3-(2,3-difluorophenoxy)azetidine or its pharmaceutically acceptable salts for use in the treatment and / or prevention of pathological apathy.

Abstract

This disclosure relates to a compound of formula I, [Formula 1] Regarding JPEG2026522917000014.jpg27166 or its pharmaceutically acceptable salts, It is used in the treatment and / or prevention of pathological apathy.

Description

[Technical Field]

[0001] This disclosure relates to pathological apathy. In particular, this disclosure relates to compound 3-(2,3-difluorophenoxy)azetidine, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy, such as apathy associated with neurodegenerative diseases or neurodegenerative disorders. [Background technology]

[0002] Apathy is a mental state of indifference, which can include, for example, a lack of interest or motivation. Many people experience apathy at some point in their lives, but it is usually a temporary experience and can be overcome without medical treatment, or even virtually without it. For example, apathy can be experienced during times of stress or as a result of trauma.

[0003] However, in a medical sense, pathological apathy is a long-term syndrome that may include symptoms such as a lack of emotion, a lack of motivation to perform or complete an activity, a lack of sensation or purpose, decreased energy levels, and / or emotional detachment from life and personal events. Often, pathological apathy is a symptom associated with a disease or disorder, such as a neurodegenerative disease or neurodegenerative disorder. For example, apathy has been reported to affect up to approximately 20% to 70% of people with Parkinson's disease, which is thought to be related to impaired neurotransmission and connectivity in the cerebral cortex and corticolimbic pathways.

[0004] To diagnose apathy and determine whether it should be considered pathological apathy, several measurement and rating scales have been developed, such as the Apathy Rating Scale (AES), the Apathy Motivation Index (AMI), the Multidimensional Apathy Scale, and / or the Reel Apathy Rating Scale.

[0005] With the global population aging and the prevalence of neurodegenerative diseases such as Parkinson's disease known to increase with age, the problem of pathological apathy is expected to become even more serious in the future.

[0006] International Publication No. 2018 / 091687 relates to a 3-phenoxy-azetidine derivative that is useful for regulating the levels of monoamines such as dopamine, norepinephrine, and serotonin in the cerebral cortical regions of the mammalian brain, and more specifically for the treatment of central nervous system disorders. The document states that these compounds may improve mental and motor functions in Parkinson's disease. However, apathy is not mentioned.

[0007] Pages 1-11 of BMJ Open2020 10(9):e037632 contain a literature review on apathy in Parkinson's disease. The compound 3-(2,3-difluorophenoxy)azetidine is not mentioned.

[0008] It should be understood that any list or discussion of previously published literature in this specification should not necessarily be interpreted as an endorsement that such documents are part of cutting-edge technology or common general knowledge.

[0009] Pathological apathy, particularly persistent pathological apathy, severely impacts quality of life by affecting many aspects of an individual, including interpersonal relationships, work performance, and overall health. Currently available medications for treating apathy include antidepressants such as selective serotonin reuptake inhibitors (SSRIs), antipsychotics, cholinesterase inhibitors, and medications that increase cerebral blood flow for stroke-related apathy. Unfortunately, however, many forms of apathy are found to be difficult to treat or resistant to treatment. Therefore, there remains a need for medicines that can treat and / or prevent pathological apathy, such as that associated with neurodegenerative disorders. In particular, there is a need for medicines that can treat and / or prevent pathological apathy associated with Parkinson's disease.

[0010] The purpose of this disclosure is to overcome or at least mitigate problems associated with the treatment and / or prevention of pathological apathy. Furthermore, the purpose of this disclosure is to provide aspects and / or advantages not provided by previously known techniques.

[0011] This disclosure relates to a compound of formula I, [ka] or a pharmaceutically acceptable salt thereof Provided for use in the treatment and / or prevention of pathological apathy.

[0012] This disclosure also relates to compounds of formula I, [ka] or a pharmaceutically acceptable salt thereof It also provides for use in the manufacture of pharmaceuticals for the treatment and / or prevention of pathological apathy.

[0013] Furthermore, this disclosure provides a method for the treatment and / or prevention of pathological apathy, the method comprising a compound of formula I, [Chemistry] including administering to a patient, such as a human or an animal, an effective amount of the compound or a pharmaceutically acceptable salt thereof, for example a therapeutically effective amount.

