Prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative disease or impulsive symptoms associated with mental disease containing brexpiprazole or salt thereof

Abstract

To provide a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative disease.SOLUTION: The present invention provides a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative disease, 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.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present invention relates to a therapeutic agent for preventing and / or treating peripheral symptoms (behavioral and psychological symptoms) associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, which contain brexpiprazole or a salt thereof.

Background Art

[0002] Brexpiprazole (OPC-34712), that is, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof and a production method thereof are described in Patent Document 1 (Japanese Patent Laid-Open No. 2006-316052 (US 2010 / 0179322 A1)). It has been described that it has a dopamine D2 receptor partial agonist action (D2 receptor partial agonist action), a serotonin 5-HT 2A receptor antagonist action (5-HT 2A receptor antagonist action) and an adrenergic α1 receptor antagonist action (α1 receptor antagonist action), and in addition to these actions, it also has a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action), and has a broad therapeutic spectrum for central nervous system diseases. However, although such patent documents describe that brexpiprazole or a salt thereof is useful for cognitive impairment associated with neurodegenerative diseases such as Alzheimer's disease, there is no description at all about the usefulness regarding peripheral symptoms of neurodegenerative diseases or impulsive symptoms associated with mental diseases.

[0003] Furthermore, it has not been described that brexpiprazole or a salt thereof significantly increased the activation of the medial prefrontal cortex (ACA: Anterior cingulate area, PL: Prelimbic area, IL: Infralimbic area).

[0004] ​Reduced activity in the medial prefrontal cortex has been reported to be associated with peripheral symptoms of neurodegenerative diseases and impulsive symptoms of mental disorders (Bipolar Disord 2009;11:628-36, J Abnorm Psychol 2013;122:558-65, Mov Disord 2011;26:225-33, Pharmacol Biochem Behav 2009;93:237-47).

[0005] Impulsive symptoms are one of the multidimensional personality traits that characterize various human behaviors, and their enhancement is often caused by central nervous system diseases, namely mental disorders and neurodegenerative diseases, etc., and is strongly associated with violence, aggressive speech, suicide, etc. According to the biopsychosocial definition of impulsivity, it is considered a pathological predisposition to rush into hasty and unplanned reactions towards oneself or non-self, even if the reaction leads to negative consequences in response to internal or external stimuli (Am J Psychiatry 2001; 158:1783-93). Also, the Barratt Impulsiveness Scale can evaluate the nature of a person's impulsivity based on three subscales: impulsivity due to attention ability, impulsivity of behavior, and impulsivity due to lack of planning (J Clin Psychol 1995; 51:768-74).

[0006] Mental disorders with impulsive symptoms include schizophrenia, major depressive disorder, bipolar disorder, attention deficit hyperactivity disorder (AD / HD), autism, antisocial personality disorder, borderline personality disorder, substance abuse / dependence, etc. can be cited.

[0007] Most patients with schizophrenia do not engage in violent behavior, but some patients show persistent aggressive behavior, which may interfere with medication treatment or burden caregivers. In a longitudinal epidemiological study conducted in Sweden from 1973 to 2006, 5.3% of the general population was involved in violent crimes whereas, in the case of patients with schizophrenia, 13.2% were reported to be involved in violent crimes (JAMA 2009; 301:2016-23). The causes of violent behavior in patients with schizophrenia are heterogeneous, i) Positive symptoms such as hallucinations and delusions, ii) impulsivity, and iii) are thought to be caused by co-existing psychopathy (Int J Clin Pract 2008; 62:1237-45). (Int J Clin Pract 2008; 62:1237-45).

[0008] Citrome et al. used clozapine, olanzapine, risperidone, and haloperidol to examine the effect of these existing antipsychotics on suppressing aggression in schizophrenia patients through a prospective randomized double-blind trial (Psychiatric Services 2001; 52:1510-14). One of the positive scales of the PANSS (Positive and Negative Symptom Scale), hostility, was used for evaluation. Clozapine was the only one that significantly reduced hostility statistically, while risperidone and haloperidol worsened hostility. Olanzapine showed only a minimal improvement effect. Thus, since clozapine has a certain effect on hostility in schizophrenia patients, it is recommended for administration to schizophrenia patients showing violent behavior. However, clozapine is a very potent antipsychotic, and its effect may have suppressed violent behavior by improving the positive symptoms in i) above, and it has not been proven whether it could suppress violent behavior derived from the impulsivity in ii). Also, clozapine has serious side effects such as agranulocytosis, so the medical institutions and patients who can use it are limited. Moreover, schizophrenia has more than 100 reported cases of genes related to its onset through family analysis and gene polymorphism analysis. Among them, the Disrupted-In-Schizophrenia 1 (Disc1) gene, which is a reciprocal translocation between chromosome 1 and chromosome 11 found in a schizophrenia multiplex family in Scotland, has attracted attention as a vulnerability factor causing schizophrenia. The Disc1 L100P point mutation has also been reported in some schizophrenia patients. has also been reported in some schizophrenia patients.

[0009] In addition, schizophrenia has more than 100 reported cases of genes related to its onset through family analysis and gene polymorphism analysis. Among them, the Disrupted-In-Schizophrenia 1 (Disc1) gene, which is a reciprocal translocation between chromosome 1 and chromosome 11 found in a schizophrenia multiplex family in Scotland, has attracted attention as a vulnerability factor causing schizophrenia. The Disc1 L100P point mutation has also been reported in some schizophrenia patients. Mice with spontaneous mutations exhibit schizophrenia-like behavioral abnormalities, and the antipsychotics clozapine and haloperidol reduce schizophrenia-like behavior. Furthermore, a decrease in brain volume and biochemical analysis have shown its usefulness as a schizophrenia model (Neuron 54(3): 387-402, 2007).

[0010] Major depressive disorder is strongly associated with suicidal tendencies, and impulsive symptoms are considered important predictors (Am J Psychiatry 1999; 156:181-89). Also, patients with major depressive disorder are more impulsive than healthy individuals (Am J Psychiatry 2005; 162:1680-7) and are more likely to attempt or commit suicide (Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:829-33, Epidemiol Psichiatr Soc 2009; 18:172-8). The selective serotonin re-uptake inhibitor (Selective Serotonin Re-uptake Inhibitor : SSRI), which is used as an antidepressant, has been associated with an increased risk of suicide. In 2004, the US Food and Drug Administration (FDA) warned that activation syndrome (AS) may occur during antidepressant use, leading to suicide. Also, Harada et al. conducted a retrospective study on the occurrence of AS in outpatients prescribed antidepressants for three months, and 4.3% of them presented with AS (Depress Anxiety 2008; 25:1014-9). Therefore, in clinical practice, when AS appears after administration of antidepressants, it is difficult to determine whether it is a side effect of the antidepressant or an exacerbation of the current illness, and physicians often struggle to decide whether to continue administering the antidepressant. Therefore, the establishment of an appropriate treatment method for patients with major depressive disorder with high impulsive symptoms is desired. y syndrome (activation syndrome)(AS) may occur, leading to suicide. A warning has been issued. Also, Harada et al. conducted a retrospective study on the occurrence of AS in outpatients prescribed antidepressants for three months, and 4.3% of them presented with AS (Depress Anxiety 2008; 25:1014-9). Therefore, in clinical practice, when AS appears after administration of antidepressants, it is difficult to determine whether it is a side effect of the antidepressant or an exacerbation of the current illness, and physicians often struggle to decide whether to continue administering the antidepressant. Therefore, the establishment of an appropriate treatment method for patients with major depressive disorder with high impulsive symptoms is desired. y syndrome (activation syndrome)(AS) may occur, leading to suicide. A warning has been issued. Also, Harada et al. conducted a retrospective study on the occurrence of AS in outpatients prescribed antidepressants for three months, and 4.3% of them presented with AS (Depress Anxiety 2008; 25:1014-9). Therefore, in clinical practice, when AS appears after administration of antidepressants, it is difficult to determine whether it is a side effect of the antidepressant or an exacerbation of the current illness, and physicians often struggle to decide whether to continue administering the antidepressant. Therefore, the establishment of an appropriate treatment method for patients with major depressive disorder with high impulsive symptoms is desired.

