USOO8524733B2
`
`(12) United States Patent
`Gant et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,524,733 B2
`Sep. 3, 2013
`
`(54) BENZOQUINOLINE INHIBITORS OF
`VESCULARMONOAMINE TRANSPORTER 2
`
`W
`WO
`
`38E. A:
`2011 106248 A3
`
`658.
`9, 2011
`
`(75) Inventors: Thomas G. Gant, Carlsbad, CA (US);
`Manoucherhr M. Shahbaz, Escondido,
`CA (US)
`(73) Assignee: Auspex Pharmaceuticals, La Jolla, CA
`(US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 555 days.
`(21) Appl. No.: 12/562,621
`(22) Filed:
`Sep. 18, 2009
`
`(*) Notice:
`
`(65)
`
`Prior Publication Data
`US 2010/O 130480 A1
`May 27, 2010
`
`Related U.S. Application Data
`(60) Provisional application No. 61/097.896, filed on Sep.
`18, 2008.
`
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`CO7D 22/06
`A6 IK3I/4353
`(52) U.S. Cl.
`USPC .............................. 514/294; 546/79:514/290
`(58) Field of Classification Search
`USPC ............................................ 546/79; 514/290
`See application file for complete search history.
`
`(56)
`
`References Cited
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`U.S. PATENT DOCUMENTS
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`8/2007 Potyen et al.
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`5, 2010 Gant et al.
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`7, 2010 Willis
`2010/0204258 A1
`8, 2010 Harris et al.
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`1/2012 Gant et al.
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`WO
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`FOREIGN PATENT DOCUMENTS
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`2, 2010
`2010044981 A2
`4/2010
`2010044981 A3
`6, 2010
`
`OTHER PUBLICATIONS
`Kushner DJ et al. Pharmaceutical uses and perspectives of heavy
`water and deuterated compounds, 1999.*
`Kenney C and Jankovik J. Tetrabenazine in the treatment of
`hyperkinetic movement disorders, 2006.*
`Alan Foster, Deuterium isotop effects in Studies of drug metabolism.
`1984.
`Helfenbein et al. Isotopic effect study of Propofol Deuteration on
`metabolism, Activity and Toxicity of the anesthetic. 2002.*
`Bauer, LA et. al., Olnfluence of long-term infusions on lidocaine
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`Borgstrom, Letal.; Comparative Pharmacokinetics of Unlabeled and
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`Browne, T.R.; Chapter 2. Isotope Effect: Implications for Pharma
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`Elison, C et al.:Effect of Deuteration of N-CHS (3)S Group on
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`Fisher, MB, et al.:The complexities inherent in attempts to decrease
`drug clearance by blocking sites of CYP-mediated metabolism, Curr
`Opin Drug Discov Develop; 2006, 9(1), 101-9.
`(Continued)
`Primary Examiner — Rita Desai
`(74) Attorney, Agent, or Firm — Dennis A. Bennett; Mike
`Sertic
`
`ABSTRACT
`(57)
`The present invention relates to new benzoquinoline inhibi
`tors of vesicular monoamine transporter 2 (VMAT2), phar
`maceutical compositions thereof, and methods of use thereof.
`
`
`
`3 Claims, No Drawings
`
`Apotex Ex. 1001
`
`Apotex v. Auspex
`IPR2021-01507
`
`

`

`US 8,524.733 B2
`Page 2
`
`(56)
`
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`OTHER PUBLICATIONS
`Foster, AB; Deuterium Isotope Effects in Studies of Drug Metabo
`lism, Trends in Pharmacological Sciences, Dec. 1984. 524-7.
`Helfenbein, Jet al.; Isotopic Effect Study of Propofol Deuteration on
`the Metabolism, Activity, and Toxicity of the Anesthetic, J. Med.
`Chem. 2002, 45,5806-5808.
`Kushner, DJ et al., Pharmacological uses and perspectives of heavy
`water and deuterated compounds, CanJPhys Pharm 1999, 77, 79-88.
`Lee, Hetal.; Deuterium Magic Angle Spinning Studies of Substrates
`Bound to Cytochrome P450, Biochemistry 1999, 38, 10808-10813.
`Mamada, Ket al., Pharmacokinetic Equivalence of Deuterium-La
`beled and Unlabeled Phenytoin, Drug Metabolism and Disposition,
`1986, 14(4), 509-11.
