New uses of 5-HT4 receptor agonist

Abstract

To provide new uses of a 5-HT4 receptor agonist, specifically isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole (Compound-1) or a pharmaceutically acceptable salts thereof, for treatment of dementia due to menopause, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment, and behavioral and psychological symptoms of dementia such as apathy / indifference, agitation, aggression, depression, anxiety, irritability / lability, dysphoria, aberrant motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and night time behavior disorders, or appetite and eating disorders, and use of the compounds in the manufacture of medicament intended for the treatment of the disorders described herein.SOLUTION: The 5-HT4 receptor agonist of the present invention can be a potent drug candidate for treatment of menopause-related memory and cognitive loss.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a novel use of 5-HT4 receptor agonists, specifically isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof, for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, such as lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders. The present invention further provides the use of said compounds in the manufacture of a medicament for the treatment of the disorders described herein. [Background technology]

[0002] Cognitive decline occurs in women during menopause. Approximately two-thirds of women report forgetfulness during menopause. Empirical evidence supports that peri- and postmenopausal women perform worse on memory and cognitive tests in the year following their last menstrual period than in the period leading up to menopause. Perimenopausal and postmenopausal women who reach this state naturally or through ovarian removal experience a significant decline in cognitive function due to the chronic hormone deprivation state. Dementia in postmenopausal women affects various components such as verbal, temporal, and visuospatial navigation, with deficits in attention and executive function that affect activities of daily living and therefore negatively impact quality of life. Memory decline is usually most noticeable within 12 months after the last menstrual period. For most women, cognitive decline after menopause cannot occur in a pattern other than that expected for normal aging. Although a woman's cognitive function is unlikely to return to its premenopausal state after menopause, she can adapt and compensate for the symptoms over time.

[0003] Hormone replacement therapy (HRT) was once considered the best treatment strategy for postmenopausal women against the inevitable abnormal physiological changes and disorders. However, recent studies conducted in menopausal women (WHIMS-Women's Health Initiative Memory Study) concluded that hormone replacement therapy has adverse effects, with increased risks of uterine, ovarian, and breast cancer, pulmonary embolism, heart disease, and stroke (JAMA, 2004, 291, 47-53, JAMA, 2002, 288, 321-333). Although some cholinesterase inhibitors are being clinically tested, there are no alternative effective treatments approved so far in this population. Generally, women will have spent one-third of their lives in a state of chronic hormone deficiency, or menopause, assuming that they transition to menopause at age 50.

[0004] 5-HT4 receptors are highly expressed in brain regions such as the hippocampus, amygdala and cerebral cortex, suggesting the involvement of the receptor in cognitive processes (Curr. Opin Pharmacol. 2011, 11, 87-93). 5-HT4 receptors may play an important role in cognitive processes through interactions between cholinergic and / or histaminergic systems in hippocampal or cortical regions. Stimulation of 5-HT4 receptors increases extracellular histamine and acetylcholine levels in these brain regions involved in cognitive functions in rodents (Neuroscience Letters 2016, 616, 197-203). 5-HT4 receptor agonists regulate amyloid precursor protein (APP)-derived peptides, amyloid beta (Aβ) and soluble amyloid precursor protein alpha (sAPPα) (Exp. Gerontol. 2003, 38, 159-66). Soluble amyloid precursor protein alpha is a non-amyloidogenic protein that has been reported to have a potent neuroprotective role against the neurotoxic effects of glutamate and beta-amyloid. 5-HT4 receptor agonists also increase the levels of acetylcholine, a neurotransmitter involved in cognitive processes (Curr. DrugTargets, 2004, 3, 39-51).

[0005] Unexpectedly, the 5-HT4 receptor agonist of the present invention is found to restore memory deficits in menopausal animal models.Therefore, the 5-HT4 receptor agonist of the present invention can be a promising drug candidate for the treatment of memory and cognitive loss associated with menopause.

[0006] Senile dementia is a disease caused by the degeneration of brain cells and is characterized by the decline of cognitive ability. This may include a person's ability to concentrate, recall information, and judge situations appropriately. Aging is the physical and mental decline that accompanies aging. Signs of aging vary in the time they appear. Surprisingly, the 5-HT4 receptor agonist of the present invention improves memory in animal models of aging.

[0007] Apathy / apathy, agitation, aggression, low mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nighttime behavior disorder, or appetite and eating disorder are common behavioral and psychological symptoms in dementia patients. These behavioral and psychological symptoms cause great distress to dementia patients and caregivers. Thus, there remains a medical need for the treatment of behavioral and psychological symptoms of dementia. The 5-HT4 receptor agonist of the present invention unexpectedly reduces aggression levels, and thus may be a potential treatment for behavioral and psychological symptoms of dementia, such as apathy / apathy, agitation, aggression, low mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nighttime behavior disorder, or appetite and eating disorder.

[0008] Cognitive impairment is a central feature of schizophrenia. Deficits range from moderate to severe across several domains, including attention, working memory, verbal learning and memory, and executive function (Neuropsychiatr Dis Treat. 2006, 2(4), 531-536; Clin Psychopharmacol Neurosci, 2018, 16(1), 7-17). There are no approved therapies for the treatment of cognitive deficits associated with schizophrenia. Surprisingly, the 5-HT4 receptor agonists of the present invention improved memory in animal models of cognitive deficits in schizophrenia.

[0009] Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells, and is the second leading cause of death worldwide after cardiovascular disease. As advanced treatment strategies have improved cancer survival rates worldwide, research has focused on "cancer survivorship" to improve the quality of life of cancer survivors worldwide. For many patients suffering from malignant tumors or cancer, chemotherapy offers the best option for disease control. Even before choosing surgery and radiation therapy in cancer treatment, chemotherapy is an invaluable tool to reduce the burden of cancer and is recommended for more fruitful results during the above treatment procedures. Although chemotherapy is an effective method to treat many types of cancer, it also brings negative side effects. The non-specific cell killing by chemotherapy, including neurons, leads to neurobiological "chemobrain" and associated cognitive deficits. Patients treated with chemotherapy are at increased risk of changes in brain structure and function. Clinical studies have revealed that up to 70% of cancer patients undergoing chemotherapy experience cognitive impairment (Clin Cancer Res,2012, 18 (7), 1954-1965). This cognitive impairment, commonly referred to as "chemobrain", can affect working memory, attention, processing speed, concentration and executive function. The deficits seen in "chemobrain" can persist up to 10 years after the last chemotherapy treatment. To date, there are no available or approved therapeutic interventions for the global cancer survivor population. Unexpectedly, the 5-HT4 receptor agonists of the present invention improved memory in an animal model of chemotherapy-associated memory deficits.

