USE OF 7-[4-(4-BENZO[B]THIOPHEN-4-IL-PIPERAZIN-1-IL)BUTOX]-1H-QUINOLIN-2-ONA OR UM SALT DESTE

Abstract

1 / 1 SUMMARY “METHOD FOR PROPHYLAXIS AND / OR TREATMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS ASSOCIATED WITH NEURODEGENERATIVE DISEASE OR IMPULSIVE SYMPTOMS ASSOCIATED WITH MENTAL DISEASE, PROPHYATIC AND / OR THERAPEUTIC AGENT FOR BEHAVIORAL SYMPTOMS AND PSYCHOLOGICAL ASSOCIATED WITH NEURODEGENERATIVE DISEASE OR IMPULSIVE SYMPTOMS ASSOCIATED WITH MENTAL DISEASE, USE OF A COMPOUND, COMPOUND, AND, PHARMACEUTICAL COMPOSITION†The present invention relates to a prophylactic and / or therapeutic for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, which contains 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl) butoxy]-1H-quinolin-2-one or a salt thereof as an active ingredient.

Description

“USE OF 7-[4-(4-BENZO[B]THIOPHEN-4-YL-PIPERAZIN-1-YL)BUTOXY]1H-QUINOLIN-2-ONE OR A SALT THEREOF.” FIELD OF THE INVENTION

[001] The present invention relates to a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, containing brexpiprazole or a salt thereof. FUNDAMENTALS OF THE INVENTION

[002] Brexpiprazole (OPC-34712), that is, 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1H-quinolin-2-one, or a salt thereof and a method of production thereof are described in patent document 1 (JP-A-2006-316052 (US 2010 / 0179322 A1)), and are described as having a partial agonist activity at the dopamine D2 receptor (partial agonist activity at the D2 receptor), a serotonin 5-HT2A antagonist activity (5-HT2a receptor antagonist activity) and an α1 adrenergic receptor antagonist activity (α1 receptor antagonist activity) and, in addition, simultaneously has a serotonin reuptake inhibitory action (or serotonin reuptake inhibitory action), and has a broad treatment spectrum for central neurological diseases.Although this patent document describes brexpiprazole or a salt thereof as being used for cognitive impairment associated with neurodegenerative diseases such as Alzheimer's disease and the like, it is completely silent on the matter. Continue to page 2. 6 / 8 2 / 42 usefulness for behavioral and psychological symptoms of neurodegenerative diseases or impulsive symptoms associated with mental illnesses.

[003] Furthermore, it does not describe that brexpiprazole or a salt thereof significantly increased activation of the medial prefrontal cortex (ACA: anterior cingulate area, PL: prelimbic area, IL: infralimbic area).

[004] It has been reported that lower activity of the medial prefrontal cortex is related to behavioral and psychological symptoms of neurodegenerative diseases, and impulsive symptoms of mental illnesses (Bipolar Disord 2009; 11:628-36, J Abnorm Psychol 2013; 122:558-65, Mov Disord 2011; 26:225-33, Pharmacol Biochem Behavior 2009; 93:237-47).

[005] Impulsive symptoms are among the multidimensional personality traits that characterize various human behaviors, and their promotion is frequently caused by central neurological diseases, namely mental illnesses, neurodegenerative diseases and the like, and strongly associated with violence, aggressive behavior, suicide and the like. According to the biopsychosocial definition of impulsivity, impulsivity is defined as a predisposition to rapid, unplanned reactions to internal or external stimuli without regard to the negative consequences of these reactions for the impulsive individual or others (Am J Psychiatry 2001; 158:1783-93).Furthermore, Barratt's impulsivity scale can assess the impulsivity properties a person has, based on three subscales of impulsivity caused by attentional capacity, behavioral impulsivity, impulsivity due to lack of planning, and similar (J Clin Psychol 1995; 51:768-74).

[006] Examples of mental illnesses with impulsive symptoms include schizophrenia, major depression, bipolar disorder, attention deficit hyperactivity disorder (AD / HD), autism, antisocial personality disorder, borderline personality disorder, substance abuse / dependency. 3 / 42 substance and similar.

[007] Although many patients with schizophrenia do not exhibit violent behavior, a portion of patients do show sustained aggressive behavior, sometimes hindering medication or placing a burden on caregivers. In a longitudinal epidemiological study conducted in Sweden from 1973 to 2006, 5.3% of the population were involved in violent crime; however, 13.2% of patients with schizophrenia were involved in violent crime (JAMA 2009; 301:2016-23). ​​The cause of violent behavior in patients with schizophrenia is not uniform, and is considered to derive from i) positive symptoms such as hallucinations, delusions, and the like, ii) impulsivity, iii) concomitant psychopathy (Int J Clin Pract 2008; 62:1237-45).

[008] Citrome et al. studied an aggression-suppressing effect of existing antipsychotic agents in patients with schizophrenia using a prospective randomized double-blind trial, using clozapine, olanzapine, risperidone, and haloperidol (Psychiatric Services 2001; 52:151014). Hostility, one of the positive scales of the PANSS (Positive and Negative Symptom Scale), was used for evaluation. Clozapine alone significantly attenuated hostility, while risperidone and haloperidol exacerbated it. Olanzapine showed only a minimal beneficial effect. Since clozapine shows some level of effect on hostility in patients with schizophrenia, its administration in schizophrenia patients exhibiting violent behavior is recommended.However, clozapine is an antipsychotic agent with extremely strong efficacy, and its effect could be the suppression of violent behavior by improving the aforementioned positive symptom (i). It has not been verified whether violent behavior stemming from impulsivity (ii) could be suppressed. Furthermore, since clozapine causes serious side effects such as agranulocytosis and similar conditions... 4 / 42 Medical instructions and patients able to use this medication are limited.

[009] There are more than 100 reports regarding genes related to the onset of schizophrenia, which are based on lineage analysis, gene polymorphism analysis, and similar methods. Among these, the Schizophrenia Interrupted 1 (Disci) gene with reciprocal shifts between chromosome 1 and chromosome 11, which were observed in families with multiple schizophrenia in Scotland, has attracted attention as a weakness factor causing schizophrenia. Mice with a mutation at the L100P point of Disc1 showed abnormal schizophrenia-like behaviors, and antipsychotic agents such as clozapine and haloperidol reduced schizophrenia-like behaviors. Furthermore, a decrease in brain volume and biochemical analyses showed its usefulness as a schizophrenia-like model (Neuron 54(3): 387-402, 2007).

[0010] Major depression is strongly associated with suicidal tendencies, and impulsive symptoms are considered important predictive factors for this (Am J Psychiatry 1999; 156:181-89). Patients with major depression are more impulsive than healthy humans (Am J Psychiatry 2005; 162:1680-7), and more prone to suicide attempts and suicide attempts (Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:829-33, Epidemiol Psichiatr Soc 2009; 18:172-8). The relationship between selective serotonin reuptake inhibitors (SSRIs) used as antidepressants and an increased risk of suicide has been highlighted, and the US Food and Drug Administration (FDA) warned in 2004 that the administration of an antidepressant can cause activation syndrome (AS) which can induce suicide. Harada et al. conducted a retrospective survey of emerging AS in outpatients prescribed antidepressants for 3 months, and observed that 4.3% of them showed AS (Depress Anxiety 2008; 25:10149).Therefore, when AS arises after administration of an antidepressant. 5 / 42 In clinical situations, it is difficult to judge whether it is a side effect of the antidepressant or a worsening of the existing malaise, and physicians often struggle to decide whether or not to continue administering the antidepressant. Thus, establishing an appropriate therapy for patients with major depression with high impulsive symptoms is desirable.

