US009125939B2
`
`(12) United States Patent
`Kikuchi et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,125,939 B2
`Sep. 8, 2015
`
`(54) CARBOSTYRIL DERIVATIVES AND MOOD
`STABILIZERS FOR TREATING MOOD
`DISORDERS
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(75)
`
`Inventors: Tetsuro Kikuchi, Tokushima (JP); Taro
`Iwamoto, Princeton, NJ (US); Tsuyoshi
`Hirose, Tokushima (JP)
`
`(73) Assignee: Otsuka Pharmaceutical Co., Ltd.,
`Tokyo (JP)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 800 days.
`
`(21) App1.No.:
`
`10/556,600
`
`(22) PCT Filed:
`
`May 19, 2004
`
`(86) PCT No.:
`
`PCT/US2004/013308
`
`§ 371 (OX1),
`(2), (4) Date:
`
`Aug. 2, 2006
`
`(87) PCT Pub. No.: WO2004/105682
`
`PCT Pub. Date: Dec. 9, 2004
`
`(65)
`
`Prior Publication Data
`
`US 2007/0031513 A1
`
`Feb. 8, 2007
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/473,378, filed on May
`23, 2003.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K31/47
`A61K31/44
`A61K33/14
`A01N59/08
`A61K 45/06
`A61K31/19
`A61K31/195
`A61K31/425
`A61K31/4704
`A61K31/496
`A61K31/497
`A61K31/55
`A61K31/7008
`A61K33/00
`(52) U.S.Cl.
`CPC ............... .. A61K 45/06 (2013.01), A61K 31/19
`(2013.01), A61K31/195 (2013.01), A61K
`31/425 (2013.01), A61K31/4704 (2013.01),
`A61K 31/496 (2013.01), A61K 31/497
`(2013.01), A61K31/55 (2013.01), A61K
`31/7008 (2013.01), A61K 33/00 (2013.01),
`A61K 33/14 (2013.01)
`(58) Field of Classification Search
`CPC .......... .. A61K31/4704; A61K 31/496; A61K
`31/497, A61K33/00; A61K33/44; A61K
`2300/00
`USPC ................. .. 514/310, 557, 299, 722, 424/722
`See application file for complete search history.
`
`5,006,528 A
`2001/0023254 A1
`2002/0173513 A1
`2003/0027817 A1
`2003/0109546 A1
`2005/0004106 A1
`
`4/1991 Oshiro et al.
`9/2001 McElroy
`11/2002 Jordan et al.
`2/2003 Tollefson
`6/2003 Fenton
`1/2005 Romano
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`0367141 A2
`0966967 A2
`WO 97/35584 A1
`WO 99/62522 A1
`WO 00/59489 A2
`W0 02/060423 A2
`W0 02/087590 A1
`W0 03/026659
`W0 03/066039 A1
`WO 2004060374 A1
`WO 2004/100992 A2
`
`9/1990
`12/1999
`10/1997
`12/1999
`10/2000
`8/2002
`11/2002
`4/2003
`8/2003
`7/2004
`11/2004
`
`OTHER PUBLICATIONS
`
`CN138-00ST, Apr. 2003.*
`RU Search Report dated Nov. 8, 2006 issued in Patent Application
`No. 2004 009073.
`Borwin Bandelow and Andreas Meier; Aripiprazole, a “Dopamine-
`Serotonin System Stabilizer” in the Treatment of Psycho sis; German
`Journal of Psychiatry, vol. 6, No. 1, 2003; pp. 9-16.
`Melissa P. Delbello, M. D., et al.; A Double-Blind, Randomized,
`Placebo-Controlled Study of Quetiapine as Adj unctive Treatment for
`Adolescent Mania; Journal of the American Academy of Child and
`Adolescent Psychiatry, vol. 41, No. 10, 2002, pp. 1216-1223.
`Mauricio Tohen, M.D. et al.; Efficacy of Olanzapine in Combination
`with Valproate or Lithium in the Treatment of Mania in Patients
`Partially Nonresponsive to Valproate or Lithium Monotherapy;
`Archives of General Psychiatry, vol. 59, No. 1, 2002, pp. 62-69.