[0010] Alzheimer's disease (AD) and depression are common mental health problems in the elderly. AD is generally accompanied by a variety of neuropsychiatric symptoms (NPS). It is known that AD is accompanied by depressive symptoms, especially in the early stages (Psychiatry Investig, 2017, 14 (3), 271-280), but the relationship between the severity of AD and the prevalence of depression has not yet been clarified. Depression in AD is very common, with the prevalence of depression in AD populations being approximately 50%, but the rate may vary depending on the diagnostic method, the degree of depression, and the study population. Furthermore, according to long-term prospective studies, the occurrence of depression during the progression of dementia or mild cognitive impairment appears to be more prevalent than in the general population. The 5-HT4 receptor agonist of the present invention has demonstrated antidepressant activity in animal models of depression. In addition to being effective alone, the 5-HT4 receptor agonist of the present invention, when combined with a selective serotonin reuptake inhibitor (SSRI), produces a synergistic effect on the extracellular levels of serotonin (5-HT) in the ventral hippocampus, suggesting that co-administration of a selective serotonin reuptake inhibitor of the present invention and a 5-HT4 receptor agonist may enhance 5-HT neurotransmission and provide potential for the treatment of depression.

[0011] Currently, there are no drugs approved for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, such as lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nighttime behavior disorders, or appetite and eating disorders. These cognitive, behavioral, and psychological symptoms cause great distress to patients suffering from cognitive impairment and their caregivers. Thus, there remains a medical need for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, such as lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nighttime behavior disorders, or appetite and eating disorders. Unexpectedly, the 5-HT4 receptor agonists of the present invention significantly reverse memory deficits in various animal models, suggesting that they may be potential drug candidates for the treatment of memory and cognitive loss associated with menopause, senile dementia, cognitive deficits associated with schizophrenia, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US9079894 [Patent Document 2] US10005711 [Non-patent literature]

[0013] [Non-Patent Document 1] JAMA, 2004, 291, 47-53 [Non-Patent Document 2] JAMA, 2002, 288, 321-333 [Non-Patent Document 3] Curr. Opin Pharmacol. 2011, 11, 87-93

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[0014] It is an object of the present invention to provide a method for treating a disease or disorder mediated through the 5-HT4 receptor using a 5-HT4 receptor agonist, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof. [Means for solving the problem]

[0015] In a first aspect, the present invention relates to a method for treating menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia comprising the step of administering to a patient in need thereof a therapeutically effective amount of a 5-HT4 receptor agonist, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0016] In another aspect, the present invention relates to a method for treating dementia due to menopause comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0017] In another aspect, the present invention relates to a method for treating senile dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0018] In another aspect, the present invention relates to a method for treating cognitive deficits associated with schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a 5-HT4 receptor agonist, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0019] In another aspect, the present invention relates to a method for treating depression comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0020] In another aspect, the present invention relates to a method of treating depression comprising administering to a patient in need thereof therapeutically effective amounts of a 5-HT4 receptor agonist and a selective serotonin reuptake inhibitor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0021] In another aspect, the present invention relates to a method of treating chemotherapy-induced cognitive impairment comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0022] In another aspect, the present invention relates to a method for treating behavioral and psychological symptoms of dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0023] In another aspect, the present invention relates to the use of a 5-HT4 receptor agonist, specifically isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof, for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychiatric symptoms of dementia such as lethargy / apathy, agitation, aggression, low mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

[0024] In another aspect, the present invention relates to the use of a 5-HT4 receptor agonist, specifically isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof, in combination with a selective serotonin reuptake inhibitor for the treatment of depression.

[0025] In another aspect, the present invention relates to a pharmaceutical composition comprising the 5-HT4 receptor agonist isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient thereof for use in the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment, behavioral and psychological symptoms of dementia. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 shows the effect of Compound-1 on cognition enhancing properties using an object recognition task in ovariectomized rats. [Diagram 2] FIG. 1 shows the effect of Compound-1 on memory deficits associated with DOX-induced cognitive impairment. [Diagram 3] FIG. 1 shows the effect of Compound-1 on memory deficits associated with MK-801-induced cognitive impairment. [Figure 4] FIG. 1 shows the effect of Compound-1 on the dominance-submission model (DSM) of depression. [Diagram 5] FIG. 1 shows the effect of Compound-1 in combination with paroxetine on serotonin regulation in the ventral hippocampus. [Figure 6] FIG. 1 shows the effect of Compound-1 on the aggression level in CD1 mice. [Figure 7] FIG. 1 shows the effect of Compound-1 in the forced swimming test in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Unless otherwise stated, the following terms used in the specification and claims have the meanings set forth below.

[0028] The term "5-HT4 receptor agonist" as used herein refers to a ligand or drug that has affinity for serotonin 5-HT4 receptor and enhances or improves the function of 5-HT4 receptor. An example of a 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or its pharmaceutically acceptable salt.

[0029] An example of a pharma- ceutically acceptable salt of the compound defined above includes, but is not limited to, isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0030] The term "selective serotonin reuptake inhibitor" as used herein refers to a chemical or drug that selectively inhibits the reabsorption or reuptake of serotonin in the brain, making serotonin more available. Examples of selective serotonin reuptake inhibitors are paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone or pharmaceutical salts thereof. More preferably, the selective serotonin reuptake inhibitor is paroxetine or pharmaceutical salts thereof.

[0031] As used herein, the term "menopausal dementia" refers to cognitive decline, memory loss, forgetfulness or memory impairment in the peri- or post-menopausal or oophorectomized female population.

[0032] As used herein, the term "senile dementia" refers to dementia resulting from natural aging that occurs in the elderly population.

[0033] As used herein, the term "cognitive deficits associated with schizophrenia" refers to cognitive deficits (one of the core symptoms) of schizophrenia that develop over the course of the disease and are moderate to severe across several domains, including attention, working memory, verbal learning and memory, and executive function.