[0011] As for violent behavior in bipolar disorder, a report was documented by Barlow et al. (Aust NZJ Psychiatry 2000; 34:967-74). A survey of 1,269 hospitalized patients with mental illness over 18 months revealed that patients with bipolar disorder in a manic state showed the highest ratio of violent behavior disparity. Furthermore, most violent behavior is considered to clearly originate from impulsivity, and many violent behaviors arose with manic episodes.

[0012] Clinically, mood stabilizers and antipsychotics are prescribed for the treatment of manic episodes. Although the effectiveness of prescribing has been reported by meta-analyses (Arch Gen Psychiatry 2007; 64:442-55, Acta Psychiatr Scand 2007; 115:1220), a test that studies violent behavior does not currently exist.

[0013] Alcohol dependence and drug dependence are mental illnesses that meet several diagnostic criteria such as resistance, craving, withdrawal symptoms and similar symptoms related to alcohol or drugs. It is well known that patients with dependence adopt impulsive behaviors. They not only cannot suppress the urge to ingest alcohol and drugs, but they take quick action to satisfy the immediate desire even though this may lead to an undesirable effect in the future. As such, patients frequently commit crimes such as violent behavior and the like. Such impulsive behavior is said to be associated with a disorder in the prefrontal cortex (Pharmacol Biochem Behav 2009; 6 / 42 93:237-47). For the treatment of alcohol dependence, opioid antagonists such as naltrexone and nalmefene are prescribed to suppress impulsive alcohol consumption and help control alcohol intake. However, the treatment effect of these is not sufficient, and the establishment of a medication and a treatment method providing a greater treatment effect is desired.

[0014] Examples of neurodegenerative disease include dementia [Alzheimer's disease (AD), Lewy body dementia, Parkinson's disease, frontotemporal dementia, cerebrovascular dementia, Huntington's disease], multiple sclerosis, and similar conditions.

[0015] Examples of behavioral and psychological symptoms in neurodegenerative diseases include behavioral and psychological symptoms of dementia and similar conditions.

[0016] Dementia is divided into “neurological symptoms,” primarily showing cognitive impairment such as memory, orientation, discernment, and the like, and “behavioral and psychological symptoms,” which are psychological and impulsive symptoms that appear in association with the “neurological symptoms.” Psychological symptoms include depression, anxiety, hallucinations, delusions, sleep disturbances, and the like, and impulsive symptoms include violence, violent language, delusions, rejection, immoral behavior, and the like. In the International Psychogeriatric Association, maintained in the USA in 1995, these behavioral disturbances were defined as “symptoms of disturbed perception, thought content, mood, or behavior that frequently occur in patients with dementia,” and hereafter referred to as BPSD (Behavioral and Psychological Symptoms of Dementia).

[0017] According to epidemiological research, 80% of dementia patients at home show behavioral abnormalities, that is, BPSD, and BPSD appears more frequently as dementia progresses. 7 / 42 from the mild stage to the moderate stage. As home care gradually becomes more difficult, the QOL (Quality of Life) of patients and caregivers is noticeably degraded. Relatively mild BPSD can sometimes be treated with "non-medication therapy" which includes appropriately improving the living environment and care. However, when the stage is moderate or high and several problems have occurred, such as increased stress not only on patients but also on caregivers, and similar issues, medication treatment is necessary in many cases.

[0018] As for Alzheimer's disease, which is a representative neurodegenerative disease, there is a report regarding the study of the effect of donepezil treatment for 12 weeks on agitation, which is one of the behavioral and psychological symptoms (N Engl J Med 2007, 357:1382-1392). Patients with highly severe Alzheimer's disease, who were cared for in a home nursing setting, were divided into a placebo group and a donepezil administration group, and a test was performed. They were assessed using the CMAI (Cohen-Mansfield Agitation Inventory) and NPI (Neuropsychiatric Inventory). As a result, each score showed no statistically significant difference between the placebo group and the donepezil administration group, and the score itself showed practically no change (p-value: CMAI 0.98, NPI 0.95). It can be interpreted that the results may mean that donepezil did not improve or promote agitation.Therefore, donepezil is expected to be a medication that improves cognitive function in Alzheimer's disease, but it shows no beneficial effect on behavioral and psychological symptoms, particularly agitation, which often places a burden on caregivers.

[0019] Alexander et al. report on a BPSD model taking note of aggression, using Tg2576 mice, which is one of the AD model mice used worldwide (Behavioral Brain). 8 / 42 (Research 2011; 216:77-83). Tg2576 is a mouse model of AD with Swedish and London type Amyloid Precursor Protein (APP) mutations. In this model, which applies a “resident-intruder” test method, an A / J (intruder) mouse from a non-aggressive strain is introduced into a cage of individually bred Tg2576 (resident). The aggressiveness of 7-month-old Tg2576 mice was studied. The time required for the first attack decreased significantly compared to the control mouse, and the number of aggressions per 10 minutes increased significantly.

[0020] Furthermore, Vloeberghs et al. report on the change in the amount of spontaneous locomotor activity based on the nocturnal circadian rhythm of APP23 mice (Eur J Neurosci 2004; 10:2757-66). APP23 mice are a model mouse of AD with a Swedish APP mutation. 12-month-old APP23 and wild-type mice were compared for 3 days. As a result, the spontaneous locomotor activity of the wild-type mouse was high at night only on the first day, and decreased significantly on days 2 and 3. On the other hand, APP23 mice showed a high increase in spontaneous locomotor activity for 3 nights. The spontaneous locomotor activity of APP23 mice on days 2 and 3 at night increased significantly compared to that of the wild-type on days 2 and 3.

[0021] As evidenced in the aforementioned reports, there are numerous research reports of AD model mice showing partial BPSD symptoms, and research and development of a therapeutic drug for BPSD is being made possible by using aggression and spontaneous locomotor activity promoted in these model mice as indices.

[0022] Dementia with Lewy bodies (DLB) is characterized by visual hallucinations and auditory hallucinations, as well as cognitive impairment. 9 / 42 progressive movement disorders similar to Parkinson's disease emerge as symptoms. Among senile degenerative dementia disorders, it is the second most frequent after Alzheimer's disease. DLB is a dementia that most frequently accompanies BPSD from the early stages and, therefore, the QOL of patients and caregivers is notably impaired. Fujita et al. took note of the genetic mutation observed in familial DLB, and succeeded in generating a novel transgenic mouse model expressing mutant P123Hp-synuclein (Nat Commun 2010; 1:110). This mouse shows cognitive symptoms in addition to several pathological findings, and additionally shows abnormal BPSD-like behaviors. Therefore, research and development of a therapeutic drug for BPSD is also possible using this mouse model.

