US 20100120756A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0120756A1 Gant et al. (43) Pub. Date: May 13, 2010

(54) PHENOTHIAZINE MODULATORS OF H1 A6IP 25/22 (2006.01) RECEPTORS A6IP 9/10 (2006.01) A6IP35/00 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA (52) U.S. Cl...... 514/226.2:544/41 (US); Sepehr Sarshar, Cardiff by the Sea, CA (US) (57) ABSTRACT Correspondence Address: The present invention relates to new phenothiazine modula Global Patent Group, LLC tors of H1 receptors, pharmaceutical compositions thereof, 10411 Clayton Road, Suite 304 and methods of use thereof. St Louis, MO 63131 (US)

(73) Assignee: AUSPEX Formula I PHARMACEUTICALS, INC., Vista, CA (US) (21) Appl. No.: 12/561,572 (22) Filed: Sep. 17, 2009 Related U.S. Application Data (60) Provisional application No. 61/097.593, filed on Sep. R2 N R7 17, 2008. Publication Classification R S R6 (51) Int. Cl. R4 Rs A6 IK3I/545 (2006.01) CO7D 279/24 (2006.01) US 2010/0120756 A1 May 13, 2010

PHENOTHAZINE MODULATORS OF H1 occurrence and/or severity of these side effects. Metabolism RECEPTORS of promethazine, occurs in part through polymorphically expressed enzymes, exacerbating interpatient variability. For example, patients who were genetically deficient in CYP2D6 0001. This application claims the benefit of priority of (poor metabolizer phenotype), could potentially have an U.S. provisional application No. 61/097.593, filed Sep. 17, exaggerated response and/or serious and toxic effects at 2008, the disclosure of which is hereby incorporated by ref therapeutic doses. erence as if written herein in its entirety. 0002 Disclosed herein are new phenothiazine com Deuterium Kinetic Isotope Effect pounds, pharmaceutical compositions made thereof, and methods to modulate H1 receptor activity in a subjectare also 0005. In order to eliminate foreign substances such as provided for, for the treatment of disorders such as motion therapeutic agents, the animal body expresses various sickness, emesis, post-operative nausea and vomiting, aller enzymes, such as the cytochrome Paso enzymes (CYPs), gic disorders, allergic rhinitis, pruritus, psychiatric disorders, esterases, proteases, reductases, dehydrogenases, and anxiety, neoplasia, cancer, periodontitis, and osteoporosis. monoamine oxidases, to react with and convert these foreign 0003 Promethazine (Anergan 25, Anergan 50, Antinaus Substances to more polar intermediates or metabolites for 50, Pentazine, Phenameth, Phenazine 25, Phenazine 50, renal excretion. Such metabolic reactions frequently involve Phencen-50, Phenergan, Phenergan Fortis, Phenergan Plain, the oxidation of a carbon-hydrogen (C H) bond to either a Phenerzine, Phenoject-50, Pro-50, Pro-Med 50, Promacot, carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. Promet, Prorex-25, Prorex-50, Prothazine, Prothazine Plain, The resultant metabolites may be stable or unstable under Shogan, V-Gan-25, and V-Gan-CAS #5058-33-3), N,N-dim physiological conditions, and can have substantially different ethyl-1-(10H-phenothiazin-10-yl)propan-2-amine, is a com pharmacokinetic, pharmacodynamic, and acute and long petitive H1 receptor antagonist. Promethazine is commonly term toxicity profiles relative to the parent compounds. For prescribed for the treatment of motion sickness, emesis, post most drugs, such oxidations are generally rapid and ulti operative nausea and Vomiting, allergic disorders, allergic mately lead to administration of multiple or high daily doses. rhinitis, pruritus, psychiatric disorders, and anxiety (Taylor et 0006. The relationship between the activation energy and al., Br. J. Clin. Pharmac. 1983, 15, 287–293; Samia et al., the rate of reaction may be quantified by the Arrhenius equa Journal of Clinical Anesthesia 1999, 11(7), 596-600; and tion, k=Ae'. The Arrhenius equation states that, at a Chia et al., Acta Anaesthesiol. Scand. 2004, 48, 625-30). given temperature, the rate of a chemical reaction depends Promethazine has also shown promise in treating neoplasia, exponentially on the activation energy (E). cancer, periodontitis, and osteoporosis (Jones et al., Medical 0007. The transition state in a reaction is a short lived state Hypotheses 1996, 46, 25-29; and WO 2004/110458). along the reaction pathway during which the original bonds have stretched to their limit. By definition, the activation energy E for a reaction is the energy required to reach the transition state of that reaction. Once the transition state is reached, the molecules can either revert to the original reac tants, or form new bonds giving rise to reaction products. A catalyst facilitates a reaction process by lowering the activa D. tion energy leading to a transition state. Enzymes are examples of biological catalysts. 0008 Carbon-hydrogen bond strength is directly propor tional to the absolute value of the ground-state vibrational O S energy of the bond. This vibrational energy depends on the Promethazine mass of the atoms that form the bond, and increases as the mass of one or both of the atoms making the bond increases. 0004 Promethazine is extensively metabolized by various Since deuterium (D) has twice the mass of protium ("H), a enzymes of the cytochrome Paso family, including CYP2D6 C-D bond is stronger than the corresponding C–H bond. If and CYP2B6, to give ring-hydroxylated, S-oxidized (i.e., a C-H bond is broken during a rate-determining step in a promethazine sulphoxide), N-dealkylated (monodesmethyl chemical reaction (i.e. the step with the highest transition promethazine and didesmethyl-promethazine), and N-oxi state energy), then Substituting a deuterium for that protium dized (promethazine-N-oxide and nitrone) metabolites will cause a decrease in the reaction rate. This phenomenon is (Clement et al., Xenobiotica 1981, 11 (9) 609-18; Clement et known as the Deuterium Kinetic Isotope Effect (DKIE). The al., Arch. Pharm. 1981, 314, 712-22: Nakamura et al., Phar magnitude of the DKIE can be expressed as the ratio between macogenetics 1996, 6, 449-457; and Taylor et al., Br. J. din. the rates of a given reaction in which a C H bond is broken, Pharmac. 1983, 15, 287-93). The hydroxylation pathway is and the same reaction where deuterium is substituted for considered to be the predominant metabolic pathway for protium. The DKIE can range from about 1 (no isotope effect) promethazine, and consequently has the most important role to very large numbers, such as 50 or more. Substitution of in metabolic inactivation of the drug. Challenges posed by tritium for hydrogen results in yet a stronger bond than deu drug metabolism to Successful treatment with promethazine terium and gives numerically larger isotope effects include its short half-life as well as unwanted metabolites that I0009 Deuterium (H or D) is a stable and non-radioactive may be responsible for undesired adverse effects. Adverse isotope of hydrogen which has approximately twice the mass effects associated with promethazine include dry mouth, of protium ("H), the most common isotope of hydrogen. drowsiness, confusion, fatigue, and rhinorrhea; however, it is Deuterium oxide (DO or “heavy water) looks and tastes like unclear if the metabolites of promethazine contribute to the HO, but has different physical properties. US 2010/0120756 A1 May 13, 2010