[0011] Regarding violent behavior in bipolar disorder, it has been reported by Barlow et al. (Aust N Z J Psychiatry 2000; 34:967-74). When 1,269 inpatients with mental disorders were examined over a period of 18 months, patients with bipolar disorder in a manic state showed the highest odds ratio of violent behavior. Also, most violent behaviors were considered to be clearly due to impulsivity, and many of them occurred during manic episodes.

[0012] Clinically, mood stabilizers and antipsychotics are prescribed for the treatment of manic episodes. Although the effectiveness of such prescriptions has been reported in meta-analyses (Arch Gen Psychiatry 2007; 64:442-55, Acta Psychiatr Scand 2007; 115:12-20), there are currently no studies examining their effect on violent behavior.

[0013] Alcohol use disorder and drug use disorder are mental disorders that meet several diagnostic criteria such as tolerance to alcohol or drugs, craving, and withdrawal symptoms. Dependent patients are well known to engage in impulsive behaviors. They not only cannot suppress the intake of alcohol or drugs but also take hasty actions to satisfy their current desires, despite the potential for undesirable future consequences. Therefore, patients often commit crimes such as violent behavior. Such impulsive behavior has also been said to be associated with damage to the prefrontal cortex (Pharmacol Biochem Behav 2009;93:237-47). As a treatment for alcohol use disorder, opioid antagonists such as naltrexone and nalmeplene are prescribed to suppress impulsive drinking and assist in controlling alcohol intake, but their treatment effects are not yet sufficient, and the establishment of more effective drugs and treatment methods is desired.

[0014] As neurodegenerative diseases, dementia [Alzheimer's disease (AD), Lewy body dementia , Parkinson's dementia, frontotemporal dementia, vascular dementia, Huntington's disease, multiple sclerosis, etc.

[0015] Peripheral symptoms in neurodegenerative diseases include, for example, peripheral symptoms of dementia.

[0016] Dementia is divided into "core symptoms" mainly characterized by cognitive function disorders such as memory, orientation, and judgment, and "peripheral symptoms" which are mental symptoms and impulsive symptoms that appear along with the "core symptoms". Mental symptoms include depression, anxiety, hallucinations, delusions, sleep disorders, etc., and impulsive symptoms include violence, abusive language, wandering, refusal, and inappropriate behavior. At the International Association for Gerontology held in the United States in 1995, these behavioral disorders were defined as "perceptual, thinking content, mood, or behavioral disorders that often appear in dementia patients", and have since been called BPSD (Behavioral and Psychological Symptoms of Dementia).

[0017] In epidemiological surveys, abnormal behavior, that is, BPSD, is observed in 80% of home-dwelling dementia patients, and it is said that BPSD appears more frequently as dementia progresses from mild to moderate. As it gradually becomes difficult to provide home care, the QOL (Quality of Life) of both patients and caregivers decreases significantly. For relatively mild BPSD, it may be possible to address it through "non-pharmacological therapy" by appropriately improving the living environment and care. However, in cases of moderate or severe BPSD where various problems such as increased stress not only for the patient but also for the caregiver occur, drug treatment is often necessary.

[0018] There is a report (N Engl J Med 2007, 357:1382-1392) examining the 12-week therapeutic effect of donepezil on agitation, one of the peripheral symptoms, in Alzheimer's disease, a representative neurodegenerative disease. A trial was conducted by dividing severely ill Alzheimer's disease patients in a nursing home into a placebo group and a donepezil-administered group, and they were evaluated using the CMAI (Cohen-Mansfield Agitation Inventory, a scale for the state of excitement) and the NPI (Neuropsychiatric Inventory, a scale for neuropsychiatric symptoms). As a result, there was no statistically significant difference between the placebo group and the donepezil-administered group in each score, and furthermore, there was almost no change in the scores themselves (p-value: CMAI 0.98, NPI 0.95). From this result, it can be interpreted that donepezil did not improve agitation or promote it either. Therefore, although donepezil is a drug that can be expected to improve the cognitive function of Alzheimer's disease, it can be said that it has no improvement effect on peripheral symptoms that are likely to be a burden on caregivers, especially agitation.

[0019] Alexander et al. reported a BPSD model focusing on aggression using the Tg2576 mouse, one of the world's widely used AD model mice (Behavioural Brain Research 2011; 216:77-83). Tg2576 is an AD model mouse with Swedish-type and London-type Amyloid Precursor Protein (APP) mutations. This model applying the "resident-intruder" test method involves introducing A / J mice (intruders), a strain without aggression, into the cages of individually housed Tg2576 (residents). When examining the aggression of 7-month-old Tg2576, the time taken to the first attack was significantly reduced compared to control mice, and furthermore, the number of attacks in 10 minutes was significantly increased.

[0020] Vloeberghs et al. also reported on the changes in spontaneous locomotor activity based on the circadian rhythm of APP23 mice (Eur J Neurosci 2004; 10:2757-66). APP23 mice are an AD model mouse with the Swedish-type APP mutation. When 12-month-old APP23 and wild-type mice were compared for 3 days, the nocturnal spontaneous locomotor activity of wild-type mice was high only on the first day and significantly decreased on the second and third days. On the other hand, APP23 mice showed an increase in high spontaneous locomotor activity over 3 nights. Also, the nocturnal spontaneous locomotor activity of APP23 mice on the second and third days was significantly higher than that of wild-type mice on the second and third days.

[0021] As reported above, numerous research reports on AD model mice presenting some BPSD symptoms have been made, and it has become possible to research and develop BPSD therapeutic drugs using the aggressive behavior and increased spontaneous locomotor activity of the model mice as indicators.

[0022] Regarding dementia with Lewy bodies (DLB), it is characterized by visual and auditory hallucinations, and both progressive cognitive impairment and Parkinson's disease-like movement disorders appear as symptoms. It is considered the second most common degenerative cognitive disorder in the elderly after Alzheimer's disease. Also, DLB is the dementia most likely to be accompanied by BPSD from the early stage, and thus the QOL of patients and their caregivers is significantly impaired. Fujita et al. focused on the gene mutations found in familial DLB and succeeded in creating a new transgenic mouse model expressing mutant P123Hβ-synuclein (Nat Commun 2010; 1:110). The mice have been shown to exhibit cognitive symptoms in addition to various pathological findings, and furthermore, since they exhibit BPSD-like abnormal behaviors, it is also possible to research and develop BPSD therapeutic drugs using this model mouse.

[0023] ​​​​As described above, when peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders occur, it places a very heavy burden on caregivers and may also pose a risk to those around them. Therefore, there is a need for drugs that can suppress such symptoms.

Summary of the Invention

[0024] An object of the present invention is to provide a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders, which has excellent safety.

[0025] In order to solve the above problems, the present inventors have conducted intensive research using the aggressiveness and increased spontaneous motor activity of AD model mice with APP gene mutations as indicators, and found that brexpiprazole or a salt thereof is effective for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders. Furthermore, it has been found that brexpiprazole or a salt thereof activates neurons in the medial prefrontal cortex, which is closely related to peripheral symptoms associated with neurodegenerative diseases and impulsive symptoms of mental disorders.

[0026] According to the present invention, there is provided a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders, which contains brexpiprazole or a salt thereof as an active ingredient.

[0027] According to the present invention, there is provided a composition (pharmaceutical composition) for the prophylaxis and / or treatment of peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders, which contains brexpiprazole or a salt thereof as an active ingredient.

[0028] According to the present invention, there is provided the use of brexpiprazole or a salt thereof for the manufacture of a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders. and / or treatment agent.

[0029] According to the present invention, there is provided a method for preventing and / or treating peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, which comprises administering to a patient in need of prevention or treatment of peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, a prophylactically or therapeutically effective amount of brexpiprazole or a salt thereof.

[0030] According to the present invention, there is provided a method for preventing and / or treating peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, which comprises administering to a patient in need of prevention or treatment of peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases and for whom commonly available antipsychotics or neurodegenerative disease therapeutic agents are insufficiently effective, a prophylactically or therapeutically effective amount of brexpiprazole or a salt thereof.