[0023] As mentioned earlier, once behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness develop, a very heavy burden is placed on caregivers, and those around them may be harmed. Therefore, a medication that suppresses such symptoms is desired. SUMMARY OF THE INVENTION

[0024] One objective of the present invention is to provide a prophylactic and / or therapeutic agent that is superior in safety for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[0025] In an attempt to solve the aforementioned problems, the present inventors conducted intensive studies using aggression and spontaneous locomotor activity promoted and similar mouse AD models with an APP genetic mutation as indices and observed that brexpiprazole or a salt thereof is effective for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness. Furthermore, they 10 / 42 observed that brexpiprazole or a salt thereof activates nerve cells in the medial prefrontal cortex that are deeply related to behavioral and psychological symptoms associated with neurodegenerative disease and impulsive symptoms of mental illness.

[0026] The present invention provides a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, containing brexpiprazole or a salt thereof as an active ingredient.

[0027] The present invention provides a composition (pharmaceutical composition) for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, containing brexpiprazole or a salt thereof as an active ingredient.

[0028] The present invention provides use of brexpiprazole or a salt thereof to produce a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[0029] The present invention provides a method for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, comprising administering brexpiprazole or a salt thereof in a prophylactic or therapeutically effective amount to a patient who requires the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[0030] The present invention provides a method for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, comprising administering brexpiprazole or a salt thereof in a 11 / 42 prophylactic or therapeutically effective amount in a patient for whom, in general, antipsychotic agents or therapeutic medications for neurodegenerative disease fail to provide a sufficient effect among patients who require prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[0031] That is, the present invention provides prophylactic and / or therapeutic agents for behavioral and psychological symptoms associated with central neurological disease, shown in the following items 1 to 59.

[0032] Item1.

[0033] A method for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, comprising administering 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof in a prophylactic or therapeutically effective amount to a patient requiring prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[0034] Item 2.

[0035] The method for the prophylaxis and / or treatment of Item 1, which is a method for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease.

[0036] Item 3.

[0037] The method for the prophylaxis and / or treatment of Item 1, which is a method for the prophylaxis and / or treatment of impulsive symptoms associated with mental illness.

[0038] Item 4.

[0039] The method for the prophylaxis and / or treatment of Item 2, where the neurodegenerative disease is selected from the group consisting of 12 / 42 dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure acne, prion disease, corticobasal degeneration, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballism, deforming muscular dystonia, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, atrophy dentatorubropalidoluisiana, Gerstmann-Straussler-Scheinker syndrome, Friedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary periodic ataxiaataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbia, Arnold-Chiari malformation, stiff-person syndrome, Klippel-Feil syndrome, Fazio-Londe disease, mild myelopathy, Dandy-Walker syndrome, spina bifida, Sjögren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy due to cerebral hemorrhage and / or associated neurological dysfunction or deficits.

[0040] Item 5.

[0041] The method for the prophylaxis and / or treatment of Item 4, where the neurodegenerative disease is dementia.

[0042] Item 6.

[0043] The method for the prophylaxis and / or treatment of Item 5, where the dementia is Alzheimer's type dementia.

[0044] Item 7. 13 / 42 The method for the prophylaxis and / or treatment of Item 5, where the dementia is dementia with Lewy bodies.

[0045] Item 8. The method for the prophylaxis and / or treatment of Item 5, where the dementia is frontotemporal dementia.

[0046] Item 9.

[0047] The method for the prophylaxis and / or treatment of Item 5, where the dementia is cerebrovascular dementia.

[0048] Item 10.

[0049] The method for the prophylaxis and / or treatment of Item 5, where the dementia is Parkinson-type dementia.

[0050] Item 11.

[0051] The method for the prophylaxis and / or treatment of Item 5, where dementia is Huntington's disease.

[0052] Item 12.

[0053] The method for the prophylaxis and / or treatment of Item 4, where the neurodegenerative disease is multiple sclerosis.

[0054] Item 13.

[0055] The method for the prophylaxis and / or treatment of Item 3, wherein the mental illness is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, chronic schizophrenia, emotional disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, vomiting, travel sickness, obesity, migraine, pain, mental retardation, autism, Tourette's syndrome, tic disorder, 14 / 42 Attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania, Down syndrome, and personality disorder.

[0056] Item 14.

[0057] The method for the prophylaxis and / or treatment of Item 13, wherein the mental illness is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia and chronic schizophrenia.

[0058] Item 15.

[0059] The method for the prophylaxis and / or treatment of Item 13, wherein the mental illness is selected from the group consisting of depression, endogenous depression, major depression, melancholic depression and treatment-resistant depression.

[0060] Item 16.

[0061] The method for the prophylaxis and / or treatment of Item 13, where the mental illness is bipolar disorder.

[0062] Item 17.

[0063] The method for the prophylaxis and / or treatment of Item 13, where the mental illness is an eating disorder.

[0064] Item 18.

[0065] The method for the prophylaxis and / or treatment of Item 13, where the mental illness is attention deficit hyperactivity disorder.

[0066] Item 19.

[0067] The method for the prophylaxis and / or treatment of Item 13, where the mental illness is an anxiety disorder.

[0068] Item 20.

[0069] The method for the prophylaxis and / or treatment of Item 19, where the anxiety disorder is obsessive-compulsive disorder.

[0070] Item 21.

[0071] The method for the prophylaxis and / or treatment of Item 19, in which 15 / 42 anxiety disorder is post-traumatic stress disorder.

[0072] Item 22.

[0073] The method for the prophylaxis and / or treatment of any of Items 1 to 21, in which the patient cannot receive a sufficient effect for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, from an antipsychotic agent or therapeutic drug generally available for neurodegenerative disease.

[0074] Item 23.

[0075] The method for the prophylaxis and / or treatment of Item 22, wherein the generally available antipsychotic agent is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propriciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxipertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliperidone, lurasidone, ziprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine or sertindole or a salt thereof.

[0076] Item 24.

[0077] The method for the prophylaxis and / or treatment of Item 22, wherein the generally available therapeutic drug for neurodegenerative disease is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, β-interferon preparation, glatiramer, teriflunomide or natalizumab or a salt thereof.

[0078] Item 25.

[0079] A prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, comprising 7-(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof. 16 / 42 as an active ingredient.

[0080] Item 26.

[0081] The prophylactic and / or therapeutic agent of Item 25, which is a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease.

[0082] Item 27.

[0083] The prophylactic and / or therapeutic agent of Item 25, which is a prophylactic and / or therapeutic agent for impulsive symptoms associated with mental illness.

[0084] Item 28.

[0085] The prophylactic and / or therapeutic agent of Item 26, wherein the neurodegenerative disease is selected from the group consisting of dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure acne, prion disease, corticobasal degeneration, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballism, muscular dystonia deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, atrophy olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubropallidoliusian atrophy, Gerstmann-Straussler-Scheinker syndromeFriedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary periodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbia, malformation of, 17 / 42 Arnold-Chiari syndrome, stiff-person syndrome, Klippel-Feil syndrome, Fazio-Londe disease, mild myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and cerebral apoplexy due to cerebral hemorrhage and / or associated neurological dysfunction or deficits.

[0086]

[0087] Item 29. The prophylactic and / or therapeutic agent of Item 28, in which the Neurodegenerative disease is dementia.

[0088]

[0089] Item 30. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is Alzheimer's type dementia.

[0090]

[0091] Item 31. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is dementia with Lewy bodies.

[0092]

[0093] Item 32. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is frontotemporal dementia.