0010 When pure DO is given to rodents, it is readily For all of the foregoing reasons, a medicine with a longer absorbed. The quantity of deuterium required to induce tox half-life may result in greater efficacy and cost savings. Vari icity is extremely high. When about 0-15% of the body water ous deuteration patterns can be used to (a) reduce or eliminate has been replaced by D.O, animals are healthy but are unable unwanted metabolites, (b) increase the half-life of the parent to gain weight as fast as the control (untreated) group. When drug, (c) decrease the number of doses needed to achieve a about 15-20% of the body water has been replaced with D.O. desired effect, (d) decrease the amount of a dose needed to the animals become excitable. When about 20-25% of the achieve a desired effect, (e) increase the formation of active body water has been replaced with DO, the animals become metabolites, if any are formed, (f) decrease the production of so excitable that they go into frequent convulsions when deleterious metabolites in specific tissues, and/or (g) create a stimulated. Skin lesions, ulcers on the paws and muzzles, and more effective drug and/or a safer drug for polypharmacy, necrosis of the tails appear. The animals also become very whether the polypharmacy be intentional or not. The deutera aggressive. When about 30% of the body water has been tion approach has the strong potential to slow the metabolism replaced with DO, the animals refuse to eat and become of promethazine 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. 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), pharmacodynamics (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 halothane, presumably by limiting the produc R17 R18 tion of reactive species such as trifluoroacetylchloride. How ever, this method may not be applicable to all drug classes. ">R15 N k"R20 For example, deuterium incorporation can lead to metabolic R14 R Switching. Metabolic Switching occurs when Xenogens, R13 R10 sequestered by Phase I enzymes, bind transiently and re-bind R12 Ro in a variety of conformations prior to the chemical reaction R Rs (e.g., oxidation). Metabolic switching is enabled by the rela tively vast size of binding pockets in many Phase I enzymes R N R and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. R3 S R6 This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori R4 Rs for any drug class. 0012 Promethazine is a competitive H1 receptor antago or a salt, Solvate, or prodrug thereof, wherein: nist. The carbon-hydrogen bonds of promethazine contain a 0016 R—R are independently selected from the naturally occurring distribution of hydrogenisotopes, namely group consisting of hydrogen and deuterium; and "H or protium (about 99.984.4%), H or deuterium (about 0017 at least one of R—R is deuterium. 0.0156%), and H or tritium (in the range between about 0.5 0018 Certain compounds disclosed herein may possess and 67 tritium atoms per 10' protium atoms). Increased useful H1 receptor modulating activity, and may be used in levels of deuterium incorporation may produce a detectable the treatment or prophylaxis of a disorder in which H1 recep Deuterium Kinetic Isotope Effect (DKIE) that could affect tors play an active role. Thus, certain embodiments also pro the pharmacokinetic, pharmacologic and/or toxicologic pro vide pharmaceutical compositions comprising one or more files of promethazine in comparison with promethazine hav compounds disclosed herein together with a pharmaceuti ing naturally occurring levels of deuterium. cally acceptable carrier, as well as methods of making and 0013 Based on discoveries made in our laboratory, as well using the compounds and compositions. Certain embodi as considering the literature, promethazine is metabolized in ments provide methods for modulating H1 receptors. Other humans at the N-dimethyl group and the C–H bonds of the embodiments provide methods for treating a H1 receptor promethazine ring. The current approach has the potential to mediated disorder in a patient in need of Such treatment, prevent metabolism at these sites. Other sites on the molecule comprising administering to said patient a therapeutically may also undergo transformations leading to metabolites effective amount of a compound or composition according to with as-yet-unknown pharmacology/toxicology. Limiting the the present invention. Also provided is the use of certain production of these metabolites has the potential to decrease compounds disclosed herein for use in the manufacture of a the danger of the administration of such drugs and may even medicament for the prevention or treatment of a disorder allow increased dosage and/or increased efficacy. All of these ameliorated by the modulation of H1 receptor. transformations can occur through polymorphically-ex 0019. The compounds as disclosed herein may also con pressed enzymes, exacerbating interpatient variability. Fur tain less prevalent isotopes for other elements, including, but ther, some disorders are best treated when the subject is not limited to, C or “C for carbon, S, S, or S for sulfur, medicated around the clock or for an extended period of time. 'N for nitrogen, and ''O or 'O for oxygen. US 2010/0120756 A1 May 13, 2010

0020. In certain embodiments, the compound disclosed to one of ordinary skill in the art, including mass spectrometry herein may expose a patient to a maximum of about and nuclear magnetic resonance spectroscopy. 0.000005% DO or about 0.00001% DHO, assuming that all 0030. The term “is/are deuterium, when used to describe of the C-D bonds in the compound as disclosed herein are a given position in a molecule Such as R—Ro or the symbol metabolized and released as DO or DHO. In certain embodi “D. when used to represent a given position in a drawing of ments, the levels of DO shown to cause toxicity in animals is much greater than even the maximum limit of exposure a molecular structure, means that the specified position is caused by administration of the deuterium enriched com enriched with deuterium above the naturally occurring distri pound as disclosed herein. Thus, in certain embodiments, the bution of deuterium. In one embodiment deuterium enrich deuterium-enriched compound disclosed herein should not ment is no less than about 1%, in another no less than about cause any additional toxicity due to the formation of DO or 5%, in another no less than about 10%, in another no less than DHO upon drug metabolism. about 20%, in another no less than about 50%, in another no 0021. In certain embodiments, the deuterated compounds less than about 70%, in another no less than about 80%, in disclosed herein maintain the beneficial aspects of the corre another no less than about 90%, or in another no less than sponding non-isotopically enriched molecules while Substan about 98% of deuterium at the specified position. tially increasing the maximum tolerated dose, decreasingtox 0031. The term “isotopic enrichment” refers to the per icity, increasing the half-life (T), lowering the maximum centage of incorporation of a less prevalent isotope of an plasma concentration (C) of the minimum efficacious element at a given position in a molecule in the place of the dose (MED), lowering the efficacious dose and thus decreas more prevalent isotope of the element. ing the non-mechanism-related toxicity, and/or lowering the 0032. The term “non-isotopically enriched’ refers to a probability of drug-drug interactions. molecule in which the percentages of the various isotopes are 0022. In certain embodiments, if R. R. R. Rs, and R Substantially the same as the naturally occurring percentages. Ra are deuterium, then at least one of R. R. Rs. R-7, 0033 Asymmetric centers exist in the compounds dis R. R. and Rs Rao is deuterium; and closed herein. These centers are designated by the symbols 0023. In certain embodiments, if R. R. R. and Rs are “R” or “S” depending on the configuration of substituents deuterium, then at least one of R. R. Rs. R-7, and Ro Ro around the chiral carbon atom. It should be understood that is deuterium. the invention encompasses all Stereochemical isomeric 0024 All publications and references cited herein are forms, including diastereomeric, enantiomeric, and epimeric expressly incorporated herein by reference in their entirety. forms, as well as D-isomers and L-isomers, and mixtures However, with respect to any similar or identical terms found thereof. Individual stereoisomers of compounds can be pre in both the incorporated publications or references and those pared synthetically from commercially available starting explicitly put forth or defined in this document, then those materials which contain chiral centers or by preparation of terms definitions or meanings explicitly put forthin this docu mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by ment shall control in all respects. separation or recrystallization, chromatographic techniques, 0025. As used herein, the terms below have the meanings direct separation of enantiomers on chiral chromatographic indicated. columns, or any other appropriate method known in the art. 0026. The singular forms “a” “an and “the may refer to Starting compounds of particular Stereochemistry are either plural articles unless specifically stated otherwise. commercially available or can be made and resolved by tech 0027. The term “about,” as used herein, is intended to niques known in the art. Additionally, the compounds dis qualify the numerical values which it modifies, denoting Such closed herein may exist as geometric isomers. The present a value as variable within a margin of error. When no particu invention includes all cis, trans, syn, anti, entgegen (E), and lar margin of error, such as a standard deviation to a mean Zusammen (Z) isomers as well as the appropriate mixtures value given in a chart or table of data, is recited, the term thereof. Additionally, compounds may exist as tautomers; all “about’ should be understood to mean that range which tautomeric isomers are provided by this invention. Addition would encompass the recited value and the range which ally, the compounds disclosed herein can exist in unsolvated would be included by rounding up or down to that figure as as well as Solvated forms with pharmaceutically acceptable well, taking into account significant figures. Solvents such as water, ethanol, and the like. In general, the 0028. When ranges of values are disclosed, and the nota Solvated forms are considered equivalent to the unsolvated tion “from n ... to n' or “n-n” is used, where n and n are forms. the numbers, then unless otherwise specified, this notation is 0034. The term “bond refers to a covalent linkage intended to include the numbers themselves and the range between two atoms, or two moieties when the atoms joined by between them. This range may be integral or continuous the bond are considered to be part of larger substructure. A between and including the end values. bond may be single, double, or triple unless otherwise speci 0029. The term “deuterium enrichment” refers to the per fied. A dashed line between two atoms in a drawing of a centage of incorporation of deuterium at a given position in a molecule indicates that an additional bond may be present or molecule in the place of hydrogen. For example, deuterium absent at that position. enrichment of 1% at a given position means that 1% of mol 0035. 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.” “syndrome.” 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 human or animal body or of one of its parts that impairs materials is about 0.0156%. The deuterium enrichment can normal functioning, is typically manifested by distinguishing be determined using conventional analytical methods known signs and Symptoms. US 2010/0120756 A1 May 13, 2010

