(12) United States Patent
`Tung
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,678,914 B2
`Mar. 16, 2010
`
`USOO7678914B2
`
`(54) DEUTERATED BENZODI1,3-DIOXOL
`DERVATIVES
`
`(75) Inventor: Roger Tung, Lexington, MA (US)
`
`(73) Assignee: Concert Pharmaceuticals Inc.,
`Lexington, MA (US)
`
`- r
`(*) Notice:
`
`-
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`
`(21) Appl. No.: 11/704,554
`
`(22) Filed:
`
`Feb. 8, 2007
`
`(65)
`
`Prior Publication Data
`US 2007/0191432 A1
`Aug. 16, 2007
`O
`O
`Related U.S. Application Data
`(63) Continuation-in-part of application No. 1 1/498.334,
`filed on Jul. 31, 2006.
`(60) Provisional application No. 60/704,073, filed on Jul.
`29, 2005.
`s
`(51) Int. Cl.
`(2006.01)
`CO7D 2L/22
`(2006.01)
`AOIN 43/62
`(52) U.S. Cl. ....................................... 546/197; 514/321
`(58) Field of Classification Search ................. 546/197;
`514/321
`See application file for complete search history.
`References Cited
`U.S. PATENT DOCUMENTS
`4.007,196 A
`2f1977 Christensen et al. ........
`5557.826 A
`1/1997 Howard et al.
`5,874.447 A
`2f1999 Benneker et al.
`6,436,938 B1
`8/2002 Howard, Jr.
`6,720,003 B2
`4/2004 Chen et al.
`2002fOO13372 A1
`1/2002 Ekins
`2007, 0112031 A1
`5, 2007 Gant et al.
`
`(56)
`
`OTHER PUBLICATIONS
`Leis et al J. Mass Spectrom. 2001, 36,923-928.*
`Foster et al Trends in Pharma. Sci. 1984, 5,524-527.*
`U.S. Appl. No. 1 1/498.334, filed Jul. 31, 2006, Tung.
`Fisher, M.B. et al., Complexities Inherent in Attempts tO Decrease
`Drug Clearance by Blocking Sites of CYP-mediated Metabolism,
`Current Opinion. In Drug Discovery & Development, vol. 9(1), pp.
`101-109 (2006).
`FDA Center for Drug Evaluation and Drug Research, NDA No.
`21-299, Clinical Pharmacology and Biopharmaceutics Review(s),
`
`Fukuto, J.M. et al., “Determination of the Mechanism of
`Demethylenation of (Methylenedioxy)phenyl Compounds by
`Cytochrome P450 Using Deuterium Isotope Effects”. J. Med. Chem.
`34:2871-2876 (1991).
`Kaye, C.M. et al., “A review of the metabolism and pharmacokinetics
`of paroxetine in man'. Acta Psychiatr. Scand. 80(Supp. 350):60-75
`(1989).
`Bertelsen, K.M. et al., "Apparent Mechanism-Based Inhibition of
`Human CYP2D6 In Vitro Bv Paroxetine: Comparison with
`Fluoxetine and Quinidine'. Dr. Metab. Dispos. Eo.
`(2003).
`k . cited by examiner
`Primary Examiner Rita J Desai
`Assistant Examiner John Mabry
`(74)Attorney, Agent, or Firm Foley & Lardner LLP, Steven
`G. Davis
`
`(7)
`
`ABSTRACT
`
`The present invention relates to an isotopologue of Com
`pound 1 substituted with deuterium at the methylene carbon
`of the benzodioxol ring. The isotopologues of this invention
`selective serotonin reuptake inhibitors (SSRIs) and possess
`unique biopharmaceutical and metabolic properties com
`pared to Compound 1. They may also be used to accurately
`determine the concentration of Compound 1 in biological
`fluids and to determine metabolic patterns of Compound 1
`and its isotopologues. The invention further provides compo
`sitions comprising these deuterated isotopologues and meth
`ods of treating diseases and conditions that are responsive to
`increased neuronal serotonin transmission, alone and in com
`
`2008.OO33011 A1* 2, 2008 Tung - - - - - - - - - - - - - - - - - - - - - - - - - - 514,321
`
`bination with additional agents.
`
`WO
`
`FOREIGN PATENT DOCUMENTS
`WO95/26325
`* 10/1995
`
`4 Claims, No Drawings
`
`Auspex Exhibit 2007
`Apotex v. Auspex
`IPR2021-01507
`Page 1
`
`

`

`1.
