firing threshold and increasing the excitatory ceutical Press and the American Pharmaceutical Association: Voltage produced by a given excitatory current. H1 receptor 2005; and Handbook of Pharmaceutical Additives, 3rd Edi antagonists typically produce drowsiness because they tion; Ash and Ash Eds. Gower Publishing Company: 2007: oppose this action, reducing neuronal excitation. Pharmaceutical Preformulation and Formulation, Gibson 0039. The term “H1 receptor-mediated disorder” refers to Ed., CRC Press LLC: Boca Raton, Fla., 2004). a disorder that is characterized by abnormal H1 receptor 0044) The terms “active ingredient”, “active compound', activity. AH1 receptor-mediated disorder may be completely and “active substance' refer to a compound, which is admin or partially mediated by modulating H1 receptors. In particu istered, alone or in combination with one or more pharma lar, a H1 receptor-mediated disorder is one in which modu ceutically acceptable excipients or carriers, to a Subject for lation of H1 receptors results in some effect on the underlying treating, preventing, or ameliorating one or more symptoms disorder e.g., administration of a H1 receptor modulator of a disorder. results in some improvement in at least Some of the patients 0045. The terms “drug”,99 “therapeutic&g agent, and “chemo being treated. therapeutic agent” refer to a compound, or a pharmaceutical 0040. The term “H1 receptor modulator, refers to the composition thereof, which is administered to a subject for ability of a compound disclosed hereinto alter the function of treating, preventing, or ameliorating one or more symptoms H1 receptors. A H1 receptor modulator may activate the of a disorder. US 2010/01 13431 A1 May 6, 2010

0046. The term “release controlling excipient” refers to an muth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) and Berge excipient whose primary function is to modify the duration or et al., J. Pharm. Sci. 1977, 66, 1-19. place of release of the active Substance from a dosage form as 0050 Suitable acids for use in the preparation of pharma compared with a conventional immediate release dosage ceutically acceptable salts include, but are not limited to, form. acetic acid, 2,2-dichloroacetic acid, acylated amino acids, 0047. The term “nonrelease controlling excipient” refers adipic acid, alginic acid, ascorbic acid, L-aspartic acid, ben to an excipient whose primary function do not include modi Zenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- fying the duration or place of release of the active Substance (1S)--10-Sulfonic acid, capric acid, caproic acid, from a dosage form as compared with a conventional imme caprylic acid, cinnamic acid, , cyclamic acid, cyclo diate release dosage form. hexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disul 0048. The term “prodrug” refers to a compound functional fonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic derivative of the compound as disclosed herein and is readily acid, formic acid, fumaric acid, galactaric acid, gentisic acid, convertible into the parent compound in vivo. Prodrugs are glucoheptonic acid, D-gluconic acid, D-glucuronic acid, often useful because, in Some situations, they may be easierto L-, C.-OXO-glutaric acid, glycolic acid, hippuric administer than the parent compound. They may, for instance, acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, be bioavailable by oral administration whereas the parent (+)-L-lactic acid, (t)-DL-lactic acid, lactobionic acid, lauric compound is not. The prodrug may also have enhanced solu acid, , (-)-L-malic acid, malonic acid, (t)-DL bility in pharmaceutical compositions over the parent com mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic pound. A prodrug may be converted into the parent drug by acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naph various mechanisms, including enzymatic processes and thoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, metabolic hydrolysis. See Harper, Progress in Drug Research oxalic acid, palmitic acid, pamoic acid, perchloric acid, phos 1962, 4, 221–294; Morozowich et al. in “Design of Biophar phoric acid, L-pyroglutamic acid, Saccharic acid, salicylic maceutical Properties through Prodrugs and Analogs. Roche acid, 4-amino-, sebacic acid, Stearic acid, Suc Ed., APHA Acad. Pharm. Sci. 1977: “Bioreversible Carriers cinic acid, Sulfuric acid, tannic acid, (+)-L-tartaric acid, thio in Drug in Drug Design, Theory and Application. Roche Ed., cyanic acid, p-toluenesulfonic acid, undecylenic acid, and APHA Acad. Pharm. Sci. 1987: “Design of Prodrugs.” Bund Valeric acid. gaard, Elsevier, 1985; Wang et al., Curr: Pharm. Design 1999, 0051 Suitable bases for use in the preparation of pharma 5,265-287: Pauletti et al., Adv. Drug. Delivery Rev. 1997.27, ceutically acceptable salts, including, but not limited to, inor 235-256; Mizen et al., Pharm. Biotech. 1998, 11, 345-365; ganic bases, such as magnesium hydroxide, calcium hydrox Gaignault et al., Pract. Med. Chem. 1996, 671-696; ide, potassium hydroxide, hydroxide, or Sodium Asgharnejad in “Transport Processes in Pharmaceutical Sys hydroxide; and organic bases, such as primary, secondary, tems. Amidon et al., Ed., Marcell Dekker, 185-218, 2000; tertiary, and quaternary, aliphatic and aromatic amines, Balant et al., Eur: J. Drug Metab. Pharmacokinet. 1990, 15, including L-arginine, benethamine, benzathine, , 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, deanol, diethanolamine, diethylamine, dimethylamine, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1-12; dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, Bundgaard, Arch. Pharm. Chem. 1979, 86, 1-39: Bundgaard, ethanolamine, ethylamine, ethylenediamine, isopropy Controlled Drug Delivery 1987, 17, 179–96: Bundgaard, Adv. lamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, Drug Delivery Rev. 1992, 8, 1-38; Fleisher et al., Adv. Drug L-, morpholine, 4-(2-hydroxyethyl)-morpholine, Delivery Rev. 1996, 19, 115-130; Fleisher et al., Methods methylamine, piperidine, piperazine, propylamine, pyrroli Enzymol. 1985, 112,360-381: Farquhar et al., J. Pharm. Sci. dine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, 1983, 72, 324-325; Freeman et al., J. Chem. Soc., Chem. , isoquinoline, secondary amines, triethanolamine, Commun. 1991, 875-877: Friis and Bundgaard, Eur: J. trimethylamine, triethylamine, N-methyl-D-glucamine, Pharm. Sci. 1996, 4, 49-59; Gangwar et al., Des. Biopharm. 2-amino-2-(hydroxymethyl)-1,3-propanediol. and Prop. Prodrugs Analogs, 1977, 409–421; Nathwani and tromethamine. Wood, Drugs 1993, 45,866-94: Sinhababu and Thakker, Adv. 0.052 While it may be possible for the compounds of the Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs Subject invention to be administered as the raw chemical, it is 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, also possible to present them as a pharmaceutical composi 39, 117-151; Taylor, Adv. Drug Delivery Rev. 1996, 19, 131 tion. Accordingly, provided herein are pharmaceutical com 148; Valentino and Borchardt, Drug Discovery Today 1997.2, positions which comprise one or more of certain compounds 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, disclosed herein, or one or more pharmaceutically acceptable 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, salts, prodrugs, or Solvates thereof, together with one or more 497-507. pharmaceutically acceptable carriers thereof and optionally 0049. The compounds disclosed herein can exist as thera one or more other therapeutic ingredients. Properformulation peutically acceptable salts. The term “therapeutically accept is dependent upon the route of administration chosen. Any of able salt as used herein, represents salts or Zwitterionic the well-known techniques, carriers, and excipients may be forms of the compounds disclosed herein which are therapeu used as Suitable and as understood in the art; e.g., in Reming tically acceptable as defined herein. The salts can be prepared ton's Pharmaceutical Sciences. The pharmaceutical compo during the final isolation and purification of the compounds or sitions disclosed herein may be manufactured in any manner separately by reacting the appropriate compound with a Suit known in the art, e.g., by means of conventional mixing, able acid or base. Therapeutically acceptable salts include dissolving, granulating, dragee-making, levigating, emulsi acid and basic addition salts. For a more complete discussion fying, encapsulating, entrapping or compression processes. of the preparation and selection of salts, refer to “Handbook The pharmaceutical compositions may also be formulated as of Pharmaceutical Salts, Properties, and Use.” Stah and Wer a modified release dosage form, including delayed-, US 2010/01 13431 A1 May 6, 2010