0036. The terms “treat,” “treating,” and “treatment” are 0041. The term “H1 receptor-mediated disorder” refers to meant to include alleviating or abrogating a disorder or one or a disorder that is characterized by abnormal H1 receptor more of the symptoms associated with a disorder, or allevi activity. AH1 receptor-mediated disorder may be completely ating or eradicating the cause(s) of the disorder itself. As used or partially mediated by modulating the H1 receptor. In par herein, reference to “treatment'of a disorder is intended to ticular, a H1 receptor-mediated disorder is one in which include prevention. The terms “prevent,” “preventing, and modulation of H1 receptors results in some effect on the “prevention” refer to a method of delaying or precluding the underlying disorder e.g., administration of a H1 receptor onset of a disorder; and/or its attendant symptoms, barring a modulator results in some improvement in at least some of the Subject from acquiring a disorder or reducing a subject's risk patients being treated. of acquiring a disorder. 0037. The term “therapeutically effective amount” refers 0042. The term “H1 receptor modulator,” “modulate H1 to the amount of a compound that, when administered, is receptors,” or “modulation of H1 receptors' refers to the sufficient to prevent development of, or alleviate to some ability of a compound disclosed hereinto alter the function of extent, one or more of the symptoms of the disorder being H1 receptors. A H1 receptor modulator may activate the treated. The term “therapeutically effective amount” also activity of H1 receptors, may activate or inhibit the activity of refers to the amount of a compound that is sufficient to elicit a H1 receptors depending on the concentration of the com the biological or medical response of a cell, tissue, system, pound exposed to the H1 receptor, or may inhibit the activity animal, or human that is being sought by a researcher, Veteri of H1 receptors. Such activation or inhibition may be contin narian, medical doctor, or clinician. gent on the occurrence of a specific event, Such as activation 0038. The term “subject” refers to an animal, including, ofa signal transduction pathway, and/or may be manifest only but not limited to, a primate (e.g., human, monkey, chimpan in particular cell types. The term “H1 receptor modulator.” Zee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, “modulate H1 receptors, or “modulation of H1 receptors' hamsters, ferrets, and the like), lagomorphs, Swine (e.g., pig, also refers to altering the function of an H1 receptor by miniature pig), equine, canine, feline, and the like. The terms increasing or decreasing the probability that a complex forms “subject' and “patient” are used interchangeably herein in between an H1 receptor and a natural binding partner. A H1 reference, for example, to a mammalian Subject, such as a receptor modulator may increase the probability that Such a human patient. complex forms between the H1 receptor and the natural bind 0039. The term “combination therapy’ means the admin ing partner, may increase or decrease the probability that a istration of two or more therapeutic agents to treat a thera complex forms between the H1 receptor and the natural bind peutic disorder described in the present disclosure. Such ing partner depending on the concentration of the compound administration encompasses co-administration of these exposed to the H1 receptor, and or may decrease the prob therapeutic agents in a Substantially simultaneous manner, ability that a complex forms between the H1 receptor and the Such as in a single capsule having a fixed ratio of active natural binding partner. In some embodiments, modulation of ingredients or in multiple, separate capsules for each active the H1 receptor may be assessed using the method described ingredient. In addition, Such administration also encom in Samia et al., Journal of Clinical Anesthesia 1999, 11(7), passes use of each type of therapeutic agent in a sequential 596-600; Hishinuma et al., Journal of Pharmacological Sci manner. In either case, the treatment regimen will provide ences (Tokyo, Japan) 2008, 107(1), 66-79; and Chia et al., beneficial effects of the drug combination in treating the Acta Anaesthesiol. Scand. 2004, 48, 625-30. disorders described herein. 0043. The term “therapeutically acceptable” refers to 0040. The term “H1 receptor refers to a class of G-protein those compounds (or salts, prodrug, tautomers, Zwitterionic coupled receptors for which histamine is the endogenous forms, etc.) which are suitable for use in contact with the ligand. There are four known histamine receptors: H1, H2, tissues of patients without excessive toxicity, irritation, aller H3, and H4. Histamine H1 receptors are metabotropic G-pro gic response, immunogenicity, are commensurate with a rea tein-coupled receptors expressed throughout the body, spe sonable benefit/risk ratio, and are effective for their intended cifically in Smooth muscles, on vascular endothelial cells, in US the heart, and in the central nervous system. The H1 receptor 0044) The term “pharmaceutically acceptable carrier.” is linked to an intracellular G-protein (Gd) which activates “pharmaceutically acceptable incipient,” “physiologically phospholipase C and the phosphatidylinositol (PIP2) signal acceptable carrier,” or “physiologically acceptable incipient’ ling pathway. The production of prostaglandin E2 synthase refers to a pharmaceutically-acceptable material, composi induces the release of histamine from neurons, consequen tion, or vehicle. Such as a liquid or solid filler, diluents, incipi tially causing systemic vasodilation along with increased cell ent, solvent, or encapsulating material. Each component must permeability due to the its action on H1 receptors. Histamine be “pharmaceutically acceptable' in the sense of being com H1 receptors are activated by endogenous histamine, which is patible with the other ingredients of a pharmaceutical formu released by neurons which have their cell bodies in the lation. It must also be suitable for use in contact with the tissue tuberomamillary nucleus of the hypothalamus. The histamin or organ of humans and animals without excessive toxicity, ergic neurons of the tuberomammillary nucleus become irritation, allergic response, immunogenicity, or other prob active during the wake cycle. In the cortex, activation of H1 lems or complications, commensurate with a reasonable ben receptors leads to inhibition of cell membrane potassium efit/risk ratio. See, Remington. The Science and Practice of channels. This depolarizes the neurons and increases the Pharmacy, 21st Edition; Lippincott Williams & Wilkins: resistance of the neuronal cell membrane, bringing the cell Philadelphia, Pa., 2005; Handbook of Pharmaceutical closer to its firing threshold and increasing the excitatory Excipients, 5th Edition; Rowe et al., Eds. The Pharmaceuti Voltage produced by a given excitatory current. H1 receptor cal Press and the American Pharmaceutical Association: antagonists typically produce drowsiness because they 2005; and Handbook of Pharmaceutical Additives, 3rd Edi oppose this action, reducing neuronal excitation. tion; Ash and Ash Eds. Gower Publishing Company: 2007: US 2010/0120756 A1 May 13, 2010

