i.
`
`"
`
`~~•...-· Sughrue
`
`SUGHRUE MION. PLLC
`
`10 /5 56 600
`JC10 Rec'd PCT/PTO 1 4 N 0 vod)R~lvania Avenue, NW
`
`~ilgton, DC 20037-3213
`T 202.293.7060
`f 202.293.7860
`
`www.sughrue.com
`
`November 14, 2005
`
`MAIL STOP PCT
`Commissioner for Patents ·
`P.O. BOX 1450
`Alexandria, VA 22313-1450
`
`Re:
`
`Application of Tetsuro KIKUCHI, Taro IWAMOTO, and Tsuyoshi HIROSE
`CARBOSTYRIL DERIVATIVES AND MOOD STABILIZERS FOR
`TREATING MOOD DISORDERS
`Assignee: OTSUKA PHARMACEUTICAL CO., LTD.
`Our Ref: Q81665
`
`Dear Sir:
`
`The following documents are submitted herewith in connection with the above
`application for the purpose of entering the National stage under 35 U.S.C. §371 and in
`accordance with the Patent Cooperation Treaty:
`
`0 a copy of the International Application.
`0 eight (8) sheets of drawings (Figs. 1-8).
`0 a copy of Notification Concerning Submission or Transmittal of Priority Document.
`
`0 an Information.Disclosure Statement and a copy of the ISR.
`0 a PTO/SB/08 A & B (modified) listing the ISR and other IDS references.
`0 a copy of each reference listed in the PTO/SB/08 A & B.
`0 a Preliminary Amendment, including a marked-up substitute specification (68 pages)
`and clean version of the substitute specification (68 pages).
`
`·"~ ~,
`
`[ '
`·).....
`
`,
`
`A copy of the Declaration and Power of Attorney, and a copy of the Assignment will be
`submitted at a later date.
`In addition to the documents submitted herewith, it is assumed that copies of the
`International Application, the International Search Report and cited references, the International
`Preliminary Examination Report, and any Articles 19 and 34 amendments as required by §37l(c)
`will be supplied directly by the International Bureau, but if further copies are needed, the
`undersigned will undertake to provide them upon request.
`
`It is expressly requested that the national stage of processing be commenced immediately
`in accordance with 35 U.S.C. § 371(±).
`The Government filing fee, after entry of the Preliminary Amendment, is calculated as
`follows:
`Total claims
`Independent claims
`
`16
`2
`
`20
`3
`
`. x $50.00
`- - - - -
`x $200.00
`
`-
`
`$.00
`$.00
`
`/I
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`. ,
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`'* P. Sughrue
`
`SUGHRUE MION. PtlC
`National Stage of PCT/US2004/013308
`
`:to l'.5 56 6 o a
`JC14Rec'dPCT/PTO 14 NOV ZDOi
`
`Base Fee
`Search Fee*
`Examination Fee*
`
`TOTAL FEE
`
`*The international search fee for all claims was paid to the USPTO, as the ISA.
`
`$300.00
`$100.00
`$200.00
`
`$600.00
`
`A check for the statutory filing fee of $600.00 is attached. The USPTO is directed and
`authorized to charge all required fees, except for the Issue Fee and the Publication Fee, to
`Deposit Account No. 19-4880. Please also credit any overpayments to said Deposit Account. A
`duplicate copy of this transmittal letter is attached.
`Benefit is claimed from:
`Country
`U.S. Provisional
`
`Application No
`60/473,378
`
`Filing Date
`May 23, 2003
`
`SUGHRUE MION, PLLC
`Telephone: (202) 293-7060
`Facsimile: (202) 293-7860
`WASHINGTON OFFICE
`
`23373
`
`CUSTOMER NUMBER
`
`Date: November 14, 2005
`
`2
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`WO 2004/105682
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`PCT/US2004/013308
`
`1
`
`DESCRIPTION
`
`CARBOSTYRIL DERIVATIVES AND MOOD STABILIZERS
`
`FOR TREATING MOOD DISORDERS
`
`FIELD OF THE INVENTION
`
`The present invention provides pharmaceutical
`
`compositions comprising carbostyril derivatives that
`
`act as dopamine-serotonin system stabilizers in
`
`5 combination with mood stabil~zers 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
`
`10
`
`invention or by separately administering these
`
`carbostyril derivatives and mood stabilizers. The
`
`carbostyril derivatives of the. present invention
`
`include but are not limited to aripiprazole and
`
`metabolites thereof, such as dehydroaripiprazole. The
`
`15 mood stabilizers include, but are not limited to,
`
`lithium, valproic acid, divalproex sodium,
`
`carbamazapine, oxcarbamazapine, zonisamide,
`
`lamotragine, topiramate, gabapentin, levetiracetarn and
`
`clonazepam.