Brief Description of the Drawings

[0014] [Figure 1] The results are shown of examining the effect of 3-(2,3-difluorophenoxy)azetidine on spontaneous locomotion in male Sprague-Dawley rats pretreated with a dose of TBZ known to produce a 50% decrease in spontaneous locomotor activity.

Mode for Carrying Out the Invention

[0015] The present disclosure provides a compound of formula I, [Chemistry] or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy.

[0016] Thus, the compound of formula I described herein is provided for use in the treatment and / or prevention of pathological apathy. Further, a pharmaceutically acceptable salt of the compound of formula I described herein is provided for use in the treatment and / or prevention of pathological apathy.

[0017] The present disclosure also provides a compound of formula I, [Chemistry] or a pharmaceutically acceptable salt thereof, It is also provided that the compounds of formula I described herein be used in the manufacture of pharmaceuticals for the treatment and / or prevention of pathological apathy. Therefore, it is provided that the compounds of formula I described herein be used in the manufacture of pharmaceuticals for the treatment and / or prevention of pathological apathy. Furthermore, it is provided that pharmaceutically acceptable salts of the compounds of formula I described herein be used in the manufacture of pharmaceuticals for the treatment and / or prevention of pathological apathy.

[0018] Furthermore, this disclosure provides a method for the treatment and / or prevention of pathological apathy, the method comprising a compound of formula I, [ka] or a pharmaceutically acceptable amount of the salt thereof, for example, a therapeutically effective amount, is administered to a mammal such as a human or animal.

[0019] Accordingly, a method for the treatment and / or prevention of pathological apathy is provided, which comprises administering an effective amount, for example, a therapeutically effective amount, of a compound of formula I described herein to a mammal such as a human or animal. Furthermore, a method for the treatment and / or prevention of pathological apathy is provided, which comprises administering an effective amount, for example, a therapeutically effective amount, of a pharmaceutically acceptable salt of a compound of formula I described herein to a patient such as a human or animal.

[0020] A pharmaceutically acceptable salt of the compound of formula I may be an acid addition salt. The acid addition salt may be a combination of the compound of formula I and an acid in a 1:n ratio, where n may be 0.33, 0.5, or 1. Therefore, the acid addition salt of formula II, [ka] A salt is provided, which is a combination of the compound of formula I described herein and an acid in a ratio of 1:n, where n may be 0.33, 0.5, or 1. For example, n may be 0.5 or 1.

[0021] The acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, boric acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, embonic acid, enanthic acid, fumaric acid, glutamic acid, glycolic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, phthalic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and any combination thereof. In one example, the acid is neither succinic acid nor tartaric acid. Therefore, the acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, boric acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, formic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, embonic acid, enanthic acid, glutamic acid, glycolic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, phthalic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, p-toluenesulfonic acid, and any combination thereof.

[0022] Therefore, the acid addition salt can be selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, ascorbate, benzenesulfonate, benzoate, cinnamicate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and any combination thereof. In one example, the acid addition salt is neither succinate nor tartrate. Therefore, the acid addition salt can be selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, ascorbate, benzenesulfonate, benzoate, cinnamicate, citrate, embonate, enanthate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, toluene-p-sulfonate, and any combination thereof.

[0023] As used herein, the term pathological apathy should be understood as an apathy that can be determined to be pathological using an apathy measure known in the art. For example, apathy can be determined to be pathological using one or more of the following: apathy rating scales, apathy motivation indicators, multidimensional apathy scales, and Reel apathy rating scales. Additionally or alternatively, pathological apathy may be an apathy associated with brain pathology in neurodegenerative diseases or neurodegenerative disorders known in the art.

[0024] Pathological apathy may include one or more of the following symptoms: lack of emotion, lack of motivation to perform or complete an activity, lack of sensation or purpose, decreased energy levels, and emotional detachment from life and personal events. Pathological apathy may affect the patient for more than one month, for example, two, three, four, five, or six months or longer.