Pharmaceutical Preformulation and Formulation, Gibson 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, Ed., CRC Press LLC: Boca Raton, Fla., 2004). 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 0045. The terms “active ingredient,” “active compound.” 497-507. and “active Substance' refer to a compound, which is admin 0050. The compounds disclosed herein can exist as thera istered, alone or in combination with one or more pharma peutically acceptable salts. The term “therapeutically accept ceutically acceptable excipients or carriers, to a Subject for able salt, as used herein, represents salts or Zwitterionic treating, preventing, or ameliorating one or more symptoms forms of the compounds disclosed herein which are therapeu tically acceptable as defined herein. The salts can be prepared of a disorder. during the final isolation and purification of the compounds or 0046. The terms “drug.” “therapeutic agent,” and “chemo separately by reacting the appropriate compound with a Suit therapeutic agent” refer to a compound, or a pharmaceutical able acid or base.Therapeutically acceptable salts include composition thereof, which is administered to a subject for acid and basic addition salts. For a more complete discussion treating, preventing, or ameliorating one or more symptoms of the preparation and selection of salts, refer to “Handbook of a disorder. of Pharmaceutical Salts, Properties, and Use.” Stah and Wer 0047. The term “release controlling incipient” refers to an muth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) and Berge incipient 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 0051 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, 0048. The term “nonrelease controlling incipient” refers adipic acid, alginic acid, ascorbic acid, L-aspartic acid, ben Zenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, to an incipient whose primary function do not include modi boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- fying the duration or place of release of the active Substance (1S)-camphor-10-Sulfonic acid, capric acid, caproic acid, from a dosage form as compared with a conventional imme caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclo diate release dosage form. hexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disul 0049. 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-glutamic acid, 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, maleic 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-salicylic acid, 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, 0.052 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, Zinc 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, choline, 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-lysine, 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. quinoline, 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. 0053 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 US 2010/0120756 A1 May 13, 2010 disclosed herein, or one or more pharmaceutically acceptable dosages suitable for Such administration. The push-fit cap salts, prodrug, or Solvates thereof, together with one or more Sules can contain the active ingredients in admixture with pharmaceutically acceptable carriers thereof and optionally filler Such as lactose, binders such as starches, and/or lubri one or more other therapeutic ingredients. Proper formulation cants such as talc or magnesium Stearate and, optionally, is dependent upon the route of administration chosen. Any of stabilizers. In soft capsules, the active compounds may be the well-known techniques, carriers, and excipients may be dissolved or Suspended in Suitable liquids, such as fatty oils, used as Suitable and as understood in the art; e.g., in Reming liquid paraffin, or liquid polyethylene glycols. In addition, ton's Pharmaceutical Sciences. The pharmaceutical compo stabilizers may be added. Dragee cores are provided with sitions disclosed herein may be manufactured in any manner Suitable coatings. For this purpose, concentrated Sugar Solu known in the art, e.g., by means of conventional mixing, tions may be used, which may optionally contain gum arabic, dissolving, granulating, dragee-making, levigating, emulsi talc, polyvinyl pyrrolidone, carbopol gel, polyethylene gly fying, encapsulating, entrapping or compression processes. col, and/or titanium dioxide, lacquer Solutions, and Suitable The pharmaceutical compositions may also be formulated as organic solvents or solvent mixtures. Dyestuffs or pigments a modified release dosage form, including delayed-, may be added to the tablets or dragee coatings for identifica extended-, prolonged-, Sustained-, pulsatile-, controlled tion or to characterize different combinations of active com accelerated- and fast-, targeted-, programmed-release, and pound doses. gastric retention dosage forms. These dosage forms can be 0057 The compounds may be formulated for parenteral prepared according to conventional methods and techniques administration by injection, e.g., by bolus injection or con known to those skilled in the art (see, Remington. The Science tinuous infusion. Formulations for injection may be presented and Practice of Pharmacy, supra; Modified-Release Drug in unit dosage form, e.g., in ampoules or in multi-dose con Deliver Technology, Rathbone et al., Eds. Drugs and the tainers, with an added preservative. The compositions may Pharmaceutical Science, Marcel Dekker, Inc.: New York, take Such forms as Suspensions, solutions or emulsions in oily N.Y., 2002: Vol. 126). or aqueous vehicles, and may contain formulatory agents 0054 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 0.058 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 0055 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. 0059. In addition to the formulations described previously, 0056 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 0060 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 diluents. 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 0061 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., US 2010/0120756 A1 May 13, 2010

