(12) Patent Application Publication (10) Pub. No.: US 2010/0113431 A1 Gant Et Al
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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 RECEPTOR (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 piperazine 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 nausea, vomiting, 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 excretion. 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, histamine 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 organophosphate anticholinesterases, rhinitis, 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 Chlorcyclizine (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 Chloride, 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 receptor antagonist. 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 ethylenediamine 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), 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 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.