`Frank I. Tarazi, et al., Long-term effects of olanzapine, risperidone,
`and quetiapine on serotonin 1A, 2A and 2C receptors in rat forebrain
`regions; Psychopharmacology, vol. 161, No. 3, 2002, pp. 263-270.
`(Continued)
`
`Primary Examiner — Shobha Kantarnneni
`(74) Attorney, Agent, or Firm — Finnegan, Henderson,
`Farabow, Garrett & Dunner LLP
`
`(57)
`
`ABSTRACT
`
`The pharmaceutical composition of the present invention
`comprises a carbostyril derivative which is a doparnine-sero-
`tonin system stabilizer and a mood stabilizer in a pharmaceu-
`tically acceptable carrier. The carbostyril derivative may be
`aripiprazole or a metabolite thereof. The mood stabilizer may
`include but is not limited to lithium, valproic acid, divalproex
`sodium, carbamaza-pine, oxcarbarnazapine, zonisamide,
`lamotragine, topirarnate, gabapentin, levetiracetarn or clon-
`azepam. These compositions are used to treat patients with
`mood disorders, particularly bipolar disorder with or without
`psychotic features, mania or mixed episodes. Methods are
`provided for separate administration of a carbostyril deriva-
`tive and a mood stabilizer to a patient with a mood disorder.
`
`10 Claims, 8 Drawing Sheets
`
`10f25
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`Alkermes, Ex. 1001
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`

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`US 9,125,939 B2
`Page 2
`
`(56)
`
`References Cited
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`OTHER PUBLICATIONS
`Merck Index 13, the Merck& Co. NJ. USA document, No. 791, 1788,
`5368, 9625,4342 and 2413, year 2001.
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologicals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 791, 2001 (year).
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologicals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 1788, 2001 (year).
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologicals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 5368, 2001 (year).
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologicals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 9625, 2001 (year).
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologicals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 4342, 2001 (year).
`The Vlerck Index, An Encyclopedia of Chemicals, Drugs and
`Biologjcals, Thirteenth Edition, Vlerck Index & Co., \TJ, L SA docu-
`ment, \To. 2413, 2001 (year).
`Gordon et al., Mood Stabilization and Weight loss with Topiramate,
`American Journal of Psychiatry, Jun. 1999, vol. 156, No. 6, pp.
`968-969, see pp. 1 and 2.
`Baldessarini et al, Hospital Use ofAntipsychotic Agents in 1989 and
`1993: Stable Dosing with Decreased Length of Stay, American Jour-
`nal ofPsychiatry, Jul. 1995, vol. 152, No. 7, pp. 1038-1044, see pp.
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`Jacobsen et al., Risperidone in the Treatment ofAffective Illness and
`Obsessive-Compulsive Disorder, Journal ofClinical Psychiatry, Sep.
`1995, vol. 56, No. 9, pp. 423-429.
`Weisler et al., Adjunctive Use of Olanzapine in Mood Disorders: Five
`Case Reports, Annals ofClinical Psychiatry, 1997, vol. 9, No. 4, pp.
`259-262.
`
`Mcelroy et al., Clozapine in the Treatment of Psychotic Mood Dis-
`orders, Schizoaffective Disorder, and Schizophrenia, J. Clin. Psy-
`chiatry, Oct. 1991, vol. 52, No. 10, pp. 411-414.
`Citrome et al., Pharmacokinetics and Safety of Aripiprazole and
`Concomitant Mood Stabilizers, 2002, vol. 5, Suppl. 1, p. S187 (P.4.E.
`035).
`Moeller et al., Treatment of Bipolar Disorder, J. Clin. Psychiatry,
`2003, vol. 64, Suppl. 6, pp. 9-17.