`Nelson, SD et al.:The Use of Deuterium Isotope Effect to Probe the
`Active Site Properties, Mechanism of Cytochrome P450-catalyzed
`Reactions, and Mechanisms of Metabolically Dependent Toxicity,
`Drug Metabolism and Disposition 31: 1481-1498, 2003.
`Nelson, SD et al.; Primary and B-Secondary Deuterium Isotope
`Effects in N-Deethylation Reactions, Journal of Medicinal Chemis
`try, 1975, vol. 18, No. 11.
`Pohl. LRet al.; Determination of toxic Pathways of Metabolism by
`Deuterium Substitution, Drug Metabolism Rev 1985 1335.
`Rampe, D et al., Deuterated Analogs of Verapamil and nifedipine.
`Synthesis and biological activity, Eur J Med Chem (1993) 28,259
`263.
`Toronto Research Chemicals, Inc.; Tetrabenazine-d7. http://www.
`trc-canada.comidetails.php?CatNumber=T284.002.
`DaSilva, JN et al.; Synthesis of 11CITetrabenazine, a Vesicular
`Monoamine Uptake Inhibitor, for PET Imaging Studies, Appl.
`Radiat, Isot, vol. 44, No. 4, pp. 673-676, 1993.
`Kilbourn, MR et al.; Absolute Configuration of (+)-a-
`Dihydrotetrabenazine, an Active Metabolite of Tetrabenazine,
`Chirality 9:59-62 (1997).
`Mehvar, R. et al...Pharmacokinetics of Tetrabenazine and Its Major
`Metabolite in Man and Rat Bloavailability and Dose Dependency
`Studies, Drug Met Disp. 1987, 15(2), 250-255.
`Paleacu, D et al.; Tetrabenazine Treatment in Movement Disorders,
`Clin Neuropharmacol 2004:27:230-233.
`Popp, FD et al.; Synthesis of potential antineoplastic agents XXVI:
`1.3.4.6.7.11b-hexahydro-9,10-dimethoxy-2H-benzo
`a 2-quinolizinone derivatives, Journal of Pharmaceutical Sciences,
`1978, 67(6), 871-873.
`Roberts, MS et al.; The Pharmacokinetics of Tetrabenazine and its
`Hydroxy Metabolite in Patients Treated for Involuntary Movement
`Disorders, Eur J. Clin Pharmacol (1986) 29: 703-708.
`Schwartz, DE et al.; Metabolic studies of tetrabenazine, a
`psychotropic drug in animals and manBiochemical Pharmacology,
`1966, 15, 645-655.
`Zheng, Get al.; Vesicular Monoamine Transporter 2: Role as a Novel
`Target for Drug Development, The AAPS Journal 2006; 8(4) Article
`78.
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`Baillie, Thomas; The Use of Stable Isotopes in Pharmaceutical
`Research, Pharmacological Reviews, 1981, 33(2), 81-132.
`Browne, Thomas; Stable Isotope Techniques in Early Drug Devel
`opment: An Economic Evaluation, J. Clin. Pharmacol., 1998, 38.
`213-220.
`Cherrah et al.; Study of Deuterium Isotope Effects on Protein Binding
`by Gas Chromatography/Mass Spectrometry. Caffeine and Deuter
`ated Isomers, Biomedical and Environmental Mass Spectrometry,
`1987, 14,653-657.
`Dyck et al.; Effects of Deuterium Substitution on the Catabolism of
`Beta-Phenethylamine: An in Vivo Study . J. Neurochem., 1986,
`46(2), 399-404.
`Gouyette, Alain: Use of Deuterium-Labelled Elliptinium and Its Use
`in Metabolic Studies, Biomedical and Environmental Mass Spec
`trometry, 1988, 15, 243-247.
`Haskins, N.J.; The Application of Stable Isotopes in Biomedical
`Research, Biomedical Mass Spectrometry, 1982, 9(7), 269-277.
`Wolen et al.; The Application of Stable Isotopes to Studies of Drug
`Bioavailibility and Bioecuivalence, J. Clin. Pharmacol., 1986, 26.
`419-424.
`Tonn et al.; Simultaneous Analysis of Diphenylhydramine and a
`Stable Isotope Analog (2H10) Diphenylhydramine Using Capillary
`Gas Chromatography With Mass Selective Detection in Biological
`Fluids From Chronically Instrumented Pregnant Ewes, Biomedical
`Mass Spectrometry, 1993, 22, 633-642.