`
`20 BACKGROUND OF THE INVENTION
`
`The number of people with mood disorders,
`
`such as bipolar disorder with or without psychotic
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`2
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`features, mania or mixed episodes is increasing every
`
`year for numerous reasons. Since the period of 1950,
`
`tricyclic antidepressant drugs (e.g., imipramine,
`
`desipramine, amitriptyline, etc.) have been developed
`
`5
`
`that act to inhibit monoamine reuptake. They are
`
`frequently used for treating patients suffering from
`
`mood disorders. However, these drugs have side(cid:173)
`
`effects, such as the following: dry mouth, hazy eyes,
`
`dysuria, constipation, recognition disturbance and the
`
`10
`
`like due to anticholinergic activity; cardiovascular
`
`side-effects such as, orthostatic hypotension,
`
`tachycardia and the like on the basis of a 1 -
`adrenoreceptor antagonist activity; side-effects such
`
`as, sedation, increase in the body weight and the like
`
`15 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 ~eterogeneous diseases, and the
`
`20 causes of these diseases are not fully understood, it
`
`is likely that the abnormalities of the monoaminergic
`
`central nervous system caused by serotonin,
`
`norepinephrine and dopamine and the like, and the
`
`abnormality of various hormones and peptides as well as
`
`25 various stressors are causes of depression and various
`
`other mood disor.ders (Kubota Masaharu et al.:
`
`"RINSHOU
`
`SEISHIN IGAKU." Vol. 29, pp 891-899, (2000)). For these
`
`reasons, even though mood stabilizer drugs, such as
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`3
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`lithium, valproic acid, divalproex sodium,
`
`carbamazapine, oxcarbamazapine, zonisamide,
`
`lamotragine, topiramate, gabapentin, levetiracetam and
`
`clonazepam have been used, these drugs are not always
`
`5 effective in treating all patients.
`
`New therapeutic trials involve proposed
`
`combined therapies using an atypical antipsychotic
`
`drug, such as olanzepine or quetiapine, which are
`
`agents for treating schizophrenia (anti-psychotic
`
`10 drug), together with mood stabilizing drug such as
`
`valproate, lithium or divalproex ((Arch. Gen.
`
`Psychiatry, 2002 Jan. 59:1) :62-69; J Am Acad Child
`
`Adolesc Psychiatry 2002 Oct;41(10) :1216-23:)
`
`Further, commercially available atypical
`
`15 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 SEISHIN YAKURI"
`
`20 Vol. 5, pp 911-925, (2002), Haupt, D. W. and Newcomer,
`
`J. W.
`
`(Translated by Fuji Yasuo and Misawa Fuminari):
`
`"RINSHOU SEISHIN YAKURI" Vol. 5, pp 1063-1082, (2002)).
`
`In fact, urgent safety alerts have been issued in Japan
`
`relating to hyperglycemia, diabetic ketoacidosis and
`
`25 diabetic coma caused by olanzapine and quetiapine,
`
`indicating that these drugs were subjected to dosage
`
`contraindication to the patients with diabetes rnellitus
`
`and patients having anamnesis of diabetes mellitus.
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`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,
`
`5 clozapine induces agranulocytosis, so that clinical use
`
`thereof is strictly restricted (van Karnmen, D. P.
`
`(Compiled under Supervision by Murasaki Mitsuroh)
`
`"RINSHOU SEISHIN YAKURI" Vol. 4, pp 483-492, {2001)).
`
`Accordingly what is needed are new
`
`10 compositions useful for treatin9 mood disorders,
`
`particularly bipolar disorder with or without psychotic
`
`features, mania or mixed episodes, which are
`
`efficacious and do not cause the deleterious side
`
`effects associated with prior art compounds.
`
`15 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 bipolar disorder, including but
`
`20 not limited to bipolar disorder I, bipolar disorder II,
`
`bipolar disorder with and without psychotic features,
`
`and mania, acute mania, bipolar depression or mixed
`
`episode.