[0094]

[0095] Item 33. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is cerebrovascular dementia.

[0096]

[0097] Item 34. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is Parkinson's type dementia.

[0098]

[0099] Item 35. The prophylactic and / or therapeutic agent of Item 29, in which the Dementia is Huntington's disease.

[00100]

[00101] Item 36. The prophylactic and / or therapeutic agent of Item 28, in which the Multiple sclerosis is a neurodegenerative disease. 18 / 42

[00102] Item 37.

[00103] The prophylactic and / or therapeutic agent of Item 27, wherein the mental illness is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, chronic schizophrenia, emotional disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, treatment-resistant melancholic depression, dysthymic disorder, cyclothymic disorder, anxiety disorder, somatoform disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, vomiting, travel sickness, obesity, migraine, pain, mental retardation, autism, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania,Down syndrome and personality disorder.

[00104] Item 38.

[00105] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, and chronic schizophrenia.

[00106] Item 39

[00107] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is selected from the group consisting of depression, endogenous depression, major depression, melancholic depression, and treatment-resistant depression.

[00108] Item 40.

[00109] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is bipolar disorder.

[00110] Item 41.

[00111] The prophylactic and / or therapeutic agent of Item 37, in which the 19 / 42 mental illness is an eating disorder.

[00112] Item 42.

[00113] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is attention deficit hyperactivity disorder.

[00114] Item 43.

[00115] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is an anxiety disorder.

[00116] Item 44.

[00117] The prophylactic and / or therapeutic agent of Item 43, where the anxiety disorder is obsessive-compulsive disorder.

[00118] Item 45.

[00119] The prophylactic and / or therapeutic agent of Item 43, where the anxiety disorder is post-traumatic stress disorder.

[00120] Item 46.

[00121] The prophylactic and / or therapeutic agent of any of Items 25 to 45, for the treatment of a patient who cannot receive a sufficient effect for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness from an antipsychotic agent or therapeutic drug generally available for neurodegenerative disease.

[00122] Item 47.

[00123] The prophylactic and / or therapeutic agent of Item 46, wherein the generally available antipsychotic agent is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propriciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxipertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliperidone, lurasidone, ziprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine or sertindole or a salt thereof. 20 / 42

[00124] Item 48.

[00125] The prophylactic and / or therapeutic agent of Item 46, wherein the therapeutic drug generally available for neurodegenerative disease is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, β-interferon preparation, glatiramer, teriflunomide or natalizumab or a salt thereof.

[00126] Item 49.

[00127] Use of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1Hquinolin-2-one or a salt thereof to produce a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[00128] Item 50.

[00129] 7-[4-(4-Benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1Hquinolin-2-one or a salt thereof for use in the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[00130] Item 51.

[00131] A pharmaceutical composition for use in the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, comprising 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]1H-quinolin-2-one or a salt thereof as an active ingredient.

[00132] Item 52.

[00133] The method for the prophylaxis and / or treatment of Item 13, where the mental illness is a substance-related disorder.

[00134] Item 53.

[00135] The method for the prophylaxis and / or treatment of Item 52, in which 21 / 42 the substance-related disorder is an alcohol-related disorder.

[00136] Item 54.

[00137] The prophylactic and / or therapeutic agent of Item 37, where the mental illness is a substance-related disorder.

[00138] Item 55.

[00139] The prophylactic and / or therapeutic agent of Item 54, where the substance-related disorder is an alcohol-related disorder.

[00140] Item 56.

[00141] The method for the prophylaxis and / or treatment of Item 6, in which the behavioral and psychological symptoms are impulsive symptoms.

[00142] Item 57.

[00143] The method for the prophylaxis and / or treatment of Item 56, where the impulsive symptom is agitation.

[00144] Item 58.

[00145] The prophylactic and / or therapeutic agent of Item 30, where the behavioral and psychological symptoms are impulsive symptoms.

[00146] Item 59.

[00147] The prophylactic and / or therapeutic agent of Item 58, where the impulsive symptom is agitation. EFFECTS OF THE INVENTION

[00148] Brexpiprazole or a salt thereof has a superior treatment effect for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness. Brexpiprazole or a salt thereof has a superior treatment effect particularly for behavioral and psychological symptoms associated with dementia (BPSD) (preferably Alzheimer's disease). It is also possible to improve these symptoms by additionally administering brexpiprazole or a salt thereof with an existing antipsychotic agent or therapeutic medication for neurodegenerative disease in a patient who cannot 22 / 42 to receive a sufficient effect from existing medications. Furthermore, brexpiprazole or a salt thereof activates nerve cells in the medial prefrontal cortex. In addition, brexpiprazole or a salt thereof is superior to existing antipsychotic agents in safety and tolerability, and can be safely administered to elderly patients with Alzheimer's disease. BRIEF DESCRIPTION OF THE DRAWINGS

[00149] Figure 1 shows the results of a preliminary test confirming the aggression promoted by Tg2576 mice.

[00150] Figure 2 shows the results of the test of a suppressive effect of brexpiprazole on aggression in Tg2576 mice.

[00151] Figure 3 shows the influence of brexpiprazole administration on average individual ethanol intake in a limited access paradigm.

[00152] Figure 4 shows the effect of brexpiprazole on the activation pattern of the medial prefrontal cortex nerve in c-fos-GFP mice, where the area with a significant increase in GFP signal relative to the vehicle group is shown in white. DETAILED DESCRIPTION OF THE INVENTION

[00153] The active ingredient in the present invention is brexpiprazole or a salt thereof. Brexpiprazole is a known compound represented by the following formula and is under clinical trials for schizophrenia and similar conditions.

[00154] The brexpiprazole salt is not particularly limited, provided it is a pharmacologically acceptable salt and, for example, metal salts such as alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.) and the like, ammonium salt, salts with an inorganic base such as 23 / 42 Alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.) and the like; salts with organic base such as tri(lower)alkylamines (e.g. trimethylamine, triethylamine, Nethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl morpholines (e.g. N-methylmorpholine, etc.), l,5-diazabicyclo[4.3.0]nonene-5 (DBN), l,8-diazabicyclo[5.4.0]undecene-7 (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO) and similar substances; salts with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate and similar substances; salts with organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate and similar substances; and similar substances may be mentioned. As used herein, “lower alkyl” means “alkyl with 1 to 6 carbon atoms”.

[00155] “Brexpiprazole or a salt thereof” includes anhydride and solvates (e.g., hydrate, preferably dihydrate) of brexpiprazole or a salt thereof, various crystalline forms of such anhydride and solvates, and mixtures thereof.

[00156] A single type of such brexpiprazole or a salt thereof may be used, or a mixture of two or more types thereof may be used. Brexpiprazole anhydride or a salt thereof may be obtained by the methods described, for example, in Example 1 and Examples 42 to 47 of patent document 1 (JPA-2006-316052 (US 2010 / 0179322 Al)).

[00157] Brexpiprazole or a salt thereof may be used in bulk or preferably in the form of a pharmaceutical preparation with a conventional pharmaceutical carrier (pharmaceutically acceptable carrier) or a 24 / 42 diluent. The dosage form is not limited to a particular form. Specifically, it can be any conventional administration form, for example, an oral solid dosage form such as a tablet, capsule, and particles; various liquid preparations suitable for oral administration; or a parenteral preparation such as an injection and suppository. The dose is not limited to a specific range. In general, the active ingredient can be used in an amount of approximately 0.01 to 10 mg / day / 1 kg of body weight. The active ingredient can be included in approximately 0.1-400 mg per dosage unit of the preparation.