`Kowatch et al., The Use of Mood Stablizers and Atypical
`Antipsychotics in Children and Adolescents with Bipolar Disorders,
`CNS Spectrums, Apr. 2003, vol. 8, No. 4, pp. 273-280.
`Shin Shiah et al., “Serotonin in Mania and in the Mechanism of
`Action of Mood Stabilizers: A Review of Clinical Studies”, Bipolar
`Disorders: An
`International
`Journal
`of
`Psychiatry
`and
`Neurosciences; Dec. 24, 2001; Abstract; vol. 2, issue 2.
`Bobula et al., “Adaptive Changes in the Reactivity of 5-HT,A and
`5-HT2 Receptors Induced in Rat Frontal Cortex by Repeated
`Imipramine
`and Citalopram”, Naunyn-Schmiedeberg’s Arch
`Pharmacol, 2003, pp. 444-450, 367.
`Ichikawa et al., “Valproate and Carbamazepine Increase Prefrontal
`Dopamine Release by 5-HT 1A Receptor Activation”, European Jour-
`nal of Pharmacology, 1999, pp. R1-R3, 367.
`Brambilla et al., “Atypical Antipsychotics and Mood Stabilization in
`Bipolar Disorder”, Psychopharmacologia, 2003, pp. 315-332, vol.
`166 No. 4.
`Robert M. Post et al., “Acute and prophylactic effects of
`anticonvulsants
`in bipolar depression”, Clinical Neuroscience
`Research 2 (2002) 228-2511.
`Yasuhiro Suzuki, “Zonisamide in West syndrome”, Brain and devel-
`opment 23 (2001), 658-661.
`English Translation of Egyptian Office Action dated Jun. 27, 2010.
`Casey, Daniel, E., “Switching Patients to Aripiprazole From Other
`Antipsychotic Agents
`a Multicenter Randomized
`Study”,
`Psychopharmacology (2003), 166, pp. 390-399.
`
`* cited by examiner
`
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`Alkermes, Ex. 1001
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`

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`U.S. Patent
`
`Sep. 8, 2015
`
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`US 9,125,939 B2
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`US 9,125,939 B2
`
`1
`CARBOSTYRIL DERIVATIVES AND MOOD
`STABILIZERS FOR TREATING MOOD
`DISORDERS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This Application is a 371 of PCT/US2004/013308, filed
`May 19, 2004, which claim priority to U.S. Provisional Appli-
`cation No. 60/473,378, filed May 23, 2003; the disclosures of
`which are incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`The present invention provides pharmaceutical composi-
`tions comprising carbostyril derivatives that act as dopamine-
`serotonin system stabilizers in combination with mood stabi-
`lizers in a pharmaceutically acceptable carrier. The present
`invention provides methods to treat mood disorders such as
`bipolar disorder with or without psychotic features, mania or
`mixed episodes using the compositions of the present inven-
`tion or by separately administering these carbostyril deriva-
`tives and mood stabilizers. The carbostyril derivatives of the
`present invention include but are not limited to aripiprazole
`and metabolites thereof, such as dehydroaripiprazole. The
`mood stabilizers include, but are not limited to, lithium, val-
`proic acid, divalproex sodium, carbamazapine, oxcarbamaza-
`pine, zonisamide, lamotragine, topiramate, gabapentin, leve-
`tiracetarn and clonazepam.
`
`BACKGROUND OF THE INVENTION
`
`The number ofpeople with mood disorders, such as bipolar
`disorder with or without psychotic features, mania or mixed
`episodes is increasing every year for numerous reasons. Since
`the period of 1950, tricyclic antidepressant drugs (e.g., imi-
`pramine, desiprarnine, amitriptyline, etc.) have been devel-
`oped that act to inhibit monoamine reuptake. They are fre-
`quently used for treating patients suffering from mood
`disorders. However, these drugs have side-effects, such as the
`following: dry mouth, hazy eyes, dysuria, constipation, rec-
`ognition disturbance and the like due to anticholinergic activ-
`ity; cardiovascular side-effects such as, orthostatic hypoten-
`sion,
`tachycardia
`and
`the
`like
`on
`the
`basis
`of
`otl-adrenoreceptor antagonist activity; side-effects such as,
`sedation, increase in the body weight and the like on the basis
`of histamine-H1 receptor antagonist activity.