[0025] For example, pathological apathy can be an apathy that occurs over a period of time of more than one month. Therefore, a compound of formula I, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment and / or prevention of pathological apathy, which is administered to a patient suffering from pathological apathy for more than one month. The patient may be human or animal.

[0026] Pathological apathy may be associated with diseases, disorders, and / or conditions that respond to the regulation of monoamines in the cerebral cortex. For example, diseases or disorders and / or conditions may be selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), motor disorders, and postural disorders. Cognitive impairment may be age-related cognitive impairment, or cognitive impairment associated with impairment(s) and / or neurodegenerative disease(s). Postural disorders may include or consist of falls(s). In further examples, diseases, disorders, and / or conditions may be selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Creutzfeldt-Jakob disease, multiple sclerosis, and Parkinson's disease. In yet another example, diseases, disorders, and / or conditions may be selected from the group consisting of dementia, Alzheimer's disease, and Parkinson's disease. Dementia may be frontotemporal dementia or Lewy body dementia. In yet another instance, the disease, disorder, and / or condition may include or consist of a neurodegenerative disease or neurodegenerative disorder such as Alzheimer's disease or Parkinson's disease.

[0027] Furthermore, compounds of formula I or pharmaceutically acceptable salts thereof may be administered to patients suffering from one or more of the diseases, disorders, and / or medical conditions described herein, namely, dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), and motor disorder. In particular, compounds of formula I or pharmaceutically acceptable salts thereof may be administered to patients suffering from Parkinson's disease.

[0028] Furthermore, a pharmaceutical composition is provided comprising a compound of formula I described herein or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable excipient, carrier, and / or diluent, the pharmaceutical composition being used for the treatment and / or prevention of pathological apathy as described herein.

[0029] It should be understood that the pharmaceutical compositions described herein may contain a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof. A pharmaceutically acceptable dose may be about 5 mg to about 80 mg once or twice daily. Furthermore, the pharmaceutical composition may be an orally administered pharmaceutical composition such as a capsule, pill, tablet, or lozenge, or a liquid formulation such as a syrup, suspension, or solution. For example, the pharmaceutical composition may be a capsule such as a caplet or a tablet.

[0030] salt In this book, the chemical structures of salts of formula II, including combinations of compounds of formula I with acids, are depicted as complexes in which the acidic proton(s) of the acid are attached to the acid. However, those skilled in the art will understand that the acidic proton(s) of the acid may be attached to the nitrogen atom of the compound of formula I, and / or may be shared between the nitrogen atom of the compound of formula I and the acid, and this is also intended to be encompassed by the salts described herein.

[0031] Labeled compounds The compounds of the present disclosure can be used in their labeled or unlabeled forms. In the context of the present disclosure, a labeled compound has one or more atoms replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Such labeling enables easy quantitative detection of the compound.

[0032] For example, one or more hydrogen atoms of a compound of formula I can be replaced by one or more isotopes such as one or more deuterium atoms.

[0033] The labeled compounds of the present disclosure can be useful as diagnostic tools, radioactive tracers, or monitoring agents in various diagnostic methods and for in vivo receptor imaging. The labeled compounds of the present disclosure can contain at least one radionuclide as a label. All positron-emitting radionuclides are candidates for use. In the context of the present disclosure, radionuclides are 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 18 O, 17 O, 19 F, and 18 F, etc., and can be selected from isotopes of hydrogen, carbon, nitrogen, fluorine, and oxygen. Substitution with heavier isotopes such as substitution of one or more hydrogen atoms with deuterium ( 2 H) is known to provide pharmacological advantages such as increased metabolic stability in some examples.

[0034] Physical methods for detecting the labeled compounds of the present disclosure can be selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial tomography (CAT), or combinations thereof.

