(12) United States Patent
`Nakamura et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,174.975 B2
`*Nov. 3, 2015
`
`US009 174975B2
`
`FOREIGN PATENT DOCUMENTS
`
`(54) REMEDY FOR INTEGRATION
`DYSFUNCTION SYNDROME
`
`(75) Inventors: Mitsutaka Nakamura, Osaka (JP);
`Masaaki Ogasa, Osaka (JP); Shunsuke
`Sami, Osaka (JP)
`(73) Assignee: SUMITOMO DAINIPPON PHARMA
`CO., LTD, Osaka (JP)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1040 days.
`
`(*) Notice:
`
`This patent 1S Subject tO a terminal dis-
`claimer.
`
`(21) Appl. No.:
`
`10/525,021
`
`(22) PCT Filed:
`
`Aug. 20, 2003
`
`(86). PCT No.:
`
`PCT/UP03/10490
`
`S371 (c)(1),
`(2), (4) Date:
`
`Feb. 18, 2005
`
`(87) PCT Pub. No.: WO2004/017973
`PCT Pub. Date: Mar. 4, 2004
`er
`
`(65)
`
`Prior Publication Data
`US 2006/OO25422 A1
`Feb. 2, 2006
`
`Related U.S. Application Data
`(60) Provisional application No. 60/404,927, filed on Aug.
`22, 2002.
`
`(2006.01)
`3.08:
`
`(51) Int. Cl
`we
`A6 IK9/00
`CR #7.
`(52) U.S. Cl
`CPC ............ C07D 417/12 (2013.01); A61K3I/496
`(2013.01)
`(58) Field of Classification Search
`USPC ..................................................... 51425.404
`See application file for complete search history.
`
`(56)
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`
`Primary Examiner — Snigdha Maewall
`(74) Attorney, Agent, or Firm — Finnegan Henderson
`Farabow Garrett & Dunner LLP
`(57)
`ABSTRACT
`
`The present invention provides a novel method for treatment
`of schizophrenia which can improve wide-ranging symptoms
`of schizophrenia, especially positive symptoms and negative
`symptoms without being accompanied by extrapyramidal
`symptoms, which comprises orally administering as an active
`compound
`(1R,2S,3R.4S), N-(1R,2R)-2-[4-(1,2-ben
`Zoisothiazol-3-yl)-1-piperazinylmethyl)-1-cyclohexylm
`ethyl-2,3-bicyclo[2.2.1]heptanedicarboxyimide or a phar
`maceutically acceptable salt thereof (e.g., hydrochloride) at a
`daily dose of 5 mg to 120 mg once a day to a patient with
`Schizophrenia, and a therapeutic agent to be used in the
`method.
`
`11 Claims, 1 Drawing Sheet
`
`Page 1 of 12
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`US 9,174.975 B2
`Page 2
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`-O-Placebo (n=49)
`-- SM-1349640 mg/day (n=49)
`-O-SM-13496 120 mg/day (n=47)
`
`1
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`2
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`3
`Time (weeks)
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`4
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`5
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`SLAYBACK EXHIBIT 1019
`
`

`

`US 9,174.975 B2
`
`1.
`REMEDY FOR INTEGRATION
`DYSFUNCTION SYNDROME
`
`This National Phase PCT Application claims priority under
`35 U.S.C. S 119(e) on U.S. Provisional Application No.
`60/404,927 filed on Aug. 22, 2002, the entire contents of
`which are hereby incorporated by reference.
`
`5
`
`2
`On the other hand, it has been known that the imide deriva
`tive of the following formula, which was found by the co
`workers of the present inventors, may be useful as an antip
`sychotic (c.f., neuroleptic agent, antiaxiety, etc.), especially
`as an agent for treatment of Schizophrenia, senile insanity,
`manic depressive psychoses, and nervous breakdown (U.S.
`Pat. No. 5,532,372).
`
`TECHNICAL FIELD
`
`The present invention relates to a novel method for treat
`ment of schizophrenia and a novel therapeutic agent used
`therein. More particularly, the present invention relates to a
`method for improving schizophrenia without being accom
`panied by extrapyramidal symptoms by orally administering
`a prescribed dose of a specific bicycloheptanedicarboximide
`derivative once a day, and a therapeutic agent used in said
`method.
`
`BACKGROUND ART
`
`10
`
`15
`
`wherein Z is
`
`Z-D-N
`
`G-Air
`
`D is a group of the formula: -(CH2)-A-(CH2) ,
`
`N- or
`
`/
`
`CH-,
`
`etc., and
`Ar is an aromatic group, or an aromatic heterocyclic group,
`etc.