[00158] Injection preparations are normally prepared in the form of a liquid, emulsion, or suspension, which are sterilized and preferably made isotonic to blood. Liquid, emulsion, or suspension preparations are normally prepared using conventional pharmaceutical diluents such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyethoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. These preparations may be prepared by mixing with an isotonic agent such as sodium chloride, glucose, or glycerol in a sufficient quantity to make them isotonic, and may additionally be prepared by mixing with conventional solubilizers, buffers, anesthetic agents, and optionally colorants, preservatives, fragrance substances, flavoring agents, or sweeteners.

[00159] Preparations such as tablets, capsules, and liquids for oral administration can be prepared by a conventional method. Tablets can be prepared by mixing brexpiprazole or a salt thereof with conventional pharmaceutical carriers such as gelatin, starches, lactose, magnesium stearate, talc, gum arabic, and the like. Capsules can be prepared by mixing brexpiprazole or a salt thereof with inert pharmaceutical fillers or diluents and filling hard gelatin capsules or 25 / 42 soft capsules containing the mixture. Oral liquid preparations such as syrups or elixirs are prepared by mixing brexpiprazole or a salt thereof with sweetening agents (e.g., sucrose), preservatives (e.g., methylparaben, propylparaben), colorings, flavorings, and the like. Preparations for parenteral administration may also be prepared by a conventional method, for example, by dissolving brexpiprazole or a salt thereof in a sterile aqueous carrier, preferably water or a saline solution. A preferred liquid preparation suitable for parenteral administration is prepared by dissolving approximately 0.1400 mg of brexpiprazole or a salt thereof in water and an organic solvent, and additionally in a polyethylene glycol with a molecular weight of 300 to 5,000, in which preferably a lubricant such as sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol may be incorporated.Preferably, the aforementioned liquid preparations may additionally comprise a disinfectant (e.g., benzyl alcohol, phenol, thimerosal), an antimicrobial agent, and optionally an isotonic agent (e.g., sucrose, sodium chloride), a topical anesthetic, a stabilizer, a buffer, and the like. To maintain stability, the preparation for parenteral administration may be placed in a small container, followed by removal of the aqueous medium by a conventional lyophilization technique. The preparation may be recovered in a liquid form by dissolving it in an aqueous medium when used.

[00160] The present invention can prevent and / or treat behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness, by administering brexpiprazole or a salt thereof.

[00161] Examples of mental illness in the present invention include schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, 26 / 42 chronic schizophrenia, emotional disorder, psychotic disorder, mood disorder, bipolar disorders (e.g., bipolar I disorder and bipolar II disorder and similar), mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorder, cyclothymic disorder, anxiety disorders (e.g., panic attack, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder and similar), somatoform disorders (e.g., hysteria, somatization disorder, conversion disorder, pain disorder, hypochondria and similar), factitious disorder, dissociative disorder, sexual disorders (e.g., sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile dysfunction, paraphilias and similar), eating disorders (e.g., anorexia nervosa,bulimia nervosa and similar disorders), sleep disorder, adjustment disorder, substance-related disorder (e.g., alcohol-related disorders (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal and similar disorders), amphetamine-related disorders (amphetamine use disorder and similar disorders), marijuana-related disorders (marijuana use disorder and similar disorders), cocaine-related disorders (cocaine use disorder and similar disorders), hallucinogen-related disorders (hallucinogen use disorder and similar disorders) and similar disorders), anhedonia (e.g., iatrogenic anhedonia, anhedonia of a psychic or mental cause, anhedonia associated with depression, anhedonia associated with schizophrenia and similar disorders), delirium, vomiting, travel sickness, obesity, migraine, pain, mental retardation, autism, Tourette's syndrome, tic disorder,Attention deficit hyperactivity disorder, conduct disorder, Down syndrome, personality disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania and similar conditions. 27 / 42

[00162] Examples of neurodegenerative disease in the present invention include dementia (for example, Alzheimer's-type dementia, Lewy body dementia, frontotemporal dementia, cerebrovascular dementia, Parkinson's-type dementia, Huntington's disease, senile dementia, mild cognitive impairment, HIV encephalopathy, corticobasal degeneration, Pick's disease, mixed dementia and the like), multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure acne, prion disease, corticobasal degeneration, chorea-acanthocytosis, benign hereditary chorea, paroxysmal choreaathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballism, deforming muscular dystonia, athetosis, spasmodic torticollis, Meige's syndrome, cerebral palsy, Wilson's disease, disease of Segawa syndrome, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy.spinocerebellar degeneration, cerebral cortical atrophy, Holmes-type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubropalidoluysian atrophy, Gerstmann-Straussler-Scheinker syndrome, Friedreich's ataxia, Roussy-Levy syndrome, May-White syndrome, congenital cerebellar ataxia, hereditary periodic ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, progressive spinal muscular atrophy, spinobulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbia, Arnold-Chiari malformation, stiff-person syndrome, Klippel-Feil syndrome, Fazio-Londe disease, mild myelopathy Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration,and cerebral apoplexy due to cerebral hemorrhage and / or associated neurological dysfunctions or deficits and similar conditions.

[00163] Behavioral and psychological symptoms in the present 28 / 42 invention are impulsive symptoms and psychological symptoms.

[00164] An impulsive symptom is a symptom of engaging in impulsive behavior. Specific examples of impulsive behavior include physical attack, delirium, restlessness, agitation, unconscious behavior and different behavior (e.g., different sexual behavior), wandering, high-pitched voice, loud speech, violent language, loss of motivation, constant questioning, shadow behavior, suicide attempt and suicide, self-harming behavior, threats, theft, overeating, threatening behavior, short-circuit reaction, panic reaction, property damage, inappropriate dressing / undressing, selling at low prices, and the like. In the preferred modality, the impulsive symptom is agitation.

[00165] Examples of psychological symptoms include hallucinations, delusions, depressed mood, insomnia, anxiety, misidentification, sleep disorders, and the like.

[00166] The method for the prophylaxis and / or treatment of behavioral and psychological symptoms in the present invention means a method of preventing and / or treating a condition with manifestation of one or multiple symptoms of the aforementioned behavioral and psychological symptoms.

[00167] The method for the prophylaxis and / or treatment of impulsive symptoms in the present invention means a method of preventing and / or treating a condition with manifestation of one or multiple symptoms of the aforementioned impulsive symptoms.

[00168] Brexpiprazole or a salt thereof in the present invention is particularly used for the prophylaxis and / or treatment of 1) behavioral and psychological symptoms associated with neurodegenerative disease, wherein the neurodegenerative disease is dementia (BPSD) (additionally, used for the prophylaxis and / or treatment of 1) behavioral and psychological symptoms associated with neurodegenerative disease wherein the disease 29 / 42 neurodegenerative disease is dementia (BPSD), particularly behavioral and psychological symptoms associated with Alzheimer's-type dementia, behavioral and psychological symptoms associated with Lewy body dementia, behavioral and psychological symptoms associated with frontotemporal dementia, behavioral and psychological symptoms associated with cerebrovascular dementia, behavioral and psychological symptoms associated with Parkinson's-type dementia, behavioral and psychological symptoms associated with Huntington's disease), or 2) behavioral and psychological symptoms associated with neurodegenerative disease, where the neurodegenerative disease is multiple sclerosis.