`Honma et al.; The Metabolism of Roxatidine Acetate Hydrochloride,
`Drug Metabolism and Disposition, 1987, 15(4), 551-559.
`Pieiaszek et al.; Moricizine Bioavailability Via Simultaneous, Dual,
`Stable Isotope Administration: Bioecuivalence Implications, J. Clin.
`Pharmacol., 1999, 39, 817-825.
`Paleacu et al...Tetrabenazine Treatment in Movement Disorders, Clin.
`Neuropharmacol., 2004, 27(5), 230-233.
`Gant et al., Benzoquinoline Inhibitors of Vesicular Monoamine
`Transporter 2, Auspex Pharmaceuticals, Inc., WO2010044981 Inter
`national Preliminary Report on Patentability, Publication Date: Apr.
`22, 2010.
`Gant et al., Benzoquinoline Inhibitors of VMAT2, Auspex Pharma
`ceuticals, Inc., WO 2011 106248 International Preliminary Report on
`Patentability, Publication Date: Sep. 1, 2011.
`Foster, A.B., Deuterium Isotope Effects in the Metabolism of Drugs
`and Xenobiotics: Implications for Drug Design, Adv. Drug Res.,
`Academic Press, London, GB, vol. 14, 1 (1985), pp. 1-40.
`Gant et al., Benzoquinoline Inhibitors of Vesicular Monoamine
`Transporter 2, Auspex Pharmaceuticals, Inc., EP2009820972—Pros
`ecution History, Downloaded Oct. 3, 2012.
`Gant et al., Benzoquinoline Inhibitors of Vesicular Monoamine
`Transporter 2, Auspex Pharmaceuticals, Inc., NZ591615—Office
`Action, Publication Date: Jul. 21, 2011.
`Gant et al., Benzoquinoline Inhibitors of Vesicular Monoamine
`Transporter 2, Auspex Pharmaceuticals, Inc., NZ591615—Notice of
`Acceptance, Publication Date: Jun. 27, 2012.
`* cited by examiner
`
`Apotex Ex. 1001
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`

`

`1.
`BENZOQUINOLINE INHIBITORS OF
`VESICULARMONOAMINE TRANSPORTER 2
`
`US 8,524,733 B2
`
`This application claims the benefit of priority of U.S. pro
`visional application No. 61/097.896, filed Sep. 18, 2008, the 5
`disclosure of which is hereby incorporated by reference as if
`written herein in its entirety.
`Disclosed herein are new benzoquinoline compounds,
`pharmaceutical compositions made thereof, and methods to
`inhibit vesicular monoamine transporter 2 (VMAT2) activity 10
`in a subject are also provided for, for the treatment of chronic
`hyperkinetic movement disorders.
`Tetrabenazine (Nitoman, Xenazine, Ro 1-9569), 1,3,4,6,7,
`11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H
`benzoaquinoline, is a vesicular monoamine transporter 2 15
`(VMAT2) inhibitor. Tetrabenazine is commonly prescribed
`for the treatment of Huntington's disease (Savani et al., Neu
`rology 2007, 68(10), 797; and Kenney et al., Expert Review of
`Neurotherapeutics 2006, 6(1), 7-17).
`
`2O
`
`O
`
`N
`
`Tetrabenazine
`
`O
`1.
`
`O
`
`25
`
`30
`
`In vivo, tetrabenazine is rapidly and extensively metabo
`lized to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6, 35
`7.11b-hexahydro-2H-pyrido2,1-aisoquinolin-2-ol, which
`then binds specifically to VMAT2 (Zhang et al., AAPSJour
`nal, 2006, 8(4), E682-692). Additional metabolic pathways
`involve O-demethylation of the methoxy groups, as well as
`hydroxylation of the isobutyl group (Schwartz et al., Bio- 40
`chem. Pharmacol., 1966, 15, 645-655). Adverse effects asso
`ciated with the administration of tetrabenazine include neu
`roleptic
`malignant syndrome, drowsiness,
`fatigue,
`nervousness, anxiety, insomnia, agitation, confusion, orthos
`tatic hypotension, nausea, dizziness, depression, and Parkin- 45
`Sonism.