[0031] That is, the present invention provides a prophylactic and / or therapeutic agent for peripheral symptoms associated with the central nervous system diseases shown in the following items 1 to 59. Item 1. A method for preventing and / or treating peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, which comprises administering to a patient in need of prevention or treatment of peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, a prophylactically or therapeutically effective amount of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.

[0032] Item 2. The prophylactic and / or therapeutic method according to item 1, which is a method for preventing and / or treating peripheral symptoms associated with neurodegenerative diseases.

[0033] Item 3. The prophylactic and / or therapeutic method according to item 1, which is a method for preventing and / or treating impulsive symptoms associated with mental diseases.

[0034] Item 4. Neurodegenerative diseases include dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, prion diseases, corticobasal degeneration, acanthocytic chorea, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballismus, degenerative muscular dystonia, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cortical cerebellar atrophy, Holmes' type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubral-pallidoluysian atrophy, Gerstmann-Sträussler-Schaffer syndrome, Item 3. The method for preventing and / or treating according to Item 2, wherein the inflammatory bowel disease is selected from the group consisting of Inca syndrome, Friedreich's ataxia, Lucy-Lewy syndrome, Maye-White syndrome, congenital cerebellar ataxia, periodic hereditary ataxia, ataxia-telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinal-bulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbar malformation, Arnold-Chiari malformation, stiff man syndrome, Klippel-Feil syndrome, Fatiu-Olondo disease, low myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and stroke due to cerebral hemorrhage and / or associated functional dysfunction or neurological deficit symptoms.

[0035] Section 5. Item 5. The method for preventing and / or treating dementia according to Item 4, wherein the neurodegenerative disease is dementia.

[0036] Section 6. Item 6. The method for preventing and / or treating dementia according to Item 5, wherein the dementia is Alzheimer's disease.

[0037] Section 7. Item 6. The method for preventing and / or treating dementia according to Item 5, wherein the dementia is dementia with Lewy bodies.

[0038] Section 8. The preventive and / or therapeutic method according to item 5, wherein the dementia is frontotemporal dementia.

[0039] Item 9. The preventive and / or therapeutic method according to item 5, wherein the dementia is vascular dementia.

[0040] Item 10. The preventive and / or therapeutic method according to item 5, wherein the dementia is Parkinson's disease dementia.

[0041] Item 11. The preventive and / or therapeutic method according to item 5, wherein the dementia is Huntington's disease.

[0042] Item 12. The preventive and / or therapeutic method according to item 4, wherein the neurodegenerative disease is multiple sclerosis.

[0043] Item 13. The preventive and / or therapeutic method according to item 3, wherein the mental disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, chronic schizophrenia, mood disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholia and treatment-resistant depression, mood lability disorder, mood cycling disorder, anxiety disorder, somatic symptom disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, vomiting, motion 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.

[0044] Item 14. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia and chronic schizophrenia.

[0045] Item 15. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is selected from the group consisting of depression, endogenous depression, major depression, melancholia, and treatment-resistant depression.

[0046] Item 16. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is bipolar disorder.

[0047] Item 17. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is an eating disorder.

[0048] Item 18. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is attention deficit hyperactivity disorder.

[0049] Item 19. The preventive and / or therapeutic method according to item 13, wherein the mental disorder is an anxiety disorder.

[0050] Item 20. The preventive and / or therapeutic method according to item 19, wherein the anxiety disorder is obsessive-compulsive disorder.

[0051] Item 21. The preventive and / or therapeutic method according to item 19, wherein the anxiety disorder is post-traumatic stress disorder.

[0052] Item 22. The preventive and / or therapeutic method according to any one of items 1 to 21, wherein the patient is a patient who is insufficiently effective for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders with commonly available antipsychotics or neurodegenerative disease therapeutics.

[0053] Item 23. The prevention and / or treatment method according to item 22, wherein the generally available antipsychotic drug is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propiomazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliprodone, lurasidone, diprasidone, asenapine, clozapine, olanzapine, quetiapine, brofaromine, aripiprazole, cariprazine or sertindole or a salt thereof.

[0054] Item 24. The prevention and / or treatment method according to item 22, wherein the generally available therapeutic agent for neurodegenerative diseases is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon β preparation, glatiramer, teriflunomide or natalizumab or a salt thereof.

[0055] Item 25. A preventive and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases, 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.

[0056] Item 26. The preventive and / or therapeutic agent according to item 25, which is a preventive and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases.

[0057] Item 27. The preventive and / or therapeutic agent according to item 25, which is a preventive and / or therapeutic agent for impulsive symptoms associated with mental diseases.

[0058] Item 28. Neurodegenerative diseases include dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, prion disease, corticobasal degeneration, myoclonus-dystonia, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, dystonic variant, dystonia musculorum deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinal cerebellar degeneration, cortical cerebellar atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph disease, dentatorubral-pallidoluysian atrophy, Gerstmann-Straussler-Scheinker syndrome, Friedreich ataxia, Lucy Levy syndrome, May White syndrome, congenital cerebellar ataxia, periodic hereditary ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, bulbospinal muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbia, Arnold Chiari malformation, stiff man syndrome, Klippel-Feil syndrome, facioscapulohumeral dystrophy, lower spinal cord disease, Dandy-Walker syndrome, split spine, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and a prophylactic and / or therapeutic agent according to item 26 selected from the group consisting of stroke due to cerebral hemorrhage and / or associated dysfunction or nerve dropout symptoms.

[0059] Item 29. A prophylactic and / or therapeutic agent according to item 28, wherein the neurodegenerative disease is dementia.

[0060] Item 30. A prophylactic and / or therapeutic agent according to item 29, wherein the dementia is Alzheimer's type dementia.

[0061] Item 31. A prophylactic and / or therapeutic agent according to item 29, wherein the dementia is Lewy body dementia.

[0062] Item 32. The preventive and / or therapeutic agent according to item 29, wherein the dementia is frontotemporal dementia.

[0063] Item 33. The preventive and / or therapeutic agent according to item 29, wherein the dementia is vascular dementia.

[0064] Item 34. The preventive and / or therapeutic agent according to item 29, wherein the dementia is Parkinson's dementia.

[0065] Item 35. The preventive and / or therapeutic agent according to item 29, wherein the dementia is Huntington's disease.

[0066] Item 36. The preventive and / or therapeutic agent according to item 28, wherein the neurodegenerative disease is multiple sclerosis.

[0067] Item 37. The preventive and / or therapeutic agent according to item 27, wherein the mental disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, chronic schizophrenia, mood disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholia and treatment-resistant depression, mood-variant disorder, mood-cycling disorder, anxiety disorder, somatic symptom disorder, factitious disorder, dissociative disorder, sexual disorder, eating disorder, sleep disorder, adjustment disorder, substance-related disorder, anhedonia, delirium, vomiting, motion 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.

[0068] Item 38. The preventive and / or therapeutic agent according to item 37, wherein the mental disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia and chronic schizophrenia.

[0069] Item 39 The prophylactic and / or therapeutic agent according to item 37, wherein the mental disorder is selected from the group consisting of depression, endogenous depression, major depression, melancholia, and treatment-resistant depression.

[0070] Item 40. The prophylactic and / or therapeutic agent according to item 37, wherein the mental disorder is bipolar disorder.

[0071] Item 41. The prophylactic and / or therapeutic agent according to item 37, wherein the mental disorder is an eating disorder.

[0072] Item 42. The prophylactic and / or therapeutic agent according to item 37, wherein the mental disorder is attention deficit hyperactivity disorder.

[0073] Item 43. The prophylactic and / or therapeutic agent according to item 37, wherein the mental disorder is an anxiety disorder.

[0074] Item 44. The prophylactic and / or therapeutic agent according to item 43, wherein the anxiety disorder is obsessive-compulsive disorder.

[0075] Item 45. The prophylactic and / or therapeutic agent according to item 43, wherein the anxiety disorder is post-traumatic stress disorder.