`DEUTERATED BENZODI1,3-DIOXOL
`DERVATIVES
`
`US 7,678,914 B2
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part of U.S. patent
`application Ser. No. 1 1/498.334, filed Jul. 31, 2006, which
`claims benefit of U.S. provisional application 60/704,073,
`filed Jul. 29, 2005, the contents of each is incorporated by
`reference herein.
`
`10
`
`TECHNICAL FIELD OF THE INVENTION
`
`15
`
`The present invention relates to novel isotopologues of
`Compound 1, its acceptable acid with additional deuterium
`and C atoms in place of the normally abundant hydrogen
`and C, respectively addition salts, solvates, hydrates and
`polymorphs thereof, substituted with deuterium on the meth
`ylene carbon atom situated between the oxygens of the ben
`Zodioxol ring, and optionally substituted. The compounds of
`this invention are selective serotonin reuptake inhibitors (SS
`RIs) and are poorer substrates for metabolism by cytochrome
`2D6, and possess unique pharmacokinetic and biopharma
`ceutical properties compared to the corresponding non-iso
`topically Substituted compounds. The invention also provides
`compositions comprising a compound of this invention and
`the use of Such compositions in methods of treating diseases
`and conditions beneficially treated by SSRIs, particularly
`those relating to major depressive disorder, obsessive com
`30
`pulsive disorder, panic disorder, social anxiety disorder, gen
`eralized anxiety disorder, post-traumatic stress disorder, and
`premenstrual dysphoric disorder. The invention further pro
`vides methods for the use of a compound of this invention to
`determine concentrations of Compound 1, particularly in bio
`35
`logical fluids, and to determine metabolism patterns of Com
`pound 1.
`
`25
`
`BACKGROUND OF THE INVENTION
`
`Compound 1, chemically described variously as (-)-trans
`4R-(4-fluorophenyl)-3S-(3',4'-methylenedioxyphenoxy)
`methylpiperidine;
`(3S,4R)-3-((benzod1.3dioxol-5-
`yloxy)methyl)-4-(4-fluorophenyl)piperidine;
`trans-(-)-3-
`(1,3-benzodioxol-5-yloxy)methyl-4-(4-fluorophenyl)
`piperidine, and its pharmaceutically acceptable
`
`40
`
`45
`
`Compound 1
`
`50
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`55
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`60
`
`65
`
`N
`
`addition salts, hydrates, and polymorphs thereof, are known
`as a useful selective serotonin reuptake inhibitor (SSRI). This
`compound and pharmaceutical compositions comprising it
`have utility in the treatment of depression, obsessive-compul
`sive disorder, generalized anxiety, post-traumatic stress,
`
`2
`major depression, panic disorder, social phobia, premenstrual
`syndrome, cardiac disorders, non-cardiac chest pain, Smok
`ing (both to cause cessation and prevent relapses), reducing
`platelet activation states, alcoholism and alcohol dependence,
`psychiatric syndromes (including anger, rejection sensitivity,
`and lack of mental or physical energy), late luteal phase
`dysphoric disorder, premature ejaculation, senile dementia,
`obesity, Parkinson's Disease, and canine affective aggres
`sion. See US Food and Drug Administration product label for
`New Drug Application (NDA) Nos. 020031, 020710, and
`020936: Christensen J A and Squires R F, U.S. Pat. No.
`4,007,196, to Ferrosan; Lassen JB, U.S. Pat. No. 4,745,122 to
`Ferrosan; Johnson AMU.S. Pat. No. 5,371,092 to Beecham
`Group: Crenshaw RT and Wiesner MG, U.S. Pat. No. 5,276,
`042: Dodman NH, U.S. Pat. Nos. 5,788,986 and 5,554,383 to
`Trustees of Tufts College: Norden MJ U.S. Pat. No. 5,789,
`449; Gleason M, U.S. Pat. No. 6,121,291 to SmithKline Bee
`cham; Cook L., U.S. Pat. No. 6,071,918 to DuPont Pharma
`ceuticals; Serebruany V L., U.S. Pat. No. 6,245,782 to
`Heartdrug Research: Steiner MX, U.S. Pat. No. 6,300,343 to
`SmithKline Beecham; Krishnan K R et. al., U.S. Pat. No.
`6,316,469 to Duke University; Jenner P N, U.S. Pat. No.
`6,372,763 to SmithKline Beecham.
`Additionally disclosed uses for Compound 1 include meth
`ods of inhibiting cancer cell growth, stimulating bone forma
`tion by osteoblast stimulation, treatment of dermatological
`diseases or disorders such as hyperproliferative or inflamma
`tory skin diseases, and treatment of premature female
`orgasm: see US Patent Applications 20040127573 (Telerman
`A et al.); 20040127573 (Stashenko P and Battaglino R):
`200500 13853 and 20040029860 (Gil-Ad I and Weizman A);
`and 2005.0054688 (May K E and Quinn P).