`Deuterium Kinetic Isotope Effect
`In order to eliminate foreign Substances such as therapeutic
`agents, the animal body expresses various enzymes, such as
`the cytochrome Paso enzymes (CYPs), esterases, proteases, 50
`reductases, dehydrogenases, and monoamine oxidases, to
`react with and convert these foreign Substances to more polar
`intermediates or metabolites for renal excretion. Such meta
`bolic reactions frequently involve the oxidation of a carbon
`hydrogen (C H) bond to either a carbon-oxygen (C–O) or 55
`a carbon-carbon (C C) L-bond. The resultant metabolites
`may be stable or unstable under physiological conditions, and
`can have Substantially different pharmacokinetic, pharmaco
`dynamic, and acute and long-term toxicity profiles relative to
`the parent compounds. For most drugs, such oxidations are 60
`generally rapid and ultimately lead to administration of mul
`tiple or high daily doses.
`The relationship between the activation energy and the rate
`of reaction may be quantified by the Arrhenius equation,
`k=Ae'. The Arrhenius equation states that, at a given 65
`temperature, the rate of a chemical reaction depends expo
`nentially on the activation energy (E).
`
`2
`The transition state in a reaction is a short lived state 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 reactants, or form
`new bonds giving rise to reaction products. A catalyst facili
`tates a reaction process by lowering the activation energy
`leading to a transition State. Enzymes are examples of bio
`logical catalysts.
`Carbon-hydrogen bond strength is directly proportional 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 stron
`ger 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 deuterium and
`gives numerically larger isotope effects
`Deuterium (H or D) is a stable and non-radioactive isotope
`of hydrogen which has approximately twice the mass of pro
`tium ("H), the most common isotope of hydrogen. Deuterium
`oxide (DO or “heavy water) looks and tastes like H2O, but
`has different physical properties.
`When pure DO is given to rodents, it is readily absorbed.
`The quantity of deuterium required to induce toxicity is
`extremely high. When about 0-15% of the body water has
`been replaced by DO, animals are healthy but are unable to
`gain weight as fast as the control (untreated) group. When
`about 15-20% of the body water has been replaced with D.O.
`the animals become excitable. When about 20-25% of the
`body water has been replaced with DO, the animals become
`so excitable that they go into frequent convulsions when
`stimulated. Skin lesions, ulcers on the paws and muzzles, and
`necrosis of the tails appear. The animals also become very
`aggressive. When about 30% of the body water has been
`replaced with DO, the animals refuse to eat and become
`comatose. Their body weight drops sharply and their meta
`bolic rates drop far below normal, with death occurring at
`about 30 to about 35% replacement with D.O.The effects are
`reversible unless more than thirty percent of the previous
`body weight has been lost due to D.O. Studies have also
`shown that the use of DO can delay the growth of cancer cells
`and enhance the cytotoxicity of certain antineoplastic agents.
`Deuteration of pharmaceuticals to improve pharmacoki
`netics (PK), pharmacodynamics (PD), and toxicity profiles
`has been demonstrated previously with some classes of drugs.
`For example, the DKIE was used to decrease the hepatotox
`icity of halothane, presumably by limiting the production of
`reactive species such as trifluoroacetyl chloride. However,
`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.
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`US 8,524,733 B2
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`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.
`Tetrabenazine is a VMAT2 inhibitor. The carbon-hydrogen
`bonds of tetrabenazine contain a naturally occurring distribu- 5
`tion of hydrogen isotopes, namely "H or protium (about
`99.984.4%), H or 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 incor
`poration may produce a detectable Deuterium Kinetic Isotope
`Effect (DKIE) that could affect the pharmacokinetic, phar
`macologic and/or toxicologic profiles of tetrabenazine in
`comparison with tetrabenazine having naturally occurring
`levels of deuterium.