[0035] Combination It should be understood that the salts(s) of this disclosure may be combined with other pharmaceuticals for use in the treatment and / or prevention of CNS disorders(s) and / or diseases(s). Other pharmaceuticals may include L-DOPA, selective serotonin reuptake inhibitors, antidepressants such as bupropion (i.e., (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, CAS number 34911-55-2), CNS stimulants and / or antipsychotics such as methylphenidate (i.e., methylphenyl(piperidine-2-yl)acetate, CAS number 20748-11-2). Accordingly, a kit of components is provided comprising (i) a salt as described herein, for example, a salt of formula III as described herein; (ii) a pharmaceutical agent selected from the group consisting of L-DOPA, selective serotonin reuptake inhibitors, antidepressants such as bupropion (i.e., (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, CAS number 34911-55-2), CNS stimulants such as methylphenidate (i.e., methylphenyl(piperidine-2-yl)acetate, CAS number 20748-11-2), and (iii) instructions for use for administering (i) and (ii) individually, simultaneously, or sequentially, at the option of choice.

[0036] As used herein, the term prevention includes references to the prevention and / or avoidance of disease, disorder, and / or medical condition. In particular, the term may mean achieving a reduction in the likelihood of a patient (or healthy subject) developing a medical condition (e.g., a reduction of at least 10%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0037] Furthermore, as used herein, the term "therapeutically effective amount" refers to the amount of a compound that produces a therapeutic effect in the patient being treated. This effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of and / or feels the effect).

[0038] The present invention will be further described by reference to the following embodiments, which are not intended to limit the scope of the invention. [Examples]

[0039] Abbreviation DA Dopamine g (grams) (multiple grams allowed) kg (kilograms) (multiple kilograms allowed) mg (milligrams) (multiple milligrams allowed) mmol (multiple micromoles) NE Norepinephrine sc subcutaneous TBZ Tetrabenazine VMAT-2 vesicle monoamine transporter-2 w / v weight / volume

[0040] General matters Compound 3-(2,3-difluorophenoxy)azetidine was supplied in the form of its hydrochloride salt by Integrative Research Laboratories Sweden AB (Gothenburg, Sweden).

[0041] Male Sprague-Dawley rats weighing 280-320g were used. Before the experiment, the animals were divided into groups, with a maximum of 5 rats per cage, and given free access to water and food. The animals were reared for at least one week before being used in surgery and experiments.

[0042] For measuring spontaneous movement, a motion measuring instrument known in the relevant art was used.

[0043] Example 1: Spontaneous motility in rats pretreated with tetrabenazine Tetrabenazine (CAS number 58-46-8, abbreviated as TBZ herein) is a compound used for the symptomatic treatment of hyperactivity. In Movement Disorders, Vol. 37, No. 6, 2022, pp. 1149-1163, studies using rodents describe how tetrabenazine biases behavior towards "less effort" options, reflecting a phenotype of apathy. For example, based on this information, TBZ treatment was used in this embodiment as a model of pathological apathy. TBZ functions as a monoamine depletor by selectively binding to vesicular monoamine transporter-2 (VMAT-2). VMAT-2 transports and stores serotonin, dopamine (DA), norepinephrine (NE), and histamine in vesicles. By binding to VMAT-2 with high affinity, TBZ acts primarily as a reversible inhibitor of monoamine uptake into granule vesicles of presynaptic neurons. This inhibition leads to the depletion of monoamines, particularly dopamine, resulting in a hypo-monoamine state. In this embodiment, the hypo-monoamine state is induced by tetrabenazine and is associated with pathological apathy, such as the apathy associated with Parkinson's disease, resulting in a decrease in spontaneous motor activity. Therefore, reversing the decrease in spontaneous motor activity caused by the hypo-monoamine state indicates the alleviation of pathological apathy, such as the apathy associated with Parkinson's disease (i.e., an experience of reduced apathy).

[0044] The effect of 3-(2,3-difluorophenoxy)azetidine on spontaneous motility was investigated in male Sprague-Dawley rats pretreated with TBZ at doses known to cause a semi-maximal decrease in spontaneous motility.