[00169] In addition, brexpiprazole or a salt thereof in the present invention is particularly used for the prophylaxis and / or treatment of 1) impulsive symptoms associated with mental illness, wherein the mental illness is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, and chronic schizophrenia, 2) impulsive symptoms associated with mental illness, wherein the mental illness is selected from the group consisting of depression, endogenous depression, major depression, melancholic depression, and treatment-resistant depression, 3) impulsive symptoms associated with mental illness, wherein the mental illness is bipolar disorder, 4) impulsive symptoms associated with mental illness, wherein the mental illness is an eating disorder, 5) impulsive symptoms associated with mental illness, wherein the mental illness is attention deficit hyperactivity disorder, or 6) impulsive symptoms associated with mental illness,where the mental illness is an anxiety disorder (additionally, used for the prophylaxis and / or treatment of 6) impulsive symptoms associated with mental illness, where the mental illness is an anxiety disorder, impulsive symptoms associated with obsessive-compulsive disorder or post-traumatic stress disorder). 30 / 42

[00170] The aforementioned symptom is sometimes not improved even in patients under medication with one or more types of antipsychotic agents and therapeutic drugs for neurodegenerative disease. The symptom may be improved by administering brexpiprazole or a salt thereof in such patients.

[00171] Examples of existing (generally available) antipsychotic agents include chlorpromazine, fluphenazine, levomepromazine, perphenazine, propiciazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxipertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliperidone, lurasidone, ziprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine, sertindole or a salt thereof, and similar agents.

[00172] Examples of existing (generally available) therapeutic drugs for neurodegenerative disease include Aricept (trademark) (donepezil hydrochloride), Reminyl (trademark) (galantamine hydrobromide), Exelon (trademark) patch (rivastigmine transdermal absorption preparation), Rivastach (trademark) patch (rivastigmine transdermal absorption preparation), Memary (trademark) (memantine hydrochloride), fingolimod hydrochloride (Gilenya (trademark) capsule, Imusera (trademark) capsule), methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, β interferon preparation, Copaxone (trademark) (glatiramer acetate), teriflunomide, Tysabri (trademark) (natalizumab) and similar drugs. Examples Example 1 1) Measurement of locomotor activity and circadian rhythm in mice

[00173] Animal: APPSL-Tg mouse (male) with APP mutations 31 / 42 Swedish and London mice, and non-Tg (male) mice without a genetic mutation as a control, were generated (Neuroscience Letters 2010; 469:273-277), bred in a breeding room, and used after they reached 6 months of age. During breeding, isolated housing was applied.

[00174] Measurement method: SUPERMEX manufactured by Muromachi Kikai Co., Ltd. was used for measuring circadian rhythm locomotor activity. The mouse was placed in an individual cage, and the mouse's spontaneous locomotor activity was measured for 3 days (total 62.5 hours) under free-feeding, water-drinking conditions. In this device, a passive infrared sensor detects infrared rays emitted by the mouse, and the number of transpositions is counted. The measured values ​​are totaled every 30 minutes and automatically totaled using specialized CompACT AMS software. The test was performed in a soundproof chamber so that the mouse's spontaneous locomotor activity would not be influenced. The lighting time in the soundproof chamber was set to 7:00-19:00 as in the breeding room. 2) Grouping by preliminary test

[00175] The amounts of spontaneous locomotor activity of non-Tg mice and APPSL-Tg mice during the dark period from 19:00-7:00 were measured beforehand. The mice were grouped in such a way as to make the mean and variance of the groups equal, using body weight and spontaneous locomotor activity during the dark period as indices. 3) Drug preparation and method of administration

[00176] Brexpiprazole was dissolved in distilled water containing 5% gum arabic, 5% distilled water of gum arabic was used for the vehicle group, and they were administered orally to each mouse. 32 / 42 4) Number of mice and dose adjustment: Group 1: 5 non-Tgs / vehicle mice; Group 2: 5 APPSL-Tgs / vehicle mice; Group 3: 6 APPSL-Tgs / 0.01 mg / kg brexpiprazole mice; Group 4: 5 APPSL-Tgs / 0.03 mg / kg brexpiprazole mice 5) Administration time

[00177] Brexpiprazole and the vehicle were administered for 3 days during the period of 17:30-18:30. After administration, measurement of the amount of locomotor activity was quickly initiated or continued. 6) Statistical analysis

[00178] The statistical test was a two-tailed test, and the significance level of the test was set at 5%. SAS (R9.1, SAS Institute Japan Ltd.) was used as statistical software. i) Comparison of a non-Tg / vehicle mouse group and an APPSL-Tg / vehicle mouse group

[00179] A repeated measures ANOVA was performed using a mixed model for Night 1 - Night 3 in each phase I, II or III of the dark period. In addition, an unpaired t-test was performed for each dark period and Night. ii) Comparison of APPSL-Tg / vehicle mouse group and APPSL-Tg / brexpiprazole administration mouse group

[00180] Dunnett's test was performed based on repeated measures ANOVA using a mixed model for Night 1 - Night 3 in each phase I, II or III of the dark period. In addition, Dunnett's test was performed for each dark period and Night. 7) Results

[00181] The test results are shown in Table 1 and Table 2. 33 / 42 [Table 1] Comparison of non-mouse groups Tg / vehicle and APPSL-Tg / vehicle mouse group non-Tg / vehicle group (n=5) APPSL-Tg / vehicle group (n=5) dark period Night 1 Night 2 Night 3 Night 1 Night 2 Night 3 p-value I(19:00-23:00) 6.204 ± 2596 6.489 ± 2.309 7.260 ± 1.524 9.377 ± 2.395 11.459 ± 3.053 12.839 ± 1.960 0.1804 II(23:00-3:00) 5.155 ± 1.561 4.678 ± 1.199 3.398 ± 518 8.162 ± 1.277 9.438 ± 2.146 13.249 ± 3.102* 0.0250 III(3:007:00) 2.534 ± 597 2.513 ± 765 3.146 ± 616 9.186 ± 955** 7469 ± 572** 10694 ± 1.329** 0.0001 mean ± standard error P-values ​​show the results of the repeated measures ANOVA using a mixed model. Additionally, they were analyzed by an unpaired t-test for each Night in each dark period (*P<0.05; **P<0.01 vs. non-Tg / vehicle group). [Table 2] Comparison of APPSLTg / vehicle mouse group and APPSL-Tg / brexpiprazole mouse group APPSL-Tg / vehicle group (n=5) APPSL-Tg / 0.01 mg / kg brexpiprazole group (n=6) Dark period Night 1 Night 2 Night 3 Night 1 Night 2 Night 3 p-value III(3:007:00) 9.186 ± 955 7.469 ± 572 10.694 ± 1329 7.256 ± 774 6.466 ± 707 4.928 ± 483** 0.049 APPSL-Tg / 0.03 mg / kg brexpiprazole group (n=5) Dark period Night 1 Night 2 Night 3 p-value III(3:007:00) 6.014 ± 1.468 5.443 ± 1.126 6.845 ± 1.554# 0.050 mean ± standard error p-values ​​show the results of Dunnett's test based on repeated measures ANOVA using a mixed model. Additionally, analyzed by Dunnett's test for each Night (**P<0.01, #P=0.068 vs APPSL-Tg / vehicle group).

