111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US009815827B2
`
`c12) United States Patent
`Nakamura et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,815,827 B2
`*Nov. 14, 2017
`
`(54) AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
`
`(71) Applicant: Sumitomo Dainippon Pharma. Co.,
`Ltd., Osaka-shi, Osaka (JP)
`
`(72)
`
`Inventors: Mitsutaka Nakamura, Kawanishi (JP);
`Masaaki Ogasa, Tokyo (JP); Shunsuke
`Sami, Kawasaki (JP)
`
`(73) Assignee: Sumitomo Dainippon Pharma Co.,
`Ltd., Osaka (JP)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 184 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 14/471,919
`
`(22)
`
`Filed:
`
`Aug. 28, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0371236 Al
`
`Dec. 18, 2014
`
`Related U.S. Application Data
`
`(63)
`
`Continuation of application No. 10/525,021, filed as
`application No. PCT/JP03/10490 on Aug. 20, 2003,
`now Pat. No. 9,174,975.
`
`(60) Provisional application No. 60/404,927, filed on Aug.
`22, 2002.
`
`(51)
`
`Int. Cl.
`C07D 417112
`A61K 311496
`(52) U.S. Cl.
`CPC .......... C07D 417112 (2013.01); A61K 311496
`(2013.01)
`
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`CPC ............................ A61K 31/496; C07D 417/12
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
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`wo
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`
`for NAMENDA™
`
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`(Continued)
`
`Primary Examiner- Snigdha Maewall
`(74) Attorney, Agent, or Firm- Obion, McClelland,
`Maier & Neustadt, L.L.P.
`
`(57)
`
`ABSTRACT
`
`The present invention provides a novel method for treatment
`of schizophrenia which can improve wide-ranging symp(cid:173)
`toms of schizophrenia, especially positive symptoms and
`negative symptoms without being accompanied by extrapy(cid:173)
`ramidal symptoms, which comprises orally administering as
`an active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-
`benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylm(cid:173)
`ethyl]-2,3-bicyclo[2.2.1]heptanedicarboxyimide or a phar(cid:173)
`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 said
`method.
`
`75 Claims, 1 Drawing Sheet
`
`Page 1 of 12
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`SLAYBACK EXHIBIT 1001
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`

`

`US 9,815,827 B2
`Page 2
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`activity without influencing reward-related behaviour in rat,"
`Behavioural Pharmacology, vol. 19, Iss. 8, pp. 765-776, (Dec.
`2008).
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`Disease," Acta Academiae Medicinae Qingdao Universitatis, vol.
`37, No.4, pp. 355-357, (2001).
`DB Allison, eta!., "Antiphychotic-induced weight gain: a compre(cid:173)
`hensive research synthesis", Am J Psychiatry, Nov. 1999;
`156( 11 ): 1686-96, 2 pages.
`Alp D~ok, et a!., "Side effects of atypical antipsychotics: a brief
`overview", World Psychiatry, Feb. 2008; 7(1):58-62, 10 pages.
`* cited by examiner
`
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`