[0045] The animals were assigned to four different treatment groups and treated as described below. Group 1: Vehicle, n=5. In this document, the vehicle is intended to be physiological saline (0.9% w / v). In this group, rats were administered sc of the vehicle, and then their spontaneous motility was recorded. The number of rats in this specification is indicated by n. Group 2 (also called the control group): TBZ 0.64 mg / kg, n=5. In this group, rats were administered sc doses of TBZ solution in physiological saline to a dose of 0.64 mg / kg, and then their spontaneous motility was recorded. Group 3: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azetidine 11 μmol / kg, n=5. In this group, rats were pre-treated by sc-administering TBZ solution in physiological saline to a dose of 0.64 mg / kg, and then left for 2 hours. Subsequently, rats were sc-administered 3-(2,3-difluorophenoxy)azetidine solution from a vehicle to a dose of 11 μmol / kg, and spontaneous motility was recorded 15 minutes after the completion of administration. Group 4: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azetidine 33 μmol / kg, n=5. In this group, rats were pre-treated by sc-administering TBZ solution in physiological saline to a dose of 0.64 mg / kg, and then left for 2 hours. Subsequently, rats were sc-administered 3-(2,3-difluorophenoxy)azetidine solution from a vehicle to a dose of 33 μmol / kg, and spontaneous motility was recorded 15 minutes after the completion of administration.

[0046] It should be understood that a dose of 11 μmol / kg of 3-(2,3-difluorophenoxy)azetidine hydrochloride is equivalent to a dose of 2.06 mg / kg of the corresponding base (i.e., pure 3-(2,3-difluorophenoxy)azetidine). Furthermore, a dose of 33 μmol / kg of 3-(2,3-difluorophenoxy)azetidine hydrochloride is equivalent to a concentration dose of 6.17 mg / kg of the corresponding base.

[0047] The results are shown in Figure 1. The spontaneous motility of the control group (i.e., group 2) was observed to be lower than that of group 1, which consisted of rats not pre-treated with TBZ. Therefore, the addition of TBZ reduced spontaneous motility. Furthermore, the spontaneous motility of group 3 was observed to be higher than that of the control group. In addition, the spontaneous motility of group 4 was observed to be significantly higher than that of the control group and group 3. In particular, the spontaneous motility of group 4 was observed to be much higher than that of group 3.

[0048] Therefore, 3-(2,3-difluorophenoxy)azetidine increased spontaneous motility in subjects such as rats in a hypo-monoamine state. Furthermore, high doses of 3-(2,3-difluorophenoxy)azetidine resulted in increased spontaneous motility compared to low doses. Thus, when 3-(2,3-difluorophenoxy)azetidine was administered to rats in a hypo-monoamine state, a dose-dependent increase in spontaneous motility was observed.

[0049] Further examples: Regarding the spontaneous motility of rats not treated with TBZ, experiments were conducted as reported in Table 1 on page 89 of International Publication No. 2018 / 091687. This table shows that, as an overall trend, spontaneous motility decreased as the dose of the compound in Example 1A was increased. This table shows that the compound in Example 1A, namely 3-(2,3-difluorophenoxy)azetidine hydrochloride, had a very slight effect on spontaneous motility when its dose was increased from 11 μmol / kg to 33 μmol / kg. Spontaneous motility increased only from 135% to 163%. Furthermore, the same table shows that when the dose of the compound in Example 1A was further increased from 33 μmol / kg to 100 μmol / kg, spontaneous motility decreased from 163% to 121%. Therefore, the conclusion regarding spontaneous motility when the compound of Example 1A was administered to untreated rats is that no dose-dependent increase in spontaneous motility was observed when the compound was administered to rats. As a result, the compound had little to no effect on spontaneous motility, and there was a tendency for spontaneous motility to decrease when the dose of the compound of Example 1A was increased. However, it should be noted that this comparative example did not include rats that had been pretreated with TBZ. Therefore, this model using rats that had not been pretreated with TBZ is not a model for apathy.

[0050] References 1. International Publication Patent No. 2018 / 091687 A1 2. Movement Disorders, Vol. 37, No. 6, 2022, pp. 1149-1163 3. BMJ Open 2020 10(9):e037632, pages 1-11.

Claims

1. Compound of formula I, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof For use in the treatment and / or prevention of pathological apathy.

2. A compound of formula I according to claim 1, for use in the treatment and / or prevention of pathological apathy.

3. A pharmaceutically acceptable salt of the compound of formula I according to claim 1, for use in the treatment and / or prevention of pathological apathy.

4. The pharmaceutically acceptable salt for use according to claim 1 or 3, wherein the pharmaceutically acceptable salt is an acid addition salt.