`Definitions and descriptions of these conditions are known
`to the skilled practitioner and are further delineated, for
`instance, in the above patents and patent applications and
`references contained therein. See also: Harrison's Principles
`of Internal Medicine 16th Edition, Kasper D Let. al. Eds.
`2004, McGraw-Hill Professional; and Robbins & Cotran
`Pathologic Basis of Disease, Kumar Vet. al. Eds., 2004, W.B.
`Saunders.
`The combination of Compound 1 with additional agents
`extends or enhances its utility in the treatment or prevention
`of depression, hypertension, generalized anxiety disorder,
`phobias, posttraumatic stress syndrome, avoidant personality
`disorder, sexual dysfunction, eating disorders (including
`bulimia, anorexia nervosa, and binge eating), obesity, chemi
`cal dependencies, clusterheadache, migraine, pain (including
`neuropathic pain, diabetic nephropathy, post-operative pain,
`psychogenic pain disorders, and chronic pain syndrome),
`Alzheimer's disease, obsessive-compulsive disorder, panic
`disorder with or without agoraphobia, memory disorders,
`Parkinson's diseases, endocrine disorders, vasospasm, cer
`ebellar ataxia, gastrointestinal tract disorders, negative symp
`toms of Schizophrenia, premenstrual syndrome, Fibromyal
`gia Syndrome, urinary incontinence (including stress
`incontinence), Tourette's syndrome, trichotillomania, klepto
`mania, male impotence, cancer, chronic paroxysmal hemic
`rania and headache in a mammal, sleep-related breathing
`disorders, cognitive deficits due to aging, stroke, head trauma,
`neurodegenerative diseases, schizophrenia, anxiety, aggres
`Sion, stress, disorders of thermoregulation, respiratory dis
`ease, bipolar disorder, psychosis, sleep disorders, mania (in
`cluding acute mania), bladder disorder, genitourinary
`disorder, cough, emesis, nausea, psychotic disorders such as
`paranoia and manic-depressive illness, tic disorder, diabetic
`cardiomyopathy, diabetic retinopathy, cataracts, myocardial
`infarction, prolonged fatigue, chronic fatigue, chronic fatigue
`
`Auspex Exhibit 2007
`Apotex v. Auspex
`IPR2021-01507
`Page 2
`
`

`

`US 7,678,914 B2
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`5
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`3
`syndrome, premature ejaculation, dysphoria, post partum
`depression, Social phobia, disruptive behavior disorders,
`impulse control disorders, borderline personality disorder,
`attention deficit disorders without hyperactivity, Shy-Drager
`Syndrome, cerebral ischemia, spinal cord trauma, Hunting
`ton's Chorea, amyotrophic lateral sclerosis, AIDS-induced
`dementia, muscular spasms, convulsions, perinatal hypoxia,
`hypoxia, cardiac arrest, hypoglycemic neuronal damage,
`ocular damage and retinopathy, brain edema, tardive dyski
`nesia, cerebral deficits Subsequent to cardiac bypass Surgery
`and grafting, affective disorders, mood disorders, agorapho
`bia without history of panic disorder, and acute stress disor
`ders. These additional agents are also useful for reducing the
`side effects of Compound 1, enhancing or potentiating its
`activity, or increasing its duration of pharmacological action.
`U.S. Pat. Nos. 5,776,969 (James SP) to Eli Lilly; 5,877,171
`(McLeod MN); 5,977,099 (Nickolson VJ) to Akzo Nobel:
`5,962,514 and 6,169,098 (Evenden J and Thorberg S-O) to
`Astra; 5,958,429 (Wong DT) to Eli Lilly; 5,945,416 (Shan
`non H E and Womer DE) to Eli Lilly: 6,066,643 (Perry KW)
`to Eli Lilly; 5,817,665 and 6,034,091 (Dante LG) to Nagle J
`S; 5.990,159 (Meulemans A L G et. al.) to Janssen Pharma
`ceutica; 6,001,848 (Noble EP) to The Regents of the Univer
`sity of California; 6,011,054 (Oxenkrug G F and Requintina
`PJ) to St. Elizabeth's Medical Center of Boston; 6,080,736
`(Landry D W and Klein D F) to Janus Pharmaceuticals;
`6,162,805 (Hefti FF) to Merck Sharp & Dohme: 6,136,861
`(Chenard BL) to Pfizer: 6,147,072 (Bymaster F Pet. al.) to
`Eli Lilly; 6,218,395 (Swartz CM); 6,169,105 (Wong DT and
`Oguiza JI) to Eli Lilly: 6,191,133 (Coppen AJ) to Scarista;
`6,239,126 and 6.242,448 (Kelly M G et. al.) to American
`Home Products; 6,372,919 (Lippa AS and Epstein JW) to
`DOV; 6,369,051 (Jenkins S N) to American Home Products:
`6,358,944 (Lederman Set. al.) to Vela Pharmaceuticals;
`6,121,259; 6,174,882; 6,348.455; 6,352,984; and 6,468,997
`(Yelle WE) to Sepracor; 6,403,597 (Wilson L. Fet. al.) to
`Vivus: 6,395,788 and 6,541,523 (Iglehart I W III) to Vela
`Pharmaceuticals; 6,127,385 and 6,395,752 (Midha K. Ket.