`
`The present invention provides solutions to
`
`25
`
`the above-mentioned problems, and demonstrates that the
`
`mood disorders, such as bipolar disorder and mania, can
`
`be treated effectively by administering to a patient
`
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`5
`
`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
`
`5 preferred carbostyril derivative of the present
`
`invention that.is a dopamine-serotonin system
`
`stabilizer is aripiprazole or a metabolite thereof.
`
`Another preferred carbostyril derivative of the present
`
`invention that is a dopamine-serotonin system
`
`10 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 Figure 8. Preferred
`
`aripiprazole metabolites are shown in Fig~re 8
`
`15
`
`indicated by the following designations: OPC-14857,
`
`DM-1458, DM-1451, DM-145.2, 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
`
`20
`
`treating schizophrenia (JP-A-2-191256, U.S. Patent
`
`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-HTu receptor agonist
`
`25 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 (WO 02/060423A2; Jordan et al
`
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`6
`
`U.S. Patent Application 2002/0173513Al)). Aripiprazole
`
`has activity as an agonist at serotonin receptors and
`
`dopamine receptors, and acts as an agonist or partial
`
`agonist at the serotonin SHTlA receptor and as an
`
`5 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
`
`10 metabolites of aripiprazole included within the present
`
`invention are shown in Figure 8. Preferred metabolites
`
`are shown in Figure 8 indicated by the following
`
`designations: OPC-14857, DM-1458, DM-1451, DM-1452,
`
`DM-1454 and DCPP.
`
`15
`
`The· at least one mood stabilizer used in the
`
`present invention includes but is not limited to the
`
`following:
`
`lithium, valproic acid, divalproex sodium,
`
`carbamazapine, oxcarbamazapine, zonisamide,
`
`lamotragine, topiramate, gabapentin, levetiracetam and
`
`20 clonazepam.
`
`The novel compositions of the present
`
`invention comprising a carbostyril derivative with
`
`activity as a dopamine-serotonin system stabilizer and
`
`at least one mood stabilizer in a pharmaceutically
`
`25 acceptable carrier may be combined in one dosage form,
`
`for example a pill. Alternatively the carbostyril
`
`derivative with activity as a dopamine-serotonin system
`
`stabilizer and the at least one mood stabilizer may be
`
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`7
`
`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
`
`5
`
`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
`
`10 provide a composition useful for treating a mood
`
`disorder, wherein the mood disorder is bipolar
`
`disorder.
`
`It is an object of the present invention to
`
`provide a composition useful for treating a mood
`
`15 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
`
`20 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
`
`25 pharmaceutically acceptable carrier, wherein the
`
`carbostyril derivative is aripiprazole or a metabolite
`
`thereof.
`
`Yet another object of the present invention
`
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`8
`
`is to provide a composition comprising a carbostyril
`
`derivative with act~vity as a dopamine-serotonin system
`
`stabilizer and at least one mood stabilizer, wherein
`
`the carbostyril derivative with activity as a dopamine-
`
`5
`
`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
`
`10 derivative with activity as a dopamine-serotonin system
`
`stabilizer and at least one mood stabilizer, wherein
`
`the carbostyril derivative is dehydroaripiprazole.
`
`It is an object of the present invention to
`
`provide a method for treating a mood disorder.
`
`15
`
`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
`
`20
`
`the mood disorder is mania.
`
`It is another object of the present invention
`
`to provide a method for treating a mood disorder
`
`comprising administration to a patient with a mood
`
`disorder of a composition comprising a carbostyril
`
`25 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
`
`10 of 1328
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`9
`
`is to provide a method for treating a 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
`
`5 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 a mood disorder
`
`10 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 in
`
`a pharmaceutically acceptable carrier, wherein the
`
`15 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 administration to a patient with a mood
`
`20 disorder of a composition comprising 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
`
`25
`
`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
`
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`10
`
`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
`
`5 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.
`
`Yet another object of the present invention
`
`10
`
`is to provide a method for treating a 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 in a pharmaceutically acceptable carrier,
`
`15 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.
`
`20
`
`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 of a composition comprising a carbostyril
`
`derivative with activity as a dopamine-serotonin system
`
`25 stabilizer and at least one mood stabilizer in a
`
`pharmaceutically acceptable carrier~ wherein the mood
`
`disorder is bipolar disorder.