[0034] As used herein, the term "depression" refers to a mental health disorder characterized by a persistently depressed mood or loss of interest in activities and causing significant impairment in daily life.

[0035] The term "chemotherapy-induced cognitive impairment" as used herein refers to chemobrain, which means cognitive changes that occur as a side effect of chemotherapy. These changes can be temporary changes in memory and thought processes. Chemotherapy-induced cognitive impairment is usually accompanied by one or more of the following symptoms: difficulty concentrating, thinking and multitasking, poor memory, reduced attention span, and / or feelings of disorganization. Chemotherapy-induced cognitive impairment can result from a wide variety of chemotherapy treatments.

[0036] The term "behavioral and psychological symptoms of dementia" refers to lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders, or appetite and eating disorders resulting from dementia. The term also refers to physical or verbal behaviors of dementia patients that have the effect of harming or repelling others, including aggressive behaviors such as hitting, kicking, biting, screaming, etc. Behavioral and psychological symptoms of dementia include the cognitive deficits of Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia (LBD), vascular dementia, and frontotemporal dementia (FTD). Preferably, the behavioural and psychological symptoms of dementia are selected from lethargy / apathy in AD, aggression in AD, agitation in AD, depressed mood in AD, anxiety in AD, irritability / lability in AD, restlessness in AD, abnormal motor behaviour in AD, delusions in AD, hallucinations in AD, elation / euphoria in AD, psychosis in AD, disinhibition in AD, sleep and nighttime behaviour disorders or appetite and eating disorders in AD, lethargy / apathy in PD, aggression in PD, agitation in PD, depressed mood in PD, anxiety in PD, irritability / lability in PD, restlessness in PD, abnormal motor behaviour in PD, delusions in PD, hallucinations in PD, elation / euphoria in PD, psychosis in PD, disinhibition in PD, sleep and nighttime behaviour disorders in PD or appetite and eating disorders in PD.

[0037] The phrase "therapeutically effective amount" is defined as an amount of a compound of the present invention that (i) treats a particular disease, condition or disorder, (ii) relieves one or more symptoms of a particular disease, condition or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition or disorder described herein.

[0038] The term "pharmaceutical acceptable salt" as used herein refers to a salt of an active compound, which is prepared by reaction with a suitable organic or inorganic acid or acid derivative, depending on the specific substituents found in the compound described herein. Pharmaceutically acceptable salts include, but are not limited to, mesylate, hydrochloride, oxalate, fumarate, succinate, benzenesulfonate, tartrate, and the like. Preferably, the pharmaceutical acceptable salt is an oxalate or fumarate. More preferably, the pharmaceutical acceptable salt is an oxalate.

[0039] As used herein, the term "patient" refers to an animal. The term "patient" preferably refers to a mammal. The term mammal includes animals such as mice, rats, dogs, rabbits, pigs, monkeys, horses, pigeons, Xenopus laevis, zebrafish, guinea pigs, and humans. More preferably, the patient is a human.

[0040] Compound-1, as used herein, is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and has the following chemical structure:

[0041] [ka]

[0042] Compound-1 and its preparation are described in US9079894 and US10005711, respectively.

[0043] The terms "therapy" or "treatment" as used herein refer to any treatment of a disease in a mammal, including (a) slowing or preventing the onset of clinical symptoms, and / or (b) causing regression of clinical symptoms.

[0044] The term "compound of use" as used herein includes any one or more of the following: (1) use of a compound, (2) a method of using a compound, (3) use in therapy, (4) use for the manufacture of a pharmaceutical composition / medicine for treatment / treatment, or (5) a method of treatment / treating / preventing / reducing / inhibiting comprising administering an effective amount of an active compound to a patient in need thereof.

[0045] Embodiment Although the present invention encompasses all examples described herein without being limited thereto, preferred aspects and elements of the present invention are described herein in the form of the following embodiments.

[0046] In one embodiment, the present invention relates to a method for treating a disease or disorder mediated through the 5-HT4 receptor using a 5-HT4 receptor agonist, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0047] In another embodiment, the present invention relates to a method for treating menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment, behavioral and psychological symptoms of dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0048] In another embodiment, the present invention relates to a method for treating dementia due to menopause, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0049] In another embodiment, the present invention relates to a method for treating senile dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0050] In another embodiment, the present invention relates to a method for treating cognitive deficits associated with schizophrenia, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0051] In another embodiment, the present invention relates to a method for treating depression, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0052] In another embodiment, the present invention relates to a method of treating depression, comprising administering to a patient in need thereof therapeutically effective amounts of a 5-HT4 receptor agonist and a selective serotonin reuptake inhibitor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0053] In another embodiment, the present invention relates to a method of treating depression comprising the step of administering to a patient in need thereof a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine, and vilazodone or a pharma- ceutically acceptable salt thereof.

[0054] In another embodiment, the present invention relates to a method of treating chemotherapy-induced cognitive impairment, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0055] In another embodiment, the present invention relates to a method for treating behavioral and psychological symptoms of dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0056] In another embodiment, the present invention relates to a method for treating behavioral and psychological symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders, or appetite and eating disorders comprising the step of administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0057] In another embodiment, the present invention relates to a method of treating apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia comprising the step of administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0058] In another embodiment, the present invention provides a method for treating apathy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and feeding disorders in Alzheimer's disease, apathy / apathy in Parkinson's disease, Parkinson's disease, ataxia / apathy in ...taxia / apathy in Parkinson's disease, ataxia / apathy in Parkinson's disease, ataxia / The present invention relates to a method for treating aggression in Parkinson's disease, agitation in Parkinson's disease, depressed mood in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behavior in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behavior disorders in Parkinson's disease, or appetite and eating disorders in Parkinson's disease, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0059] In another embodiment, the present invention relates to a method for treating menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment, behavioral and psychological symptoms of dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0060] In another embodiment, the present invention relates to a method for treating dementia due to menopause comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0061] In another embodiment, the present invention relates to a method for treating senile dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0062] In another embodiment, the present invention relates to a method for treating cognitive deficits associated with schizophrenia, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0063] In another embodiment, the present invention relates to a method for treating depression, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0064] In another embodiment, the present invention relates to a method of treating depression comprising administering to a patient in need thereof therapeutically effective amounts of a 5-HT4 receptor agonist and a selective serotonin reuptake inhibitor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0065] In another embodiment, the present invention relates to a method for treating depression comprising administering to a patient in need thereof a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone or a pharmaceutical salt thereof.