`al.) to Pharmaquest Limited; 6.380.200 (Mylari B L) to
`Pfizer; 6.387,956 (Shapira N A et al.) to University of Cin
`cinnati; 6,444,665 (Helton D Ret. al.) to Eli Lilly: 6,541,478
`(O'Malley Set. al.) to Yale University; 6.541,043 (Lang PC)
`to DexGen Pharmaceuticals; 6,562,813 (Howard H R) to
`Pfizer: 6,579,899 (Wurtman JJ and Wurtman RJ) to Massa
`chusetts Institute of Technology: 6,627,653 (Plata-Salaman C
`45
`Ret. al.) to Ortho-McNeil; 6,649,614 (Carlson E J and Rup
`niak N M) to Merck Sharp & Dohme: 6,667,329 (MajJ) to
`Boehringer Ingelheim; 6,727,242 (Radulovacki M and Car
`ley D W) to The Board of Trustees of the University of
`Illinois; 6,656,951: 6,780,860; 6,815,448; 6,821,981; and
`6,861,427 (Stack; Gary Pet. al.) to Wyeth: 6.878,732 (Wrob
`leski ML) to Schering Corporation; and 6,894,053 (Childers
`W E et al.) to Wyeth.
`Further disclosed are additional combinations of Com
`pound 1 with other agents extending or enhancing its utility in
`55
`the treatment or prevention of autism, dyskinesia, disthymic
`disorder, obesity due to genetic or environmental causes,
`polycystic ovary disease, craniopharyngeoma, Prader-Willi
`Syndrome. Frohlich's Syndrome, Type II diabetes, growth
`hormone deficiency, Turner's Syndrome; pro-inflammatory
`cytokine secretion or production, jet lag, insomnia, hyper
`Somnia, nocturnal enuresis, restless-legs syndrome, vaso-oc
`clusive events, hyperglycemia, hyperinsulinaemia, hyperlipi
`daemia, hypertriglyceridemia, diabetes, insulin resistance,
`impaired glucose metabolism, conditions of impaired glu
`cose tolerance (IGT), conditions of impaired fasting plasma
`glucose, glomerulosclerosis, syndrome X, coronary heart dis
`
`4
`ease, angina pectoris, vascular restenosis, endothelial dys
`function, impaired vascular compliance, or congestive heart
`failure; or to increase the onset of action of Compound 1. US
`Patent
`Applications
`20020032197,
`20020002137,
`20020086865, 20020077323, 20020103249, 20020094960,
`2003.0109544, 20030092770, 2003.014.4270, 20030158173,
`2003.0139395, 20030055070, 2003.0139429, 20040044005,
`20010014678, 20040044005, 20030235631, 20030027817,
`20030229001, 20030212060, 20040132797, 20040204469,
`20040204401, 2004.0171664, 20040229940, 20040229941,
`20040229942, 20040229911, 20040224943, 20040229866,
`20040224.942, 20040220153, 20040229849, 20050069596,
`20050059654, 20050014848, 20050026915, 20050026946,
`20050143350, 20020035105, 20050143314, 20050137208,
`20040010035, 20040013741, 20050136127, 200501 19248,
`200501 19160, 20050085477, 20050085475, 20010003749,
`20050009815, 20040248956, 20050014786, 20050009870,
`2005.0054659, 20050143381, 20050080087, 20050070577,
`and 20050080084.
`Compound 1 has been characterized by in vitro studies of
`binding to rat cortical membranes, wherein radiolabeled
`Compound 1 was found to bind to a single, high affinity,
`saturable site. See e.g. Habert E et. al., Eur. J. Pharmacol.
`1985 118: 107.