`Based on discoveries made in our laboratory, as well as
`considering the literature, tetrabenazine is metabolized in
`humans at the isobutyl and methoxy groups. The current
`approach has the potential to prevent metabolism at these
`sites. Other sites on the molecule may also undergo transfor
`mations leading to metabolites with as-yet-unknown pharma
`cology/toxicology. Limiting the production of these metabo
`lites has the potential to decrease the danger of the
`administration of Such drugs and may even allow increased
`dosage and/or increased efficacy. All of these transformations
`can occur through polymorphically-expressed enzymes,
`exacerbating interpatient variability. Further, some disorders
`are best treated when the subject is medicated around the
`clock or for an extended period of time. For all of the forego
`ing reasons, a medicine with a longer half-life may result in
`greater efficacy and cost savings. Various deuteration patterns
`can be used to (a) reduce or eliminate unwanted metabolites,
`(b) increase the half-life of the parent drug, (c) decrease the
`number of doses needed to achieve a desired effect, (d)
`decrease the amount of a dose needed to achieve a desired
`effect, (e) increase the formation of active metabolites, if any
`are formed, (f) decrease the production of deleterious
`metabolites in specific tissues, and/or (g) create a more effec
`tive drug and/or a safer drug for polypharmacy, whether the
`40
`polypharmacy be intentional or not. The deuteration
`approach has the strong potential to slow the metabolism of
`tetrabenazine and attenuate interpatient variability.
`Novel compounds and pharmaceutical compositions, cer
`tain of which have been found to inhibit VMAT2 have been
`discovered, together with methods of synthesizing and using
`the compounds, including methods for the treatment of
`VMAT2-mediated disorders in a patient by administering the
`compounds as disclosed herein.
`In certain embodiments of the present invention, com
`pounds have structural Formula I:
`50
`
`4
`or a salt, Solvate, or prodrug thereof, wherein:
`R-R, are independently selected from the group consist
`ing of hydrogen and deuterium; and
`at least one of R-R-7 is deuterium.
`In certain embodiments, Formula I can include a single
`enantiomer, a mixture of the (+)-enantiomer and the (-)-
`enantiomer, a mixture of about 90% or more by weight of the
`(-)-enantiomer and about 10% or less by weight of the (+)-
`enantiomer, a mixture of about 90% or more by weight of the
`(+)-enantiomer and about 10% or less by weight of the (-)-
`enantiomer, an individual diastereomer, or a mixture of dias
`tereomers thereof.
`Certain compounds disclosed herein may possess useful
`VMAT2 inhibiting activity, and may be used in the treatment
`or prophylaxis of a disorder in which VMAT2 plays an active
`role. Thus, certain embodiments also provide pharmaceutical
`compositions comprising one or more compounds disclosed
`herein together with a pharmaceutically acceptable carrier, as
`well as methods of making and using the compounds and
`compositions. Certain embodiments provide methods for
`inhibiting VMAT2. Other embodiments provide methods for
`treating a VMAT2-mediated disorder in a patient in need of
`Such treatment, comprising administering to said patient a
`therapeutically effective amount of a compound or composi
`tion according to the present invention. Also provided is the
`use of certain compounds disclosed herein for use in the
`manufacture of a medicament for the prevention or treatment
`of a disorder ameliorated by the inhibition of VMAT2.
`The compounds as disclosed herein may also contain less
`prevalent isotopes for other elements, including, but not lim
`ited to, C or C for carbon, S, S, or S for sulfur, 'N
`for nitrogen, and 'O or "O for oxygen.
`In certain embodiments, the compound disclosed herein
`may expose apatient to a maximum of about 0.000005% DO
`or about 0.00001% DHO, assuming that all of the C-D bonds
`in the compound as disclosed herein are metabolized and
`released as DO or DHO. In certain embodiments, the levels
`of DO shown to cause toxicity in animals is much greater
`than even the maximum limit of exposure caused by admin
`istration of the deuterium enriched compound as disclosed
`herein. Thus, in certain embodiments, the deuterium-en
`riched compound disclosed herein should not cause any addi
`tional toxicity due to the formation of DO or DHO upon drug
`metabolism.
`In certain embodiments, the deuterated compounds dis
`closed herein maintain the beneficial aspects of the corre
`sponding non-isotopically enriched molecules while Substan
`tially increasing the maximum tolerated dose, decreasing
`toxicity, increasing the half-life (T), lowering the maxi
`mum plasma concentration (C) of the minimum effica
`cious dose (MED), lowering the efficacious dose and thus
`decreasing the non-mechanism-related toxicity, and/or low
`ering the probability of drug-drug interactions.
`All publications and references cited herein are expressly
`incorporated herein by reference in their entirety. However,
`with respect to any similar or identical terms found in both the
`incorporated publications or references and those explicitly
`put forth or defined in this document, then those terms defi
`nitions or meanings explicitly put forth in this document shall
`control in all respects.
