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(12) Patent Application Publication (10) Pub. No.: US 2010/0291151 A1 Gant Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0291151 A1 Gant Et Al US 2010O291151A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0291151 A1 Gant et al. (43) Pub. Date: Nov. 18, 2010 (54) 1-METHYLPYRAZOLE MODULATORS OF A63L/485 (2006.01) SUBSTANCE P, CALCITONIN A6IP 25/22 (2006.01) GENE-RELATED PEPTIDE, ADRENERGIC A6IP 25/24 (2006.01) RECEPTOR, AND/OR 5-HT RECEPTOR A6IP 25/18 (2006.01) A6IPI3/06 (2006.01) (75) Inventors: Thomas G. Gant, Carlsbad, CA A6IPI3/00 (2006.01) (US); Sepehr Sarshar, Cardiff by A6IP 25/04 (2006.01) the Sea, CA (US) (52) U.S. Cl. ................... 424/239.1: 548/375.1: 514/406; Correspondence Address: 514/17.2: 424/692; 514/245; 514/217: 514/282 GLOBAL PATENT GROUP - APX (57) ABSTRACT 1005 North Warson Road, Suite 201 ST. LOUIS, MO 63132 (US) The present invention relates to new 1-methylpyrazole modu lators of Substance P release, calcitonin gene-related peptide (73) Assignee: AUSPEX activity, adrenergic receptor activity, and/or 5-HT receptor PHARMACEUTICALS, INC., activity, pharmaceutical compositions thereof, and methods Vista, CA (US) ofuse thereof. (21) Appl. No.: 12/764,494 Formula I (22) Filed: Apr. 21, 2010 Related U.S. Application Data (60) Provisional application No. 61/171,140, filed on Apr. 21, 2009. Publication Classification (51) Int. Cl. A6 IK 3L/45 (2006.01) CO7D 23L/2 (2006.01) A6 IK 38/39 (2006.01) A6 IK33/08 (2006.01) A6 IK 39/08 (2006.01) A6 IK3I/53 (2006.01) A6 IK3I/55 (2006.01) US 2010/0291151 A1 Nov. 18, 2010 1-METHYLPYRAZOLE MODULATORS OF most drugs, such oxidations are generally rapid and ulti SUBSTANCE P. CALCITONIN mately lead to administration of multiple or high daily doses. GENE-RELATED PEPTIDE, ADRENERGIC 0006. The relationship between the activation energy and RECEPTOR, AND/OR 5-HT RECEPTOR the rate of reaction may be quantified by the Arrhenius equa tion, k=Ae'. The Arrhenius equation states that, at a given temperature, the rate of a chemical reaction depends 0001. This application claims the benefit of priority of exponentially on the activation energy (E). U.S. provisional application No. 61/171,140, filed Apr. 21, 0007. The transition state in a reaction is a short lived state 2009, the disclosure of which is hereby incorporated by ref along the reaction pathway during which the original bonds erence as if written herein in its entirety. have stretched to their limit. By definition, the activation 0002 Disclosed herein are new 1-methylpyrazole com energy E for a reaction is the energy required to reach the pounds, pharmaceutical compositions made thereof, and transition state of that reaction. Once the transition state is methods to modulate Substance P release, calcitonin gene reached, the molecules can either revert to the original reac related peptide activity, adrenergic receptor activity, and/or tants, or form new bonds giving rise to reaction products. A 5-HT receptor activity in a subject are also provided for, for catalyst facilitates a reaction process by lowering the activa the treatment of disorders such as anxiety, depression, Schizo tion energy leading to a transition state. Enzymes are phrenia, stress urinary incontinence, urge urinary inconti examples of biological catalysts. nence, and chronic neuropathic pain. 0008 Carbon-hydrogen bond strength is directly propor 0003 Cizolirtine Cizolirtine citrate, E-4018, E-3710 cit tional to the absolute value of the ground-state vibrational rate, E-4960 ((R)-isomer), E-4961 ((S)-isomer), CAS if energy of the bond. This vibrational energy depends on the 142155-43-9, N,N-dimethyl-2-(1-methyl-1H-pyrazol-5- mass of the atoms that form the bond, and increases as the yl)phenylmethoxyethanamine, is a Substance P release mass of one or both of the atoms making the bond increases. modulator, a calcitonin gene-related peptide modulator, an Since deuterium (D) has twice the mass of protium (1H), a adrenergic receptor agonist, and a 5-HT receptor agonist. C D bond is stronger than the corresponding C–H bond. Cizolirtine is currently undergoing clinical investigation for If a C-H bond is broken during a rate-determining step in a the treatment of stress urinary incontinence, urge urinary chemical reaction (i.e. the step with the highest transition incontinence, and neuropathic pain (Moncket al., Curr. Opin. state energy), then Substituting a deuterium for that protium Invest. Drugs 2001, 209), 1269-1272). Cizolirtine has also will cause a decrease in the reaction rate. This phenomenon is shown promise in treating anxiety, depression, and schizo known as the Deuterium Kinetic Isotope Effect (DKIE). The phrenia (Monck et al., Curr. Opin. Invest. Drugs 2001, 209), magnitude of the DKIE can be expressed as the ratio between 1269-1272). 