`Although the mood disorders including bipolar disorder
`with or without psychotic features, mania or mixed episodes
`are heterogeneous diseases, and the causes of these diseases
`are not fully understood, it is likely that the abnormalities of
`the monoaminergic central nervous system caused by seroto-
`nin, norepinephrine and dopamine and the like, and the abnor-
`mality of various hormones and peptides as well as various
`stressors are causes of depression and various other mood
`disorders (Kubota Masaharu et al.: “RINSHOU SEISHIN
`IGAKU” Vol. 29, pp 891-899, (2000)). For these reasons,
`even though mood stabilizer drugs, such as lithium, valproic
`acid, divalproex sodium, carbamazapine, oxcarbamazapine,
`zonisamide, lamotragine, topiramate, gabapentin, levetirac-
`etam and clonazeparn have been used, these drugs are not
`always effective in treating all patients.
`New therapeutic trials involve proposed combined thera-
`pies using an atypical antipsychotic drug, such as olanzepine
`or quetiapine, which are agents for treating schizophrenia
`(anti-psychotic drug), together with mood stabilizing drug
`such as valproate, lithium or divalproex ((Arch. Gen. Psy-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`chiatry, 2002 January 59:1):62-69; JAmAcad Child Adolesc
`Psychiatry 2002 October; 41(10) :1216-23.)
`Further, commercially available atypical antipsychotic
`drugs have significant problems relating to their safety. For
`example, clozapine, olanzapine and quetiapine increase body
`weight and enhance the risk of diabetes mellitus (Newcomer,
`J. W. (Supervised Translated by Aoba Anri): “RINSHOU
`SEISHINYAKURI”Vol. 5, pp 911-925, (2002), Haupt, D. W.
`and Newcomer, J. W. (Translated by Fuji Yasuo and Misawa
`Fuminari): “RINSHOU SEISHINYAKURI”Vol. 5, pp 1063-
`1082, (2002)). In fact, urgent safety alerts have been issued in
`Japan relating to hyperglycemia, diabetic ketoacidosis and
`diabetic coma caused by olanzapine and quetiapine, indicat-
`ing that these drugs were subjected to dosage contraindica-
`tion to the patients with diabetes mellitus and patients having
`anamnesis of diabetes mellitus. Risperidone causes increases
`serum prolactin levels and produces extrapyramidal side
`effects at high dosages. Ziprasidone enhances the risk of
`severe arrhythmia on the basis of cardio-QTc prolongation
`action. Further, clozapine induces agranulocytosis, so that
`clinical use thereof is strictly restricted (van Kammen, D. P.
`(Compiled under Supervision by Murasaki Mitsuroh) “RIN-
`SHOU SEISHINYAKURI” Vol. 4, pp 483-492, (2001)).
`Accordingly what is needed are new compositions useful
`for treating mood disorders, particularly bipolar disorder with
`or without psychotic features, mania or mixed episodes,
`which are efiicacious and do not cause the deleterious side
`
`effects associated with prior art compounds.
`
`SUMMARY OF THE INVENTION
`
`The present invention solves the problems described above
`by providing novel compositions and methods of using these
`compositions for treating mood disorders, particularly bipo-
`lar disorder, including but not limited to bipolar disorder I,
`bipolar disorder II, bipolar disorder with and without psy-
`chotic features, and mania, acute mania, bipolar depression or
`mixed episode.
`The present invention provides solutions to the above-
`mentioned problems, and demonstrates that the mood disor-
`ders, such as bipolar disorder and mania, can be treated effec-
`tively by administering to a patient with such disorder a
`composition comprising at least one carbostyril derivative
`that is a dopamine-serotonin system stabilizer in combination
`with at
`least one mood stabilizer in a pharmaceutically
`acceptable carrier. A preferred carbostyril derivative of the
`present invention that is a dopamine-serotonin system stabi-
`lizer is aripiprazole or a metabolite thereof. Another preferred
`carbo styril derivative ofthe present invention that is a dopam-
`ine-serotonin system stabilizer is a metabolite of aripiprazole
`called dehydroaripiprazole, also known as OPC-14857.