`As used herein, the terms below have the meanings indi
`cated.
`The singular forms “a,” “an and “the may refer to plural
`articles unless specifically stated otherwise.
`The term “about as used herein, is intended to qualify the
`numerical values which it modifies, denoting Such a value as
`variable within a margin of error. When no particular margin
`of error, such as a standard deviation to a mean value given in
`
`35
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`US 8,524,733 B2
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`a chart or table of data, is recited, the term “about should be
`understood to mean that range which would encompass the
`recited value and the range which would be included by
`rounding up or downto that figure as well, taking into account
`significant figures.
`When ranges of values are disclosed, and the notation
`“from n ... to n' or “n-n' is used, where n and n are the
`numbers, then unless otherwise specified, this notation is
`intended to include the numbers themselves and the range
`between them. This range may be integral or continuous
`between and including the end values.
`The term “deuterium enrichment” refers to the percentage
`of incorporation of deuterium at a given position in a mol
`ecule in the place of hydrogen. For example, deuterium
`enrichment of 1% at a given position means that 1% of mol
`ecules in a given sample contain deuterium at the specified
`position. Because the naturally occurring distribution of deu
`terium is about 0.0156%, deuterium enrichment at any posi
`tion in a compound synthesized using non-enriched starting
`materials is about 0.0156%. The deuterium enrichment can
`be determined using conventional analytical methods known
`to one of ordinary skill in the art, including mass spectrometry
`and nuclear magnetic resonance spectroscopy.
`The term “is/are deuterium, when used to describe a given
`position in a molecule such as R-R-7 or the symbol “D’.
`when used to represent a given position in a drawing of a
`molecular structure, means that the specified position is
`enriched with deuterium above the naturally occurring distri
`bution of deuterium. In one embodiment deuterium enrich
`ment is no less than about 1%, in another no less than about
`5%, in another no less than about 10%, in another no less than
`about 20%, in another no less than about 50%, in another no
`less than about 70%, in another no less than about 80%, in
`another no less than about 90%, or in another no less than
`about 98% of deuterium at the specified position.
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`The term “isotopic enrichment” refers to the percentage of
`incorporation of a less prevalent isotope of an element at a
`given position in a molecule in the place of the more prevalent
`isotope of the element.
`The term “non-isotopically enriched refers to a molecule
`in which the percentages of the various isotopes are Substan
`tially the same as the naturally occurring percentages.
`Asymmetric centers exist in the compounds disclosed
`herein. These centers are designated by the symbols “R” or
`“S” depending on the configuration of Substituents around
`the chiral carbonatom. It should be understood that the inven
`tion encompasses all Stereochemical isomeric forms, includ
`ing diastereomeric, enantiomeric, and epimeric forms, as
`well as D-isomers and L-isomers, and mixtures thereof. Indi
`vidual stereoisomers of compounds can be prepared syntheti
`cally from commercially available starting materials which
`contain chiral centers or by preparation of mixtures of enan
`tiomeric products followed by separation Such as conversion
`to a mixture of diastereomers followed by separation or
`recrystallization, chromatographic techniques, direct separa
`tion of enantiomers on chiral chromatographic columns, or
`any other appropriate method known in the art. Starting com
`pounds of particular Stereochemistry are either commercially
`available or can be made and resolved by techniques known in
`the art. Additionally, the compounds disclosed herein may
`exist as geometric isomers. The present invention includes all
`cis, trans, syn, anti, entgegen (E), and Zusammen (Z) isomers
`as well as the appropriate mixtures thereof. Additionally,
`compounds may exist as tautomers; all tautomeric isomers
`are provided by this invention. Additionally, the compounds
`disclosed herein can exist in unsolvated as well as Solvated
`forms with pharmaceutically acceptable solvents such as
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`water, ethanol, and the like. In general, the Solvated forms are
`considered equivalent to the unsolvated forms.
`The term “bond refers to a covalent linkage between two
`atoms, or two moieties when the atoms joined by the bond are
`considered to be part of larger substructure. A bond may be
`single, double, or triple unless otherwise specified. A dashed
`line between two atoms in a drawing of a molecule indicates
`that an additional bond may be present or absent at that
`position.
`The term “disorder as used herein is intended to be gen
`erally synonymous, and is used interchangeably with, the
`terms “disease”, “syndrome', and “condition' (as in medical
`condition), in that all reflect an abnormal condition of the
`human or animal body or of one of its parts that impairs
`normal functioning, is typically manifested by distinguishing
`signs and Symptoms.