[0066] In another embodiment, the present invention relates to a method of treating chemotherapy-induced cognitive impairment, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0067] In another embodiment, the present invention relates to a method for treating behavioral and psychotic symptoms of dementia comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0068] In another embodiment, the present invention relates to a method for treating behavioral and psychotic symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders, or appetite and eating disorders comprising the step of administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0069] In another embodiment, the present invention relates to a method of treating apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia comprising the step of administering a therapeutically effective amount of a 5-HT4 receptor agonist to a patient in need thereof, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0070] In another embodiment, the present invention provides a method for treating lethargy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and eating disorders in Alzheimer's disease, lethargy / apathy in Parkinson's disease, ataxia in Alzheimer's disease, ataxia in Parkinson ... The present invention relates to a method of treating aggression in Parkinson's disease, agitation in Parkinson's disease, depressed mood in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behavior in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behavior disorders in Parkinson's disease, or appetite and eating disorders in Parkinson's disease, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0071] In yet another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in the treatment of a disease or disorder mediated through the 5-HT4 receptor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0072] In yet another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0073] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia.

[0074] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of dementia due to menopause.

[0075] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of senile dementia.

[0076] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of cognitive deficits associated with schizophrenia.

[0077] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof, in the treatment of depression.

[0078] In another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in combination with a selective serotonin reuptake inhibitor for the treatment of depression, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0079] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in combination with a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone, for the treatment of depression.

[0080] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of chemotherapy-induced cognitive impairment.

[0081] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of behavioral and psychological symptoms of dementia.

[0082] In another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of behavioral and psychological symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

[0083] In another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia.

[0084] In another embodiment, the present invention provides a treatment for apathy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and feeding disorders in Alzheimer's disease, apathy / apathy in Parkinson's disease, aggression in Parkinson's disease The present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the treatment of agitation in Parkinson's disease, depression in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behavior in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behavior disorders in Parkinson's disease or appetite and eating disorders in Parkinson's disease.

[0085] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia.

[0086] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of menopausal dementia.

[0087] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of senile dementia.

[0088] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of cognitive deficits associated with schizophrenia.

[0089] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of depression.

[0090] In another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in combination with a selective serotonin reuptake inhibitor for the treatment of depression, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0091] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone, for the treatment of depression.

[0092] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of chemotherapy-induced cognitive impairment.

[0093] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate for treating behavioral and psychological symptoms of dementia.

[0094] In another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of behavioral and psychological symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

[0095] In another embodiment the invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia.

[0096] In another embodiment, the present invention provides a treatment for lethargy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and feeding disorders in Alzheimer's disease, lethargy / apathy in Parkinson ... the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the treatment of aggression in Parkinson's disease, agitation in Parkinson's disease, depression in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behaviour in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behaviour disorders in Parkinson's disease or appetite and eating disorders in Parkinson's disease.

[0097] In yet another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in the manufacture of a medicament for the treatment of a disease or disorder mediated through the 5-HT4 receptor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0098] In yet another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in the manufacture of a medicament for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, wherein the 5-HT4 agonist is the compound isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

[0099] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia.

[0100] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dementia due to menopause.

[0101] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of senile dementia.

[0102] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cognitive deficits associated with schizophrenia.

[0103] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of depression.

[0104] In another embodiment, the present invention relates to the use of a combination comprising therapeutically effective amounts of a 5-HT4 receptor agonist and a selective serotonin reuptake inhibitor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of depression.

[0105] In another embodiment, the present invention relates to the use of a combination comprising a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone, in the manufacture of a medicament for the treatment of depression.

[0106] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chemotherapy-induced cognitive impairment.

[0107] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of behavioral and psychological symptoms of dementia.

[0108] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of behavioral and psychotic symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

[0109] In another embodiment, the invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for the treatment of apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia.

[0110] In another embodiment, the present invention provides a treatment for apathy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and feeding disorders in Alzheimer's disease, apathy / apathy in Parkinson's disease, aggression in Parkinson's disease, The present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof for the treatment of agitation in Parkinson's disease, depression in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behavior in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behavior disorders in Parkinson's disease, or appetite and eating disorders in Parkinson's disease.

[0111] In yet another embodiment, the present invention relates to the use of a 5-HT4 receptor agonist in the manufacture of a medicament for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia, wherein the 5-HT4 agonist is the compound isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

[0112] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of dementia due to menopause.

[0113] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of senile dementia.

[0114] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of cognitive deficits associated with schizophrenia.

[0115] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of depression.

[0116] In another embodiment, the present invention relates to the use of a combination comprising therapeutically effective amounts of a 5-HT4 receptor agonist and a selective serotonin reuptake inhibitor, wherein the 5-HT4 receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate, in the manufacture of a medicament for the treatment of depression.

[0117] In another embodiment, the present invention relates to the use of a combination comprising a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone, in the manufacture of a medicament for the treatment of depression.

[0118] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of chemotherapy-induced cognitive impairment.

[0119] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of behavioral and psychological symptoms of dementia.

[0120] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of behavioral and psychotic symptoms of dementia selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

[0121] In yet another embodiment, the present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of apathy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behaviour in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nocturnal behaviour disorders in dementia or appetite and eating disorders in dementia.

[0122] In another embodiment, the present invention provides a treatment for apathy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease or appetite and feeding disorders in Alzheimer's disease, apathy / apathy in Parkinson's disease, aggression in Parkinson's disease, The present invention relates to the use of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate in the manufacture of a medicament for the treatment of agitation in Parkinson's disease, depression in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behaviour in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behaviour disorders in Parkinson's disease or appetite and eating disorders in Parkinson's disease.

[0123] In another embodiment, the present invention relates to a pharmaceutical composition for use in the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia comprising the 5-HT4 agonist isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutical acceptable salt thereof and a pharma- ceutical acceptable excipient thereof.

[0124] The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharma- ceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, glidants, polymers, coating agents, solvents, cosolvents, preservatives, wetting agents, thickeners, antifoaming agents, sweeteners, flavoring agents, antioxidants, colorants, solubilizers, plasticizers, dispersing agents, and the like.