`Other such metabolites of aripiprazole included within the
`present invention are shown in FIG. 8. Preferred aripiprazole
`metabolites are shown in FIG. 8 indicated by the following
`designations: OPC-14857, DM-1458, DM-1451, DM-1452,
`DM-1454 and DCPP.
`
`Aripiprazole, also called 7-{4-[4-(2,3-dichlorophenyl)-1-
`piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone,
`is
`a
`carbostyril and is useful for treating schizophrenia (JP-A-2-
`191256, U.S. Pat. No. 5,006,528). Aripiprazole is also known
`as 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-
`dihydrocarbostyril, Abilify, OPC-14597, OPC-31 and BMS-
`337039. Aripiprazole possesses 5-HT1A receptor agonist
`activity, and is known as a useful compound for treating types
`of depression and refractory depression, such as endogenous
`depression, major depression, melancholia and the like (W0
`02/060423A2; Jordan et al U.S. Patent Application 2002/
`
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`US 9,125,939 B2
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`3
`01735 l3Al)). Aripiprazole has activity as an agonist at sero-
`tonin receptors and dopamine receptors, and acts as an ago-
`nist or partial agonist at the serotonin SHTIA receptor and as
`an agonist or partial agonist at the dopamine D2 receptor.
`Aripiprazole is a dopamine-serotonin system stabilizer.
`Metabolites of aripiprazole are included within the scope of
`the present invention. One such metabolite of aripiprazole is
`called dehydroaripiprazole. Other such metabolites of arip-
`iprazole included within the present invention are shown in
`FIG. 8. Preferred metabolites are shown in FIG. 8 indicated
`
`by the following designations: OPC-14857, DM-1458,
`DM-1451, DM-1452, DM-1454 and DCPP.
`The at least one mood stabilizer used in the present inven-
`tion includes but is not limited to the following: lithium,
`valproic acid, divalproex sodium, carbamazapine, oxcarbam-
`azapine, zonisarnide, lamotragine, topiramate, gabapentin,
`levetiracetam and clonazepam.
`The novel compositions of the present invention compris-
`ing a carbostyril derivative with activity as a doparnine-sero-
`tonin system stabilizer and at least one mood stabilizer in a
`pharmaceutically acceptable carrier may be combined in one
`dosage form, for example a pill. Alternatively the carbostyril
`derivative with activity as a dopamine-serotonin system sta-
`bilizer and the at least one mood stabilizer may be in separate
`dosage forms, each in a pharmaceutically acceptable carrier.
`These compositions are administered to a patient with a mood
`disorder, such as bipolar disorder or mania, in an amount and
`dose regimen effective to treat the mood disorder.
`Accordingly, it is an object of the present invention to
`provide a composition useful for treating a mood disorder.
`It is an object of the present invention to provide a compo-
`sition useful for treating a mood disorder, wherein the mood
`disorder is bipolar disorder.
`It is an object of the present invention to provide a compo-
`sition useful for treating a mood disorder, wherein the mood
`disorder is mania.
`
`It is another object of the present invention to provide a
`composition comprising a carbostyril derivative with activity
`as a dopamine-serotonin system stabilizer and at least one
`mood stabilizer in a pharmaceutically acceptable carrier.
`Yet another object of the present invention is to provide a
`composition comprising a carbostyril derivative with activity
`as a dopamine-serotonin system stabilizer and at least one
`mood stabilizer in a pharmaceutically acceptable carrier,
`wherein the carbostyril derivative is aripiprazole or a metabo-
`lite thereof.