containing conventional Suppository bases such as cocoa but 0070. In the case wherein the patient's status does ter, polyethylene glycol, or other glycerides. improve, upon the doctor's discretion the administration of 0062 Certain compounds disclosed herein may be admin the compounds may be given continuously or temporarily istered topically, that is by non-systemic administration. This Suspended for a certain length of time (i.e., a "drug holiday'). includes the application of a compound disclosed herein 0071. Once improvement of the patient's conditions has externally to the epidermis or the buccal cavity and the instil occurred, a maintenance dose is administered if necessary. lation of Sucha compound into the ear, eye and nose, such that Subsequently, the dosage or the frequency of administration, the compound does not significantly enter the blood stream. or both, can be reduced, as a function of the symptoms, to a In contrast, Systemic administration refers to oral, intrave level at which the improved disorder is retained. Patients can, nous, intraperitoneal and intramuscular administration. however, require intermittent treatment on a long-term basis 0063 Formulations suitable for topical administration upon any recurrence of symptoms. include liquid or semi-liquid preparations Suitable for pen 0072 Disclosed herein are methods of treating an H1 etration through the skin to the site of inflammation Such as receptor-mediated disorder comprising administering to a gels, liniments, lotions, creams, ointments or pastes, and Subject having or Suspected of having Such a disorder, a drops Suitable for administration to the eye, ear or nose. therapeutically effective amount of a compound as disclosed 0064. For administration by inhalation, compounds may herein or a pharmaceutically acceptable salt, Solvate, or pro be delivered from an insufflator, nebulizer pressurized packs drug thereof. or other convenient means of delivering an aerosol spray. 0073 H1 receptor antagonist-mediated disorders, include, Pressurized packs may comprise a suitable propellant Such as but are not limited to, motion sickness, emesis, post-operative dichlorodifluoromethane, trichlorofluoromethane, dichlo nausea and vomiting (PONV), allergic disorders, allergic rotetrafluoroethane, carbon dioxide or other suitable gas. In rhinitis, pruritus, psychiatric disorders, anxiety, neoplasia, the case of a pressurized aerosol, the dosage unit may be cancer, periodontitis and osteoporosis, and/or any disorder determined by providing a valve to deliver a metered amount. which can lessened, alleviated, or prevented by administering Alternatively, for administration by inhalation or insufflation, a H1 receptor modulator. the compounds according to the invention may take the form 0074. In certain embodiments, a method of treating a H1 ofa dry powder composition, for example a powder mix of the receptor-mediated disorder comprises administering to the compound and a Suitable powder base Such as lactose or Subject a therapeutically effective amount of a compound of starch. The powder composition may be presented in unit as disclosed herein, or a pharmaceutically acceptable salt, dosage form, in for example, capsules, cartridges, gelatin or solvate, or prodrug thereof, so as to affect: (1) decreased blister packs from which the powder may be administered inter-individual variation in plasma levels of the compound or with the aid of an inhalator or insufflator. a metabolite thereof; (2) increased average plasma levels of 0065 Preferred unit dosage formulations are those con the compound or decreased average plasma levels of at least taining an effective dose, as herein below recited, oran appro one metabolite of the compound per dosage unit; (3) priate fraction thereof, of the active ingredient. decreased inhibition of, and/or metabolism by at least one 0066 Compounds may be administered orally or via cytochrome Paso or monoamine oxidase isoform in the Sub injection at a dose of from 0.1 to 500 mg/kg per day. The dose ject; (4) decreased metabolism via at least one polymorphi range for adult humans is generally from 5 mg to 2 g/day. cally-expressed cytochrome Paso isoform in the Subject; (5) at Tablets or other forms of presentation provided in discrete least one statistically-significantly improved disorder-control units may conveniently contain an amount of one or more and/or disorder-eradication endpoint; (6) an improved clini compounds which is effective at Such dosage or as a multiple cal effect during the treatment of the disorder, (7) prevention of the same, for instance, units containing 5 mg to 500 mg. of recurrence, or delay of decline or appearance, of abnormal usually around 10 mg to 200 mg. alimentary or hepatic parameters as the primary clinical ben 0067. The amount of active ingredient that may be com efit, or (8) reduction or elimination of deleterious changes in bined with the carrier materials to produce a single dosage any diagnostic hepatobiliary function endpoints, as compared form will vary depending upon the host treated and the par to the corresponding non-isotopically enriched compound. ticular mode of administration. 0075. In certain embodiments, inter-individual variation 0068. The compounds can be administered in various in plasma levels of the compounds as disclosed herein, or modes, e.g. orally, topically, or by injection. The precise metabolites thereof, is decreased; average plasma levels of amount of compound administered to a patient will be the the compound as disclosed herein are increased; average responsibility of the attendant physician. The specific dose plasma levels of a metabolite of the compound as disclosed level for any particular patient will depend upon a variety of herein are decreased; inhibition of a cytochrome Paso or factors including the activity of the specific compound monoamine oxidase isoform by a compound as disclosed employed, the age, body weight, general health, sex, diets, herein is decreased; or metabolism of the compound as dis time of administration, route of administration, rate of excre closed herein by at least one polymorphically-expressed tion, drug combination, the precise disorder being treated, cytochrome Paso isoform is decreased; by greater than about and the severity of the disorder being treated. Also, the route 5%, greater than about 10%, greater than about 20%, greater of administration may vary depending on the disorder and its than about 30%, greater than about 40%, or by greater than severity. about 50% as compared to the corresponding non-isotopi 0069. In the case wherein the patient's condition does not cally enriched compound. improve, upon the doctor's discretion the administration of 0076 Plasma levels of the compound as disclosed herein, the compounds may be administered chronically, that is, for or metabolites thereof, may be measured using the methods an extended period of time, including throughout the duration described by Li et al. Rapid Communications in Mass Spec of the patient’s life in order to ameliorate or otherwise control trometry 2005, 19, 1943-1950, Cho et al., Yakche Hakhoechi or limit the symptoms of the patient’s disorder. 2006, 36(1), 23-29; Leelavathi et al., Journal of chromatog US 2010/0120756 A1 May 13, 2010

raphy 1985,339(1), 105-15; Vanapalliet al., Journal of Chro have minimal therapeutic benefit, but in combination with matographic Science 2001, 39(2), 70-72; and Taylor et al., another therapeutic agent, the overall therapeutic benefit to Analytical Letters 1979, 12(B14), 1435-42; and any refer the patient is enhanced). ences cited therein and any modifications made thereof. I0086 Such other agents, adjuvants, or drugs, may be 0077. Examples of cytochrome Paso isoforms in a mam administered, by a route and in an amount commonly used malian subject include, but are not limited to, CYP1A1, therefor, simultaneously or sequentially with a compound as CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, disclosed herein. When a compound as disclosed herein is CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, used contemporaneously with one or more other drugs, a CYP2E1, CYP2G1 CYP2J2, CYP2R1, CYP2S1, CYP3A4, pharmaceutical composition containing such other drugs in CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, addition to the compound disclosed herein may be utilized, but is not required. I0087. In certain embodiments, the compounds disclosed herein can be combined with one or more decongestant treat CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, ments known in the art, including, but not limited to, phenyl CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and propanolamine hydrochloride, pseudoephedrine, phenyleph CYP51. rine, ephedrine, tuaminoheptane, Xylometazoline, 0078 Examples of monoamine oxidase isoforms in a tetry Zoline, naphazoline, cyclopentamine, tramaZoline, meti mammalian Subject include, but are not limited to, MAO Zoline, fenoxazoline, tymazoline, and oxymetazoline. and MAO. I0088. In certain embodiments, the compounds disclosed 007.9 The inhibition of the cytochrome Paso isoform is herein can be combined with one or more antitussive treat measured by the method of Ko et al. (British Journal of ments known in the art, including, but not limited to, dex Clinical Pharmacology, 2000, 49, 343-351). The inhibition tromethorphan, ethylmorphine, hydrocodone, codeine, of the MAO isoform is measured by the method of Weyler et normetandone, noscapine, pholcodine, thebacon, dimemor al. (J. Biol Chem. 1985,260, 13199-13207). The inhibition of fan, and actyldihydrocodeine, benzonatate, benproperine, the MAO isoform is measured by the method of Uebelhack clobutinol, isoaminile, pentoxyverine, oxolamine, oxeladin, et al. (Pharmacopsychiatry, 1998, 31, 187-192). clofedanol, pipaZetate, bibenzonium bromide, butamirate, 0080 Examples of polymorphically-expressed cyto fedrilate, Zipeprol, dibunate, droxypropine, prenoxdiazine, chrome Paso isoforms in a mammalian Subject include, but are dropropizine, cloperastine, meprotixol, piperidione, tipepi not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. dine, morclofone, nepinalone, levodropropizine, and 0081. The metabolic activities of liver microsomes, cyto dimethoxanate. chrome Paso isoforms, and monoamine oxidase isoforms are I0089. In certain embodiments, the compounds disclosed measured by the methods described herein. herein can be combined with one or more mucolytic treat 0082 Examples of improved disorder-control and/or dis ments known in the art, including, but not limited to, acetyl order-eradication endpoints or improved clinical effects cysteine, bromhexine, carbocisteine, eprazinone, mesna, include, but are not limited to, reduction of nausea and ambroXol, Sobrerol, domiodol, letosteine, Stepronin, tiopro reduced incidence of Vomiting. nin, dornase alfa, melteneZine and erdosteine. 0083. Examples of diagnostic hepatobiliary function end 0090. In certain embodiments, the compounds disclosed points include, but are not limited to, alanine aminotrans herein can be combined with one or more expectorant treat ferase (ALT), serum glutamic-pyruvic transaminase ments known in the art, including, but not limited to, tylox (“SGPT), aspartate aminotransferase (AST or “SGOT), apol, potassium iodide, guaifenesin, ipecacuanha, althea root, ALT/AST ratios, serum aldolase, alkaline phosphatase Senega, antimony pentasulfide, creosote, guaiacolsulfonate, (ALP), ammonia levels, bilirubin, gamma-glutamyl and levoverbenone. transpeptidase (“GGTP” “Y-GTP or “GGT), leucine ami 0091. In certain embodiments, the compounds disclosed nopeptidase (“LAP), liver biopsy, liver ultrasonography, herein can be combined with one or more antiallergic non liver nuclear Scan, 5'-nucleotidase, and blood protein. Hepa steroidal treatments known in the art, including, but not lim tobiliary endpoints are compared to the stated normal levels ited to, cromoglicic acid, levocabastine, azelastine, antaZo as given in “Diagnostic and Laboratory Test Reference', 4' line, spaglumic acid, thonzylamine, nedocromil and edition, Mosby, 1999. These assays are run by accredited olopatadine. laboratories according to standard protocol. 0092. In certain embodiments, the compounds disclosed 0084 Besides being useful for human treatment, certain herein can be combined with one or more steroidal drugs compounds and formulations disclosed herein may also be known in the art, including, but not limited to, aldosterone, useful for veterinary treatment of companion animals, exotic beclometaSone, betamethasone, deoxycorticosterone acetate, animals and farm animals, including mammals, rodents, and fludrocortisone acetate, hydrocortisone (cortisol), predniso the like. More preferred animals include horses, dogs, and lone, prednisone, methylprenisolone, dexamethasone, and Cats. triamcinolone, flunisolide, flucticaSone, mometasone furoate, tiXocortol, and budesonide. Combination Therapy 0093. In certain embodiments, the compounds disclosed herein can be combined with one or more antihistamine treat 0085. The compounds disclosed herein may also be com ments known in the art, including, but not limited to, bined or used in combination with other agents useful in the mepyramine, antazoline, diphenhydramine, carbinoxamine, treatment of H1 receptor-mediated disorders. Or, by way of doxylamine, dimenhydrinate, pheniramine, chlorophe example only, the therapeutic effectiveness of one of the namine, brompheniramine, triprolidine, cyclizine, chlorcy compounds described herein may be enhanced by adminis clizine, hydroxy Zine, meclizine, promethazine, alimemazine, tration of an adjuvant (i.e., by itself the adjuvant may only cyproheptadine, azatadine, and ketotifen. US 2010/0120756 A1 May 13, 2010

