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(12) Patent Application Publication (10) Pub. No.: US 2011/0206782 A1 Zhang (43) Pub US 2011020.6782A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0206782 A1 Zhang (43) Pub. Date: Aug. 25, 2011 (54) PIPERIDINE MODULATORS OF DOPAMINE A 6LX 3/59 (2006.01) RECEPTOR A63/4985 (2006.01) A63L/485 (2006.01) (75) Inventor: Chengzhi Zhang, San Diego, CA A63L/48 (2006.01) (US) A6IP 25/6 (2006.01) (52) U.S. Cl. ......... 424/722:546/236; 514/317; 514/321; (73) Assignee: AUSPEX 514/217: 514/237.8: 514/211.13: 514/214.02: PHARMACEUTICALS, INC. 514/253.04: 514/226.2: 514/323: 514/220; Vista, CA (US) 514/259.41: 514/250; 514/282: 514/284 (21) Appl. No.: 13/027,586 (57) ABSTRACT (22) Filed: Feb. 15, 2011 The present invention relates to new piperidine modulators of dopamine receptors, pharmaceutical compositions thereof, Related U.S. Application Data and methods of use thereof. (60) Provisional application No. 61/307,724, filed on Feb. 24, 2010. Formula I Publication Classification (51) Int. Cl. A6 IK33/00 (2006.01) CO7D 2L/20 (2006.01) A6 IK 3/445 (2006.01) A6 IK 3L/4525 (2006.01) A6 IK3I/55 (2006.01) R22 A 6LX 3/5.375 (2006.01) A 6LX 3/553 (2006.01) R21 A 6LX 3L/2197 (2006.01) A6 IK3I/545 (2006.01) A6 IK 3L/454 (2006.01) A6 IK3I/55 (2006.01) A6 IK3I/554 (2006.01) US 2011/020.6782 A1 Aug. 25, 2011 PPERDINE MODULATORS OF DOPAMINE Substances to more polar intermediates or metabolites for RECEPTOR renal excretion. Such metabolic reactions frequently involve the oxidation of a carbon-hydrogen (C H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) JU-bond. 0001. This application claims the benefit of priority of The resultant metabolites may be stable or unstable under U.S. provisional application No. 61/307,724, filed Feb. 24, physiological conditions, and can have substantially different 2010, the disclosure of which is hereby incorporated by ref pharmacokinetic, pharmacodynamic, and acute and long erence as if written herein in its entirety. term toxicity profiles relative to the parent compounds. For 0002 Disclosed herein are new piperidine compounds and most drugs, such oxidations are generally rapid and ulti compositions and their application as pharmaceuticals for the mately lead to administration of multiple or high daily doses. treatment of disorders. Methods of modulation of dopamine 0006. The relationship between the activation energy and receptor activity in a subject are also provided for the treat the rate of reaction may be quantified by the Arrhenius equa ment of disorders such as Huntington's disease, attention tion, k=Ae'. The Arrhenius equation states that, at a defecit hyperactivity disorder, Parkinson's disease, and given temperature, the rate of a chemical reaction depends Schizophrenia. exponentially on the activation energy (E). 0003 Pridopidine (Huntexilr), ACR-16 ASP-2314, (-)- 0007. The transition state in a reaction is a short lived state OSU6162, (S)-(-)-OSU-6162, OSU6162, PNU-96391A, along the reaction pathway during which the original bonds PNU-96391, CAS #195159-35-4), (3S)-3-3-(methylsulfo have stretched to their limit. By definition, the activation nyl)phenyl-1-propyl-piperidine, is a dopamine receptor energy E for a reaction is the energy required to reach the mixed antagonist/agonist with antagonist-like effects of brain transition state of that reaction. Once the transition state is neurochemistry and agonist-like effects on normal behavior. reached, the molecules can either revert to the original reac Pridopidine is under investigation for the treatment of Hun tants, or form new bonds giving rise to reaction products. A tington's disease, attention defecit hyperactivity disorder, catalyst facilitates a reaction process by lowering the activa Parkinson's disease, and schizophrenia. WO 2001/46145; tion energy leading to a transition state. Enzymes are and Natesan et al., J. Pharmacol. Exp. Ther..., 2006, 318(2), examples of biological catalysts. 