[00182] Until then, Vloeberghs et al. reported, with reference to the spontaneous locomotor activity of APP-Tg model mice in a 12-hour / 12-hour light-dark cycle, that spontaneous locomotor activity during the dark period is promoted as aging occurs (Eur J Neurosci. 2004; 10:2757-66). The APPSL-Tg mice used in the present invention also showed significantly greater spontaneous locomotor activity in phase II and phase III compared to the non-Tg group (phase II: P<0.05; phase III: P<0.01). Furthermore, for each Night in each dark period, spontaneous locomotor activity increased significantly on Night 3, dark period phase II (P<0.05) or on Night 1 34 / 42 Night 3, Phase III (P<0.01) (Table 1).

[00183] Brexpiprazole was administered to APPSL-Tg mice immediately before the dark period (17:30-18:30) at a dose of 0.01 and 0.03 mg / kg, and measurement of spontaneous locomotor activity was initiated. Brexpiprazole was administered at the same time on Day 2 and Day 3, and measurement of spontaneous locomotor activity continued. As a result, the 0.01 mg / kg and 0.03 mg / kg groups significantly suppressed spontaneous locomotor activity in phase III of the dark period compared to the vehicle group (0.01 mg / kg group: P<0.05; 0.03 mg / kg group: P=0.050). Furthermore, for each Night in phase III of the dark period, 0.01 mg / kg of brexpiprazole significantly suppressed spontaneous locomotor activity on Night 3 (P<0.01, Table 2). Moreover, 0.03 mg / kg of brexpiprazole also tended to suppress activity on Night 3 (P=0.068, Table 2). On the other hand, in non-Tg mice, brexpiprazole did not decrease spontaneous locomotor activity during the dark period.

[00184] Previous results have clarified that brexpiprazole can suppress, even at a low dose, abnormal nighttime behavior in a mouse model of AD with a genetic mutation of APP. Example 2 1) Resident-Intruder Test (study of impulsive symptoms)

[00185] Animal: Tg2576 (male) mice with a Swedish APP mutation (K670N, M671L) and non-Tg (male) mice without the same genetic mutation as a control were acquired from Taconic, and bred and aged to 5–6 months of age. During breeding, isolated housing was applied.

[00186] Measurement method: For the experiment, Tg2576 or non-Tg [Resident] mice and A / J [Intruder] mice with almost no aggression were used. Resident mice established a sufficient territory by being housed in isolation for 14 days. Then, Intruder mice were moved to the cage of 35 / 42 Resident aggressive behavior was observed for 10 minutes. As aggressive behavior, biting was noted, and the time required for the first bite and the total number of bites over 10 minutes were measured. The measurement was performed during the first dark period (4 hours) when the amount of locomotor activity in mice is highest. 2) Confirmation of assault by preliminary test

[00187] Tg2576 mice (48 mice) and non-Tg mice (10 mice) were subjected to a Resident-Intruder test beforehand, and the promotion of aggression in the Tg2576 mouse was confirmed. Five non-aggressive Tg2576 mice were excluded, and 43 mice were used for the test. 3) Grouping of Tg2576 mice and dose adjustment

[00188] The mice were grouped into 3 groups in such a way as to make the mean and variance of the groups equal using the time required for the first attack and total number of bites per 10 minutes, which were obtained in the preliminary test, as indices (total 43 mice). Group 1: 15 Tg2576 / vehicle mice; Group 2: 14 Tg2576 / 0.01 mg / kg brexpiprazole (OPC-34712) mice; Group 3: 14 Tg2576 / 0.03 mg / kg brexpiprazole (OPC-34712) mice 4) Drug preparation and method of administration

[00189] Brexpiprazole was dissolved in distilled water containing 5% gum arabic, 5% distilled water of gum arabic was used for the vehicle group, and they were administered orally to each mouse. 5) Administration time

[00190] Brexpiprazole and vehicle were administered 1 hour before the start of the test. 6) Statistical analysis 36 / 42

[00191] The significance level of the test was set at 5%. SAS (R9.1, SAS Institute Japan Ltd.) was used as statistical software. To confirm the aggression promoted in the Tg2576 mouse, analysis by a Wilcoxon rank-sum test was performed compared with the non-Tg mouse. As for a suppressive effect of aggression by brexpiprazole administration, a Shirley-Williams multiple comparison test was performed for analysis using the following combinations. i) Tg2576 / vehicle mouse group and Tg2576 / 0.01 mg / kg brexpiprazole mouse group ii) Tg2576 / vehicle mouse group and Tg2576 / 0.03 mg / kg brexpiprazole mouse group 7) Results

[00192] The test results are shown in Figure 1 and Figure 2.

[00193] Until then, Alexander et al. reported, with reference to aggression in Tg2576 mice, the promotion of aggression using a Resident-Intruder test (Behavioural Brain Research 2011; 216:77-83). The Tg2576 mouse used in the present invention was also evaluated by the Resident-Intruder test. As a result, the time required for the first bite was significantly reduced compared to the non-Tg group (Figure 1a, P<0.05, Wilcoxon rank-sum test). In addition, the total number of bites per 10 minutes was also analyzed. As a result, the Tg2576 mouse showed a significant increase in the number of bites (Figure 1b, P<0.01, Wilcoxon rank-sum test). In this way, the aggression-suppressing effect of brexpiprazole was continuously studied using the same Tg2576 mouse, showing a clear promotion of aggressive behavior.

[00194] Brexpiprazole was administered to Tg2576 mice at doses of 0.01 and 0.03 mg / kg 1 hour before the start of the Resident-Intruder test, The suppressive effect of brexpiprazole on aggression, as measured by mouse Tg2516, was studied. Based on the measurement results, the time required for the first bite was analyzed. As a result, the time required for the first bite was significantly increased in the 0.03 mg / kg group compared to the vehicle group (Figure 2a, vehicle group vs. 0.03 mg / kg group: *P<0.05, Shirley-Williams multiple comparison test). The number of bites was also analyzed using the same test. Consequently, mice administered with 0.03 mg / kg of brexpiprazole tended to show a lower number of bites compared to the vehicle group (Figure 2b, vehicle group vs. 0.03 mg / kg group: P=0.0109).