[0125] In yet another embodiment, the active compounds of the present invention may be formulated in the form of pills, tablets, coated tablets, capsules, powders, granules, pellets, patches, implants, films, liquids, semisolids, gels, aerosols, emulsions, elixirs, and the like. Such pharmaceutical compositions and methods for preparing the same are disclosed herein. It is well known in the art.

[0126] In yet another embodiment, the pharmaceutical composition of the present invention comprises 1-90% by weight, 5-75% by weight, and 10-60% by weight of the compound of the present invention or a pharma- ceutically acceptable salt thereof. The amount of the active compound or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition can be from about 1 mg to about 2000 mg, or from about 5 mg to about 1800 mg, or from about 5 mg to about 1000 mg, or from about 7 mg to about 350 mg, or any range within the broader range of 1 mg to 2000 mg. EXAMPLES

[0127] The following examples are provided by way of illustration only, and therefore should not be construed as limiting the scope of the present invention. Abbreviation 5-HT4: 5-hydroxytryptamine 4 receptor ANOVA: Analysis of variance BCCL: Bilateral common carotid artery ligation cAMP: cyclic adenosine monophosphate CD1: Surface antigen classification 1 EC 50 : Median effective concentration EDTA: Ethylenediaminetetraacetic acid GPCR: G protein-coupled receptor HCl: Hydrochloric acid h: time ip: intraperitoneal iv: intravenous im: intramuscular K i : Inhibition constant mg: milligram MgCl2: Magnesium chloride min:minutes mM: millimolar nmol / L: nanomoles per liter nM: nanomolar po: oral sc: subcutaneous SEM: mean standard error μM: micromolar

[0128] Example 1 EC at 5-HT4 receptor 50 Determining Values A stable CHO cell line expressing recombinant human 5-HT4 receptor and pCRE-Luc reporter system was used for the cell assay. This assay is a non-radioactive approach to identify binding of compounds to GPCRs. The specific assay measures the level of intracellular cAMP, which is modulated by activation or inhibition of this receptor. The recombinant cells carry a luciferase reporter gene under the control of a cAMP response element. The cells were grown in Ham's F12 medium with 10% fetal bovine serum (FBS) in 96-well clear-bottom white plates. Cells were serum-starved overnight before adding compounds or standard agonists. Standard internal agonist serotonin and test compounds were incubated with cells separately in individual wells at 37°C, 5% CO2 for 4 hours in Opti-MEM medium at 11 test concentrations starting from 10 μM in 3-fold serial dilutions down to 0.1 nM. The medium was removed and cells were washed with phosphate-buffered saline. Luciferase activity was measured in individual wells using luciferin substrate in a Victor Light luminometer (PerkinElmer). The maximal response with each drug was normalized to the maximal response induced by 5-HT. Data were analyzed using Graphpad Prism software and EC values ​​were calculated, which correspond to the concentration of agonist required to obtain half-maximal stimulation of adenylyl cyclase. 50 derived the value. Reference: British Journal of Pharmacology. 2000, 129, 771-781.

[0129] result Compound-1 exhibits agonist activity at the human recombinant 5-HT4 receptor in cell-based reporter gene assays and end-point luminescence assays. The EC 50 The value was 58.7 ± 9.9 nM (E max :28.6±0.5%).

[0130] Example 2 Determination of Ki value at 5-HT4 receptor Compounds were tested at Caliper Life Sciences Laboratories according to the following procedure.

[0131] Materials and Methods Receptor: Recombinant human 5-HT4 receptor membrane protein Radioligand: [3H]-GR113808 (83.9Ci / mmol) Final ligand concentration: -[0.2nM] Non-specific ligand: 10 μM serotonin (5-HT) Reference compound: serotonin Positive control: serotonin

[0132] Incubation conditions: The reaction was carried out in 50 mM Tris-HCl (pH 7.4) at 25°C for 30 min. The reaction was stopped by rapid vacuum filtration onto glass fiber filters. To confirm any interaction of the test compounds with the serotonin 5-HT4 binding site, the radioactivity trapped on the filters was measured and compared to the control value. Reference: British Journal of Pharmacology. 1993, 109, 618-24.

[0133] result Compound-1 selectively binds to the 5-HT4 receptor when tested in an in vitro radioligand binding assay on human recombinant 5-HT4 receptors, with an in vitro Ki value of 23.9 nM.

[0134] Example 3 Object Recognition Task (in vivo model of menopausal dementia) Bilateral ovariectomy surgery was performed in 7-8 week old female rats. Briefly, animals were anesthetized with Avertin (2,2,2-tribromoethanol) 150 mg / kg (ip) and laid on the operating table. A midline incision was made in the dorsal region under the rib cage and 1 cm lateral on either side of the midline, and a small incision was made in the fascia to locate the fat supporting the ovaries. The adipose tissue was gently pulled out, the ovaries were identified and excised, and the uterine horns were ligated with silk sutures. The fascia was also covered with sutures, and the same procedure was repeated on the other side. The epidermal layer was sutured, and gentamicin (15 mg / kg, sc) was administered as an antibiotic and meloxicam (1 mg / kg, im) as an analgesic, and finally povidone-iodine was applied to the epidermal layer. Episodic memory, which is the memory of autobiographical events in a situation related to time, place, etc., was assessed approximately 12 months after surgery using an object recognition task.

[0135] On the first day of the experiment, rats were transferred to the experimental room for acclimation. On the second day of the experiment, all animal groups were acclimated to their respective test arenas for 30 minutes before test-1. Compound-1 of the present invention was administered 60 minutes before test-1. In test-1, ovariectomized aged female rats were introduced to unfamiliar young rats in their respective test arenas, i.e., in their home cages, for 5 minutes. The time spent by the adult rats to socially investigate the young rats was recorded. After a 60-minute interval between tests, the adult rats were subjected to test-2. In test-2, ovariectomized aged female rats were introduced to young newcomer rats and familiar young rats (presented in test-1) in their respective test arenas for 5 minutes. In test-2, the time spent by the adult rats to socially investigate the familiar young rats or the young newcomer rats was recorded. Discrimination index (b-a3 / b+a3) was calculated and compared between groups.

[0136] result Compound-1 reversed object recognition memory deficits in ovariectomized female Wistar rats (Figure 1).