`The terms “treat,” “treating.” and “treatment are meant to
`include alleviating or abrogating a disorder or one or more of
`the symptoms associated with a disorder, or alleviating or
`eradicating the cause(s) of the disorder itself. As used herein,
`reference to “treatment of a disorder is intended to include
`prevention. The terms “prevent,” “preventing, and “preven
`tion” refer to a method of delaying or precluding the onset of
`a disorder, and/or its attendant symptoms, barring a subject
`from acquiring a disorder or reducing a subject’s risk of
`acquiring a disorder.
`The term “therapeutically effective amount” refers to the
`amount of a compound that, when administered, is sufficient
`to prevent development of oralleviate to some extent, one or
`more of the symptoms of the disorder being treated. The term
`“therapeutically effective amount” also refers to the amount
`of a compound that is sufficient to elicit the biological or
`medical response of a cell, tissue, system, animal, or human
`that is being sought by a researcher, Veterinarian, medical
`doctor, or clinician.
`The term “subject” refers to an animal, including, but not
`limited to, a primate (e.g., human, monkey, chimpanzee,
`gorilla, and the like), rodents (e.g., rats, mice, gerbils, ham
`sters, ferrets, and the like), lagomorphs, Swine (e.g., pig,
`miniature pig), equine, canine, feline, and the like. The terms
`“subject' and “patient” are used interchangeably herein in
`reference, for example, to a mammalian Subject, such as a
`human patient.
`The term “combination therapy’ means the administration
`of two or more therapeutic agents to treat a therapeutic dis
`order described in the present disclosure. Such administration
`encompasses co-administration of these therapeutic agents in
`a Substantially simultaneous manner, Such as in a single cap
`Sule having a fixed ratio of active ingredients or in multiple,
`separate capsules for each active ingredient. In addition, Such
`administration also encompasses use of each type of thera
`peutic agent in a sequential manner. In either case, the treat
`ment regimen will provide beneficial effects of the drug com
`bination in treating the disorders described herein.
`The term "chronic hyperkinetic movement disorders'
`refers to disorders characterized by non-purposeful, repeti
`tive, disordered motor acts, variously termed “compulsive'.
`“rhythmical’, or “stereotyped.” In humans, chronic hyperki
`netic movement disorders can be psychogenic (e.g., tics),
`idiopathic (as in, e.g., Tourette's syndrome and Parkinson's
`Disease, genetic (as in, e.g., the chorea characteristic of Hun
`tington's Disease), infectious (as in, e.g., Sydenham's Cho
`rea), or, as in tardive dyskinesia, drug-induced. Unless other
`wise stated, "chronic hyperkinetic movement disorders'
`refers to and includes all psychogenic, idiopathic, genetic,
`and drug-induced movement disorders.
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`The term “stereotyped refers to a repeated behavior that
`appears repetitively with slight variation or, less commonly,
`as a complex series of movements.
`The term “VMAT2 refers to vesicular monoamine trans
`porter 2, an integral membrane protein that acts to transport 5
`monoamines—particularly neurotransmitters such as
`dopamine, norepinephrine, serotonin, and histamine—from
`cellular cytosol into synaptic vesicles.
`The term “VMAT2-mediated disorder” refers to a disorder
`that is characterized by abnormal VMAT2 activity. A 10
`VMAT2-mediated disorder may be completely or partially
`mediated by modulating VMAT2. In particular, a VMAT2
`mediated disorder is one in which inhibition of VMAT2
`results in Some effect on the underlying disorder e.g., admin
`istration of a VMAT2 inhibitor results in some improvement 15
`in at least Some of the patients being treated.
`The term “VMAT2 inhibitor, “inhibit VMAT2, or “inhi
`bition of VMAT2 refers to the ability of a compound dis
`closed herein to alter the function of VMAT2. A VMAT2
`inhibitor may block or reduce the activity of VMAT2 by 20
`forming a reversible or irreversible covalent bond between
`the inhibitor and VMAT2 or through formation of a nonco
`valently bound complex. Such inhibition may be manifest
`only in particular cell types or may be contingent on a par
`ticular biological event. The term “VMAT2 inhibitor, 25
`“inhibit VMAT2', or “inhibition of