[00195] Previous results have clarified that brexpiprazole can suppress aggression in aggressive behavior in AD model mice with an APP gene mutation. Example 3

[00196] Suppression of behavioral and psychological symptoms by brexpiprazole can be assessed by performing locomotor activity measurement of circadian rhythm conducted in Example 1 and the Resident-Intruder test in Example 2, and general behavioral assessment studies (higher maze test, forced swimming test, tail suspension test, light / dark box test, ball burying behavior test, cliff aversion response test), using a novel transgenic mouse model expressing PI23I β-synuclein mutant. Example 4

[00191] Taking note of the impulsive symptoms of a mouse with a Disci L100P point mutation, suppression of impulsive symptoms by brexpiprazole can be evaluated by performing circadian rhythm locomotor activity measurement conducted in Example 1 and the ResidentIntruder test in Example 2 and general behavioral assessment studies (higher maze test, forced swim test, tail suspension test, 38 / 42 light / dark box test, sphere burying behavior test, cliff aversion response test). Example 5

[00198] A placebo-controlled, double-blind, randomized, multicenter study to examine the treatment effect, safety, and tolerability of brexpiprazole (OPC-34712) in the treatment of subjects with agitation associated with Alzheimer's-type dementia. Test method

[00199] Patients aged 55 to 90 years diagnosed with Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) were enrolled, with a Mini-Mental State Examination (MMSE) score of 5 to 22, and a score > 4 on the agitation / aggression item of the Neuropsyehicrie Inventory in Nursing Home Version (NPI-NH). The experiment consisted of a continuous 12-week double-blind treatment period. Subjects were assigned to one of the following groups: • Plaeebo • Brexpiprazole 0.5 mg (titrated from 0.25 mg / day to 0.5 mg / day) • Brexpiprazole 1 mg (titrated from 0.25 mg / day to 1 mg / day) • Brexpiprazole 2 mg (titrated from 0.25 mg / day to 2 mg / day) Evaluation Method

[00200] The endpoint was the evaluation of the efficacy, safety, and tolerability of brexpiprazole by comparing the improvement in agitation associated with Alzheimer's-type dementia between brexpiprazole and placebo groups from patient recruitment to the final day of the test period (week 12).

[00201] For effectiveness assessment, the change in the Cohen-Mansfield Agitation Inventory (CMAI) score, the Clinical Global Impression of Severity (CGI-S) score, and the CMAI subscale scores were used. 39 / 42 NPI-NH score (total, psychosis subscale, or individual item), Clinical Global Impression-Improvement (CGI-I) score, and Clinical Global Impression-Efficacy Index (CGI-E) score.

[00202] The suppression of behavioral and psychological symptoms associated with Alzheimer's disease by brexpiprazole and the safety and tolerability of brexpiprazole can be evaluated by performing the above. Example 6 1) Measuring alcohol intake using a limited access paradigm

[00203] Measurement method: Impulsive alcohol craving behavior was assessed as follows, with reference to the method of Sinclair et al. (Alcohol 1992; 9:441-44 and Alcohol & Alcoholism 2001; 36:210). First, male Wistar rats were allowed to freely consume 10% aqueous ethanol solution and tap water for several weeks under isolated housing. After stabilization of ethanol intake for each animal, a limited access paradigm allowing ethanol intake for only 1 hour per day was initiated, and ethanol intake for 1 hour was measured each day. Ethanol intake was calculated from the weight measurements of the water supply bottle filled with 10% aqueous ethanol solution, immediately before the start of the limited access paradigm and immediately after its termination.An animal that was showing more than 0.4 g / kg / hour in terms of 100% ethanol as an average ethanol intake in the limited access paradigm for 4 days immediately prior to drug evaluation was used. The limited access paradigm test was conducted between 9:00 AM and 12:00 PM. 2) Drug preparation and method of administration

[00204] Brexpiprazole was suspended in distilled water containing 5% gum arabic. The drug was administered orally to each rat once daily 1 hour before the start of the limited access paradigm for 4 40 / 42 days. 3) Number of animals and dose adjustment

[00205] Five rats were used. The selected dose of brexpiprazole was 0.1 mg / kg, which does not influence the spontaneous locomotor activity of Wistar rats (data not indicated) in novel environments. 4) Statistical analysis

[00206] The significance level of the test was set at 5%. SAS (R9.3, SAS Institute Japan Ltd.) was used as statistical software. Mean ethanol intake in the 4-day limited-access paradigm immediately before drug assessment and mean ethanol intake in the 4-day limited-access paradigm after drug administration were analyzed using a two-tailed paired t-test. 5) Results

[00207] The test results are shown in Figure 3.

[00208] A rat that was showing more than 0.4 g / kg / hour as an average ethanol intake in the limited access paradigm for 4 days immediately prior to drug evaluation was administered brexpiprazole one hour prior at a dose of 0.1 mg / kg for 4 days, and average ethanol intake in the limited access paradigm was calculated. As a result, brexpiprazole was confirmed to have shown statistically significant suppression of ethanol intake. When observed individually, all rats showed a decrease in ethanol intake.

[00209] Previous results clarified that brexpiprazole can suppress impulsive ethanol intake behavior in Wistar rats at a low dose in the limited access paradigm to 10% aqueous ethanol solution. Since nalmefene has been reported to clinically suppress impulsive alcohol consumption behavior in alcohol-dependent patients and allow control of alcohol intake, the effect 41 / 42 shown in this assessment system (Alcohol & Alcoholism 2001;36:2-10), brexpiprazole also suppresses impulsive alcohol consumption behavior in alcohol-dependent patients. Example 7 1) Measurement of nerve activation pattern in cfos-GFP (green fluorescent protein osteosarcoma FBJ oncogene) mice

[00210] Measurement method: c-fos is an indirect marker for neuronal activity, which is expressed upon nerve cell activation. Using a transgenic mouse introduced with a green fluorescent protein (GFP) gene downstream of the c-fos gene promoter (c-fosGFP mouse), the nerve activation pattern in the brain was measured. Brexpiprazole or vehicle was administered and the brain was isolated 3 hours later. GFP signals from serial sections of the whole brain were stored on a computer using a two-photon microscope and, after three-dimensional reconstruction, the nerve activation patterns of brexpiprazole (OPC-34712) and vehicle groups were quantitatively analyzed using brain map information. 2) Preparation of the medicament and method of administration

[00211] Brexpiprazole was suspended in distilled water containing 5% gum arabic and administered orally to c-fos-GFP mice. 3) Number of mice and dose adjustment

[00212] Five to seven mice were used. The brexpiprazole dose was 0.3 and 1 mg / kg. 4) Statistical analysis

[00213] The significance level of the test was set at 5%. In the comparison between groups in each brain region, Tukey's multiple comparison test was conducted. 5) Results

[00214] The test results are shown in Figure 4. The area with 42 / 42 a significant increase in the GFP signal relative to the vehicle group is shown in white.

[00215] Brexpiprazole significantly increased GFP signaling in the medial prefrontal cortex (ACA: anterior cingulate area, PL: prelimbic area, IL: infralimbic area) at 0.3 and 1 mg / kg.

[00216] Previous results confirmed that brexpiprazole activates nerve cells in the medial prefrontal cortex. INDUSTRIAL APPLICABILITY

[00217] Brexpiprazole or a salt thereof is used as a prophylactic and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental illness.

[00218] This application is based on US provisional patent applications Nos. 61 / 718,305 and 61 / 782,467, the contents of which are incorporated herein by reference in their entirety.

Claims

1. Use of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]1H-quinolin-2-one or a salt thereof, characterized in that it is for producing a prophylactic and / or therapeutic agent for agitation associated with Alzheimer's-type dementia.

2. Use according to claim 1, characterized in that the prophylactic and / or therapeutic agent is for the treatment of a patient for whom a therapeutic drug for dementia fails to provide a therapeutic effect for agitation associated with Alzheimer's type dementia.

3. Use according to claim 2, characterized in that the therapeutic drug for dementia is donepezil, galantamine, rivastigmine or memantine, or a salt thereof.

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