[0137] Example 4 Object Recognition Task (an in vivo model of chemotherapy-induced cognitive impairment) The cognition-enhancing properties of Compound-1 in chemotherapy-associated deficits were estimated using an animal model of cognition, namely the object recognition task.

[0138] Male Wistar rats (230-280 g) were used as experimental animals. Four animals were housed in each cage. The rats were acclimated to the laboratory conditions for 7 days (days 1-7). Chemotherapy-induced cognitive impairment was induced by injecting doxorubicin (DOX) at 2.5 mg / kg, ip, once every 5 days for up to 8 cycles (days 8-49). After 4 cycles, the rats were also treated with Compound-1 together with DOX (ip). The object recognition task was performed in a 50 x 50 cm circular open field made of acrylic. On the 50th day of the experiment, 60 min after treatment, the animals were acclimated to the arena for 45 min. On the 51st day, the animals were treated with the respective formulations 60 min before the acclimation test (T1), in which the rats were presented with two identical objects, namely silver Milton flasks (a1 and a2), for 3 min. After a 30 min interval, rats were subjected to a 3 min choice test (T2) with one familiar (silver, a3) and one novel (red, b) object. During T1 and T2 trials, the examination time for each object (defined as sniffing, licking, biting, or whisker movement while pointing the nose towards the object at a distance of <1 cm) was recorded separately with a hand-held stopwatch. Reference: Behavioural Brain Research, 1988, 31, 47-59

[0139] result Compound-1 shows significantly higher discrimination index indicating a positive effect on cognition (Figure 2).

[0140] Example 5 Effect of Compound-1 on memory deficits associated with MK-801-induced cognitive impairment Male Wistar rats (8-10 weeks old) were used as experimental animals. Four animals were housed in each cage. The animals were kept in a 20% fasting state from 1 day before the experiment. Water was available ad libitum throughout the experiment. The animals were maintained in a temperature- and humidity-controlled room with a 12-h light / dark cycle. The experiments were performed in a 50 × 50 cm circular arena made of acrylic. On the first day, rats were allowed to acclimate to each arena for a maximum of 45 min in the absence of any objects.

[0141] On the second day, animals were administered vehicle or Compound-1 60 min before the habituation phase, and vehicle or MK-801 20 min before the habituation phase. During the habituation phase (T1), rats were separately placed in an arena with two identical objects (a1 and a2) located 10 cm from the wall for 3 min. 90 min after T1, a choice phase was performed. Rats were placed in the same arena in which they were placed in the T1 test. During the choice phase (T2), rats were allowed to explore the arena containing one replica of the familiar object (a3) ​​and one novel object (b) for 3 min. During the T1 and T2 tests, a stopwatch was used to record the exploration time of each object (defined as sniffing, licking, biting, or wiggling while pointing the nose towards the object at a distance of less than 1 cm). Discrimination index was calculated as the ratio of the time spent examining the novel object minus the time spent examining the familiar object divided by the sum of the time spent examining the novel and familiar objects in the choice trial (Figure 3). Reference: Object recognition tests were performed as described in Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats - Behavioural data, Behav. Brain Res., 31, 47-59.

[0142] result Compound-1 reversed the MK-801-induced memory deficits in the NORT at doses of 0.3 and 1 mg / kg, po (FIG. 3).

[0143] Example 6 Effects of Compound-1 on the Dominance / Submission Model (DSM) of Depression The test apparatus was constructed of transparent plastic and consisted of two identical chambers (24 × 17 × 14 cm) connected by a tunnel (6 × 6 × 52 cm). A total of 220 male Wistar rats (110 pairs) weighing approximately 150–200 g were selected. The animals were randomized based on body weight and weight-matched for each pair. The pairs were acclimated to the test apparatus and milk for 5 min per day for 5 days (first week). The animals were housed so that the pairs met only during the test period. Each pair had equal access to milk containing 9% sucrose in a beaker (10 mL) placed in an opening in the floor at the midpoint of the tunnel. In the second week, the time that the paired rats spent drinking milk was recorded and scored for 5 min. After the end of this 5 min period, the rats in the pair were returned to their home cages. For this study, rat pairs that met the following criteria were selected: 1) There was a significant difference between the mean drinking scores of the pairs (two-tailed t-test, p<0.05). 2) Dominant animals score 25% higher than submissive animals. Pairs that met the above criteria were selected and randomized based on the level of dominance. Both dominant and submissive animals in the control group were treated with vehicle (sterile water, 4 mL / kg, po). For the Compound-1 treatment group, the submissive animals were treated with Compound-1 (3 mg / kg, po) and their dominant partners were treated with vehicle (sterile water, 4 mL / kg, po). During the test period (3 weeks), the time spent drinking milk was recorded for 5 min for each animal in the pair. Once testing of all animals in a group was completed, free access to food was allowed for 1 h. On test days, treatments were administered 1 h before testing, and on non-test days, treatments were administered between 10:00 am and 4:00 pm. Animals were allowed free access to food from Friday afternoon to Sunday evening (weekend, non-test days). Levels of dominance (mean difference in daily drinking scores between dominant and submissive partners during the test period) were analyzed using a repeated measures one-way analysis of variance (ANOVA) followed by Tukey's test for levels of dominance in the second week (Fig. 4).

[0144] result The level of dominance in the Compound-1, 3 mg / kg (po) treated group decreased over time during the treatment period, reaching significance at week 5 (p < 0.05). However, the dominance / submissive relationship formed at week 2 did not change over the entire time course of the study in the vehicle 10 mL / kg (po) treated group. Compound-1 demonstrated antidepressant activity (Figure 4).

[0145] Example 7 In vivo brain microdialysis: Effects of combination of Compound-1 and paroxetine on serotonin regulation in the ventral hippocampus Under isoflurane anesthesia, male Wistar rats (body weight 240–300 g) were stereotaxically implanted with microdialysis guide cannulas into the ventral hippocampus (AP: -5.2 mm, ML: + 5.0 mm, DV: -3.8 mm). Coordinates were taken according to the rat brain atlas (Paxinos and Watson, 2004), with reference points taken from the bregma and perpendicular to the skull. Rats were allowed to recover individually for 4–5 days in round-bottom Plexiglas bowls with free access to food and water.

