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.