[0076] Item 46. The prophylactic and / or therapeutic agent according to any one of items 25 to 45 for treating patients in whom generally available antipsychotics or neurodegenerative disease therapeutic agents are insufficiently effective for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders.

[0077] Item 47. The prophylactic and / or therapeutic agent according to item 46, wherein the generally available antipsychotic drug is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propiomazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliprodone, lurasidone, diprasidone, asenapine, clozapine, olanzapine, quetiapine, brofaromine, aripiprazole, cariprazine or sertindole or a salt thereof.

[0078] Item 48. The prophylactic and / or therapeutic agent according to item 46, wherein the generally available therapeutic agent for neurodegenerative diseases is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon beta preparation, glatiramer, teriflunomide or natalizumab or a salt thereof.

[0079] Item 49. Use of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof for producing a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases.

[0080] Item 50. For preventing and / or treating peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof used therefor.

[0081] Item 51. A pharmaceutical composition for preventing and / or treating peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders, 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.

[0082] Item 52. The method for prevention and / or treatment according to item 13, wherein the mental disorder is a substance-related disorder.

[0083] Item 53. The method for prevention and / or treatment according to item 52, wherein the substance-related disorder is an alcohol-related disorder.

[0084] Item 54. The preventive and / or therapeutic agent according to item 37, wherein the mental disorder is a substance-related disorder.

[0085] Item 55. The preventive and / or therapeutic agent according to item 54, wherein the substance-related disorder is an alcohol-related disorder.

[0086] Item 56. The method for prevention and / or treatment according to item 6, wherein the peripheral symptom is an impulsive symptom.

[0087] Item 57. The method for prevention and / or treatment according to item 56, wherein the impulsive symptom is anxiety.

[0088] Item 58. The preventive and / or therapeutic agent according to item 30, wherein the peripheral symptom is an impulsive symptom.

[0089] Item 59. The preventive and / or therapeutic agent according to item 58, wherein the impulsive symptom is anxiety.

Advantages of the Invention

[0090] Brexipiprazole or a salt thereof has an excellent therapeutic effect on peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders. Brexipiprazole or a salt thereof has an excellent therapeutic effect particularly on peripheral symptoms (BPSD) associated with dementia (preferably Alzheimer's disease). In addition, for patients who are insufficiently effective with existing antipsychotics or drugs for treating neurodegenerative diseases, such symptoms can be improved by adding and administering brexipiprazole or a salt thereof. Furthermore, brexipiprazole or a salt thereof activates neurons in the medial prefrontal cortex. Moreover, brexipiprazole or a salt thereof is superior in safety and tolerability compared to existing antipsychotics and can be safely administered even to elderly Alzheimer's disease patients.

Brief Description of the Drawings

[0091]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0092] The active ingredient in the present invention is brexipiprazole or a salt thereof. Brexipiprazole is a known compound represented by the following formula and is in clinical trials for schizophrenia and the like.

[0093]

Chemical

[0094] The salts of brexpiprazole are not particularly limited as long as they are pharmacologically acceptable salts, and examples thereof include 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.), ammonium salts, 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.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); salts of organic bases such as tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower)alkyl-morpholine (e.g., N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.; salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, glutamate, etc. Here, “(lower)alkyl” means “alkyl having 1 to 6 carbon atoms”. In addition, “brexpiprazole or a salt thereof” includes anhydrides, solvates (e.g., hydrates, preferably dihydrates), various crystal forms of these anhydrides and solvates, and mixtures thereof of brexpiprazole or a salt thereof. These brexpiprazole or its salts may be used alone or in combination of two or more. The anhydride of brexpiprazole or its salts can be obtained, for example, by the methods described in Examples 1 and 42 - 47 of Patent Document 1 (Japanese Patent Application Laid - Open No. 2006 - 316052 (US 2010 / 0179322 A1)).

[0095] Brexpiprazole or its salts can be used in bulk or preferably in the form of a pharmaceutical preparation with a normal pharmaceutical carrier (pharmaceutically acceptable carrier) or diluent. The dosage form is not limited to a specific form. Specifically, it can be any normal dosage form, for example, preparations for oral administration such as tablets, capsules, granules, various liquid preparations suitable for oral administration, or preparations for parenteral administration such as injections, suppositories. The dosage is not limited to a specific range, but usually, the amount of the compound containing the active ingredient is preferably about 0.01 - 10 mg per kg of body weight per day. Also, in the preparation of the dosage unit form, the active ingredient is contained in the range of about 0.1 - 400 mg is desirable.

[0096] Injections are usually prepared in the form of solutions, emulsions or suspensions, sterilized, and more preferably made isotonic with respect to blood. Preparations in the form of solutions, emulsions or suspensions are generally prepared using normal pharmaceutical diluents such as water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters. These preparations may be mixed with isotonic agents such as sodium chloride, glucose, glycerin in an amount sufficient to make them isotonic, and further may be mixed with normal solubilizers, buffers, anesthetics, and optionally, coloring agents, preservatives, fragrances, flavorings or sweeteners.

[0097] Formulations such as tablets, capsules, and oral liquid preparations can be prepared by conventional methods. Tablets can be prepared by mixing brexpiprazole or a salt thereof with conventional pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc. Capsules can be prepared by mixing brexpiprazole or a salt thereof with an inert pharmaceutical filler or diluent and filled into hard gelatin capsules or soft capsules. Oral liquid preparations such as syrups or elixirs are prepared by mixing brexpiprazole or a salt thereof with a sweetening agent (e.g., sucrose), a preservative (e.g., methylparaben, propylparaben), a coloring agent, a flavoring agent, etc. Parenteral preparations can also be prepared by conventional methods, for example, by dissolving brexpiprazole or a salt thereof in a sterile aqueous carrier, preferably water or a physiological saline aqueous solution. Preferred liquid preparations suitable for parenteral administration are prepared by dissolving about 0.1 - 400 mg of brexpipraz -ole or a salt thereof in water and an organic solvent, and further in polyethylene glycol having a molecular weight of 300 - 5000, and preferably mixed with lubricants such as sodium carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol. The above liquid preparations preferably further contain a disinfectant (e.g., benzyl alcohol, phenol, thimerosal), a bactericide, and optionally, an isotonic agent (e.g., sucrose, sodium chloride), a local anesthetic, a stabilizer, a buffer, etc. To maintain stability, parenteral preparations can be filled into small containers and subsequently the aqueous solvent can be removed by conventional lyophilization techniques, and obtained by dissolving this in an aqueous solvent to return to a liquid preparation when in use.

[0098] The present invention can prevent and / or treat peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases by administration of brexpiprazole or a salt thereof.

[0099] The mental disorders of the present invention include schizophrenia, treatment-resistant schizophrenia, intractable schizophrenia, chronic schizophrenia, affective disorders, psychotic disorders, mood disorders, bipolar disorder (such as bipolar I disorder and bipolar II disorder, etc.), mania, depression, endogenous depression, major depression, melancholia and treatment-resistant depression, mood-cycling disorder, mood-circular disorder, anxiety disorders (such as panic attacks, panic disorder, agoraphobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, acute stress disorder, etc.), somatic symptom disorders (such as hysteria, somatic symptom disorder, conversion disorder, pain disorder, hypochondriasis, etc.), factitious disorder, dissociative disorders, sexual disorders (such as sexual dysfunction, sexual desire disorder, sexual arousal disorder, erectile disorder, paraphilia, etc.), eating disorders (such as anorexia nervosa, bulimia nervosa, etc.), sleep disorders, adjustment disorders, substance-related disorders (such as alcohol-related disorders (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal, etc.), amphetamine-related disorders (amphetamine use disorder, etc.), cannabis-related disorders (cannabis use disorder, etc.), cocaine-related disorders (cocaine use disorder, etc.), hallucinogen-related disorders (hallucinogen use disorder, etc.), etc.), anhedonia (such as iatrogenic anhedonia, anhedonia caused by psychological or mental reasons, anhedonia associated with depression, anhedonia associated with schizophrenia, etc.), delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, Tourette's disorder, tic disorder, attention deficit hyperactivity disorder, conduct disorder, Down syndrome, personality disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania, etc.).