[0146] One day prior to the microdialysis experiments, rats were tethered to a quartz-lined, two-channel liquid swivel (Instech, UK) on a counterbalanced lever arm that allowed unrestricted movement of the animals. Approximately 16 hours before the start of the study, a pre-equilibrated microdialysis probe (4 mm dialysis membrane) was inserted into the ventral hippocampus through the guide cannula. On the study day, the probe was perfused with artificial cerebrospinal fluid (CSF; 147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2, and 1.2 mM MgCl2, pH 6.2) at a flow rate of 1.5 μL / min. After a 1-hour stabilization period, four basal samples were collected at 30-minute intervals before paroxetine (5 mg / kg, ip) was administered. Thirty minutes after paroxetine administration, compound-1 (3 mg / kg, po) was administered and samples were collected for a further 3.5 hours. Dialysates were flash frozen and stored at −70°C until analysis. After the dialysis period, animals were subjected to verification of probe placement, and correct probe placement was taken as the criterion for selection of data from animals.

[0147] Quantitation of Serotonin Using LC-MS / MS The concentration of serotonin in the dialysates was measured using LC-MS / MS following the analysis described by Nirogi et al.

[2013] with minor modifications. Samples were subjected to derivatization with dansyl chloride and the following precursor-product ion pairs were monitored at m / z 853.1-170.1, m / z 869.2-170.1, and m / z 643.3-170.1 for dansylated dopamine, norepinephrine, and serotonin, respectively. Analytes were quantified using a triple quadrupole tandem mass spectrometer in positive ionization mode using an atmospheric pressure ionization source. Analytes were separated by interferences on an Agilent Poroshell 120EC-C18 external porous particulate column using gradient elution.

[0148] statistical analysis Absolute values ​​of serotonin (nmol / L) were converted to percent change from mean basal values ​​(%) ± SEM, with the average of the four pre-dose values ​​taken as 100%. Statistical significance between mean AUC values ​​of percent increase or decrease in neurotransmitter levels in vehicle-treated groups was calculated using one-way ANOVA followed by Dunnett's test. Percent increase or decrease in serotonin levels after treatment was compared to the paroxetine group using two-way ANOVA (time vs. treatment) followed by Bonferroni multiple comparison test. Statistical analysis was performed with GraphPad Prism (version 4) and significance was determined at a p-value of less than 0.05 (Figure 5). Probe misplacement was considered as a criterion for rejecting data from an animal. reference 1. Paxinos G. and Watson C. (2004) Rat brain in stereotaxic coordinates. Academic Press, New York 2. Nirogi R et al. (2013) J Chromatogr B Analyt Technol Biomed Life Sci 913-914, 41-47.

[0149] result In combination with paroxetine, compound-1 of the present invention showed synergistic effects on the extracellular levels of serotonin in the ventral hippocampus. Treatment with compound-1 (3 mg / kg, po) alone increased hippocampal serotonin levels to 22% above pre-treatment levels. Similarly, paroxetine (5 mg / kg, ip) alone increased hippocampal serotonin levels to an average maximum level of 114% above pre-treatment levels. Compound-1 in combination with paroxetine (5 mg / kg, ip) showed a significantly higher increase in serotonin than that seen with either of these individual treatments or the sum of their effects on serotonin. The average maximum increase in serotonin levels was observed to be 253% above pre-treatment levels (Figure 5). It was observed that the mean area under the curve (AUC) calculated after combined treatment of Compound-1 and paroxetine was significantly higher compared to each individual treatment alone. The enhancing effect of paroxetine on Compound-1 administration suggests that co-administration of SSRIs and a 5-HT4 receptor agonist (Compound-1) may enhance 5-HT neurotransmission, offering potential for the treatment of depression (Figure 5).

[0150] Example 8 Resident / Intruder Tasks Male CD1 mice (residents) weighing 20–35 g, male CD1 mice (intruders) weighing 15–25 g, and ovariectomized female mice (20–25 g) were used. Resident mice were habituated to ovariectomized female mice individually in their own cages. A dose of 0.2 mg / kg (sc) of β-estradiol was administered to the female mice during habituation. Intruders were allowed to socialize for 1 week.

[0151] On the first and second days, the intruder was exposed to the resident mouse in the resident's home cage for 10 min, and the aggression period was recorded. During this exposure period, the female mouse was removed from the cage. On the fourth day, the animals were randomized based on the aggression period and given the respective treatment. Compound-1 (3, 10 and 30 mg / kg, po) and vehicle were administered to the resident mice 60 min before the test. After a post-administration interval, the resident mice were exposed to the same intruder for 10 min, and the aggression period was recorded.

[0152] result The aggression level in CD1 mice was reduced by Compound-1 at 30 mg / kg (po) (Figure 6).

[0153] Example 9 Forced swimming test in mice Male Swiss albino mice weighing between 30 and 45 g were used. Mice were administered vehicle or SUVN-D4010. Water was used as the vehicle. Thirty minutes after treatment, animals from all groups were placed separately for 6 min in a Plexiglas cylinder (40 cm high × 17 cm wide) with a depth of 12 cm and maintained at a temperature of 24 ± 1°C. The resting and swimming periods of the mice during the last 4 min were recorded.

[0154] result Compound-1 significantly shortened the resting period, demonstrating an antidepressant-like effect (Figure 7).

Claims

1. Therapeutic doses of 5-HT 4 2. A method for treating the behavioral and psychological symptoms of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and dementia, comprising administering to a patient in need thereof a 5-HT receptor agonist, 4 The method, wherein the receptor agonist is the compound isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

2. 2. The method of claim 1, wherein the pharma- ceutically acceptable salt of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole is selected from mesylate, hydrochloride, oxalate, succinate, fumarate and tartrate salts.

3. 3. The method of claim 1, wherein the pharma- ceutically acceptable salt of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

4. 2. A method of treating menopausal dementia as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

5. 2. A method for treating senile dementia as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

6. 2. A method of treating cognitive deficits associated with schizophrenia as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

7. 2. A method for treating depression as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

8. 8. A method for treating depression as defined in claim 7, comprising administering to a patient in need thereof a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate and a selective serotonin reuptake inhibitor, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone or a pharmaceutically acceptable salt thereof.

9. 2. A method of treating chemotherapy-induced cognitive impairment as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

10. 2. A method of treating behavioral and psychological symptoms of dementia as defined in claim 1, comprising administering a therapeutically effective amount of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate to a patient in need thereof.