`Compound 1 has also been characterized in a number of
`animal model systems. For instance, in models of depression,
`obesity, and anxiety, treatment with Compound 1 accurately
`produced results that are correlated with human clinical
`effects. See, e.g. Akegawa Y et. al. Methods Find Exp Clin
`Pharmacol 1999 21:599; Lassen JB, U.S. Pat. No. 4,745,122
`to Ferrosan; and Hascoet Met. al., Pharmacol. Biochem.
`Behav. 2000 65: 339.
`In human clinical studies, Compound 1 demonstrated good
`tolerability and statistical efficacy in patients suffering from
`major depression, minor depression and dysthymia, obses
`sive-compulsive disorder, panic disorder, Social anxiety dis
`order, generalized anxiety disorder, and post-traumatic stress
`disorder. Compound 1 is highly effective, for instance dem
`onstrating Superior antidepressant effects to other compounds
`with the same mechanism of action in a number of direct
`comparison studies. See, e.g. US Food and Drug Administra
`tion product label for New Drug Application (NDA) Nos.
`020031,020710, and 020936: WagstaffAJet. al., Drugs 2002
`62: 655; Katona C and Livingston G. J. Affect. Disord. 2002
`69: 47.
`Following oral administration to humans, Compound 1 is
`well absorbed, after which it undergoes extensive oxidative
`and phase II metabolism. Its major metabolic pathway pro
`ceeds by oxidative cleavage of the benzodioxol ring to form
`ing a catechol metabolite. Subsequent phase II metabolism
`involves mainly methylation, glucuronidation and Sulfation.
`See Scheme I. In vitro measurements indicate that these
`metabolites possess <2% of the potency of Compound 1 and
`therefore do not contribute pharmacodynamically to its
`action. During a 10-day post-dosing period following a 30 mg
`oral solution dose of radiolabeled Compound 1 in healthy
`volunteers, approximately 64% of Compound 1 was found to
`be excreted in the urine, comprising 2% as the parent com
`pound and 62% as metabolites. About 3.6% was excreted in
`the feces, mostly as metabolites andless than 1% as the parent
`compound during this period. US FDA approved label for
`NDA # 020031, approved Jan. 12, 2005.
`
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`Auspex Exhibit 2007
`Apotex v. Auspex
`IPR2021-01507
`Page 3
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`

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`5
`The benzodioxol ring Scission is carried out in significant
`part by cytochrome 2D6 (CYP2D6), which acts as a high
`affinity, but relatively low capacity, oxidant. Compound 1
`also acts as a highly potent, mechanism based inactivator of
`CYP2D6, possibly through formation of a carbene interme
`diate during the metabolic oxidation step or by formation of
`an ortho-quinone and Subsequent reaction with active-site
`nucleophiles. Bertelsen K M et. al., Drug Metab. Dispos.
`200331: 289; Murray M, Curr. Drug Metab. 20001: 67: Ortiz to
`de Montellano and Correi MA in “Cytochrome P450 Struc
`ture, Mechanism and Biochemistry” (Ortiz de Montellano PR
`ed) pp. 305-366, 1995 Plenum Press, New York; Wu et al.,
`Biochem. Pharmacol. 199753: 1605; Bolton J Let. al., 1994
`Chem. Res. Toxicol. 7: 443.
`Clinically, this mechanism-based inactivation manifests in
`several ways. For instance, Compound 1 displays signifi
`cantly non-linearity pharmacokinetics, with steady state
`doses several times the levels expected from a single dose as 20
`a result of auto-inhibition of its metabolism. Compound 1
`also causes a dose-dependent, highly significant reduction in
`CYP2D6 activity. CYP2D6 comprises the main metabolic
`pathway for a number of other clinically important drugs,
`including for instance anti-cancer agents, other anti-depres
`sants, and antipsychotics; as well as drugs of abuse Such as the
`widely used drug "Ecstasy”. Co-dosing Compound 1 with
`those agents causes clinically significant increases in their
`blood levels, leading to the potential for increased toxicity. 30
`Jeppesen Uet. al., Eur. J. Clin. Pharmacol. 199651: 73; US
`FDA approved label for NDA # 020935, approved Jan. 12,
`2005; Laugesen Set. al., Clin Pharmacol Ther. 2005 77:312:
`Jin Yet. al., J. Natl. Cancer Inst. 200597:30; Joos AAB et al.,
`Pharmacopsychiat. 1997.30,266; Segura Met. al., Clin Phar
`macokinet. 2005 44: 649.