[0100] Examples of neurodegenerative diseases of the present invention include dementia (e.g., Alzheimer's disease, Lewy body dementia, frontotemporal dementia, vascular dementia, Parkinson's disease dementia, Huntington's disease, senile dementia, mild cognitive impairment, AIDS encephalopathy, corticobasal degeneration, Pick's disease, mixed dementia, etc.), multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, prion disease, corticobasal ganglionic degeneration, myoclonus-dystonia, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ataxia, dystonia musculorum deformans, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa's disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cortical cerebellar atrophy, Holmes type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubropallidoluysian atrophy, Gerstmann-Straussler-Scheinker syndrome, Friedreich's ataxia, Lucy Levy syndrome, May White syndrome, congenital ataxia, periodic hereditary ataxia, ataxia telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, bulbospinal muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbia, Arnold-Chiari malformation, stiff man syndrome, Klippel-Feil syndrome, faciobrachial dystonic epilepsy, lower spinal cord disease, Dandy-Walker syndrome, split spine, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and stroke due to cerebral hemorrhage and / or associated dysfunction or neuronal dropout symptoms, etc.

[0101] The peripheral symptoms of the present invention are impulsive symptoms and psychiatric symptoms.

[0102] Impulsive symptoms refer to symptoms of taking impulsive actions. Specific examples of impulsive actions include physical attacks, wandering, restlessness, agitation, unreasonable actions or deviant behaviors (e.g., sexual Acts of undressing, vagrancy, the sound of cutting, crying out, abusive language, decreased motivation, repetitive questioning, following, suicide attempts or suicide, self-harm, threats, theft, overeating, coercive behavior, short-circuit reactions, panic reactions, damage to utensils, inappropriate dressing and undressing, and unauthorized sales, etc. are included. In a preferred embodiment, the impulsive symptom is anxiety.

[0103] Examples of mental symptoms include hallucinations, delusions, depressive mood, insomnia, anxiety, misidentifications, sleep disorders, etc.

[0104] The method for preventing and / or treating the peripheral symptoms of the present invention means a method for preventing and / or treating a state in which one or more of the above peripheral symptoms appear.

[0105] The method for preventing and / or treating the impulsive symptoms of the present invention means a method for preventing and / or treating a state in which one or more of the above impulsive symptoms appear.

[0106] The brexpiprazole or a salt thereof of the present invention is particularly useful for the prevention and / or treatment of 1) peripheral symptoms associated with neurodegenerative diseases (BPSD) where the neurodegenerative disease is dementia (more particularly, among the peripheral symptoms associated with neurodegenerative diseases (BPSD) where the neurodegenerative disease is dementia, especially the peripheral symptoms associated with Alzheimer's disease, Lewy body dementia, frontotemporal dementia, vascular dementia, Parkinson's dementia, and Huntington's disease), or 2) the prevention and / or treatment of peripheral symptoms associated with a neurodegenerative disease where the neurodegenerative disease is multiple sclerosis.

[0107] Furthermore, the brexpiprazole or a salt thereof of the present invention is particularly useful for 1) impulsive symptoms associated with mental diseases where the mental disease is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, refractory schizophrenia, and chronic schizophrenia, and 2) mental diseases such as depression, endogenous depression, major depression. Impulsive symptoms associated with mental disorders selected from the group consisting of melancholia and treatment-resistant depression, 3) Impulsive symptoms associated with mental disorders where the mental disorder is bipolar disorder, 4) Impulsive symptoms associated with mental disorders where the mental disorder is an eating disorder, 5) Impulsive symptoms associated with mental disorders where the mental disorder is attention deficit hyperactivity disorder, or 6) Impulsive symptoms associated with mental disorders where the mental disorder is an anxiety disorder (furthermore, among the impulsive symptoms associated with mental disorders where the mental disorder is an anxiety disorder, useful for the prevention and / or treatment of impulsive symptoms associated with obsessive-compulsive disorder or post-traumatic stress disorder).

[0108] Even in patients who have used one or more of antipsychotics and drugs for treating neurodegenerative diseases, the above symptoms may not be improved. For such patients, the administration of brexpiprazole or a salt thereof can improve such symptoms.

[0109] Examples of existing (commercially available) antipsychotics include chlorpromazine, fluphenazine, levomepromazine, perphenazine, prochlorperazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliparidone, lurasidone, diprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine, sertindole or a salt thereof, etc.

[0110] Existing (commonly available) neurodegenerative disease treatment drugs include Aricept (registered trademark) (donepezil hydrochloride), Reminyl (registered trademark) (galantamine hydrobromide), Exelon (registered trademark) patch (rivastigmine transdermal absorption formulation), Rivastach (registered trademark) patch (rivastigmine transdermal absorption formulation), Memary (registered trademark) (memantine hydrochloride), fingolimod hydrochloride (Gilenya (registered trademark) capsules, Imusera (registered trademark) capsules), methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon beta preparations, Copaxone (registered trademark) (glatiramer acetate), teriflunomide, Tysabri (registered trademark) (natalizumab), and the like. EXAMPLES

[0111] Example 1 1) Measurement of circadian rhythmic activity in mice Animals: APPSL-Tg mice (male) carrying the Swedish and London APP mutations, control mice, As a role, non-Tg mice (male) that do not have the same gene mutation were generated (Neuroscience Letters 2010; 469:273-277), and were used when they reached 6 months of age after being bred in a breeding room. Measurement method: Circadian rhythmic locomotion was measured using SUPERMEX manufactured by Muromachi Kikai Co., Ltd. Mice were placed in individual cages and their spontaneous locomotion was measured for three days and nights (total of 62.5 hours) under conditions of free access to food and water. This device uses a passive infrared sensor to detect infrared radiation emitted from the mouse and count the number of positional movements. Measurement values ​​were collected every 30 minutes and automatically analyzed using the dedicated software Compact AMS. The mice were dynamically counted. The test was conducted in a soundproof room so as not to affect the spontaneous locomotor activity of the mice. The lighting hours in the soundproof room were set to be on from 7:00 to 19:00, the same as in the breeding room.

[0112] 2) Grouping based on preliminary test The spontaneous locomotor activity of non-Tg mice and APPSL-Tg mice was measured in advance from 19:00 to 7:00 in the dark period. Measurement was performed. Furthermore, grouping was carried out so that the mean values and variances were equal using body weight and the amount of spontaneous movement during the dark period as indices.

[0113] 3) Drug preparation and administration method Bremxpiprazole was dissolved in distilled water containing 5% gum arabic, and 5% gum arabic distilled water was used for the solvent group, and each mouse was orally administered.

[0114] 4) Number of animals and dose setting Group 1: 5 non-Tg mice / solvent Group 2: 5 APPsl-Tg mice / solvent Group 3: 6 APPsl-Tg mice / 0.01 mg / kg bremxpiprazole Group 4: 5 APPsl-Tg mice / 0.03 mg / kg bremxpiprazole

[0115] 5) Administration time For all 3 days, bremxpiprazole and the solvent were administered between 17:30 and 18:30, and immediately after administration, measurement of the amount of movement was started or continued promptly.

[0116] 6) Statistical analysis The test was a two-sided test, and the significance level of the test was set at 5%. The statistical software used was SAS (R9.1, SAS Institute Japan). i) Comparison between non-Tg mice / solvent group and APPsl-Tg mice / solvent group For each of the first to third phases of the dark period, analysis of variance using a mixed model was performed for Night 1 to 3. Furthermore, an unpaired t-test was performed for each of the dark period and Night. ii) Comparison between APPsl-Tg mice / solvent group and APPsl-Tg mice / bremxpiprazole-administered group For each of the first to third phases of the dark period, Dunnett's test based on analysis of variance using a mixed model was performed for Night 1 to 3. Furthermore, Dunnett's test was performed for each of the dark period and Night.

[0117] 7) Results The test results are shown in Table 1 and Table 2.