`
`Yet another object of the present invention is to provide a
`composition comprising a carbostyril derivative with activity
`as a dopamine-serotonin system stabilizer and at least one
`mood stabilizer, wherein the carbostyril derivative with activ-
`ity as a dopamine-serotonin system stabilizer is a metabolite
`of aripiprazole and is OPC-14857, DM-1458, DM-1451,
`DM-1452, DM-1454 or DCPP.
`Yet another object of the present invention is to provide a
`composition comprising a carbostyril derivative with activity
`as a dopamine-serotonin system stabilizer and at least one
`mood stabilizer, wherein the carbostyril derivative is dehy-
`droaripiprazole.
`It is an object of the present invention to provide a method
`for treating a mood disorder.
`It is an object of the present invention to provide a method
`for treating a mood disorder wherein the mood disorder is
`bipolar disorder.
`It is an object of the present invention to provide a method
`for treating a mood disorder wherein the mood disorder is
`mania.
`
`5
`
`10
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`15
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`20
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`25
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`30
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`35
`
`40
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`45
`
`50
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`60
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`65
`
`4
`
`It is another object of the present invention to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer and at least one mood stabilizer in
`a pharmaceutically acceptable carrier.
`Yet another object of the present invention is to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer in a pharmaceutically acceptable
`carrier and a composition comprising at least one mood sta-
`bilizer in a pharmaceutically acceptable carrier.
`It is another object of the present invention to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer and at least one mood stabilizer
`together in a pharmaceutically acceptable carrier, wherein the
`carbostyril derivative is aripiprazole or a metabolite thereof.
`Yet another object of the present invention is to provide a
`method for treating. a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer in a pharmaceutically acceptable
`carrier, wherein the carbostyril derivative is aripiprazole or a
`metabolite thereof, and a composition comprising at least one
`mood stabilizer in a pharmaceutically acceptable carrier.
`Still another object of the present invention is to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer and at least one mood stabilizer in
`a pharmaceutically acceptable carrier, wherein the carbostyril
`derivative is a metabolite of aripiprazole and is dehydroarip-
`iprazole (OPC-14857), DM-1458, DM-1451, DM-1452,
`DM-1454 or DCPP.
`
`Yet another object of the present invention is to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer in a pharmaceutically acceptable
`carrier, wherein the carbostyril derivative is a metabolite of
`aripiprazole and is dehydroaripiprazole
`(OPC-14857),
`DM-1458, DM-1451, DM-1452, DM-1454 or DCPP, and a
`composition comprising at least one mood stabilizer in a
`pharmaceutically acceptable carrier.
`Yet another object of the present invention is to provide a
`method for treating mood disorder comprising administration
`to a patient with a mood disorder ofa composition comprising
`a carbostyril derivative with activity as a dopamine-serotonin
`system stabilizer and at least one mood stabilizer in a phar-
`maceutically acceptable carrier, wherein the mood disorder is
`bipolar disorder.
`Yet another object of the present invention is to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer in a pharmaceutically acceptable
`carrier and a composition comprising at least one mood sta-
`bilizer in a pharmaceutically acceptable carrier, wherein the
`mood disorder is bipolar disorder.
`Yet another object of the present invention is to provide a
`method for treating mood disorder comprising administration
`to a patient with a mood disorder ofa composition comprising
`a carbostyril derivative with activity as a dopamine-serotonin
`
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`US 9,125,939 B2
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`5
`system stabilizer and at least one mood stabilizer in a phar-
`maceutically acceptable carrier, wherein the mood disorder is
`mania.
`
`Yet another object of the present invention is to provide a
`method for treating a mood disorder comprising administra-
`tion to a patient with a mood disorder of a composition com-
`prising a carbostyril derivative with activity as a dopamine-
`serotonin system stabilizer in a pharmaceutically acceptable
`carrier and a composition comprising at least one mood sta-
`bilizer in a pharmaceutically acceptable carrier, wherein the
`mood disorder is mania.
`
`It is another object of the present invention to provide a
`method for treating mood disorder comprising administration
`to a patient with a mood disorder of a composition comprising
`a carbostyril derivative with activity as a dopamine-serotonin
`system stabilizer and at least one mood stabilizer in a phar-
`maceutically acceptable carrier.