extended-, prolonged-, Sustained-, pulsatile-, controlled may be added to the tablets or dragee coatings for identifica accelerated- and fast-, targeted-, programmed-release, and tion or to characterize different combinations of active com gastric retention dosage forms. These dosage forms can be pound doses. prepared according to conventional methods and techniques 0056. The compounds may be formulated for parenteral known to those skilled in the art (see, Remington. The Science administration by injection, e.g., by bolus injection or con and Practice of Pharmacy, supra, Modified-Release Drug tinuous infusion. Formulations for injection may be presented Deliver Technology, Rathbone et al., Eds. Drugs and the in unit dosage form, e.g., in ampoules or in multi-dose con Pharmaceutical Science, Marcel Dekker, Inc.: New York, tainers, with an added preservative. The compositions may take Such forms as Suspensions, solutions or emulsions in oily N.Y., 2002: Vol. 126). or aqueous vehicles, and may contain formulatory agents 0053. The compositions include those suitable for oral, Such as Suspending, stabilizing and/or dispersing agents. The parenteral (including Subcutaneous, intradermal, intramuscu formulations may be presented in unit-dose or multi-dose lar, intravenous, intraarticular, and intramedullary), intraperi containers, for example sealed ampoules and vials, and may toneal, transmucosal, transdermal, rectal and topical (includ be stored in powder form or in a freeze-dried (lyophilized) ing dermal, buccal, Sublingual and intraocular) condition requiring only the addition of the sterile liquid administration although the most Suitable route may depend carrier, for example, saline or sterile pyrogen-free water, upon for example the condition and disorder of the recipient. immediately prior to use. Extemporaneous injection solu The compositions may conveniently be presented in unit dos tions and Suspensions may be prepared from sterile powders, age form and may be prepared by any of the methods well granules and tablets of the kind previously described. known in the art of pharmacy. Typically, these methods 0057 Formulations for parenteral administration include include the step of bringing into association a compound of aqueous and non-aqueous (oily) sterile injection Solutions of the Subject invention or a pharmaceutically salt, prodrug, or the active compounds which may contain antioxidants, buff solvate thereof (“active ingredient') with the carrier which ers, bacteriostats and solutes which render the formulation constitutes one or more accessory ingredients. In general, the isotonic with the blood of the intended recipient; and aqueous compositions are prepared by uniformly and intimately and non-aqueous sterile Suspensions which may include Sus bringing into association the active ingredient with liquid pending agents and thickening agents. Suitable lipophilic carriers or finely divided solid carriers or both and then, if Solvents or vehicles include fatty oils such as sesame oil, or necessary, shaping the product into the desired formulation. synthetic fatty acid esters, such as ethyl oleate or triglycer 0054 Formulations of the compounds disclosed herein ides, or liposomes. Aqueous injection suspensions may con Suitable for oral administration may be presented as discrete tain Substances which increase the Viscosity of the Suspen units such as capsules, cachets or tablets each containing a Sion, such as Sodium carboxymethyl cellulose, Sorbitol, or predetermined amount of the active ingredient; as a powder or dextran. Optionally, the Suspension may also contain Suitable granules; as a solution or a suspension in an aqueous liquid or stabilizers or agents which increase the solubility of the com a non-aqueous liquid; or as an oil-in-water liquid emulsion or pounds to allow for the preparation of highly concentrated a water-in-oil liquid emulsion. The active ingredient may also Solutions. be presented as a bolus, electuary or paste. 0058. In addition to the formulations described previously, 0055 Pharmaceutical preparations which can be used the compounds may also be formulated as a depot prepara orally include tablets, push-fit capsules made of gelatin, as tion. Such long acting formulations may be administered by well as Soft, sealed capsules made of gelatin and a plasticizer, implantation (for example Subcutaneously or intramuscu Such as glycerol or Sorbitol. Tablets may be made by com larly) or by intramuscular injection. Thus, for example, the pression or molding, optionally with one or more accessory compounds may be formulated with Suitable polymeric or ingredients. Compressed tablets may be prepared by com hydrophobic materials (for example as an emulsion in an pressing in a suitable machine the active ingredient in a free acceptable oil) or ion exchange resins, or as sparingly soluble flowing form such as a powder or granules, optionally mixed derivatives, for example, as a sparingly soluble salt. with binders, inert diluents, or lubricating, surface active or 0059 Forbuccal or sublingual administration, the compo dispersing agents. Molded tablets may be made by molding in sitions may take the form of tablets, lozenges, pastilles, or a suitable machine a mixture of the powdered compound gels formulated in conventional manner. Such compositions moistened with an inert liquid diluent. The tablets may may comprise the active ingredient in a flavored basis such as optionally be coated or scored and may be formulated so as to Sucrose and acacia or tragacanth. provide slow or controlled release of the active ingredient 0060. The compounds may also be formulated in rectal therein. All formulations for oral administration should be in compositions such as Suppositories or retention enemas, e.g., dosages suitable for Such administration. The push-fit cap containing conventional Suppository bases such as cocoa but Sules can contain the active ingredients in admixture with ter, polyethylene glycol, or other glycerides. filler Such as lactose, binders such as starches, and/or lubri 0061 Certain compounds disclosed herein may be admin cants such as talc or magnesium Stearate and, optionally, istered topically, that is by non-systemic administration. This stabilizers. In soft capsules, the active compounds may be includes the application of a compound disclosed herein dissolved or Suspended in Suitable liquids, such as fatty oils, externally to the epidermis or the buccal cavity and the instil liquid paraffin, or liquid polyethylene glycols. In addition, lation of such a compound into the ear, eye and nose, such that stabilizers may be added. Dragee cores are provided with the compound does not significantly enter the blood stream. Suitable coatings. For this purpose, concentrated Sugar Solu In contrast, Systemic administration refers to oral, intrave tions may be used, which may optionally contain gum arabic, nous, intraperitoneal and intramuscular administration. talc, polyvinyl pyrrolidone, carbopol gel, polyethylene gly 0062 Formulations suitable for topical administration col, and/or titanium dioxide, lacquer Solutions, and Suitable include liquid or semi-liquid preparations Suitable for pen organic solvents or solvent mixtures. Dyestuffs or pigments etration through the skin