5. A pharmaceutically acceptable salt for use according to claim 4, wherein the acid addition salt is selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, and any combination thereof.

6. A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 5, wherein the pharmaceutically acceptable salt is not a succinate or tartrate.

7. A compound for use according to claim 1 or 2, wherein one or more hydrogen atoms of the compound of formula I are substituted with deuterium, or A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 6.

8. A compound for use according to any one of claims 1, 2, or 7, administered to a patient suffering from pathological apathy for more than one month, A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 7.

9. The compound for use according to any one of claims 1, 2, 7, or 8, wherein the pathological apathy includes apathy as defined according to an apathy measurement scale, or A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 8.

10. The compound for use according to claim 9, wherein the apathy measurement scale is one or more of the following: an apathy assessment scale, an apathy motivation index, a multidimensional apathy scale, or a Reel apathy assessment scale. A pharmaceutically acceptable salt for use according to claim 9.

11. The aforementioned pathological apathy is associated with a scale disorder, impairment, and / or condition that responds to the regulation of monoamines in the cerebral cortex, according to any one of the compounds for use according to claim 1, 2, or 7-10, or A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 10.

12. The compound for use according to claim 11, wherein the aforementioned scale disorder, disability, and / or medical condition is selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), motor disorder, and postural disorder, or A pharmaceutically acceptable salt for use according to claim 11.

13. The compound for use according to claim 11 or 12, wherein the aforementioned scale disease, disorder, and / or condition includes neurodegenerative disease or neurodegenerative disorder, or A pharmaceutically acceptable salt for use according to claim 11 or 12.

14. The compound for use according to claim 13, wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Creutzfeldt-Jakob disease, multiple sclerosis, and Parkinson's disease, or A pharmaceutically acceptable salt for use according to claim 13.

15. The aforementioned neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, and Parkinson's disease, and the compound for use according to claim 13 or 14, or A pharmaceutically acceptable salt for use according to claim 13 or 14.

16. The compound for use according to any one of claims 13 to 15, wherein the neurodegenerative disease or neurodegenerative disorder is Parkinson's disease, A pharmaceutically acceptable salt for use according to any one of claims 13 to 15.

17. A compound for use according to any one of claims 1, 2, or 7-16, administered to a patient suffering from a disease, disorder, and / or condition described in any one of claims 11 to 16, or A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 16.

18. A compound for use according to any one of claims 1, 2, or 7 to 17, administered to a patient suffering from Parkinson's disease, A pharmaceutically acceptable salt for use according to any one of claims 1 or 3 to 17.

19. A mixture comprising a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof as defined in any one of claims 4 to 7, with a pharmaceutically acceptable excipient, carrier, and / or diluent, A pharmaceutical composition for use in the treatment and / or prevention of pathological apathy according to any one of claims 1 to 18.

20. Equation I, 【Chemistry 2】 The compound or a pharmaceutically acceptable salt thereof Use for the manufacture of pharmaceuticals for the treatment and / or prevention of pathological apathy.

21. The use according to claim 20, wherein the compound of formula I is provided for the manufacture of a pharmaceutical product for the treatment and / or prevention of pathological apathy.

22. The use according to claim 21, wherein a pharmaceutically acceptable salt of the compound of formula I is provided for the manufacture of a pharmaceutical for the treatment and / or prevention of pathological apathy.

23. The use according to claim 20 or 22, wherein the pharmaceutically acceptable salt is an acid addition salt.

24. The use according to claim 23, wherein the acid addition salt is selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, p-toluenesulfonate, and any combination thereof.

25. The use according to any one of claims 20 or 22-24, wherein the pharmaceutically acceptable salt is not a succinate or tartrate.

26. The use according to any one of claims 20 to 25, wherein one or more of the hydrogen atoms in the compound of formula I are substituted with deuterium.

27. The use according to any one of claims 20 to 26, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from pathological apathy for more than one month.

28. The use according to any one of claims 20 to 27, wherein the pathological apathy includes apathy as defined according to an apathy measurement scale.

29. The use according to claim 28, wherein the apathy measurement scale is one or more of the following: an apathy evaluation scale, an apathy motivation index, a multidimensional apathy scale, and a Reel apathy evaluation scale.