`Compound 1 is Subject to Substantial inter-patient varia
`tion. Patients possessing relatively low and relatively high
`levels of CYP2D6 activity have been shown to metabolize 40
`Compound 1 at Substantially different rates, leading to an
`approximately 3-fold longer half-life in a European cohort of
`poor metabolizers (PMs) with low CYP2D6-mediated oxida
`tive efficiency versus extensive metabolizers (EMs) with
`higher CYP2D6 activity: Sindrup S Het. al., Clin. Pharmacol. 45
`1992 51: 278. Even when measured at steady state, at which
`time variability is Substantially less than on initial dosing,
`high variability of Compound 1 was observed in a test popu
`lation (about 30-70% coefficients of variability across maxi- so
`mal and minimal plasma concentrations (Cmax and Cmin)
`and overall exposure measured as area under the plasma
`concentration-time curve (AUC)). Kaye C Met. al., Acta
`Psychiatr. Scand. 80(Suppl. 350): 60.
`CYP2D6 is the source of substantial variability in the phar
`macokinetics of a number of drugs due to well-known poly
`morphisms resulting in low CYP2D6 activity in a substantial
`percentage of the population, including about 2% of Asians
`and 7-8% of Caucasians (Wolf C R and Smith G, IARC Sci.
`Publ. 1999 148: 209 (chapter 18); Mura Cet. al., Br. J. Clin.
`Pharmacol. 1993 35: 161; Shimizu Tet. al., Drug Metab.
`Pharmacokinet. 2003 18: 48). Notably, different CYP2D6
`polymorphisms exist across racial types, and it is possible that
`the even greater variability may exist in other patient popu- 65
`lations with different pharmacogenomic backgrounds. Shi
`mada Tet. al., Pharmacogenetics 2001 11: 143.
`
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`US 7,678,914 B2
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`Scheme I
`Compound 1
`Enzymatic
`Oxidation
`
`F
`
`OH
`
`OH
`
`O
`
`N
`H
`
`/ Penis
`
`\
`
`F
`
`OH
`
`F
`
`Y,
`
`F
`
`O
`
`W
`
`O
`
`w
`
`O
`H
`- w
`
`N
`H
`
`N
`H
`
`N
`H
`
`O-Glucuronidation and Sulfation, Excretion
`
`It is therefore desirable to create a compound displaying
`the beneficial activities of Compound 1, but with a decreased
`metabolic liability for CYP2D6, to further extend its pharma
`cological effective life in extensive metabolizers, decrease
`population pharmacokinetic variability and/or decrease its
`potential for dangerous drug-drug interactions.
`
`SUMMARY OF THE INVENTION
`
`The present invention solves the problems set forth above
`by providing an isolated compound of Formula I:
`
`Formula I
`
`N
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`Auspex Exhibit 2007
`Apotex v. Auspex
`IPR2021-01507
`Page 4
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`US 7,678,914 B2
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`or a salt thereof, or a prodrug, or a salt of a prodrug thereof; or
`a hydrate, solvate, or polymorph thereof; wherein:
`D is deuterium;
`each Y is independently selected from deuterium or hydro
`gen,
`each hydrogen is independently optionally replaced with
`deuterium; and
`each carbon is independently optionally replaced with C.
`A compound of Formula I reduces the efficiency of benzo
`dioxol ring cleavage by CY2D6 and beneficially decreases
`the rate of mechanism-based CYP2D6 inhibition relative to
`Compound 1.
`The decreased CYP2D6 inhibition is important in reducing
`the pharmacokinetic interactions between Compound 1 and
`other drugs metabolized by that enzyme. This provides
`increased safety as compared to Compound 1.
`In particular, this would produce benefits in the treatment
`of co-morbidities and the use of combinations of medications,
`which is common in patients suffering from depression, anxi
`ety and other psychiatric disorders. Moreover, it would be
`useful in patients taking Compound 1, while being treated by
`different healthcare providers without disclosing all of their
`medications to each of them. It would also be beneficial in
`patients who are using drugs of abuse while taking Com
`pound 1 without the knowledge of their physician.
`25
`The decreased substrate efficiency for CYP2D6 at the
`methylenedioxy portion of the benzodioxol ring demon
`strated by the compounds of this invention will provide the
`further benefit of reducing inter-patient pharmacokinetic
`variability observed for Compound 1.
`The compounds of the present invention comprising addi
`tional deuterium for hydrogen replacement at the methylene
`dioxy carbon demonstrate the added benefit of reduced
`metabolism by other cytochrome P450 enzymes. This is
`important for poor metabolizers of Compound 1, wherein the
`main metabolic pattern of Compound 1 proceeds largely by
`Scission of the benzodioxol ring, likely due to oxidative attack
`by another cytochrome enzyme. Also, a relatively minor
`amount of ring Scission (complete cleavage of the benzo
`dioxol ring, forming 4-(4-fluorophenyl)-3-hydroxymethylpi
`peridine) observed in normal metabolizers, which could
`result from oxidation of the methylene carbon attached to the
`piperidine ring, may become more predominant if the benzo
`dioxol ring is metabolically stabilized. Therefore, com
`pounds of this invention that are deuterated at that carbon will
`45
`also be beneficial to the clearance rate of the compound.