to the site of inflammation Such as US 2010/01 13431 A1 May 6, 2010 gels, liniments, lotions, creams, ointments or pastes, and having or suspected of having such a disorder, a therapeuti drops suitable for administration to the eye, ear or nose. cally effective amount of a compound as disclosed herein or 0063 For administration by inhalation, compounds may a pharmaceutically acceptable salt, solvate, or prodrug be delivered from an insufflator, nebulizer pressurized packs thereof. or other convenient means of delivering an aerosol spray. (0072 H1 receptor-mediated disorders, include, but are not Pressurized packs may comprise a suitable propellant such as limited to, acute nausea and vomiting, delayed onset nausea dichlorodifluoromethane, trichlorofluoromethane, dichlo and vomiting, postoperative nausea and Vomiting, motion rotetrafluoroethane, carbon dioxide or other suitable gas. In sickness, rhinitis, histamine reactions, hay fever, conjunctivi the case of a pressurized aerosol, the dosage unit may be tis, urticaria, immune disorders, human immunodeficiency determined by providing a valve to deliver a metered amount. virus, tumor growth, cancer, and toxicity resulting from expo Alternatively, for administration by inhalation or insufflation, sure to organophosphate anticholinesterases, and/or any dis the compounds according to the invention may take the form order which can lessened, alleviated, or prevented by admin ofa dry powder composition, for example a powder mix of the istering a H1 receptor modulator. compound and a suitable powder base such as lactose or 0073. In certain embodiments, a method of treating a H1 starch. The powder composition may be presented in unit receptor-mediated disorder comprises administering to the dosage form, in for example, capsules, cartridges, gelatin or subject a therapeutically effective amount of a compound as blister packs from which the powder may be administered disclosed herein, or a pharmaceutically acceptable salt, Sol with the aid of an inhalator or insufflator. vate, or prodrug thereof, so as to affect: (1) decreased inter 0064 Preferred unit dosage formulations are those con individual variation in plasma levels of the compound or a taining an effective dose, as herein below recited, oran appro metabolite thereof; (2) increased average plasma levels of the priate fraction thereof, of the active ingredient. compound or decreased average plasma levels of at least one 0065 Compounds may be administered orally or via metabolite of the compound per dosage unit; (3) decreased injection at a dose of from 0.1 to 500 mg/kg per day. The dose inhibition of, and/or metabolism by at least one cytochrome range for adult humans is generally from 5 mg to 2 g/day. Pso or monoamine oxidase isoform in the subject; (4) Tablets or other forms of presentation provided in discrete decreased metabolism via at least one polymorphically-ex units may conveniently contain an amount of one or more pressed cytochrome Paso isoform in the subject; (5) at least compounds which is effective at such dosage or as a multiple one statistically-significantly improved disorder-control and/ of the same, for instance, units containing 5 mg to 500 mg. or disorder-eradication endpoint; (6) an improved clinical usually around 10 mg to 200 mg. effect during the treatment of the disorder, (7) prevention of 0066. The amount of active ingredient that may be com recurrence, or delay of decline or appearance, of abnormal bined with the carrier materials to produce a single dosage alimentary or hepatic parameters as the primary clinical ben form will vary depending upon the host treated and the par efit, or (8) reduction or elimination of deleterious changes in ticular mode of administration. any diagnostic hepatobiliary function endpoints, as compared 0067. The compounds can be administered in various to the corresponding non-isotopically enriched compound. modes, e.g. orally, topically, or by injection. The precise 0074. In certain embodiments, inter-individual variation amount of compound administered to a patient will be the in plasma levels of the compounds as disclosed herein, or responsibility of the attendant physician. The specific dose metabolites thereof, is decreased; average plasma levels of level for any particular patient will depend upon a variety of the compound as disclosed herein are increased; average factors including the activity of the specific compound plasma levels of a metabolite of the compound as disclosed employed, the age, body weight, general health, sex, diets, herein are decreased; inhibition of a cytochrome Paso or time of administration, route of administration, rate of excre monoamine oxidase isoform by a compound as disclosed tion, drug combination, the precise disorder being treated, herein is decreased; or metabolism of the compound as dis and the severity of the disorder being treated. Also, the route closed herein by at least one polymorphically-expressed of administration may vary depending on the disorder and its cytochrome Paso isoform is decreased; by greater than about severity. 5%, greater than about 10%, greater than about 20%, greater 0068. In the case wherein the patient's condition does not than about 30%, greater than about 40%, or by greater than improve, upon the doctor's discretion the administration of about 50% as compared to the corresponding non-isotopi the compounds may be administered chronically, that is, for cally enriched compound. an extended period of time, including throughout the duration 0075 Plasma levels of the compound as disclosed herein, of the patient's life in order to ameliorate or otherwise control or metabolites thereof, may be measured using the methods or limit the symptoms of the patient’s disorder. described by Li et al. Rapid Communications in Mass Spec 0069. In the case wherein the patient's status does trometry 2005, 19, 1943-1950; Reubsaet et al., Journal of improve, upon the doctor's discretion the administration of Chromatography, A 2004, 1031(1-2), 203-211; Mueller et the compounds may be given continuously or temporarily al., Rapid Communications in Mass Spectrometry 2005, suspended for a certain length of time (i.e., a "drug holiday). 19(10), 1332-1338; and any references cited therein and any 0070). Once improvement of the patient's conditions has modifications made thereof. occurred, a maintenance dose is administered if necessary. (0.076 Examples of cytochrome Paso isoforms in a mam Subsequently, the dosage or the frequency of administration, malian subject include, but are not limited to, CYP1A1, or both, can be reduced, as a function of the symptoms, to a CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, level at which the improved disorder is retained. Patients can, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, however, require intermittent treatment on a long-term basis CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, upon any recurrence of symptoms. CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, (0071. Disclosed herein are methods of treating a H1 recep CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, tor-mediated disorder comprising administering to a subject CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, US 2010/01 13431 A1 May 6, 2010

CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, pharmaceutical composition containing such other drugs in CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, addition to the compound disclosed herein may be utilized, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and but is not required. CYP51. I0086. In certain embodiments, the compounds disclosed 0077. Examples of monoamine oxidase isoforms in a herein can be combined with one or more anti-histamine mammalian Subject include, but are not limited to, MAO treatments or anti-emetics. and MAO. I0087. In certain embodiments, the compounds provided 0078. The inhibition of the cytochrome Paso isoform is herein can be combined with one or more anti-histamine measured by the method of Ko et al., British Journal of treatments known in the art, including, but not limited to, Clinical Pharmacology 2000, 49,343-351. The inhibition of , , , , the MAO isoform is measured by the method of Weyler et , , , bromphe al., J. Biol Chem. 1985, 260, 13199-13207. The inhibition of niramine, , , dexchlor the MAO isoform is measured by the method of Uebelhack , , pheniramine, , et al., Pharmacopsychiatry, 1998, 31, 187-192. , , , methapy 0079. Examples of polymorphically-expressed cyto rilene, (Pyribenzamine), , chrome Paso isoforms in a mammalian Subject include, but are , , meduitazine, not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. , , , , ceti 0080. The metabolic activities of microsomes, cyto rizine, , , hydroxy Zine, , chrome Paso isoforms, and monoamine oxidase isoforms are , , , , , measured by the methods described herein. , , , dimebon, , 0081 Examples of improved disorder-control and/or dis , , , , phenin order-eradication endpoints, or improved clinical effects damine, , , , triproli include, but are not limited to, prevention and alleviation of dine, , , , , fex acute nausea and Vomiting, delayed onset nausea and vomit ofenadine, , , antazoline, azelastine, ing, prevention of postoperative nausea and Vomiting, alle , epinastine, ketotifen, , cromylin viation of immune related disorders, sedation, and protection Sodium and theophylline. from toxicity resulting from exposure to organophosphate I0088. In certain embodiments, the compounds disclosed anticholinesterases. herein can be combined with one or more anti-emetics 0082 Examples of diagnostic hepatobiliary function end Selected from the group consisting of , , points include, but are not limited to, aminotrans , , and , , ferase (ALT), serum glutamic-pyruvic transaminase , , , promethazine, (“SGPT), aspartate aminotransferase (AST or “SGOT), , , , cyclizine, ALT/AST ratios, serum aldolase, alkaline phosphatase diphenhydramine, , meclizine, promethaz (ALP), ammonia levels, bilirubin, gamma-glutamyl ine, prochlorperazine, , , , transpeptidase (“GGTP” “Y-GTP or “GGT), leucine ami , , hyoscine, , aprepi nopeptidase (“LAP), liver biopsy, liver ultrasonography, tant, , , and . liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa I0089. The compounds disclosed herein can also be admin tobiliary endpoints are compared to the stated normal levels istered in combination with other classes of compounds, as given in “Diagnostic and Laboratory Test Reference', 4' including, but not limited to, anti-retroviral agents; CYP3A edition, Mosby, 1999. These assays are run by accredited inhibitors; CYP3A inducers; protease inhibitors; anti-cholin laboratories according to standard protocol. ergics; mast cell stabilizers; Xanthines; leukotriene antago 0083 Besides being useful for human treatment, certain nists; glucocorticoids treatments; local or general ; compounds and formulations disclosed herein may also be non-steroidal anti-inflammatory agents (NSAIDs). Such as useful for veterinary treatment of companion animals, exotic ; antibacterial agents, such as amoxicillin; choles animals and farm animals, including mammals, rodents, and teryl ester transfer protein (CETP) inhibitors, such as anace the like. More preferred animals include horses, dogs, and trapib; anti-fungal agents, such as isoconazole; sepsis treat Cats. ments, such as drotrecogin-C: steroidals, such as ; local or general anesthetics, such as ket Combination Therapy amine; norepinephrine reuptake inhibitors (NRIs) such as ; reuptake inhibitors (DARIs). Such as 0084. The compounds disclosed herein may also be com methylphenidate; -norepinephrine reuptake inhibi bined or used in combination with other agents useful in the tors (SNRIs), such as ; sedatives. Such as diaz treatment of H1 receptor-mediated disorders. Or, by way of epham; norepinephrine-dopamine example only, the therapeutic effectiveness of one of the (NDRIs), Such as ; serotonin-norepinephrine compounds described herein may be enhanced by adminis dopamine-reuptake-inhibitors (SNDRIs), such as Venlafax tration of an adjuvant (i.e., by itself the adjuvant may only ine; monoamine oxidase inhibitors, such as ; hypo have minimal therapeutic benefit, but in combination with thalamic phospholipids; endothelin converting enzyme another therapeutic agent, the overall therapeutic benefit to (ECE) inhibitors, such as phosphoramidon; , Such as the patient is enhanced). ; thromboxane receptor antagonists, such as 0085. Such other agents, adjuvants, or drugs, may be ifetroban; openers; thrombin inhibitors, administered, by a route and in an amount commonly used Such as hirudin; hypothalamic phospholipids; growth factor therefor, simultaneously or sequentially with a compound as inhibitors, such as modulators of PDGF activity; platelet acti disclosed herein. When a compound as disclosed herein is Vating factor (PAF) antagonists; anti-platelet agents, such as used contemporaneously with one or more other drugs, a GPIb/IIIa blockers (e.g., abdximab, eptifibatide, and US 2010/01 13431 A1 May 6, 2010

tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopi 0090 Thus, in another aspect, certain embodiments pro dine and CS-747), and ; anticoagulants, such as war vide methods for treating H1 receptor-mediated disorders in a farin; low molecular weight heparins, such as enoxaparin; human or animal Subject in need of Such treatment compris Factor VIIa Inhibitors and Factor Xa Inhibitors; renin inhibi ing administering to said Subject an amount of a compound tors; neutral endopeptidase (NEP) inhibitors; vasopepsidase disclosed herein effective to reduce or prevent said disorder in inhibitors (dual NEP-ACE inhibitors), such as omapatrilat the Subject, in combination with at least one additional agent and gemopatrilat; HMG CoA reductase inhibitors, such as for the treatment of said disorder. In a related aspect, certain pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 embodiments provide therapeutic compositions comprising (a.k.a. itavastatin, nis vastatin, or nisbastatin), and ZD-4522 at least one compound disclosed herein in combination with (also known as rosuvastatin, or atavastatin or visastatin); one or more additional agents for the treatment of H1 recep squalene synthetase inhibitors; fibrates; bile acid seques tor-mediated disorders. trants. Such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel General Synthetic Methods for Preparing Compounds blockers, such as besylate; potassium channel 0091) Isotopic hydrogen can be introduced into a com activators; alpha-muscarinic agents; beta-muscarinic agents, pound as disclosed herein by synthetic techniques that Such as and metoprolol; antiarrhythmic agents; employ deuterated reagents, whereby incorporation rates are diuretics, such as chlorothlazide, hydrochiorothiazide, flu pre-determined; and/or by exchange techniques, wherein methiazide, hydroflumethiazide, bendroflumethiazide, meth incorporation rates are determined by equilibrium conditions, ylchlorothiazide, trichioromethiazide, polythiazide, benzoth and may be highly variable depending on the reaction condi lazide, ethacrynic acid, tricrynafen, chlorthalidone, tions. Synthetic techniques, where tritium or deuterium is furosenilde, musolimine, bumetanide, , directly and specifically inserted by tritiated or deuterated , and spironolactone; thrombolytic agents, such as reagents of known isotopic content, may yield high tritium or tissue plasminogen activator (tPA), recombinant tRA, strep deuterium abundance, but can be limited by the chemistry tokinase, urokinase, prourokinase, and anisoylated plasmino required. Exchange techniques, on the other hand, may yield gen streptokinase activator complex (APSAC); anti-diabetic lower tritium or deuterium incorporation, often with the iso agents, such as biguanides (e.g. metformin), glucosidase tope being distributed over many sites on the molecule. inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repa 0092. The compounds as disclosed herein can be prepared glinide), Sulfonylureas (e.g., , glyburide, and glip by methods known to one of skill in the art and routine izide), thioZolidinediones (e.g. troglitaZone, rosiglitaZone modifications thereof, and/or following procedures similar to and pioglitaZone), and PPAR-gamma ; mineralocor those described in the Example section herein and routine ticoid receptor antagonists, such as Spironolactone and modifications thereof, and/or procedures found in Sengmany eplerenone; growth hormone secretagogues; aP2 inhibitors; et al., Tetrahedron 2007. 63(18), 3672-3681; and U.S. Pat. phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., No. 2,630,435, which are hereby incorporated in their cilostazol) and PDE V inhibitors (e.g., , . entirety, and references cited therein and routine modifica ); protein tyrosine kinase inhibitors; antiinflamma tions thereof. Compounds as disclosed herein can also be tories; antiproliferatives, such as methotrexate, FK506 (tac prepared as shown in any of the following schemes and rou rolimus, Prograf), mycophenolate mofetil: chemotherapeutic tine modifications thereof. agents; immunosuppressants; anticancer agents and cyto 0093. The following schemes can be used to practice the toxic agents (e.g., alkylating agents, such as nitrogen mus present invention. Any position shown as hydrogen may tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria optionally be replaced with deuterium. Zenes); antimetabolites, such as folate antagonists, purine analogues, and pyrridine analogues; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and Scheme I plicamycin; enzymes, such as L-asparaginase; farnesyl-pro R tein transferase inhibitors; hormonal agents, such as gluco corticoids (e.g., cortisone), estrogens/antiestrogens, andro R2 C gens/antiandrogens, progestins, and luteinizing hormone -- releasing hormone anatagonists, and octreotide acetate; Rs microtubule-disruptor agents, such as ecteinascidins; micro R4 tubule-stablizing agents, such as pacitaxel, docetaxel, and epothilones A-F; plant-derived products, such as Vinca alka O R3 loids, epipodophyllotoxins, and taxanes; and topoisomerase 1 inhibitors; prenyl-protein transferase inhibitors; and R16 cyclosporins; steroids, such as prednisone and dexametha R10 Sone; cytotoxic drugs, such as azathiprine and cyclophospha R R mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti NN 14 Brzin R9 bodies or soluble TNF receptor, such as etanercept, R19 R13 + --- rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) R20 R12 inhibitors, such as and ; and miscella N R6 Rs neous agents such as, hydroxyurea, procarbazine, mitotane, R-1 H R11 hexamethylmelamine, gold compounds, platinum coordina R7 tion complexes, such as cisplatin, satraplatin, and carbopl 2 3 atin. US 2010/01 13431 A1 May 6, 2010 10