30. The use according to any one of claims 20 to 29, wherein the pathological apathy is related to a disease, disorder, and / or pathological condition that responds to the regulation of monoamines in the cerebral cortex.

31. The use according to claim 30, wherein the disease, disorder, and / or condition is selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), motor disorder, and postural disorder.

32. The use according to claim 30 or 31, wherein the disease, disorder, and / or condition includes a neurodegenerative disease or neurodegenerative disorder.

33. The use according to claim 31 or 32, wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Creutzfeldt-Jakob disease, multiple sclerosis, and Parkinson's disease.

34. The use according to claim 32 or 33, wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, and Parkinson's disease.

35. The use according to any one of claims 32 to 34, wherein the neurodegenerative disease or neurodegenerative disorder is Parkinson's disease.

36. The use according to any one of claims 20 to 35, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from a disease, disorder and / or condition as defined in any one of claims 31 to 36.

37. The use according to any one of claims 20 to 36, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from Parkinson's disease.

38. The use according to any one of claims 20 to 37, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is provided as a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof in a mixture with a pharmaceutically acceptable excipient, carrier, and / or diluent.

39. A method for the treatment and / or prevention of pathological apathy, wherein the method involves administering formula I to a patient such as a human or animal. 【Transformation 3】 A method comprising administering an effective amount, such as a therapeutically effective amount, of the compound or a pharmaceutically acceptable salt thereof.

40. The above method involves administering formula I to a patient such as a human or animal. 【Chemistry 4】 The method according to claim 39, comprising administering an effective amount of the compound, such as a therapeutically effective amount.

41. The method according to claim 39, wherein the method comprises administering to a patient such as a human or animal an effective amount, such as a therapeutically effective amount, of a pharmaceutically acceptable salt of the compound of formula I.

42. The method according to claim 39 or 41, wherein the pharmaceutically acceptable salt is an acid addition salt.

43. The method according to claim 42, wherein the acid addition salt is selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, p-toluenesulfonate, and any combination thereof.

44. The method according to any one of claims 39 or 41 to 43, wherein the pharmaceutically acceptable salt is not a succinate or tartrate.

45. The method according to any one of claims 39 to 44, wherein one or more of the hydrogen atoms in the compound of formula I are substituted with deuterium.

46. The method according to any one of claims 39 to 45, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from pathological apathy for one month or more.

47. The method according to any one of claims 39 to 46, wherein the pathological apathy includes apathy as defined according to an apathy measurement scale.

48. The method according to claim 47, wherein the apathy measurement scale is one or more of the following: an apathy evaluation scale, an apathy motivation index, a multidimensional apathy scale, and a Reel apathy evaluation scale.

49. The method according to any one of claims 39 to 48, wherein the pathological apathy is related to a disease, disorder, and / or condition that responds to the regulation of monoamines in the cerebral cortex.

50. The method according to claim 49, wherein the disease, disorder, and / or condition is selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), motor disorder, and postural disorder.

51. The method according to claim 49 or 50, wherein the disease, disorder, and / or condition includes a neurodegenerative disease or neurodegenerative disorder.

52. The method according to claim 51, wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, Huntington's disease, Creutzfeldt-Jakob disease, multiple sclerosis, and Parkinson's disease.

53. The method according to claim 52, wherein the neurodegenerative disease or neurodegenerative disorder is selected from the group consisting of dementia, Alzheimer's disease, and Parkinson's disease.

54. The method according to any one of claims 51 to 53, wherein the neurodegenerative disease or neurodegenerative disorder is Parkinson's disease.

55. The method according to any one of claims 39 to 54, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from a disease, disorder, and / or medical condition as defined in any one of claims 50 to 56.

56. The method according to claim 55, wherein the compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient suffering from Parkinson's disease.

57. The above method involves administering formula I to a patient such as a human or animal. 【Transformation 5】 Effective amounts such as therapeutically effective amounts of the compound or its pharmaceutically acceptable salt The method according to any one of claims 39 to 56, comprising administering a pharmaceutical composition contained in a mixture with pharmaceutically acceptable excipients, carriers, and / or diluents.

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