`
`Yet another object of the present invention
`
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`11
`
`is to provide a method for treating a 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
`
`5 stabilizer in a pharmaceutically acceptable carrier and
`
`a composition comprising at least one mood stabilizer
`
`in a pharmaceutically acceptable carrier, wherein the
`
`mood disorder is bipolar disorder.
`
`Yet another object of the present invention
`
`10
`
`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
`
`15 pharmaceutically 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 administration to a patient with a mood
`
`20 disorder of a composition 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, wherein the
`
`25 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
`
`13 of 1328
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`12
`
`disorder of 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.
`
`5
`
`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 composition comprising a carbostyril
`
`derivative with activity as a dopamine-serotonin system
`
`10 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
`
`15 comprising administ+ation 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
`
`20 carbostyril 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
`
`25 disorder of 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
`
`14 of 1328
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`13
`
`carbostyril derivative wherein the carbostyril
`
`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
`
`5 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
`
`10
`
`Figure 1 is the thermogravimetric/
`
`differential thermogram of the aripiprazole hydrate A
`
`obtained in Reference Example 4.
`
`Figure 2 is the 1H-NMR spectrum (DMSO-d6 , TMS)
`of the aripiprazole hydrate A obtained in Reference
`
`15 Example 4.
`
`Figure 3 is the powder X-ray diffraction
`
`diagram of the aripiprazole hydrate A obtained in
`
`Reference Example 4.
`
`Figure ·4 is the 1H-NMR spectrum (DMSO-d6 , TMS)
`20 of the aripiprazole anhydride crystals B obtained in
`
`Example 1.
`
`Figure 5 is the powder X-ray diffraction
`
`diagram of the aripiprazole anhydride crystals B
`
`obta·ined in Example 1.
`
`25
`
`Figure 6 is the
`
`thermogravimetric/differential therrnogram of the
`
`aripiprazole hydrate obtained in Reference Exa~ple 3.
`
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`
`Figure 7 is the powder X-ray diffraction
`
`diagram of aripiprazole hydrate obtained in Reference
`
`Example 3.
`
`Figure 8 is a schematic representation of the·
`
`5 chemical structures 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.
`
`DETAILED DESCRIPTION
`
`10
`
`The pharmaceutical composition of the present
`
`invention comprises a first ingredient comprising a
`
`carbostyril derivative active as a dopamine-serotonin
`
`system stabilizer and a second ingredient comprising a
`
`mood stabilizer, in a pharmaceutically acceptable
`
`15 carrier. The pharmaceutical compositions of the
`
`present invention are useful in treating mood
`
`disorders, including bipolar disorder and mania.
`
`The pharmaceutical composition:
`
`the first ingredient
`
`The first ingredient comprises a carbostyril
`
`20 derivative 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 5HTM
`
`25
`
`receptor and as an agonist or partial agonist at the
`
`dopamine D2 receptor. Carbostyril derivatives are
`
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`
`described in U.S. Patent 5,006,528 and U.S. published
`
`patent application 2002/0173513Al.
`
`In one embodiment
`
`of the present invention, the carbostyril derivatives
`
`represented by the following formula (1) are used:
`
`5
`
`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
`
`10
`
`the carbostyril derivative is as an agonist or partial
`
`agonist at the SHT~ receptor and an agonist or partial
`
`agonist at the dopamine 0 2 receptor subtype.
`preferred embodiment, the carbostyril derivative to be
`
`In another
`
`used as a first component in the present invention is
`
`15 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
`
`20
`
`shown in Figure 8 as OPC-14857, DM-1458, DM-1451, DM-
`
`1452, DM-1454 and DCPP.
`
`Structures and names of. aripiprazole
`
`metabolites shown in Figure 8 are provided below.