810-818. Pridopidine has also shown promise in treating 0008 Carbon-hydrogen bond strength is directly propor bradykinesia, depression, neurodegenerative disorders, brain tional to the absolute value of the ground-state vibrational injury, drug-indused psychosis, impulse control disorders, energy of the bond. This vibrational energy depends on the Stuttering, eating disorders, anxiety disorders, personality mass of the atoms that form the bond, and increases as the disorders, conversion hysteria, movement disorders, restless mass of one or both of the atoms making the bond increases. leg syndrome, narcolepsy, tremor, headache, vascular brain Since deuterium (D) has twice the mass of protium (H), a injury, and traumatic brain injury. WO 2001/46145. 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 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 Pridopidine 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 0004 Pridopidine is subject to CYP2D6-, CYP2C19-, of protium ("H), the most common isotope of hydrogen. CYP3A4-, CYP1A2-, and CYP1A1-mediated oxidative Deuterium oxide (DO or "heavy water) looks and tastes like N-dealkylation, with CYP2D6-mediated metabolism the HO, but has different physical properties. dominant route of N-dealkylation. Wienkers et al., Drug 0010 When pure DO is given to rodents, it is readily Metab. Disp., 2002, 30(12), 1372-1377: Yamazaki et al., absorbed. The quantity of deuterium required to induce tox Drug Metab. Disp., 2004, 32(4), 398-404: Yamazaki et al., icity is extremely high. When about 0-15% of the body water Drug Metab. Disp., 2009, 37(5), 937–945; and Rodriguez et has been replaced by D.O, animals are healthy but are unable al., J. Clin. Pharmacol., 2004, 44, 276-283. Adverse effects to gain weight as fast as the control (untreated) group. When associated with pridopidine include dizziness, headache, nau about 15-20% of the body water has been replaced with D.O. sea, paresthesia, taste perversion, and Somnolence. Rod the animals become excitable. When about 20-25% of the riguez et al., J. Clin. Pharmacol., 2004, 44, 276-283. 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 US 2011/020.6782 A1 Aug. 25, 2011 about 30 to about 35% replacement with D.O.The effects are 0014 Novel compounds and pharmaceutical composi reversible unless more than thirty percent of the previous tions, certain of which have been found to modulate dopam body weight has been lost due to D.O. Studies have also ine receptors have been discovered, together with methods of shown that the use of DO candelay the growth of cancer cells synthesizing and using the compounds, including methods and enhance the cytotoxicity of certain antineoplastic agents. for the treatment of dopamine receptor-mediated disorders in 0011 Deuteration of pharmaceuticals to improve pharma a patient by administering the compounds. cokinetics (PK), pharmacodynamics (PD), and toxicity pro 0015. In certain embodiments of the present invention, files has been demonstrated previously with some classes of compounds have structural Formula I: drugs. For example, the DKIE was used to decrease the hepa totoxicity of halothane, presumably by limiting the produc tion of reactive species such as trifluoroacetylchloride. How (I) 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 R23 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. R13 R14 0012 Pridopidine is a dopamine receptor mixed antago nist/agonist with antagonist-like effects of brain neurochem istry and agonist-like effects on normal behavior. The carbon or a salt thereof, wherein: hydrogen bonds of pridopidine contain a naturally occurring 0016 R-R are independently selected from the group distribution of hydrogen isotopes, namely "H or protium consisting of hydrogen and deuterium; and (about 99.984.4%), Hordeuterium (about 0.0156%), and H I0017 at least one of R-R is deuterium.
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