[0118]

Table 1

[0119]

Table 2

[0120] So far, Vloeberghs et al. have reported that in the APP-Tg mouse model under a 12-hour / 12-hour light-dark cycle, the amount of spontaneous locomotion during the dark period increases with aging (Eur J Neurosci. 2004; 10:2757-66). In the APPSL-Tg mice used in the present invention, the amount of spontaneous locomotion in the second and third phases was significantly increased compared to the Non-Tg group (second phase: P<0.05; third phase : P<0.01). Furthermore, for each dark period and each night, the amount of spontaneous locomotion on the second day during the second phase of the dark period (P<0.05) or on the first to third days during the third phase (P<0.01) was significantly increased (Table 1).

[0121] Bremxpiprazole was administered to APPSL-Tg mice at doses of 0.01 and 0.03 mg / kg immediately before the dark period (17:30-18:30), and the measurement of the amount of spontaneous locomotion was started. Administration was also carried out at the same time on the second and third days, and the measurement of the amount of spontaneous locomotion was continued. As a result, compared with the solvent group, the 0.01 mg / kg group and the 0.03 mg / kg group significantly suppressed the amount of spontaneous locomotion in the third phase of the dark period (0.01 mg / kg group: P<0.05; 0.03 mg / kg group: P=0.050). Furthermore, for each night in the third phase of the dark period, 0.01 mg / kg of bremxpiprazole significantly suppressed the amount of spontaneous locomotion on the third day (P<0.01, Table 2). In addition, 0.03 mg / kg of bremxpiprazole also showed a tendency to suppress on the third day (P=0.068, Table 2). On the other hand, in non-Tg mice 、Bremxiprazole did not reduce the amount of spontaneous movement during the dark period.

[0122] From the above results, it became clear that bremxiprazole can suppress abnormal behavior at a low dose in the nocturnal abnormal behavior of AD model mice with APP gene mutation.

[0123] Example 2 1) Resident-intruder test (examination of impulsive symptoms) Animals: Tg2576 mice (male) with Swedish-type APP mutation (K670N, M671L) and non-Tg mice (male) without the same gene mutation were purchased from Taconic as controls and reared and aged until 5-6 months old. During the rearing, single isolation rearing was performed. Measurement method: In the experiment, Tg2576 or non-Tg mice [Resident] and A / J mice [Intruder] with little aggression were used. The residents were reared in single isolation for 14 days to form sufficient territoriality. Then, the intruder was transferred to the cage of the resident, and the aggressive behavior for 10 minutes was observed. Regarding the biting as the aggressive behavior, the time required until the first bite and the total number of bites in 10 minutes were measured. The measurement was carried out within the first phase (4 hours) of the dark period when the activity level of the mice was the highest.

[0124] 2) Confirmation of aggression by preliminary test For 48 Tg2576 and 10 non-Tg mice, the resident-intruder test was performed in advance to confirm the enhanced aggression of Tg2576 mice. Five Tg2576 mice without observable aggression were excluded, and 43 individuals were used in this test.

[0125] 3) Grouping and dose setting of Tg2576 mice Based on the time required until the first attack and the total number of bites in 10 minutes obtained from the preliminary test, the mice were grouped into 3 groups (total 43 mice) so that the average value and variance were equal. Group 1: 15 Tg2576 mice / solvent Group 2: 14 Tg2576 mice / 0.01 mg / kg brexpiprazole (OPC-34712) Group 3: 14 Tg2576 mice / 0.03 mg / kg brexpiprazole (OPC-34712)

[0126] 4) Drug preparation and administration method Brexpiprazole was dissolved in distilled water containing 5% gum arabic, and 5% gum arabic distilled water was used for the solvent group. It was orally administered to each mouse.

[0127] 5) Administration time Brexpiprazole and the solvent were administered 1 hour before the start of the test.

[0128] 6) Statistical analysis The test was performed at a significance level of 5%. The statistical software used was SAS (R9.1, SAS Institute Japan). For the confirmation of enhanced aggression in Tg2576 mice, it was analyzed by the Wilcoxon rank sum test compared with non-Tg mice. Also, for the aggression inhibitory effect by brexpiprazole administration, it was analyzed by the Shirley Williams multiple comparison test with the following combinations. i) Tg2576 mice / solvent group and Tg2576 mice / 0.01 mg / kg brexpiprazole administration group ii) Tg2576 mice / solvent group and Tg2576 mice / 0.03 mg / kg brexpiprazole administration group

[0129] 7) Results The test results are shown in Figures 1 and 2.

[0130] Previously, Alexander et al. reported an increase in aggression in Tg2576 mice using the resident-intruder test (Behavioural Brain Research 2011; 216:77-83). The Tg2576 mice used in the present invention were also evaluated by the resident-intruder test, and the time required to the first bite was significantly shortened compared to the Non-Tg group (Figure 1a, P<0.05, Wilcoxon rank sum test). Furthermore, when the total number of bites in 10 minutes was analyzed, the number of bites in Tg2576 mice was significantly increased (Figure 1b, P<0.01, Wilcoxon rank sum test). Thus, using the Tg2576 mouse individuals showing obvious enhanced aggressive behavior, the inhibitory effect of brexpiprazole on aggression was continuously examined.

[0131] 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, and the inhibitory effect of brexpiprazole on aggression was examined. Based on the measurement results, when the time required to the first bite was analyzed, the time required to the first bite in the 0.03 mg / kg group was significantly prolonged compared to the solvent group (Figure 2a, solvent group vs 0.03 mg / kg group: P<0.05, Shirley Williams' multiple comparison test). Also * when the number of bites was analyzed by the same test method, the number of bites in Tg2576 mice administered 0.03 mg / kg brexpiprazole tended to decrease compared to the solvent group (Figure 2b, solvent group vs 0.03 mg / kg group: P=0.0709). From the above results, it became clear that brexpiprazole can suppress the aggression in the aggressive behavior of AD model mice with APP gene mutation.

[0132]

[0133] ​​Example 3 Using a novel transgenic mouse model expressing mutant P123H β - synuclein, the circadian motor activity measurement performed in Example 1, the resident - intruder test of Example 2, and further general behavior evaluation tests (elevated plus - maze test, forced swimming test, tail suspension test, light - dark box test, marble - burying test, cliff - avoidance reaction test) were conducted to evaluate the suppression of peripheral symptoms by brexpiprazole.

[0134] Example 4 Focusing on the impulsive symptoms of mice with the Disc1 L100P point mutation, the circadian motor activity measurement performed in Example 1, the resident - intruder test of Example 2, and further general behavior evaluation tests (elevated plus - maze test, forced swimming test, tail suspension test, light - dark box test, marble - burying test, cliff - avoidance reaction test) were conducted to evaluate the suppression of impulsive symptoms by brexpiprazole.

[0135] Example 5 In the treatment of patients with agitation associated with Alzheimer's dementia, a multi - center, randomized, double - blind, placebo - controlled comparative trial was conducted to examine the therapeutic effect, safety, and tolerability of brexpiprazole (OPC - 34712).

[0136] Test method Patients aged 55 to 90 years old diagnosed with Alzheimer's disease according to the Alzheimer's disease diagnostic criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS - ADRDA), and with a Mini Mental State Examination (MMSE) score of 5 - 22, and further Patients with a score of 4 or higher on the agitation / aggression item of the Neuropsychiatric Inventory in Nursing Home Version (NPI-NH) were enrolled. The trial consisted of a 12-week double-blind treatment period. It was composed of. Patients were assigned to one of the following groups. · Placebo · Brexpiprazole 0.5 mg (dose gradually increased from 0.25 mg / day to 0.5 mg / day) · Brexpiprazole 1 mg (dose gradually increased from 0.25 mg / day to 1 mg / day) · Brexpiprazole 2 mg (dose gradually increased from 0.25 mg / day to 2 mg / day)

[0137] Evaluation method The evaluation items were to compare the improvement of agitation associated with Alzheimer's disease-type dementia from the time of patient enrollment to the end of the trial period (12 weeks) between the brexpiprazole group and the placebo group, and to evaluate the efficacy, safety, and tolerability of brexpiprazole.