`
`DISCLOSURE OF INVENTION
`
`The present inventor has intensively studied on a series of
`imide derivatives with respect to many aspects including a use
`and a dose thereof in order to find a novel agent for treatment
`ofschizophrenia, which may exhibit an excellent effect in the
`treatment of Schizophrenia and have no side effect Such as
`extrapyramidal symptoms, which are often observed in many
`conventional antipsychotics, and can safely be administered
`for a long time. As a result, the present inventors have found
`that
`(1R,2S,3R,4S) N-(1R,2R)-2-[4-(1,2-benzoisothia
`Zol-3-yl)-1-piperazinylmethyl-1-cyclohexylmethyl-2,3-bi
`cyclo[2.2.1]heptanedicarboximide of the following formula:
`
`
`
`(1)
`
`60
`
`65
`
`or a pharmaceutically acceptable salt thereof such as a hydro
`chloride thereof is effective for relieving the wide-ranging
`symptoms of Schizophrenia, and may treat schizophrenia
`quite safely without being accompanied by extrapyramidal
`symptoms by orally administering a prescribed dose thereof
`once a day.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Schizophrenia (split personality) is a kind of endogenous
`psychosis, and it is developed mainly during adolescence, and
`after a chronic course, the personality of patient is progres
`sively decayed, and Some of patients may culminate in a
`mental decay. The symptoms of this disease are, for example,
`positive symptoms often observed during the early stage of
`the disease such as hallucination, delusion, etc., or negative
`symptoms such as apathy and withdrawal, or cognitive dys
`function Such as impairments of concentration and learning
`abilities, etc. Moreover, there are other symptoms such as
`depression, anxiety, etc. as related symptoms thereof.
`Medication is mainly employed in the treatment of schizo
`phrenia, but the treatment of schizophrenia should be contin
`ued for a long time, and even though Schizophrenia is once
`healed, there is a large risk of reoccurring of Schizophrenia
`after drug withdrawal so that it is necessary to continue the
`medication forever. Therefore, any side effects of medication
`may always be serious problems, and based on this perspec
`tive, it has been desired to develop a medicine being suitable
`for prolonged medication.
`The agents for treatment of Schizophrenia are various
`medicaments such as ones classified in the category of antip
`sychotic, for example, phenothiazine derivatives (e.g., chlo
`rpromazine, methoxy-promazine, etc.), thioxanthin deriva
`tives having a similar structure to phenothiazine (e.g.,
`chlorprothixene, flupentixol, etc.), benzamide derivatives
`(e.g., Sulpiride, Sultopride, etc.), thienodiazepine derivatives
`(e.g., clotiazepam, etizolam, etc.), and further butyrophenone
`derivatives (e.g., haloperidol, triperidol, etc.), diphenylbuty
`lamine derivatives (e.g., pimozide, etc.), etc.
`However, phenothiazine derivatives, phenothiazine ana
`logues, and butyrophenone derivatives may cause serious
`side effects of extrapyramidal symptoms showing parkin
`Sonism Such as the stiff gait of skeletal muscles, tremor of
`muscles, lack of facial expression, salivation, etc. Further,
`diphenylbutylamine derivatives may cause extrapyramidal
`symptoms in addition to insomnia. In addition, these conven
`tional antipsychotics may be effective on only some of symp
`toms among positive symptoms, negative symptoms, cogni
`tive dysfunctions of Schizophrenia, and there has been no
`drug being effective on all of these symptoms.
`Therefore, it has been desired to develop a safe medica
`ment which exhibits an excellent effect on various schizo
`phrenia as an antipsychotic without causing side effects Such
`as extrapyramidal symptoms.
`
`Page 6 of 12
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`SLAYBACK EXHIBIT 1019
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`

`

`US 9,174.975 B2
`
`3
`Namely, the present invention provides a method for treat
`ment of Schizophrenia without being accompanied by
`extrapyramidal symptoms by orally administration of a pre
`scribed amount of (1R,2S,3R.4S) N-(1R,2R)-2-[4-(1,2-
`benzoisothiazol-3-yl)-1-piperazinylmethyl-1-cyclohexylm
`ethyl-2,3-bicyclo[2.2.1]heptanedicarboximide of the above
`formula (1) or a pharmaceutically acceptable salt thereof
`once a day, and further provides an agent for treatment of
`Schizophrenia which is used in said method.
`
`BRIEF DESCRIPTION OF DRAWINGS
`
`FIG. 1 is a graph showing the change with time in scores of
`Brief Psychiatric Rating Scale: BPRS, which are indexes for
`the effects on schizophrenia, of the active compound of the
`present invention, (1R,2S,3R.4S) N-(1R,2R)-2-[4-(1,2-
`benzoisothiazol-3-yl)-1-piperazinylmethyl-1-cyclohexylm
`ethyl-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochlo
`ride and placebo in the double blind clinical trial.
`
`DETAILED DESCRIPTION OF INVENTION
`
`4
`long time at a dose as low as possible, and in Such a case, the
`daily dose of the active compound is in the range of 5 mg to 80
`mg, preferably in the range of 5 mg to 60 mg, more preferably
`in the range of 10 mg to 40 mg, and it is orally administered
`once a day.
`The therapeutic agent used in the method for treatment of
`schizophrenia of the present invention is in the form of an oral
`preparation, which contains the compound of the above for
`mula (1) or a pharmaceutically acceptable salt thereof, espe
`cially (1R,2S,3R,4S) N-(1R,2R)-2-[4-(1,2-benzoisothia
`Zol-3-yl)-1-piperazinylmethyl-1-cyclohexylmethyl-2,3-
`bicyclo[2.2.1]heptanedicarboximide hydrochloride in an
`amount of 5 mg to 120 mg, preferably in an amount of 10 mg
`to 100 mg, more preferably in an amount of 20 mg to 80 mg
`per a single dosage unit. The oral preparation includes, for
`example, tablets, granules, fine granules, powders, capsules,
`syrups, etc. These preparations should be in the form of a
`preparation for administration once a day.