0094. The compounds disclosed herein can also be admin tories; antiproliferatives, such as methotrexate, FK506 (tac istered in combination with other classes of compounds, rolimus, Prograf), mycophenolate mofetil: chemotherapeutic including, but not limited to, anti-retroviral agents: CYP3A agents; immunosuppressants; anticancer agents and cyto inhibitors: CYP3A inducers; protease inhibitors; adrenergic toxic agents (e.g., alkylating agents, such as nitrogen mus agonists; anti-cholinergics; mast cell stabilizers; Xanthines; tards, alkyl Sulfonates, nitrosoureas, ethylenimines, and tria leukotriene antagonists; glucocorticoids treatments; local or Zenes); antimetabolites, such as folate antagonists, purine general anesthetics, adrenergic agonists; anti-cholinergics; analogues, and pyrridine analogues; antibiotics, such as mast cell stabilizers; non-steroidal anti-inflammatory agents anthracyclines, bleomycins, mitomycin, dactinomycin, and (NSAIDs). Such as naproxen; antibacterial agents, such as plicamycin; enzymes, such as L-asparaginase; farnesyl-pro amoxicillin; cholesteryl ester transfer protein (CETP) inhibi tein transferase inhibitors; hormonal agents, such as gluco tors, such as anacetrapib; anti-fungal agents, such as isocona corticoids (e.g., cortisone), estrogens/antiestrogens, andro Zole; sepsis treatments. Such as drotrecogin-a; Steroidals, gens/antiandrogens, progestins, and luteinizing hormone Such as hydrocortisone; local or general anesthetics, such as releasing hormone anatagonists, and octreotide acetate; ketamine; norepinephrine reuptake inhibitors (NRIs) such as microtubule-disruptor agents, such as ecteinascidins; micro atomoxetine; dopamine reuptake inhibitors (DARIs), such as tubule-stablizing agents, such as pacitaxel, docetaxel, and methylphenidate; serotonin-norepinephrine reuptake inhibi epothilones A-F; plant-derived products. Such as Vinca alka tors (SNRIs), such as milnacipran; sedatives. Such as diaz loids, epipodophyllotoxins, and taxanes; and topoisomerase epham; norepinephrine-dopamine reuptake inhibitor inhibitors; prenyl-protein transferase inhibitors; and (NDRIs). Such as bupropion; serotonin-norepinephrine cyclosporins; steroids. Such as prednisone and dexametha dopamine-reuptake-inhibitors (SNDRIs), such as Venlafax Sone; cytotoxic drugs, such as azathiprine and cyclophospha ine; monoamine oxidase inhibitors, such as selegiline; hypo mide; TNF-alpha inhibitors, such as tenidap; anti-TNF anti thalamic phospholipids; endothelin converting enzyme bodies or soluble TNF receptor, such as etanercept, (ECE) inhibitors, such as phosphoramidon; opioids. Such as rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) tramadol; thromboxane receptor antagonists, such as inhibitors, such as celecoxib and rofecoxib; and miscella ifetroban; potassium channel openers; thrombin inhibitors, neous agents such as, hydroxyurea, procarbazine, mitotane, Such as hirudin; hypothalamic phospholipids; growth factor hexamethylmelamine, gold compounds, platinum coordina inhibitors, such as modulators of PDGF activity; platelet acti tion complexes, such as cisplatin, satraplatin, and carbopl Vating factor (PAF) antagonists; anti-platelet agents, such as atin. GPIb/IIIa blockers (e.g., abdximab, eptifibatide, and I0095 Thus, in another aspect, certain embodiments pro tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopi vide methods for treating H1 receptor-mediated disorders in a dine and CS-747), and aspirin; anticoagulants, such as war human or animal Subject in need of Such treatment compris farin; low molecular weight heparins, such as enoxaparin; ing administering to said Subject an amount of a compound Factor VIIa Inhibitors and Factor Xa Inhibitors; renin inhibi disclosed herein effective to reduce or prevent said disorder in tors; neutral endopeptidase (NEP) inhibitors; vasopepsidase the Subject, in combination with at least one additional agent inhibitors (dual NEP-ACE inhibitors), such as omapatrilat for the treatment of said disorder. In a related aspect, certain and gemopatrilat; HMG CoA reductase inhibitors, such as embodiments provide therapeutic compositions comprising pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 at least one compound disclosed herein in combination with (a.k.a. itavastatin, nis vastatin, or nisbastatin), and ZD-4522 one or more additional agents for the treatment of H1 recep (also known as rosuvastatin, or atavastatin or visastatin); tor-mediated disorders. squalene synthetase inhibitors; fibrates; bile acid seques trants. Such as questran; niacin; anti-atherosclerotic agents, General Synthetic Methods for Preparing Compounds such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel 0096) 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 carvedilol 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, triamterene, directly and specifically inserted by tritiated or deuterated amiloride, 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 0097. The compounds as disclosed herein can be prepared glinide), Sulfonylureas (e.g., glimepiride, 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 agonists; mineralocor those described in the Example section herein and routine ticoid receptor antagonists, such as Spironolactone and modifications thereof, and/or procedures found in Galons et eplerenone; growth hormone secretagogues; aP2 inhibitors; al., Chem. Pharm. Bull. 1985,33(11), 5108-09; and Madridet phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., al., Bioorganic & Medicinal Chemistry Letters 2007, (17) 11, cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil. 3.014-17, which are hereby incorporated in their entirety, and Vardenafil); protein tyrosine kinase inhibitors; antiinflamma references cited therein and routine modifications thereof. US 2010/0120756 A1 May 13, 2010

Compounds as disclosed herein can also be prepared as deuterium substitutions can be used. To introduce deuterium shown in any of the following schemes and routine modifi at one or more positions of Rs—Rs, compound 2 with the cations thereof. corresponding deuterium Substitutions can be used. To intro 0098. The following schemes can be used to practice the duce deuterium at one or more positions of R. R. com present invention. Any position shown as hydrogen may be pound 5 with the corresponding deuterium Substitutions can optionally replaced with deuterium. be used.