[0138] For the evaluation of efficacy, the Cohen-Mansfield Agitation Inventory (CMAI), Clinical Global Impression-Severity (CGI-S) score, CMAI subscale scores, NPI-NH scores (total score, subscores of mental symptoms, or individual items), Clinical Global Impression-Improvement (CGI-I) score, and Clinical Global Impression-Efficacy (CGI-E) score were used. By performing the above, the suppression of peripheral symptoms associated with Alzheimer's disease by brexpiprazole, and the safety and tolerability of brexpiprazole can be evaluated.

[0139]

[0140] Example 6 1) Measurement of alcohol intake by the restricted access paradigm Measurement method: Impulsive behavior such as the desire to drink alcohol was evaluated as follows with reference to the method of Sinclair et al. (Alcohol 1992; 9:441-44 and Alcohol & Alcoholism 2001; 36:2-10). First, male Wistar rats were individually housed and allowed to freely consume a 10% aqueous ethanol solution and tap water for several weeks. After the ethanol intake of each individual stabilized, the rats were transferred to a limited access paradigm in which ethanol was available for only 1 hour per day, and the daily ethanol intake amount was measured. The ethanol intake amount was calculated from the results of weighing the water bottles filled with a 10% aqueous ethanol solution immediately before and after the start of the limited access paradigm. Individuals with an average ethanol intake amount of 0.4 g / kg / hr or more in terms of 100% ethanol during the 4-day limited access paradigm immediately before the evaluation of the drug were used. The limited access paradigm test was conducted between 9:00 AM and 12:00 PM.

[0141] 2) Drug preparation and administration method Brempiprazole was suspended in distilled water containing 5% gum arabic. The drug was orally administered to each rat once a day for 4 days, 1 hour before the start of the limited access paradigm.

[0142] 3) Number of animals and dose setting Five rats were used. The dose of brempiprazole was selected as 0.1 mg / kg, which did not affect the spontaneous locomotor activity (data not shown) of Wistar rats in a novel environment.

[0143] 4) Statistical analysis The significance level of the test was set at 5%. The statistical software used was SAS (R9.3, SAS Institute Japan). The average ethanol intake amount during the 4-day limited access paradigm immediately before the evaluation of the drug and the average ethanol intake amount during the 4-day limited access paradigm after drug administration were compared in a paired​ Analysis was performed by a two-sided t-test.

[0144] 5) Results The test results are shown in Fig. 3.

[0145] For rats that were confirmed to ingest ethanol at an average of 0.4 g / kg / hr or more for 4 days in the restricted access paradigm, brexpiprazole was administered at a dose of 0.1 mg / kg 1 hour before for 4 days, and the average ethanol intake in the restricted access paradigm was calculated. As a result, it was confirmed that brexpiprazole significantly suppressed ethanol intake statistically. Even when looking at each individual, the ethanol intake decreased in all individuals.

[0146] From the above results, it was revealed that brexpiprazole can suppress impulsive ethanol intake behavior at a low dose in the restricted access paradigm for 10% aqueous ethanol solution in Wistar rats. Nalmefene, which has been confirmed to suppress impulsive drinking behavior in alcohol-dependent patients clinically and enable control of alcohol intake, has been reported to show an effect in this evaluation system (Alcohol & Alcoholism 2001;36:2-10). Therefore, brexpiprazole also suppresses impulsive drinking behavior in alcohol-dependent patients.

[0147] Example 7 1) Measurement of the neural activation pattern of c-fos-GFP (Cellar oncogene FBJ osteosarcoma green fluorescent protein) mice Measurement method: c-fos is an indirect neural activity marker that is expressed when nerve cells are activated. Using transgenic mice (c-fos-GFP mice) in which the green fluorescent protein (GFP) gene was introduced downstream of the promoter of this c-fos gene, the neural activation pattern in the brain was measured.​​ Determined. Brexpiprazole or the solvent was administered, and the brain was removed 3 hours later. From the serial sections of the whole brain, the GFP signal was captured into the computer using a two-photon microscope. After three-dimensional reconstruction, using the brain map information, the neural activation patterns of the brexpiprazole (OPC-34712) group and the solvent (vehicle) group were quantitatively analyzed.

[0148] 2) Drug Preparation and Administration Method Brexpiprazole was suspended in distilled water containing 5% gum arabic and orally administered to c-fos-GFP mice. 3) Number of Animals and Dosage Setting Five to seven mice were used. The dosage of brexpiprazole used was 0.3 and 1 mg / kg.

[0149] 4) Statistical Analysis The significance level of the test was set at 5%. For the comparison between groups for each brain region, Tukey's multiple comparison test was performed.

[0150] 5) Results The test results are shown in Fig. 4. The areas where the GFP signal is significantly increased compared to the solvent (vehicle) group are shown in white.

[0151] Brexpiprazole significantly increased the GFP signal in the anterior cingulate area (ACA), prelimbic area (PL), and infralimbic area (IL) of the medial prefrontal cortex at 0.3 and 1 mg / kg.

[0152] From the above results, it was confirmed that brexpiprazole activates neurons in the medial prefrontal cortex.

Industrial Applicability

[0153] ​​​​​Brempiprazole or a salt thereof is useful as a prophylactic and / or therapeutic agent for peripheral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental diseases.

[0154] This application is based on U.S. Provisional Patent Application Nos. 61 / 718,305 and 61 / 782,467, the contents of which are hereby incorporated by reference in their entirety.

Claims

1. A method for preventing and / or treating behavioral and psychological symptoms associated with neurodegenerative diseases or impulsive symptoms associated with mental disorders, comprising administering a prophylactically or therapeutically effective amount of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof to a patient in need of such prevention or treatment.

2. The method for prevention and / or treatment according to claim 1, which is a method for prevention and / or treatment of behavioral and psychological symptoms associated with a neurodegenerative disease.

3. The method for prevention and / or treatment according to claim 1, which is a method for prevention and / or treatment of impulsive symptoms associated with a mental disorder.

4. Neurodegenerative diseases include dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, prion diseases, corticobasal degeneration, acanthocytic chorea, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballismus, degenerative muscular dystonia, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cortical cerebellar atrophy, Holmes' type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubral-pallidoluysian atrophy, Gerstmann-Sträussler-Schein syndrome, 3. The method for preventing and / or treating according to claim 2, wherein the cause is selected from the group consisting of cerebellar ataxia, Friedreich's ataxia, Lucy-Lewy syndrome, May-White syndrome, congenital cerebellar ataxia, periodic hereditary ataxia, ataxia-telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinal-bulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbar malformation, Arnold-Chiari malformation, stiff man syndrome, Klippel-Feil syndrome, Fatiu-Olondo disease, low myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and stroke due to cerebral hemorrhage and / or associated functional dysfunction or neurological deficit symptoms.

5. The method for prevention and / or treatment according to claim 4, wherein the neurodegenerative disease is dementia.

6. The method for the prevention and / or treatment of claim 5, wherein the dementia is Alzheimer's disease.

7. The method for prevention and / or treatment according to claim 5, wherein the dementia is Lewy body dementia.

8. The method for preventing and / or treating dementia according to claim 5 , wherein the dementia is frontotemporal dementia.

9. The method for preventing and / or treating dementia according to claim 5, wherein the dementia is vascular dementia.

10. The method for prevention and / or treatment of claim 5, wherein the dementia is Parkinson's dementia.

11. The method for prevention and / or treatment according to claim 5 , wherein the dementia is Huntington's disease.

12. The method for prevention and / or treatment according to claim 4, wherein the neurodegenerative disease is multiple sclerosis.

13. Mental illness: schizophrenia, treatment-resistant schizophrenia, treatment-refractory schizophrenia, chronic schizophrenia 4. The method for prevention and / or treatment of claim 3, wherein the prophylactic and / or therapeutic agent is selected from the group consisting of: affective disorders, psychotic disorders, mood disorders, bipolar disorders, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant depression, dysthymic disorders, cyclothymic disorders, anxiety disorders, somatoform disorders, factitious disorder, dissociative disorders, sexual disorders, eating disorders, sleep disorders, adjustment disorders, substance-related disorders, anhedonia, delirium, vomiting, motion sickness, obesity, migraine, pain, mental retardation, autism, Tourette's syndrome, tic disorders, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania, Down's syndrome and personality disorders.

14. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, treatment-refractory schizophrenia and chronic schizophrenia.

15. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is selected from the group consisting of depression, endogenous depression, major depression, melancholia and treatment-resistant depression.

16. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is bipolar disorder.

17. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is an eating disorder.

18. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is attention deficit hyperactivity disorder.

19. The method for prevention and / or treatment according to claim 13, wherein the psychiatric disorder is an anxiety disorder.

20. The method for prevention and / or treatment according to claim 19, wherein the anxiety disorder is obsessive-compulsive disorder.

21. The method for prevention and / or treatment according to claim 19, wherein the anxiety disorder is post-traumatic stress disorder.

22. The method for prevention and / or treatment according to any one of claims 1 to 21, wherein the patient is a patient for whom a commonly available antipsychotic drug or a therapeutic drug for a neurodegenerative disease is insufficiently effective for treating behavioral symptoms associated with a neurodegenerative disease or impulsive symptoms associated with a psychiatric disease.

23. The method for prevention and / or treatment according to claim 22, wherein the commonly available antipsychotic is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propericiazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliperidone, lurasidone, ziprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine or sertindole, or a salt thereof.

24. The method for prevention and / or treatment according to claim 22, wherein the commonly available therapeutic drug for neurodegenerative diseases is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon beta preparations, glatiramer, teriflunomide or natalizumab or a salt thereof.

25. A preventive and / or therapeutic agent for behavioral and psychological symptoms associated with neurodegenerative diseases or impulsive symptoms associated with psychiatric disorders, 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.

26. The preventive and / or therapeutic agent according to claim 25, which is a preventive and / or therapeutic agent for behavioral and psychological symptoms associated with a neurodegenerative disease.

27. The prophylactic and / or therapeutic agent according to claim 25, which is a prophylactic and / or therapeutic agent for impulsive symptoms associated with a mental disorder.

28. Neurodegenerative diseases include dementia, multiple sclerosis, Parkinson's syndrome, juvenile parkinsonism, striatonigral degeneration, progressive supranuclear palsy, pure akinesia, prion diseases, corticobasal degeneration, acanthocytic chorea, benign hereditary chorea, paroxysmal choreoathetosis, essential tremor, essential myoclonus, Gilles de la Tourette syndrome, Rett syndrome, degenerative ballismus, degenerative muscular dystonia, athetosis, spasmodic torticollis, Meige syndrome, cerebral palsy, Wilson's disease, Segawa disease, Hallervorden-Spatz syndrome, neuroaxonal dystrophy, pallidal atrophy, spinocerebellar degeneration, cortical cerebellar atrophy, Holmes' type cerebellar atrophy, olivopontocerebellar atrophy, hereditary olivopontocerebellar atrophy, Joseph's disease, dentatorubral-pallidoluysian atrophy, Gerstmann-Sträussler-Schein syndrome, 27. The prophylactic and / or therapeutic agent according to claim 26, wherein the agent is selected from the group consisting of cerebral ataxia, cerebral palsy, Friedreich's ataxia, Lucy-Lewy syndrome, May-White syndrome, congenital cerebellar ataxia, periodic hereditary ataxia, ataxia-telangiectasia, amyotrophic lateral sclerosis, progressive bulbar palsy, spinal progressive muscular atrophy, spinal-bulbar muscular atrophy, Werdnig-Hoffmann disease, Kugelberg-Welander disease, hereditary spastic paraplegia, syringomyelia, syringobulbar malformation, Arnold-Chiari malformation, stiff man syndrome, Klippel-Feil syndrome, Fatiu-Ohlondo disease, low myelopathy, Dandy-Walker syndrome, spina bifida, Sjogren-Larsson syndrome, radiation myelopathy, age-related macular degeneration, and stroke due to cerebral hemorrhage and / or associated functional dysfunction or neurological deficit symptoms.

29. The preventive and / or therapeutic agent according to claim 28 , wherein the neurodegenerative disease is dementia.

30. The preventive and / or therapeutic agent according to claim 29, wherein the dementia is Alzheimer's disease.

31. The preventive and / or therapeutic agent according to claim 29, wherein the dementia is Lewy body dementia.

32. The preventive and / or therapeutic agent according to claim 29, wherein the dementia is frontotemporal dementia.

33. The preventive and / or therapeutic agent according to claim 29, wherein the dementia is vascular dementia.

34. The preventive and / or therapeutic agent according to claim 29, wherein the dementia is Parkinson's dementia.

35. The method according to claim 29, wherein the dementia is Huntington's disease.

36. The preventive and / or therapeutic agent according to claim 28, wherein the neurodegenerative disease is multiple sclerosis.

37. 28. The prophylactic and / or therapeutic agent according to claim 27, wherein the psychiatric disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, treatment-refractory schizophrenia, chronic schizophrenia, affective disorder, psychotic disorder, mood disorder, bipolar disorder, mania, depression, endogenous depression, major depression, melancholic and treatment-resistant 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, motion sickness, obesity, migraine, pain, mental retardation, autism, Tourette's syndrome, tic disorder, attention deficit hyperactivity disorder, conduct disorder, intermittent explosive disorder, kleptomania, pyromania, pathological gambling, trichotillomania, Down's syndrome and personality disorder.

38. The prophylactic and / or therapeutic agent according to claim 37, wherein the psychiatric disorder is selected from the group consisting of schizophrenia, treatment-resistant schizophrenia, treatment-refractory schizophrenia and chronic schizophrenia.

39. The method according to claim 37, wherein the psychiatric disorder is selected from the group consisting of depression, endogenous depression, major depression, melancholia and treatment-resistant depression.

40. The method according to claim 37, wherein the psychiatric disorder is bipolar disorder.

41. The method of claim 37, wherein the psychiatric disorder is an eating disorder.

42. The preventive and / or therapeutic agent according to claim 37, wherein the psychiatric disorder is attention deficit hyperactivity disorder.

43. The method according to claim 37, wherein the psychiatric disorder is an anxiety disorder.

44. The preventive and / or therapeutic agent according to claim 43, wherein the anxiety disorder is obsessive-compulsive disorder.

45. The method according to claim 43, wherein the anxiety disorder is post-traumatic stress disorder.

46. The prophylactic and / or therapeutic agent according to any one of claims 25 to 45, for treating patients for whom a commonly available antipsychotic drug or a therapeutic drug for a neurodegenerative disease is insufficiently effective for treating behavioral and psychological symptoms associated with a neurodegenerative disease or an impulsive symptom associated with a psychiatric disease.

47. The prophylactic and / or therapeutic agent according to claim 46, wherein the commonly available antipsychotic is chlorpromazine, fluphenazine, levomepromazine, perphenazine, propericiazine, bromperidol, haloperidol, pipamperone, timiperone, nemonapride, sulpiride, sultopride, carpipramine, clocapramine, mosapramine, pimozide, oxypertine, zotepine, amisulpride, risperidone, iloperidone, perospirone, paliperidone, lurasidone, ziprasidone, asenapine, clozapine, olanzapine, quetiapine, blonanserin, aripiprazole, cariprazine or sertindole, or a salt thereof.

48. The preventive and / or therapeutic agent according to claim 46, wherein the commonly available therapeutic drug for neurodegenerative diseases is donepezil, galantamine, rivastigmine, memantine, fingolimod, methylprednisolone, azathioprine, mitoxantrone, cyclophosphamide, interferon beta preparations, glatiramer, teriflunomide or natalizumab or a salt thereof.

49. Use of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof for producing an agent for the prophylaxis and / or treatment of behavioral and psychological symptoms associated with neurodegenerative diseases or impulsive symptoms associated with psychiatric disorders.

50. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof for use in preventing and / or treating behavioral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with psychiatric disorders.

51. A pharmaceutical composition for preventing and / or treating behavioral and behavioral symptoms associated with neurodegenerative diseases or impulsive symptoms associated with psychiatric disorders, 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.

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