-continued -continued R16 D

R NN R 14 "N." R19 R13 C D N D

D D D

C D D D,

D D

D 0094 Compound 1 is reacted with compound 2 and com pound 3 in an appropriate solvent, Such as acetonitrile, to give D "N." D N compound of formula 4. D D 0095 Deuterium can be incorporated into different posi tions synthetically, according to the synthetic procedures as D D shown in Scheme I, by using appropriate deuterated interme D N. Y. D diates. For example, to introduce deuterium at one or more positions of R-Rs, compound 1 with the corresponding deu D D terium substitutions can be used. To introduce deuterium at one or more positions of Re-Ro compound 3 with the cor responding deuterium Substitutions can be used. To introduce C D D D, deuterium at one or more positions of R-R-, compound 2 with the corresponding deuterium Substitutions can be used. D D 0096. The following compounds can generally be made using the methods described above. It is expected that these compounds when made will have activity similar to those described in the examples above. D D "N." D 'N' D N D D C D N D D D P Y P D D D D D C D D D, D D C D D D,

D D

D D N N D D

D D D Y D D N D D D D D D D

C D D D, C D D D,

D D

US 2010/01 13431 A1 May 6, 2010 13

-continued -continued

D D N D D

D D N D D D D

C D D,

D

CN D O D C D D,

D D

0097 Changes in the metabolic properties of the com pounds disclosed herein as compared to their non-isotopi cally enriched analogs can be shown using the following assays. Compounds listed above which have not yet been made and/or tested are predicted to have changed metabolic properties as shown by one or more of these assays as well. Biological Activity Assays In Vitro Liver Microsomal Stability Assay 0.098 Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-gener ating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chlo ride). Test compounds are prepared as solutions in 20% aceto US 2010/01 13431 A1 May 6, 2010