`U.S. Patent
`
`Nov. 14, 2017
`
`US 9,815,827 B2
`
`2
`
`3
`Time (weeks)
`
`4
`
`6
`
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`US 9,815,827 B2
`
`1
`AGENT FOR TREATMENT OF
`SCHIZOPHRENIA
`
`This is a continuation application of application Ser. No.
`10/525,021, filed Feb. 18, 2005, which is a national stage
`applicationofPCT/JP2003/010490, filedAug. 20,2003, and
`claims priority to U.S. Provisional Application 60/404,927,
`filed Aug. 22, 2002, the contents of which are incorporated
`herein by reference.
`
`TECHNICAL FIELD
`
`2
`Therefore, it has been desired to develop a safe medica(cid:173)
`ment which exhibits an excellent effect on various schizo(cid:173)
`phrenia as an antipsychotic without causing side effects such
`as extrapyramidal symptoms.
`On the other hand, it has been known that the imide
`derivative of the following formula, which was found by the
`co-workers of the present inventors, may be useful as an
`antipsychotic (c.f., neuroleptic agent, antiaxiety, etc.), espe(cid:173)
`cially as an agent for treatment of schizophrenia, senile
`10 insanity, manic depressive psychoses, and nervous break(cid:173)
`down (U.S. Pat. No. 5,532,372).
`
`The present invention relates to a novel method for
`treatment of schizophrenia and a novel therapeutic agent
`used therein. More particularly, the present invention relates
`to a method for improving schizophrenia without being
`accompanied by extrapyramidal symptoms by orally admin(cid:173)
`istering a prescribed dose of a specific bicycloheptane
`dicarboximide derivative once a day, and a therapeutic agent 20
`used in said method.
`
`15
`
`BACKGROUND ART
`
`wherein Z is
`
`1 \
`Z-D-N
`G-Ar
`\__)
`
`40
`
`30
`
`Schizophrenia (split personality) is a kind of endogenous 25
`psychosis, and it is developed mainly during adolescence,
`and after a chronic course, the personality of patient is
`progressively 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 dysfunction such as impairments of concentration
`and learning abilities, etc. Moreover, there are other symp(cid:173)
`toms such as depression, anxiety, etc. as related symptoms 35
`thereof.
`Medication is mainly employed in the treatment of
`schizophrenia, but the treatment of schizophrenia should be
`continued for a long time, and even though schizophrenia is
`once healed, there is a large risk of reoccurring of schizo(cid:173)
`phrenia 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 perspective, it has been desired to develop a medicine 45
`being suitable for prolonged medication.
`The agents for treatment of schizophrenia are various
`medicaments such as ones classified in the category of
`antipsychotic, for example, phenothiazine derivatives (e.g.,
`chlorpromazine, methoxy-promazine, etc.),
`thioxanthin 50
`derivatives 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 butyrophe(cid:173)
`none derivatives (e.g., haloperidol, triperidol, etc.), diphe- 55
`nylbutylamine derivatives (e.g., pimozide, etc.), etc.
`However, phenothiazine derivatives, phenothiazine ana(cid:173)
`logues, and butyrophenone derivatives may cause serious
`side effects of extrapyramidal symptoms showing parkin(cid:173)
`sonism such as the stiff gait of skeletal muscles, tremor of 60
`muscles, lack of facial expression, salivation, etc. Further,
`diphenylbutylamine derivatives may cause extrapyramidal
`symptoms in addition to insonmia. In addition, these con(cid:173)
`ventional antipsychotics may be effective on only some of
`symptoms among positive symptoms, negative symptoms, 65
`cognitive dysfunctions of schizophrenia, and there has been
`no drug being effective on all of these symptoms.
`
`Dis a group of the formula: -(CH2)P-A-(CH2)q-,
`
`G H·
`
`r~
`
`\
`N - or \ CH-,
`I
`1
`
`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 of schizophrenia, 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-benzoisothiazol-3-yl)-1-piperazinylmethyl]-
`1-cyclohexy lmethy 1]-2,3 -bicyclo [2 .2 .1]heptane-dicarboxi(cid:173)
`mide of the following formula:
`
`(1)
`
`Page 6 of 12
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`US 9,815,827 B2
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`3
`or a pharmaceutically acceptable salt thereof such as a
`hydrochloride thereof is effective for relieving the wide(cid:173)
`ranging symptoms of schizophrenia, and may treat schizo(cid:173)
`phrenia quite safely without being accompanied by extrapy(cid:173)
`ramidal symptoms by orally administering a prescribed dose 5
`thereof once a day.
`Namely, the present invention provides a method for
`treatment of schizophrenia without being accompanied by
`extrapyramidal symptoms by orally administration of a
`prescribed amount of (1R,2S,3R,4S) -N-[(1R,2R)-2-[4-(1,2- 10
`benzoisothiazol-3-yl)-1-piperazinyl-methyl]-1-cyclohexyl(cid:173)
`methyl]-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.
`
`15
`
`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,2 S,3R,4 S) -N-[(1R,2R)-2-[4-(1,
`2-benzoisothiazol-3 -y 1)-1-piperaziny 1-methyl]-1-cyclohex(cid:173)
`ylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydro(cid:173)
`chloride and placebo in the double blind clinical trial.
`
`DETAILED DESCRIPTION OF INVENTION
`
`4
`cardiogram, hepatic dysfunction are hardly observed, and
`hence, the present method may be quite safely used and
`suitable for a prolonged medication.
`Besides, when the present method is applied to a patient
`with schizophrenia in chronic phase, the above active com(cid:173)
`pound should preferably be administered to said patient for
`a 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
`formula (1) or a pharmaceutically acceptable salt thereof,
`especially
`(1R,2S,3R,4S)-N-[(1R,2R)-2-[ 4-(1,2-benzoiso(cid:173)
`thiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,
`3-bicyclo[2.2.1]heptanedicarboximide hydrochloride in an
`20 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, cap(cid:173)
`sules, syrups, etc. These preparations should be in the form
`25 of a preparation for administration once a day.
`The above preparations may be prepared by a conven(cid:173)
`tional method by using a conventional pharmaceutically
`acceptable carrier which is usually used in the preparation of
`a conventional pharmaceutical formulation, for example,
`30 excipients such as lactose, white sugar, glucose, starch,
`calcium carbonate, kaolin, talc, crystalline cellulose, silicic
`acid, etc, binders such as water, ethanol, gelatin, carboxym(cid:173)
`ethylcellulose, shellac, methylcellulose, gum arabic, traga-
`35 canth powder, polyvinylpyrrolidone, etc., disintegrating
`agents such as sodium arginate, agar powder, laminaran
`powder, sodium hydrogen carbonate, polyoxyethylenesorbi(cid:173)
`tan fatty acid esters, sodium laurylsulfate, stearic acid mono(cid:173)
`glyceride, etc., lubricants such as purified talc, stearate, boric
`40 acid powder, polyethyleneglycol, etc.
`
`As shown in Examples as described hereinafter, when
`orally administering a prescribed dose of (1R,2S,3R,4S)-N(cid:173)
`[ (1 R,2R)-2-[ 4-(1 ,2-benzoisothiazol-3-yl)-1-piperazinylm(cid:173)
`ethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicar(cid:173)
`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 conven(cid:173)
`tional 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
`schizophrenia including positive symptoms, negative symp(cid:173)
`toms, and cognitive dysfunction, especially positive symp- 45
`toms and negative symptoms, without being accompanied
`by extrapyramidal 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-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboxim-
`ide of the above formula (1) or a pharmaceutically
`acceptable salt thereof, especially a hydrochloride thereof, to
`a patient with schizophrenia once a day.
`The present invention also provides a novel agent for
`treatment 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,2S3R,4S)-N-[(1R,
`2R)-2-[ 4-(1 ,2-benzoisothiazol-3-yl) -1-piperazinylmethyl]-
`1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]-heptanedicarboxi(cid:173)
`mide 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 therapeutic method of the present invention, 65
`side effects such as extrapyramidal symptoms such as par(cid:173)
`kinsonism, dyskinesia, akathisia, etc., abn