`The compounds of this invention, and compositions com
`prising them, are useful for treating or lessening the severity
`of disorders characterized by reduced serotonin-dependent
`neurological activity. Preferred applications for compounds
`of formula I include methods of use in treating depression,
`anxiety, stress, phobias, panic, dysphoria, and other psychi
`atric disorders, and pain.
`The compounds and compositions of this invention are also
`useful as analytical reagents for determining the concentra
`tion of the Compound 1 in solution. “Compound 1 as used
`herein refers to a compound wherein all hydrogen and all
`carbon atoms are present at their natural isotopic abundance
`percentages. It is recognized that some variation of natural
`isotopic abundance occurs depending upon the origin of
`chemical materials. The concentration of naturally abundant
`stable hydrogen and carbon isotopes, notwithstanding this
`variation, is Small and immaterial with respect to the degree of
`stable isotopic Substitution of compounds of this invention.
`See for instance Wada E and HanbaY. Seikagaku 1994.66:15:
`Ganes L. Zet. al., Comp. Biochem. Physiol. A Mol. Integr.
`Physiol. 1998 119: 725.
`
`55
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`8
`Incorporation of deuterium in place of hydrogen is known
`in certain instances to have significant effects on the physi
`ological and pharmacological activities of the Substituted
`compound. For instance, N-nitrosamines Substituted with
`deuterium can display increased, decreased, or unchanged
`carcinogenicity depending on where in the compound hydro
`gen is replaced with deuterium and on the identity of the
`compound to which Substitutions are made (Lijinsky Wet. al.,
`Food Cosmet. Toxicol. 1982 20:393: Lijinsky Wet. al., JCNI
`1982 69: 1127). Similarly, both increases and decreases in
`bacterial mutagenicity of deuterium-substituted aza-amino
`acids are known, depending on the identity of the amino acid
`derivative and position of substitution (Mangold J B et. al.,
`Mutation Res. 1994.308:33). Reduced hepatotoxicity of cer
`tain deuterium-substituted compounds is known (Gordon W
`Pet. al., Drug Metab. Dispos. 1987 15:589: Thompson DC
`et. al., Chem. Biol. Interact. 1996 101: 1). Deuterium substi
`tution can affect compounds odors (Turin L. Chem. Senses
`1996 21: 773) and plasma protein binding (Echmann MLet.
`al., J. Pharm. Sci. 1962 51: 66; Cherrah Y. et al., Biomed.
`Environm. Mass Spectrom. 1987 14: 653; Cherrah Y. et al.,
`Biochem. Pharmacol. 198837: 1311). Changes in the biodis
`tribution and clearance of certain deuterium-Substituted com
`pounds suggests changes in their recognition by active trans
`port mechanisms (Zello GA et al., Metabolism 199443: 487;
`Gately SJet. al., J. Nucl. Med. 1986 27:388; Wade D, Chem.
`Biol. Interact. 1999 117: 191).
`Replacement of hydrogen with deuterium at sites Subject to
`oxidative metabolism by, for instance, heme proteins such as
`cytochrome P450 and peroxidase enzymes, is known in cer
`tain, but not all, cases to produce a significant reduction in the
`rate of metabolism due to the primary isotope effect of break
`ing the C H versus C H bond (see, e.g., Guengerich FP
`et. al., J. Biol. Chem. 2002 277: 33711; Kraus, J A and
`Guengerich, F P. J. Biol. Chem. 2005 280: 19496; Mitchell K
`Het. al., Proc. Natl. Acad. Sci. USA 2003 109:3784; Nelson
`SD and Trager WF, Drug Metab. Dispos. 200331: 1481; Hall
`L R and Harzlik R. P. J. Biol. Chem. 1990 265: 12349; Oka
`Zaki 0 and Guengerich F P. J. Biol. Chem. 268, 1546; Iwar
`nura Set. al., J. Pharmacobio-Dyn. 1987 10: 229). If the
`C-H bond breaking step is rate-limiting, a Substantial iso
`tope effect can be observed. If other steps determine the
`overall rate of reaction, the isotope effect may be insubstan
`tial. In cases where a rate-limiting step of a reaction involves
`rehybridization of the attached carbon from sp2 to sp3, deu
`terium Substitution often creates a negative isotope effect,
`speeding up the reaction rate. Introducing deuterium into a
`compound at a site subject to enzymatic oxidation does not
`predictably produce a significant pharmacokinetic change.