nitrile-water and added to the assay mixture (final assay con Screening for Chlorcyclizine in Human Plasma by Using centration 5 microgram per mL) and incubated at 37°C. Final QTrap LC-MS with Automated Library Searching. concentration of acetonitrile in the assay should be <1%. 0103) The procedure is carried out as described in Mueller Aliquots (50 uL) are taken out at times 0, 15, 30, 45, and 60 et al., Rapid Communications in Mass Spectrometry 2005, minutes, and diluted with ice cold acetonitrile (200 uL) to 19(10), 1332-1338, which is hereby incorporated by refer stop the reactions. Samples are centrifuged at 12,000 RPM ence in its entirety. for 10 minutes to precipitate proteins. Supernatants are trans ferred to microcentrifuge tubes and stored for LC/MS/MS Inhibition of Histamine-Induced Spasm of the Guinea Pig analysis of the degradation half-life of the test compounds. Ileum In Vitro Metabolism. Using Human Cytochrome Pso 0104. The procedure is carried out as described in Castillo Enzymes et al., J. Pharmacol. Exp. Ther: 1949, 96(4), 388-395, which 0099. The cytochrome Paso enzymes are expressed from is hereby incorporated by reference in its entirety. the corresponding human cDNA using a baculovirus expres sion system (BD Biosciences, San Jose, Calif.). A 0.25 mil Inhibition of Histamine-Induced Vasodialation in Dogs liliter reaction mixture containing 0.8 milligrams per millili 0105. The procedure is carried out as described in Castillo ter protein, 1.3 millimolar NADI), 3.3 millimolar glucose et al., J. Pharmacol. Exp. Ther: 1949, 96(4), 388-395, which 6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, is hereby incorporated by reference in its entirety. 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically 0106 From the foregoing description, one skilled in the art enriched compound or standard or control in 100 millimolar can ascertain the essential characteristics of this invention, potassium phosphate (pH 7.4) is incubated at 37° C. for 20 and without departing from the spirit and scope thereof, can minutes. After incubation, the reaction is stopped by the addi make various changes and modifications of the invention to tion of an appropriate solvent (e.g., acetonitrile, 20% trichlo adapt it to various usages and conditions. roacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% What is claimed is: perchloric acid, 94% acetonitrile/6% glacial acetic acid) and 1. A compound of structural Formula I centrifuged (10,000 g) for 3 minutes. The supernatant is ana lyzed by HPLC/MS/MS.

(I)

Cytochrome Paso Standard CYP1A2 CYP2A6 Coumarin CYP2B6 'C-(S)-mephenytoin CYP2C8 Paclitaxel CYP2C9 CYP2C19 'C-(S)-mephenytoin CYP2D6 (+/-)-Bufuralol CYP2E1 CYP3A4 Testosterone CYP4A 'C-Lauric acid

Monoamine Oxidase A Inhibition and Oxidative Turnover 0100. The procedure is carried out using the methods described by Weyler et al., Journal of Biological Chemistry 1985, 260, 13199-13207, which is hereby incorporated by or a salt thereof, wherein: reference in its entirety. Monoamine oxidase A activity is R-R are independently selected from the group consist measured spectrophotometrically by monitoring the increase ing of hydrogen and deuterium; and in absorbance at 314 nm on oxidation of kynuramine with at least one of R-R is deuterium. formation of 4-hydroxyquinoline. The measurements are car 2. The compound as recited in claim 1 wherein at least one ried out, at 30°C., in 50 mM sodium phosphate buffer, pH 7.2. of R-R- independently has deuterium enrichment of no less containing 0.2% Triton X-100 (monoamine oxidase assay than about 10%. buffer), plus 1 mM kynuramine, and the desired amount of 3. The compound as recited in claim 1 wherein at least one enzyme in 1 mL total Volume. of R-R- independently has deuterium enrichment of no less Monooamine Oxidase B Inhibition and Oxidative Turnover than about 50%. 0101 The procedure is carried out as described in Uebel 4. The compound as recited in claim 1 wherein at least one hacket al., Pharmacopsychiatry 1998, 31(5), 187-192, which of R-R- independently has deuterium enrichment of no less is hereby incorporated by reference in its entirety. than about 90%. 5. The compound as recited in claim 1 wherein at least one Screening for Chlorcyclizine in Human Plasma by LC-MS of R-R- independently has deuterium enrichment of no less 0102 The procedure is carried out as described in Reub than about 98%. saet et al., Journal of Chromatography, A 2004, 1031 (1-2), 6. The compound as recited in claim 1 wherein said com 203-211, which is hereby incorporated by reference in its pound has a structural formula selected from the group con entirety. sisting of

US 2010/01 13431 A1 May 6, 2010 16

-continued -continued US 2010/01 13431 A1 May 6, 2010 17

-continued -continued D D

C C

C

C

C US 2010/01 13431 A1 May 6, 2010 18

-continued -continued

D N 7. The compound as recited in claim 1 wherein said com C N D poundsisting hasof a structural formula selected from the group con N D

N D D s D N C

C O D O- C Cho US 2010/01 13431 A1 May 6, 2010 19

12. The compound as recited in claim 7 wherein said com -continued pound has the structural formula: D D D

N)

C 13. The compound as recited in claim 7 wherein said com pound has the structural formula:

D D N D D

D D N D D

C 14. The compound as recited in claim 7 wherein said com pound has the structural formula: D

D 'N' D N D D

D D N D D

C 15. The compound as recited in claim 7 wherein said com pound has the structural formula: D D D

8. The compound as recited in claim 7 wherein each posi tion represented as D has deuterium enrichment of no less than about 10%. N) 9. The compound as recited in claim 7 wherein each posi tion represented as D has deuterium enrichment of no less than about 50%. 10. The compound as recited in claim 7 wherein each position represented as Dhas deuterium enrichment of no less C than about 90%. 11. The compound as recited in claim 7 wherein each 16. A pharmaceutical composition comprising a com position represented as Dhas deuterium enrichment of no less pound as recited in claim 1 together with a pharmaceutically than about 98%. acceptable carrier. US 2010/01 13431 A1 May 6, 2010 20