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`DCPP:
`
`1-(2,3-dichlorophenyl)piperazine, and N-2,3-
`
`dichlorophenylpiperazine
`
`5 DM-14857, OPC-14857: 7-{4-[4-(2,3-dichlorophenyl)-l-
`
`piperazinyl]butoxy}-2-(lH)-quinolinone, also called
`
`dehydroaripiprazole
`
`DM-1451: 7-{4-[4-(2,3-dichloro-4-hydroxyphenyl}-1-
`
`piperazinyl]butoxy}-3,4-dihydro-
`
`10 2-(lH)-quinolinone, and hydroxyaripiprazole
`
`DM-1458: 2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-
`
`tetrahydroquinolin-7-yloxy)-butyl] -
`
`piperazin-1-yl}-phenyl sulfate, and sulfated
`
`15 hydroxyaripiprazole
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`DM-1452: 7-{4-(4-(2,3-dichlorophenyl)-l(cid:173)
`
`piperazinyl]butoxy}-3, 4-dihydro-4-hydroxy-
`
`2-(lH)-quinolinone, and benzyl hydroxyaripiprazole
`
`HOOC
`
`5
`
`OH
`
`DM-1454: DM-1454 is the glucuronide of DM-1451. This
`
`structure is also know by the following names:
`
`1~-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-
`
`tetrahydroquinolin-7-yloxy)-butyl] -
`
`10 piperazin-1-yl}-phenoxy)-D-glucopyaranuronic acid,
`
`1~-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-
`
`tetrahydroquinolin-7-yloxy)-butyl]-piperazin-l-yl}(cid:173)
`
`phenyl-beta)-D-glucopyaranosiduronic acid,
`
`1~-(2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-
`
`15
`
`tetrahydroquinolin-7-yloxy)-butyl]-piperazin-l-yl}(cid:173)
`
`phenyl)-beta)-D-Glucuronide,
`
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`1~-( 2,3-dichloro-4-{4-[4-(2-oxo-1,2,3,4-
`
`tetrahydroquinolin-7-yloxy)-butyl]-piperazin-1-yl}(cid:173)
`
`phenyl-beta)-D-glucuronic acid, and glucuronide
`
`aripiprazole.
`
`5 All of the 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-
`
`10 2(1H)-quinolinone, is a carbostyril compound useful as
`
`the effective ingredient for treating schizophrenia
`
`(JP-A-2-191256, U.S. Patent 5,006,528). Aripiprazole
`
`is also known as 7-[4-[4-(2,3-dichlorophenyl)-1-
`
`piperazinyl]butoxy]-3,4-dihydrocarbostyril, Abilify,
`
`15 OPC-14597, OPC-31 and BMS-337039. Aripiprazole
`
`possesses 5-HT~ 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
`
`20
`
`(WO 02/060423A2; Jordan et al. U.S. Patent Application
`
`2002/0173513Al). Aripiprazole has activity as an
`
`agonist at serotonin receptors and dopamine receptors,
`
`and acts as an agonist or partial agonist at the
`
`serotonin SHTlA receptor and as an agonist or partial
`
`25 agonist at the dopamine D2 receptor.'
`
`Aripiprazole is an antipsychotic drug having
`
`new mechanism of action which is different from that of
`
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`19
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`other atypical antipsychotic drugs. The available
`
`typical and atypical antipsychotic drugs act as
`
`antagonists at the dopamine-D2 receptors.
`
`In contrast,
`
`aripiprazole acts as a partial agonist at th~ dopamine
`
`5 D2 receptor (Ishigooka Jyunya and Inada Ken: RINSHO
`
`SEISHIN YAKURI, Vol. 4, pp 1653-1664, (2001); Burris,
`
`K. D. et al.: J. Pharmacol. Exp. Ther., 302, pp 381-
`
`389, (2002)).
`
`In addition to the partial agonist
`
`action at dopamine-D2 receptors, aripiprazole has
`
`10 activity as a partial agonist at the serotonin 5-HT~
`
`receptor, as well as antagonist action serotonin 5-HTa
`
`receptors. Accordingly, aripiprazole is a drug
`
`belonging to new category defined as a dopamine(cid:173)
`
`serotonin system stabilizer (dopamine-serotonin nervous
`
`15 system stabilizer (Burris, K. D. et al., J. Pharmacol.
`
`Exp. Ther., 302, pp 381-389, 2002; Jordan, S. et al.,
`
`Eur. J. Pharmacol. 441, pp 137-140, 2002).
`
`Methods of Preparing AripiprazoJe
`
`Aripiprazole and aripiprazole metabolites to
`
`20 be used in the present invention may be any of form,
`
`for example, free bases, polymorphisms of every type of
`
`crystal, hydrate, salt {acid addition salts, etc.) and
`
`the like. Among of these forms, aripiprazole anhydride
`
`crystals B is a preferred form.
`
`25
`
`As to method for preparing the aripiprazole
`
`anhydride crystals B, for example it is prepared by
`
`heating. aripiprazole hydrate A as follows.