Scheme I R8 Br R7

R R6 R Rs R Rs H H R2 NH2 Rs R2 N R7 R2 N R7

2 He

R3 R3 R6 R3 S R6 R4 R4 Rs R4 Rs 1 4

R17 R18

R17 R18 R15"> N k"R20 R16 k" R 14 R15>N R20 R13 R11 R R10 14 R11 R2 Ro R 13 R10 C R2 Ro R Rs R N R

R S R6 R4 Rs

0099 Compound 1 is reacted with compound 2 in the 0101 All IUPAC names were generated using Cam presence of an appropriate base. Such as aqueous tripotassium bridgeSoft's ChemDraw 10.0. phosphate, and in the presence of an appropriate catalyst, 0102 The following compounds can generally be made such as a mixture of 2-dicyclohexylphosphino-2',4',6'-triiso using the methods described above. It is expected that these propylbiphenyl and tris(dibenzylideneacetone) dipalladium compounds when made will have activity similar to those (0), in an appropriate solvent, such as toluene, to give com described in the examples above. pound 3. Compound 3 is reacted with sulfur in the presence of an appropriate catalyst, Such as iodine, in an appropriate Solvent, such as water, to give compound 4. Compound 4 is D N1 N1 reacted with compound 5, in the presence of an appropriate D D base, such as potassium hydroxide, and in the presence of an D appropriate catalyst, such as Aliquat 336, to give a compound D 6 of structural Formula I. D 0100 Deuterium can be incorporated into different posi N N tions synthetically, according to the synthetic procedures as shown in Scheme I, by using appropriate deuterated interme diates. For example, to introduce deuterium at one or more S S positions of R—R, compound 1 with the corresponding US 2010/0120756 A1 May 13, 2010 11

-continued -continued

Q| US 2010/0120756 A1 May 13, 2010 12

-continued -continued

US 2010/0120756 A1 May 13, 2010 13

-continued -continued US 2010/0120756 A1 May 13, 2010 14

-continued -continued US 2010/0120756 A1 May 13, 2010 15

-continued -continued D D

">Nuk"D N D D D D D D D D D

D N D

D S D.

D D

0103 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 0104. In vitro Liver Microsomal Stability Assay 0105 Liver microsomal stability assays are conducted at 1 mg per mL liver microsome protein with an NADPH-gener ating system in 2% sodium bicarbonate (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM magnesium chlo ride). Test compounds are prepared as solutions in 20% aceto nitrile-water and added to the assay mixture (final assay con centration 5 microgram per mL) and incubated at 37°C. Final concentration of acetonitrile in the assay should be <1%. Aliquots (50 uL) are taken out at times 0, 15, 30, 45, and 60 minutes, and diluted with ice cold acetonitrile (200 uL) to stop the reactions. Samples are centrifuged at 12,000 RPM for 10 minutes to precipitate proteins. Supernatants are trans ferred to microcentrifuge tubes and stored for LC/MS/MS analysis of the degradation half-life of the test compounds. In vitro Metabolism. Using Human Cytochrome Pso Enzymes 0106 The cytochrome Paso enzymes are expressed from the corresponding human cDNA using a baculovirus expres sion system (BD Biosciences, San Jose, Calif.). A 0.25 mil D liliter reaction mixture containing 0.8 milligrams per millili ter protein, 1.3 millimolar NADP", 3.3 millimolar glucose 6-phosphate, 0.4U/mL glucose-6-phosphate dehydrogenase, 3.3 millimolar magnesium chloride and 0.2 millimolar of a compound of Formula I, the corresponding non-isotopically enriched compound or standard or control in 100 millimolar potassium phosphate (pH 7.4) is incubated at 37° C. for 20 minutes. After incubation, the reaction is stopped by the addi tion of an appropriate solvent (e.g., acetonitrile, 20% trichlo roacetic acid, 94% acetonitrile/6% glacial acetic acid, 70% perchloric acid, 94% acetonitrile/6% glacial acetic acid) and centrifuged (10,000 g) for 3 minutes. The supernatant is ana lyzed by HPLC/MS/MS. US 2010/0120756 A1 May 13, 2010 16

In vitro Assay Measuring Promethazine's Inhibition of Car bachol-Induced Contractions of Isolated Guinea Pig Trachea lis Muscle Cytochrome P4so Standard 0114. The procedure is carried out as described in CYP1A2 Phenacetin Orzechowski et al., European Journal of Pharmacology CYP2A6 Coumarin 2005, 506(3), 257-264, which is hereby incorporated by ref CYP2B6 'C-(S)-mephenytoin erence in its entirety. CYP2C8 Paclitaxel CYP2C9 Diclofenac In vivo Bioassay Comparing Systemic Hypotensive CYP2C19 'C-(S)-mephenytoin Responses to Bolus i.v. Injections of Acetylcholine Before CYP2D6 (+/-)-Bufuralol and After Infusions of Promethazine in Anesthetized Rats CYP2E1 ChlorZoxazone 0115 The procedure is carried out as described in CYP3A4 Testosterone Orzechowski et al., European Journal of Pharmacology CYP4A "C-Lauric acid 2005, 506(3), 257-264, which is hereby incorporated by ref erence in its entirety. Monoamine Oxidase A Inhibition and Oxidative Turnover Measuring Promethazine's Effect on Human Platelet Aggre 0107 The procedure is carried out using the methods gation. described by Weyler, Journal of Biological Chemistry 1985, 0116. The procedure is carried out as described in Gilaniet 260, 13199-13207, which is hereby incorporated by reference al., Biochemical Society Transactions 1990, 18(2), 287-8, in its entirety. Monoamine oxidase A activity is measured which is hereby incorporated by reference in its entirety. spectrophotometrically by monitoring the increase in absor 0117. From the foregoing description, one skilled in the art bance at 314 nm on oxidation of kynuramine with formation can easily ascertain the essential characteristics of this inven of 4-hydroxyquinoline. The measurements are carried out, at tion, and without departing from the spirit and scope thereof, 30°C., in 50 mM sodium phosphate buffer, pH 7.2, contain can make various changes and modifications of the invention ing 0.2% Triton X-100 (monoamine oxidase assay buffer), to adapt it to various usages and conditions. plus 1 mM kynuramine, and the desired amount of enzyme in 1 mL total volume. What is claimed is: 1. A compound of structural Formula I Monooamine Oxidase B Inhibition and Oxidative Turnover 0108. The procedure is carried out as described in Uebel (I) hack, Pharmacopsychiatry 1998, 31(5), 187-192, which is R17 R18 hereby incorporated by reference in its entirety. "> uk" A HPLC Method for Detecting Promethazine Metabolism in R15 N R20 Humans R14 R R13 R10 0109 The procedure is carried out as described in Cho et al., Yakche Hakhoechi 2006, 36(1), 23-29, which is hereby R12 Ro incorporated by reference in its entirety. R Rs Determination of Promethazine in Human Plasma by Auto R2 N R7 mated HPLC with Electrochemical Detection and by GC-MS 0110. The procedure is carried out as described in Leelav athi et al., Journal of chromatography 1985, 339(1), 105-15, which is hereby incorporated by reference in its entirety. R3 S R6 R4 Rs A Liquid Chromatographic Method for the Simultaneous Determination of Promethazine and Three of its Metabolites or a salt thereof, wherein: in Plasma Using Electrochemical and UV Detectors R—Rao are independently selected from the group con 0111. The procedure is carried out as described in Vana sisting of hydrogen and deuterium; palli et al., Journal of Chromatographic Science 2001, 39(2), at least one of R—Ro is deuterium; 70-72, which is hereby incorporated by reference in its if R. R. R. Rs, and R. Rare deuterium, then at least entirety. one of R2, R is. R-7, Ro R, and Rs Rao is deute rium; and Determination of Promethazine in Biological Fluids if R. R. R. and Rs are deuterium, then at least one of R, 0112 The procedure is carried out as described in Taylor Ra Rs. R7, and R. R. is deuterium. et al., Analytical Letters 1979, 12(B14), 1435-42, which is 2. The compound as recited in claim 1 wherein at least one hereby incorporated by reference in its entirety. of R—Ro independently has deuterium enrichment of no less than about 10%. Receptor Internalization Assays to Predict Promethazine 3. The compound as recited in claim 1 wherein at least one Binding to H1-Receptors in Intact Cells of R—Ro independently has deuterium enrichment of no 0113. The procedure is carried out as described in Hishi less than about 50%. numa et al., Journal of Pharmacological Sciences (Tokyo, 4. The compound as recited in claim 1 wherein at least one Japan) 2008, 107(1), 66-79, which is hereby incorporated by of R—Ro independently has deuterium enrichment of no reference in its entirety. less than about 90%. US 2010/0120756 A1 May 13, 2010 17