`The above preparations may be prepared by a conventional
`method by using a conventional pharmaceutically acceptable
`carrier which is usually used in the preparation of a conven
`tional pharmaceutical formulation, for example, excipients
`Such as lactose, white Sugar, glucose, starch, calcium carbon
`ate, kaolin, talc, crystalline cellulose, silicic acid, etc., binders
`Such as water, ethanol, gelatin, carboxymethylcellulose, shel
`lac, methylcellulose, gum arabic, tragacanth powder, polyvi
`nylpyrrolidone, etc., disintegrating agents such as sodium
`arginate, agar powder, laminaran powder, Sodium hydrogen
`carbonate, polyoxyethylenesorbitan fatty acid esters, sodium
`laurylsulfate, Stearic acid monoglyceride, etc., lubricants
`such as purified talc, stearate, boric acid powder, polyethyl
`eneglycol, etc.
`Experiments
`The method for treatment of the present invention and the
`effects thereofare illustrated in more detail by Experiments as
`described hereinafter.
`The active compound SM-13496 used in Experiments
`means (1R,2S,3R,4S) N-(1R,2R)-2-[4-(1,2-benzoisothia
`Zol-3-yl)-1-piperazinylmethyl-1-cyclohexylmethyl-2,3-bi
`cyclo[2.2.1]heptanedicarboximide hydrochloride, and the
`meanings of the abbreviations used in Experiments are as
`follows.
`DSM-IV: Diagnostic and Statistical Manual of Mental Dis
`orders, 4th ed.
`CGI-S: Clinical Global Impressions scale-Severity of Illness
`CGI-I: Clinical Global Impressions scale-Improvement
`AIMS: Abnormal Involuntary Movement Scale
`EPS: Extrapyramidal symptoms
`LOCF: Last Observation Carried Forward
`(LOCFAnalysis: a method of using last not-missing data in
`cases of dropouts)
`BAS: Barnes Akathisia Scale
`SAS: Simpson-Angust Rating Scale
`(Rating Scale For Extrapyramidal Reactions)
`PANSS: Positive and Negative Syndrome Scale
`(Rating Scale For Positive Negative symptoms)
`Experiment 1
`First Stage Phase II Clinical Trial
`(1) Test Method
`According to the procedures as shown in Table 1 as
`described below, the placebo-controlled double blind experi
`ment was done on 149 patients with schizophrenia in the
`acute exacerbation phase at 15 facilities in USA. The efficacy
`and safeness were studied when SM-13496 at a dose of 40 mg
`or 120 mg, or a placebo was orally administered once a day
`for 6 weeks after placebo washout.
`
`10
`
`15
`
`30
`
`35
`
`As shown in Examples as described hereinafter, when
`orally administering a prescribed dose of (1R,2S,3R.4S) N
`(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylm
`25
`ethyl-1-cyclohexylmethyl-2,3-bicyclo[2.2.1]heptanedicar
`boximide hydrochloride once a day for 6 weeks to the patients
`with Schizophrenia in the acute exacerbation, the present
`inventors have found that the excellent effects on the wide
`ranging symptoms were obtained, and Surprisingly, any
`extrapyramidal symptoms as observed in the conventional
`antipsychotics were hardly observed, especially, abnormal
`electrocardiogram which progresses to Sudden death is not
`recognized, and hence, that this compound may be quite
`safely used in the treatment of schizophrenia.
`Namely, the present invention provides a novel method for
`treatment of schizophrenia improving a wide-ranging schizo
`phrenia including positive symptoms, negative symptoms,
`and cognitive dysfunction, especially positive symptoms and
`negative symptoms, without being accompanied by extrapy
`ramidal symptoms which comprises orally administering a
`prescribed dose of (1R,2S,3R.4S) N-(1R,2R)-2-[4-(1,2-
`benzoisothiazol-3-yl)-1-piperazinylmethyl-1-cyclohexylm
`ethyl-2,3-bicyclo[2.2.1]heptanedicarboximide of the above
`formula (1) or a pharmaceutically acceptable salt thereof,
`especially a hydrochloride thereof, to a patient with schizo
`phrenia once a day.
`The present invention also provides a novel agent for treat
`ment of Such schizophrenia.
`According to the present invention, excellent improving
`effects on the wide-ranging symptoms of Schizophrenia may
`be obtained by orally administering (1R,2S,3R,4S) N-(1R,
`2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl
`1-cyclohexylmethyl-2,3-bicyclo[2.2.1-heptanedicarbox
`imide or a pharmaceutically acceptable salt thereof, for
`example, a hydrochloride, at a daily dose of 5 mg to 120 mg.
`preferably at a daily dose of 10 mg to 100 mg, more preferably
`at a daily dose of 20 mg to 80 mg. once a day. Further, in the
`therapeuti