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`Aripiprazole Hydrate A
`
`The aripiprazole hydrate A having the
`
`physicochemical properties shown in (1) -
`
`(5) as
`
`follows:
`
`5
`
`(1) It has an endothermic curve which is
`
`substantially identical to the
`
`thermogravimetric/differential thermal analysis
`
`(heating rate 5°C/min) endothermic curve shown in
`
`Figure 1. Specifically, it is characterized by the
`
`10 appearance of a small peak at about 71°C anq a gradual
`
`endothermic peak around 60°C to 120°C.
`
`(2) It has an 1H-NMR spectrum which is
`
`substantially identical to the 1H-NMR spectrum {DMSO-d6 ,
`
`TMS) shown in Figure 2. Specifically, it has
`
`15 characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-
`
`1.78 ppm (m, 2H), 2.35-2.46 ppm {m, 4H), 2.48-2.56 ppm
`
`(m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H), 2.97 ppm
`(brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H),
`
`6.43 ppm {d, J = 2.4 Hz, lH), 6.49 ppm {dd, J = 8.4 Hz,
`
`20
`
`J = 2.4 Hz, lH), 7.04 ppm (d, J = 8.1 Hz, lH), 7.11-
`
`7.17 ppm (m, lH), 7.28-7.32 ppm (m, 2H) and 10.00 ppm
`
`( s, lH) .
`
`(3) It has a powder x-ray diffraction
`
`spectrum which is substantially identical to the powder
`
`25 x-ray diffraction spectrum shown in Figure 3.
`
`Specifically, it has characteristic peaks at 20
`
`12.6°,
`
`15. 4 °, 1 7 . 3 ° , 18 . 0 ° , 18. 6 °, 2 2. 5 ° and 2 4 . 8 ° •
`
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`{4) It has clear infrared absorption bands at
`
`2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784
`
`cnC 1 on the IR (KBr} spectrum.
`
`{5) It has a mean particle size of 50 µm or
`
`5
`
`less.
`
`Method for Preparing Aripiprazole Hydrate A
`
`Aripiprazole hydrate A is prepared by milling
`
`conventional aripiprazole hydrate. Conventional
`
`milling methods can be used to mill conventional
`
`10 aripiprazole hydrate. For example, conventional
`
`aripiprazole hydrate can be milled in a milling
`
`machine. A widely used milling machine such as an
`
`atomizer, pin mill, jet mill or ball mill can be used.
`
`Among of these, the atomizer is preferably used.
`
`15
`
`Regarding the specific milling conditions
`
`when using an atomizer, a rotational speed of 5000-
`
`15000 rpm could be used for the main axis, for example,
`
`with a feed rotation of 10-30 rpm and a screen hole
`
`size of 1-5 mm.
`
`20
`
`The mean particle size of the aripiprazole
`
`hydrate A obtained by milling may be normally 50 µm or
`
`less, preferably 30 µm or less. Mean particle size can
`
`be ascertained by the particle size measuring method
`
`described hereinafter.
`
`25 Aripiprazole Anhydride Crystals B
`
`Aripiprazole anhydride crystals B of the
`
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`
`present invention have the physicochemical properties
`
`given in (6)-(10} below.
`
`{6) They have an 1H-NMR spectrum which is
`
`substantially identical to the 1H-NMR spectrum (DMSO-d6 ,
`
`5 TMS) shown in Figure 4. Specifically, they have
`
`characteristic.peaks at 1.55-1.63 ppm (m, 2H), 1.68-
`
`1.78 ppm (m, 2H}, 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm
`
`(m, 4H + DMSO), 2.78 ppm (t, J = 7.4 Hz, 2H), 2.97 ppm
`
`(brt, J = 4.6 Hz, 4H), 3.92 ppm (t, J = 6.3 Hz, 2H),
`
`10 6.43 ppm (d, J = 2.4 Hz, lH), 6.49 ppm (dd, J = 8.4 Hz,
`
`J = 2.4 Hz, lH), 7.04 ppm (d, J = 8.1 Hz, lH), 7.11-
`
`7.17 ppm (m,
`
`lH), 7.28-7.32 ppm (m, 2H) and 10.00 ppm
`
`(s, lH).
`
`(7) They have a powder x-ray diffraction
`
`15
`
`spectrum which is substantially identical to the powder
`
`x-ray diffraction spectrum shown in
`
`Figure 5. Specifically, they have characteristic peaks
`
`at 20 =