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) to very large numbers, such as 50 or more. Substitution of tritium for hydrogen results in yet a stronger bond than deu terium and gives numerically larger isotope effects. I0009 Deuterium (H or D) is a stable and non-radioactive \ isotope of hydrogen which has approximately twice the mass N 1\-N of protium ("H), the most common isotope of hydrogen. Deuterium oxide (DO or “heavy water) looks and tastes like N HO, but has different physical properties. Cizolirtine 0010 When pure DO is given to rodents, it is readily absorbed. The quantity of deuterium required to induce tox icity is extremely high. When about 0-15% of the body water 0004 Cizolirtine is subject to oxidative N-demethylation has been replaced by DO, animals are healthy but are unable of the amine and heterocyclic methyl groups, as well as oxi to gain weight as fast as the control (untreated) group. When dative deamination of the dimethylamino group via oxidation about 15-20% of the body water has been replaced with D.O. of the N-methylene group (Martinez et al., Xenobiotica 1999, the animals become excitable. When about 20-25% of the 29(8), 859-871). body water has been replaced with DO, the animals become so excitable that they go into frequent convulsions when Deuterium Kinetic Isotope Effect stimulated. Skin lesions, ulcers on the paws and muzzles, and 0005. In order to eliminate foreign substances such as necrosis of the tails appear. The animals also become very therapeutic agents, the animal body expresses various aggressive. When about 30% of the body water has been enzymes, such as the cytochrome Paso enzymes (CYPs), replaced with DO, the animals refuse to eat and become esterases, proteases, reductases, dehydrogenases, and comatose. Their body weight drops sharply and their meta monoamine oxidases, to react with and convert these foreign bolic rates drop far below normal, with death occurring at Substances to more polar intermediates or metabolites for about 30 to about 35% replacement with D.O.The effects are renal excretion. Such metabolic reactions frequently involve reversible unless more than thirty percent of the previous the oxidation of a carbon-hydrogen (C-H) bond to either a body weight has been lost due to D.O. Studies have also carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. shown that the use of DO candelay the growth of cancer cells The resultant metabolites may be stable or unstable under and enhance the cytotoxicity of certain antineoplastic agents. physiological conditions, and can have Substantially different 0011 Deuteration of pharmaceuticals to improve pharma pharmacokinetic, pharmacodynamic, and acute and long cokinetics (PK), pharmacodynamics (PD), and toxicity pro term toxicity profiles relative to the parent compounds. For files has been demonstrated previously with some classes of US 2010/0291151 A1 Nov. 18, 2010 drugs. For example, the DKIE was used to decrease the hepa or 5-HT receptor-mediated disorders in a patient by admin totoxicity of halothane, presumably by limiting the produc istering the compounds as disclosed herein. tion of reactive species such as trifluoroacetylchloride. How 0015. In certain embodiments of the present invention, ever, this method may not be applicable to all drug classes. compounds have structural Formula I: 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 (I) tively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity. Such pitfalls are non-obvious and are not predictable a priori for any drug class. 0012 Cizolirtine is a substance P modulator, calcitonin gene-related peptide modulator, adrenergic receptor agonist, and 5-HT receptor agonist. The carbon-hydrogen bonds of cizolirtine contain a naturally occurring distribution of hydro gen isotopes, namely H or protium (about 99.984.4%), Hor deuterium (about 0.0156%), and H or tritium (in the range between about 0.5 and 67 tritium atoms per 10' protium atoms). Increased levels of deuterium incorporation may pro duce a detectable Deuterium Kinetic Isotope Effect (DKIE) that could effect the pharmacokinetic, pharmacologic and/or or a pharmaceutically acceptable salt thereof, wherein: toxicologic profiles ofcizolirtine in comparison with cizolir 0016 R-R are independently selected from the group tine having naturally occurring levels of deuterium. consisting of hydrogen and deuterium; and 0013 Based on discoveries made in our laboratory, as well 0017 at least one of R-R is deuterium.
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