11. 11. The method of claim 1 and claim 10, wherein the behavioral and psychological symptoms of dementia are selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders or appetite and eating disorders.

12. 12. The method of claim 10, wherein the behavioral and psychological symptoms of dementia are selected from: lethargy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behavior in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nighttime behavior disorders or appetite and eating disorders in dementia.

13. The behavioral and psychological symptoms of dementia include lethargy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease, or appetite and food intake in Alzheimer's disease.

13. The method of claim 10 to 12, wherein the therapeutic effect is selected from the group consisting of: impairment, apathy / apathy in Parkinson's disease, aggression in Parkinson's disease, agitation in Parkinson's disease, depression in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behaviour in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nighttime behaviour disorders in Parkinson's disease or appetite and eating disorders in Parkinson's disease.

14. 5-HT for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia 4 Use of a 5-HT receptor agonist, 4 The use, wherein the receptor agonist is the compound isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

15. 15. The 5-HT agonist of claim 14, wherein the pharma- ceutically acceptable salt of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole is selected from the group consisting of mesylate, hydrochloride, oxalate, succinate, fumarate and tartrate. 4 Use of receptor agonists.

16. The use according to claim 14 and claim 15, wherein the pharma- ceutically acceptable salt of isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole oxalate.

17. 5-HT according to claims 14 to 16 for the treatment of dementia due to menopause. 4 Use of receptor agonists.

18. 5-HT according to claims 14 to 16 for the treatment of senile dementia. 4 Use of receptor agonists.

19. 5-HT as claimed in claims 14 to 16 for the treatment of cognitive deficits associated with schizophrenia. 4 Use of receptor agonists.

20. 5-HT according to claims 14 to 16 for the treatment of depression. 4 Use of receptor agonists.

21. 5-HT according to claims 14 to 16 in combination with a selective serotonin reuptake inhibitor for the treatment of depression. 4 Use of receptor agonists.

22. 22. The use of the combination according to claim 21, wherein the selective serotonin reuptake inhibitor is selected from paroxetine, citalopram, escitalopram, fluoxetine, sertraline, dapoxetine and vilazodone or a pharma- ceutically acceptable salt thereof.

23. 5-HT according to claims 14 to 16 for the treatment of chemotherapy-induced cognitive impairment 4 Use of receptor agonists.

24. 5-HT as claimed in claims 14 to 16 for treating behavioural and psychological symptoms of dementia. 4 Use of receptor agonists.

25. 25. The 5-HT monotherapy of claim 24, wherein the behavioral and psychological symptoms of dementia are selected from lethargy / apathy, agitation, aggression, depressed mood, anxiety, irritability / lability, restlessness, abnormal motor behavior, delusions, hallucinations, elation / euphoria, psychosis, disinhibition, sleep and nocturnal behavior disorders, or appetite and eating disorders. 4 Use of receptor agonists.

26. 26. The 5-HT monoclonal antibody for treatment of claim 24, wherein the behavioral and psychological symptoms of dementia are selected from lethargy / apathy in dementia, aggression in dementia, agitation in dementia, depressed mood in dementia, anxiety in dementia, irritability / lability in dementia, restlessness in dementia, abnormal motor behavior in dementia, delusions in dementia, hallucinations in dementia, elation / euphoria in dementia, psychosis in dementia, disinhibition in dementia, sleep and nighttime behavior disorders in dementia or appetite and eating disorders in dementia. 4 Use of receptor agonists.

27. said behavioral and psychological symptoms of dementia include lethargy / apathy in Alzheimer's disease, aggression in Alzheimer's disease, agitation in Alzheimer's disease, depressed mood in Alzheimer's disease, anxiety in Alzheimer's disease, irritability / lability in Alzheimer's disease, restlessness in Alzheimer's disease, abnormal motor behavior in Alzheimer's disease, delusions in Alzheimer's disease, hallucinations in Alzheimer's disease, elation / euphoria in Alzheimer's disease, psychosis in Alzheimer's disease, disinhibition in Alzheimer's disease, sleep and nighttime behavior disorders in Alzheimer's disease, or appetite and eating disorders in Alzheimer's disease; 27. The 5-HT agonist for treatment of Parkinson's disease according to claims 24 to 26, wherein the agonist is selected from lethargy / apathy in Parkinson's disease, aggression in Parkinson's disease, agitation in Parkinson's disease, depressed mood in Parkinson's disease, anxiety in Parkinson's disease, irritability / lability in Parkinson's disease, restlessness in Parkinson's disease, abnormal motor behaviour in Parkinson's disease, delusions in Parkinson's disease, hallucinations in Parkinson's disease, elation / euphoria in Parkinson's disease, psychosis in Parkinson's disease, disinhibition in Parkinson's disease, sleep and nocturnal behaviour disorders in Parkinson's disease or appetite and eating disorders in Parkinson's disease. 4 Use of receptor agonists.

28. 5-HT-1-phosphate dehydrogenase (5-HT-1-phosphate dehydrogenase) according to claims 14 to 27 in the manufacture of a medicament for the treatment of menopausal dementia, senile dementia, cognitive deficits associated with schizophrenia, depression, chemotherapy-induced cognitive impairment and behavioral and psychological symptoms of dementia. 4 Use of a 5-HT receptor agonist, 4 The use wherein the receptor agonist is isopropyl-3-{5-[1-(3-methoxypropyl)piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-1H-indazole or a pharma- ceutically acceptable salt thereof.

29. 5-HT according to claims 21 and 22 in the manufacture of a medicament for the treatment of depression. 4 Use of a combination comprising a receptor agonist and a selective serotonin reuptake inhibitor.

30. 5-HT as defined in any one of claims 1 to 29 4 A pharmaceutical composition comprising a receptor agonist and a pharma- ceutically acceptable excipient or a combination thereof.

31. 31. A pharmaceutical composition according to claim 30 for use in the treatment of menopausal dementia, senile dementia, cognitive deficits in vascular dementia, chemotherapy-induced cognitive impairment and behavioural and psychological symptoms of dementia.

32. 31. The pharmaceutical composition of claim 30, which is administered to a patient by oral, nasal, topical, dermal or parenteral route.

33. 32. The pharmaceutical composition of claim 30 or 31, which is administered to a patient from 1 to 3 times daily, from 1 to 3 times weekly, or from 1 to 3 times monthly.

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