`It is another object of the present invention to provide a
`method for treating mood disorder comprising separate
`administration to a patient with a mood disorder of a compo-
`sition comprising a carbostyril derivative with activity as a
`dopamine-serotonin system stabilizer in a pharmaceutically
`acceptable carrier, and a composition comprising at least one
`mood stabilizer in a pharmaceutically acceptable carrier.
`It is another object of the present invention to provide a
`method for treating mood disorder comprising administration
`to a patient with a mood disorder of a composition comprising
`a carbostyril derivative with activity as a dopamine-serotonin
`system stabilizer and at least one mood stabilizer together
`with a pharmaceutically acceptable carrier, wherein the car-
`bostyril derivative is aripiprazole or a metabolite thereof.
`Still another object of the present invention is to provide a
`method for treating mood disorder comprising administration
`to a patient with a mood disorder of a composition comprising
`a carbostyril derivative with activity as a dopamine-serotonin
`system stabilizer and at least one mood stabilizer in a phar-
`maceutically acceptable carrier, wherein the carbostyril
`derivative wherein the carbo styril derivative is a metabolite of
`aripiprazole and is OPC-14857, DM-1458, DM-1451,
`DM-1452, DM-1454 or DCPP.
`These and other objects, advantages, and uses of the
`present invention will reveal themselves to one of ordinary
`skill in the art after reading the detailed description of the
`preferred embodiments and the attached claims.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is the thermogravimetric/differential thermogram of
`the aripiprazole hydrate A obtained in Reference Example 4.
`FIG. 2 is the 1H-NMR spectrum (DMSO-d6, TMS) of the
`aripiprazole hydrate A obtained in Reference Example 4.
`FIG. 3 is the powder X-ray diffraction diagram of the
`aripiprazole hydrate A obtained in Reference Example 4.
`FIG. 4 is the 1H-NMR spectrum (DMSO-d6, TMS) of the
`anhydrous aripiprazole crystals B obtained in Example 1.
`FIG. 5 is the powder X-ray diffraction diagram of the
`anhydrous aripiprazole crystals B obtained in Example 1.
`FIG. 6 is the thermogravimetric/differential thermogram of
`the aripiprazole hydrate obtained in Reference Example 3.
`FIG. 7 is the powder X-ray diffraction diagram of aripipra-
`zole hydrate obtained in Reference Example 3.
`FIG. 8 is a schematic representation of the chemical struc-
`tures of aripiprazole and metabolites thereof. Some of the
`metabolites may be formed through other possible pathways;
`for example, DM-1431 could be formed by N-dealkylation of
`DM-1451 and DM-1459.
`
`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`60
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`65
`
`6
`DETAILED DESCRIPTION
`
`The pharmaceutical composition of the present invention
`comprises a first ingredient comprising a carbostyril deriva-
`tive active as a dopamine-serotonin system stabilizer and a
`second ingredient comprising a mood stabilizer, in a pharrna-
`ceutically acceptable carrier. The pharmaceutical composi-
`tions of the present invention are useful in treating mood
`disorders, including bipolar disorder and mania.
`
`The Pharmaceutical Composition: the First Ingredient
`
`ingredient comprises a carbostyril derivative
`The first
`active as a dopamine-serotonin system system stabilizer.
`Such carbostyril derivative has activity as an agonist or partial
`agonist at some serotonin receptors and some dopamine
`receptors, preferably as an agonist or partial agonist at the
`serotonin SHTIA receptor and as an agonist or partial agonist
`at the dopamine D2 receptor. Carbostyril derivatives are
`described in U.S. Pat. No. 5,006,528 and U.S. published
`patent application 2002/0l735l3Al. In one embodiment of
`the present invention, the carbostyril derivatives represented
`by the following formula (1) are used:
`
`Cl
`
`O(CH2)4—N
`\_/
`
`wherein the carbon-carbon bond between 3- and 4-positions
`in the carbostyril skeleton is a single or a double bond.