5. The compound as recited in claim 1 wherein at least one of R-Ro independently has deuterium enrichment of no less -continued than about 98%. D D D D D D 6. The compound as recited in claim 1 wherein said com- N -k > -k pound has a structural formula selected from the group con- D N D D N D sisting of: D D D D D D N1 N1 N N

D D s s D S S D D D N N D D D D D D D N D s D N D S S D D D D "> D D D N1 D N1 D D N N D D

D S S N N D D

S s COOS D>-k N D N 1. D D D "> D D D D D N1 > 1. D D D D N D D N N D D

D S S N N D N1 s D N D S S D N1 "> D D D N 1. N uk" DD D D D N D D D D D N D N D D D s s N N D S D S

D D s D S S N 1 D D D D N 1. uk" uk" D-Y 1." D N D N D N D D D D D D D D D D D N D N D N N

OC D S s D S s s S D D US 2010/0120756 A1 May 13, 2010 18

-continued -continued

US 2010/0120756 A1 May 13, 2010 19

-continued -continued US 2010/0120756 A1 May 13, 2010 20

continued -continued

US 2010/0120756 A1 May 13, 2010 21

-continued -continued D D

">Nuk"D N D D D D D D

D D N D

D D S D.

D D D D D D> -k D 7. The compound as recited in claim 1 wherein said com D N D pound has a structural formula selected from the group con sisting of:

D D

D N D D D

">Nuk"D N D D S D, D D D D

D N D

D D ">Nuk" D Y S Y D, D N D D D D D N 1.

> uk > uk" N 1. US 2010/0120756 A1 May 13, 2010 22

iting, allergic disorders, allergic rhinitis, pruritus, psychiatric -continued disorders, anxiety, neoplasia.cancer, periodontitis, and D D osteoporosis. D D D D D D 16. The method as recited in claim 14 further comprising D N D the administration of an additional therapeutic agent. D N D D 17. The method as recited in claim 16 wherein said addi D tional therapeutic agent is selected from the group consisting D D D of decongestant treatments, antitussive treatments, mucolytic D D D treatments, expectorant treatments, antiallergic non-steroidal treatments, steroidal drugs, antihistamine treatments, anti cholinergics, mast cell stabilizers, Xanthines, and leukotriene , and receptor antagonists. 18. The method as recited in claim 14, further resulting in at least one effect selected from the group consisting of: a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereofas compared to the non-isotopically enriched compound; ... increased average plasma levels of said compound per dosage unit thereofas compared to the non-isotopically enriched compound; c. decreased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com pared to the non-isotopically enriched compound; d. increased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com 8. The compound as recited in claim 7 wherein each posi pared to the non-isotopically enriched compound; and tion represented as D has deuterium enrichment of no less e. an improved clinical effect during the treatment in said Subject per dosage unit thereofas compared to the non than about 10%. isotopically enriched compound. 9. The compound as recited in claim 7 wherein each posi 19. The method as recited in claim 14, further resulting in tion represented as D has deuterium enrichment of no less at least two effects selected from the group consisting of than about 50%. a. decreased inter-individual variation in plasma levels of 10. The compound as recited in claim 7 wherein each said compound or a metabolite thereofas compared to position represented as Dhas deuterium enrichment of no less the non-isotopically enriched compound; than about 90%. ... increased average plasma levels of said compound per 11. The compound as recited in claim 7 wherein each dosage unit thereofas compared to the non-isotopically position represented as Dhas deuterium enrichment of no less enriched compound; than about 98%. c. decreased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com 12. The compound as recited in claim 7 wherein said com pared to the non-isotopically enriched compound; pound has the structural formula: d. increased average plasma levels of at least one metabo lite of said compound per dosage unit thereofas com D D pared to the non-isotopically enriched compound; and D D e. an improved clinical effect during the treatment in said Subject per dosage unit thereofas compared to the non D >N-k D isotopically enriched compound. 20. The method as recited in claim 14, wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cyto chrome Paso isoform in the subject, as compared to the cor responding non-isotopically enriched compound. 21. The method as recited in claim 20, wherein the cyto CCS chrome Paso isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 13. A pharmaceutical composition comprising a com 22. The method as recited claim 14, wherein said com pound as recited in claim 1 together with a pharmaceutically pound is characterized by decreased inhibition of at least one cytochrome Paso or monoamine oxidase isoform in said Sub acceptable carrier. ject per dosage unit thereofas compared to the non-isotopi 14. A method of treatment of a H1 receptor-mediated dis cally enriched compound. order comprising the administration of a therapeutically 23. The method as recited in claim 22, wherein said cyto effective amount of a compound as recited in claim 1 to a chrome Paso or monoamine oxidase isoform is selected from patient in need thereof. the group consisting of CYP1A1, CYP1A2, CYP1B1, 15. The method as recited inclaim 14 wherein said disorder CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, is motion sickness, emesis, post-operative nausea and Vom CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1. US 2010/0120756 A1 May 13, 2010

CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, group consisting of alanine aminotransferase (ALT), serum CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, glutamic-pyruvic transaminase (“SGPT), aspartate ami CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, notransferase (AST,” “SGOT), ALT/AST ratios, serum aldolase, alkaline phosphatase (ALP), ammonia levels, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, bilirubin, gamma-glutamyl transpeptidase (“GGTP CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, “Y-GTP “GGT), leucine aminopeptidase (“LAP), liver CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, biopsy, liver ultrasonography, liver nuclear Scan, 5'-nucleoti CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO and dase, and blood protein. MAO. 26. A compound as recited in claim 1 for use as a medica 24. The method as recited in claim 14, wherein the method ment. reduces a deleterious change in a diagnostic hepatobiliary 27. A compound as recited in claim 1 for use in the manu function endpoint, as compared to the corresponding non facture of a medicament for the prevention or treatment of a isotopically enriched compound. disorder ameliorated by the modulation of H1 receptors. 25. The method as recited in claim 24, wherein the diag nostic hepatobiliary function endpoint is selected from the c c c c c