`See for instance Mamada Ket. al., Drug Metab. Dispos. 1986
`14: 509; Streeter A Jet. al., Arch. Toxicol. 1990 64: 109:
`Morgan D Set. al., Int. Arch. Occup. Environ. Health 1993
`65(1 Suppl.): S139.
`Although incorporation of deuterium into specific organic
`compounds can change their pharmacological properties,
`general exposure to and incorporation of deuterium is safe
`within levels potentially achieved by use of compounds of
`this invention as medicaments. For instance, the weight per
`centage of hydrogen in a mammal (approximately 9-10%)
`and natural abundance of deuterium (approximately 0.015%)
`indicates, for instance that an average adult US male normally
`contains approximately 1.2 grams of deuterium (see e.g.
`Harper V Wet. al. “Review of Physiological Chemistry' 16"
`Edition, 1977 Lange Medical Publications: Ogden C Let. al.
`CDC Adv. Data 2004 347: 1; www.cdc.gov/nchs/data/ad/
`ad347.pdf).
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`Auspex Exhibit 2007
`Apotex v. Auspex
`IPR2021-01507
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`9
`Furthermore, replacement of up to about 15% of normal
`hydrogen with deuterium has been effected and maintained
`for a period of days to weeks in mammals, including rodents
`and dogs, with minimal observed adverse effects (Czajka D
`Mand Finkel AJ, Ann. N.Y. Acad. Sci. 1960 84: 770; Thom
`son J. F. Ann. N.Y. Acad. Sci. 196084: 736: Czaka D Met. al.,
`Am. J. Physiol. 1961 201: 357). Higher deuterium concen
`trations, usually in excess of 20%, can be toxic in animals.
`However, acute replacement of as high as 15%-23% of the
`hydrogen in humans fluids with deuterium was found not to
`cause toxicity (Blagojevic Net. al. in “Dosimetry & Treat
`ment Planning for Neutron Capture Therapy'. Zamenhof R,
`Solares G and Harling O Eds. 1994. Advanced Medical Pub
`lishing, Madison Wis. pp. 125-134.). These authors report a
`clinical protocol in their practice involving oral administra
`tion of up to 1 liter per day of deuterated water (DO) for up
`to 5 days, followed by intravenous administration of 4 liters of
`deuterated waterprior to radiation procedures; this deuterated
`water is readily incorporated throughout the body beyond the
`fluid compartment, including in glucose and glycogen, fats,
`and cholesterol and thus cell walls (e.g. see Diabetes Metab.
`1997 23:251).
`In a 70kg human, 15% replacement of the hydrogen in the
`fluid compartment with deuterium corresponds to incorpora
`tion of approximately 1 kg of deuterium or the equivalent of
`approximately 5 kg of deuterated water. These quantities are
`orders of magnitude beyond the conceived level of adminis
`tration of any of the deuterium-containing compounds of this
`invention.
`Deuterium tracers including as deuterium-labeled drugs
`and doses, in Some cases repeatedly, of thousands to tens of
`thousands of milligrams of deuterated water, are also used in
`healthy humans of all ages including neonates and pregnant
`women, without reported incident (e.g. Pons G and Rey E.
`Pediatrics 1999 104: 633: Coward WAet. al., Lancet 1979 7:
`13; Schwarcz HP, Control. Clin. Trials 19845(4 Suppl): 573:
`Eckhardt C Let. al. Obes. Res. 2003 11: 1553; Rodewald LE
`et. al., J. Pediatr. 1989 114: 885; Butte N F et. al., Br. J. Nutr.
`1991 65: 3; MacLennan A Het. al., Am. J. Obstet. Gynecol.
`1981 139:948). Thus, it is clear that any deuterium released,
`for instance during the metabolism of compounds of this
`invention, poses no health risk.
`The compounds of this invention display decreased mecha
`nism-based inactivation of CYP2D6 than Compound 1 and
`therefore display a reduced rate of oxidative metabolism and
`decreased mechanism-based inactivation of CYP2D6. This
`reduces the extent of undesirable metabolic drug-drug inter
`actions observed with Compound 1, reducing the need for
`dose adjustments of other drugs taken by patients treated with
`these agents.
`The altered properties of the compounds of this invention
`will not obliterate their ability to bind to their protein target.
`This is because such binding is primarily dependent upon
`non-covalent binding between the protein and the inhibitor
`which may be impacted both positively and negatively by
`isotopic Substitution, depending on the specific Substitution
`involved, and any negative effects that a heavy atom of this
`invention may have on the highly optimized non-covalent
`binding between compounds