`
`In a preferred embodiment, this activity of the carbostyril
`derivative is as an agonist or partial agonist at the 5HT1A
`receptor and an agonist or partial agonist at the dopamine D2
`receptor subtype. In another preferred embodiment, the car-
`bostyril derivative to be used as a first component in the
`present invention is aripiprazole, or a metabolic derivative
`thereof. Metabolic derivatives of aripiprazole include but are
`not limited to dehydroaripiprazole, also called OPC-14857.
`Other metabolic derivatives of aripiprazole include but are
`not limited to the chemical structures shown in FIG. 8 as
`OPC-14857, DM-1458, DM-1451, DM-1452, DM-1454 and
`DCPP.
`
`Structures and names of aripiprazole metabolites shown in
`FIG. 8 are provided below.
`
`C1
`
`C1
`
`DCPP: l-(2,3 -dichlorophenyl)piperazine, and N-2,3 -dichlo-
`rophenylpiperazine
`
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`US 9,125,939 B2
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`7
`
`C1
`
`C1
`
` N N/\/\o
`
`\_/
`
`\
`
`N
`
`,1,
`
`o
`
`DM-14857, OPC-14857: 7- {4- [4-(2,3 -dichlorophenyl)-1-
`piperazinyl]butoxy}-2-(1H)-quinolinone,
`also
`called
`dehydroaripiprazole
`
`O
`
`O
`
`HO
`
`N/ \Ng/\O O
`
`\_/
`
`IH
`
`DM-1451: 7-{4-[4-(2,3 -dichloro-4-hydroxyphenyl)-1-piper-
`azinyl]butoxy}-3,4-dihydro-2-(1H)-quinolinone,
`and
`hydroxyaripiprazole
`
`C1
`
`0
`
`HO3S—O
`
`\_/
`
`11
`
`DM-145 8: 2,3 -dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydro-
`quinolin-7-yloxy) -butyl] -piperazin- 1 -yl} -phenyl
`sulfate,
`and sulfated hydroxyaripiprazole
`
`C1
`
`C1
`
` /N N/\/\o
`
`\_/
`
`OH
`
`\
`
`N
`
`11
`
`o
`
`DM-1452: 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]bu-
`toxy}-3,4-dihydro-4-hydroxy-2-(1H)-quinolinone,
`and
`benzyl hydroxyaripiprazole
`
`Cl
`
`0
`
`8
`DM-1454: DM-1454 is the glucuronide of DM-1451. This
`structure is also know by the following names:
`1[3-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquino-
`lin-7-yloxy)-butyl]piperazin-1-yl}-phenoxy)-D-glucop-
`yaranuronic acid,
`1[3-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquino-
`lin-7 -yloxy)-butyl] -piperazin-1 -yl } -phenyl-beta) -D-glu-
`copyaranosiduronic acid,
`1[3-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquino-
`lin-7-yloxy)-butyl]-piperazin-1-yl}-phenyl)-beta)-D-Glu-
`curonide,
`1[3-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-tetrahydroquino-
`lin-7 -yloxy)-butyl] -piperazin-1 -yl } -phenyl-beta) -D-glu-
`curonic acid, and glucuronide aripiprazole.
`All ofthe aforementioned carbostyril derivatives may be used
`as a first component in the practice of the present invention.
`Aripiprazole, also called 7-{4-[4-(2,3-dichlorophenyl)-1-
`piperazinyl]butoxy}-3,4-dihydro-2(1H)-quinolinone,
`is
`a
`carbostyril compound useful as the effective ingredient for
`treating schizophrenia (JP-A-2-191256, U.S. Pat. No. 5,006,
`528).Aripiprazole is also known as 7-[4-[4-(2,3-dichlorophe-
`nyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril, Abilify,
`OPC-14597, OPC-31 and BMS-337039. Aripiprazole pos-
`sesses 5-HT1A receptor agonist activity, and is known as a
`useful compound for trea