17. A method of treatment of a H1 receptor-mediated dis 24. The method as recited in claim 17, further resulting in order comprising the administration of a therapeutically at least two effects selected from the group consisting of effective amount of a compound as recited in claim 1 to a a. decreased inter-individual variation in plasma levels of patient in need thereof. said compound or a metabolite thereofas compared to 18. The method as recited inclaim 17 wherein said disorder the non-isotopically enriched compound; is selected from the group consisting of acute nausea and b. increased average plasma levels of said compound per Vomiting, delayed onset nausea and Vomiting, postoperative dosage unit thereofas compared to the non-isotopically nausea and Vomiting, motion sickness, histamine reactions, enriched compound; and immune disorders, toxicity resulting from exposure to c. decreased average plasma levels of at least one metabo organophosphate anticholinesterases, rhinitis, hay fever, con lite of said compound per dosage unit thereofas com junctivitis, urticaria, human immunodeficiency virus, tumor pared to the non-isotopically enriched compound; growth, and cancer. d. increased average plasma levels of at least one metabo 19. The method as recited in claim 17 further comprising lite of said compound per dosage unit thereofas com the administration of an additional therapeutic agent. pared to the non-isotopically enriched compound; and 20. The method as recited in claim 19 wherein said addi e. an improved clinical effect during the treatment in said tional therapeutic agent is selected from the group consisting Subject per dosage unit thereofas compared to the non of anti-histamine treatments and anti-emetics. isotopically enriched compound. 21. The method as recited in claim 20 wherein said anti 25. The method as recited in claim 17, wherein the method histamine treatment is selected from the group consisting of effects a decreased metabolism of the compound per dosage bromazine, carbinoxamine, clemastine, chlorphenoxamine, unit thereof by at least one polymorphically-expressed cyto diphenylpyraline, diphenhydramine, doxylamine, bromphe chrome Paso isoform in the subject, as compared to the cor niramine, chlorphenamine, dexbrompheniramine, dexchlor responding non-isotopically enriched compound. pheniramine, dimetindene, pheniramine, talastine, 26. The method as recited in claim 25, wherein the cyto chloropyramine, histapyrrodine, mepyramine, methapy chrome Paso isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. rilene, tripelennamine (Pyribenzamine), alimemazine, 27. The method as recited claim 17, wherein said com hydroxyethylpromethazine, isothipendyl, meduitazine, pound is characterized by decreased inhibition of at least one methdilazine, oxomemazine, promethazine, buclizine, ceti cytochrome Paso or monoamine oxidase isoform in said Sub rizine, cinnarizine, cyclizine, hydroxy Zine, levocetirizine, ject per dosage unit thereofas compared to the non-isotopi meclizine, niaprazine, Oxatomide, antazoline, azatadine, cally enriched compound. bamipine, cyproheptadine, deptropine, dimebon, ebastine, 28. The method as recited in claim 27, wherein said cyto epinastine, ketotifen, mebhydrolin, mizolastine, phenin chrome Paso or monoamine oxidase isoform is selected from damine, pimethixene, pyrrobutamine, rupatadine, triproli the group consisting of CYP1A1, CYP1A2, CYP1B1, dine, acrivastine, astemizole, azelastine, desloratadine, fex CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, ofenadine, loratadine, terfenadine, antazoline, azelastine, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. emedastine, epinastine, ketotifen, olopatadine, cromylin CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, Sodium, and theophylline. CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, 22. The method as recited in claim 20 wherein said anti CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, emetic is selected from the group consisting of dolasetron, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, granisetron, ondansetron, tropisetron, and palonosetron, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, domperidone, droperidol, haloperidol, chlorpromazine, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, promethazine, prochlorperazine, metoclopramide, aliza CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO, and pride, cyclizine, diphenhydramine, dimenhydrinate, mecliz MAO. ine, promethazine, prochlorperazine, hydroxyzine, dronab 29. The method as recited in claim 17, wherein the method inol, nabilone, midazolam, lorazepam, hyoscine, reduces a deleterious change in a diagnostic hepatobiliary dexamethasone, , casopitant, trimethobenzamide, function endpoint, as compared to the corresponding non and propofol. isotopically enriched compound. 23. The method as recited in claim 17, further resulting in 30. The method as recited in claim 29, wherein the diag at least one effect selected from the group consisting of: nostic hepatobiliary function endpoint is selected from the a. decreased inter-individual variation in plasma levels of group consisting of alanine aminotransferase (ALT), serum said compound or a metabolite thereofas compared to glutamic-pyruvic transaminase (“SGPT), aspartate ami the non-isotopically enriched compound; notransferase (AST,” “SGOT), ALT/AST ratios, serum b. increased average plasma levels of said compound per aldolase, alkaline phosphatase (ALP), ammonia levels, dosage unit thereofas compared to the non-isotopically bilirubin, gamma-glutamyl transpeptidase (“GGTP enriched compound; “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver c. decreased average plasma levels of at least one metabo biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti lite of said compound per dosage unit thereofas com dase, and blood protein. pared to the non-isotopically enriched compound; 31. A compound as recited in claim 1 for use as a medica d. increased average plasma levels of at least one metabo ment. lite of said compound per dosage unit thereofas com 32. A compound as recited in claim 1 for use in the manu pared to the non-isotopically enriched compound; and facture of a medicament for the prevention or treatment of a e. an improved clinical effect during the treatment in said disorder ameliorated by the modulation of H1 receptors. Subject per dosage unit thereofas compared to the non isotopically enriched compound. c c c c c