3-(2,3-difluorophenoxy)azetidine, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy

Abstract

The disclosure concerns a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy.

Description

[0001] 3-(2,3-DIFLUOROPHENOXY)AZETIDINE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, FOR USE IN THE TREATMENT AND / OR PREVENTION OF PATHOLOGICAL APATHY

[0002] Technical field

[0003] The present disclosure concerns pathological apathy. In particular, the present disclosure concerns the 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 a neurodegenerative disease or disorder.

[0004] Background

[0005] Apathy is a mental state of indifference in an individual wherein the state may include e.g. lack of interest and / or motivation. Many people experience apathy at some point in their lives, but it is usually a temporary experience that may be overcome without or substantially without medical treatment. For example, apathy may be experienced during times of stress or as a result of trauma.

[0006] However, in a medical sense pathological apathy is a long-term syndrome which may include symptoms such as absence of emotions, lack of motivation to do or complete activities, lack of sense or purpose, low energy levels and / or detachment from life and personal events. Often, pathological apathy is a symptom associated with a disease or disorder such as a neurodegenerative disease or disorder. For example, apathy has been reported to affect up to about from 20 to 70 percent of people suffering from Parkinson 's disease which is believed to be linked to impaired neurotransmission and connectivity in cortical and cortico-limbic pathways.

[0007] In order to diagnose apathy to find out whether or not it should be considered as pathological apathy several measurement and evaluation scales have been developed such as, for instance, the Apathy Evaluation Scale (AES), Apathy Motivation Index (AMI), Dimensional Apathy Scale and / or Lille Apathy rating Scale.

[0008] As aging populations grow worldwide and the prevalence of neurodegenerative diseases such as Parkinson 's disease is known to increase with age it is expected that the problem with pathological apathy will aggravate even more in the years to come WO 2018 / 091687 relates to 3-phenoxy-azetidine derivatives useful for modulating levels of monoamines, such as dopamine, norepinephrine and serotonin, in cerebral cortical areas of the mammalian brain, and more specifically for the treatment of central nervous disorders. It is described that the compounds may be used to improve mental and motor function in Parkinson 's disease. However, apathy is not mentioned.

[0009] BMJ Open 2020 10(9): e037632, pages 1-11 provides a review of the literature on apathy in Parkinson 's disease. The compound 3-(2,3-difluorophenoxy)azetidine is not mentioned.

[0010] It will be appreciated that the listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

[0011] Pathological apathy, in particular pathological persistent apathy, has a very negative impact on the quality of life as it affects many aspects of the individual such as her or his relationships, ability to work, overall wellness etc. Currently, medications that are available for the treatment of apathy include antidepressants such as selective serotonin reuptake inhibitors (so-called SSRIs), antipsychotics, cholinesterase inhibitors and medications to increase cerebral blood flow for apathy caused by stroke. Unfortunately, however, it has been found that apathy is often difficult to treat or is even treatment resistant. Therefore, there remains a need for a pharmaceutical drug allowing for the treatment and / or prevention of pathological apathy such as pathological apathy associated with a neurodegenerative disorder. In particular, there is a need for a pharmaceutical drug allowing for the treatment and / or prevention pathological apathy associated with Parkinson 's disease.

[0012] Summary

[0013] It is an object of the present disclosure to overcome or at least mitigate problems associated with treatment and / or prevention of pathological apathy. Further, it is an object of the present disclosure to provide aspects and / or advantages not provided by hitherto known technique.

[0014] The present disclosure provides a compound of Formula I:

[0015] Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy.

[0016] The present disclosure also provides the use of a compound of Formula I:

[0017] Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of pathological apathy.

[0018] Further, the present disclosure provides a method for the treatment and / or prevention of pathological apathy, said method comprising administering to a patient, such as a human or an animal, an effective amount, such a therapeutically effective amount, of a compound of Formula I:

[0019] Formula I or a pharmaceutically acceptable salt thereof.

[0020] Description

[0021] The present disclosure provides a compound of Formula I:

[0022] Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy.

[0023] Thus, there is provided a compound of Formula I as described herein for use in the treatment and / or prevention of pathological apathy. Further, there is provided a pharmaceutically acceptable salt of the compound of Formula I as described herein for use in the treatment and / or prevention of pathological apathy. The present disclosure also provides the use of a compound of Formula I:

[0024] Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of pathological apathy. Thus, there is provided the use of a compound of Formula I as described herein for the manufacture of a medicament for the treatment and / or prevention of pathological apathy. Further, there is provided the use of a pharmaceutically acceptable salt of the compound of Formula I as described herein for the manufacture of a medicament for the treatment and / or prevention of pathological apathy.

[0025] Further, the present disclosure provides a method for the treatment and / or prevention of pathological apathy, said method comprising administering to a mammal, such as a human or animal, an effective amount, such as a therapeutically effective amount, of a compound of Formula I:

[0026] Formula I or a pharmaceutically acceptable salt thereof.

[0027] Thus, there is provided a method for the treatment and / or prevention of pathological apathy, said method comprising administering to a mammal, such as a human or animal, an effective amount, such a therapeutically effective amount, of a compound of Formula I as described herein. Further, there is provided a method for the treatment and / or prevention of pathological apathy, said method comprising administering to a patient, such as a human or animal, an effective amount, such a therapeutically effective amount, of a pharmaceutically acceptable salt of a compound of Formula I as described herein.

[0028] The 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 taken in a ratio of l:n, wherein n may be 0.33, 0.5 or 1.

[0029] Thus, there is provided an acid addition salt of Formula II: acid n

[0030] Formula II said salt being a combination of a compound of Formula I as described herein and an acid taken in a ratio of l :n, wherein n may be 0.33, 0.5 or 1. For example n may be 0.5 or 1.

[0031] The acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, boric acid, nitric acid, perchloric acid, phosphoric acid, sulphuric acid, formic acid, acetic acid, ascorbic acid, benzenesulphonic 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, methanesulphonic acid, naphthalene-2- sulphonic acid, phtalic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulphonic acid, and any combination thereof. In an example, the acid is not succinic acid ortartaric acid. Thus, the acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, boric acid, nitric acid, perchloric acid, phosphoric acid, sulphuric acid, formic acid, acetic acid, ascorbic acid, benzenesulphonic acid, benzoic acid, cinnamic acid, citric acid, embonic acid, enanthic acid, glutamic acid, glycolic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulphonic acid, naphthalene-2-sulphonic acid, phtalic acid, propionic acid, salicylic acid, sorbic acid, stearic acid, p-toluenesulphonic acid, and any combination thereof.

[0032] It follows that the acid addition salt may be selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and any combination thereof. In an example, the acid addition salt is not a succinate salt or a tartrate salt. Thus, the acid addition salt may be selected from the group consisting of hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulphate, formate, acetate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, toluene-p-sulphonate, and any combination thereof. As used herein, the term pathological apathy is understood to be apathy that may be determined to be pathological using an apathy measurement scale as known in the art. For instance, the apathy may be determined to be pathological using one or more of the following: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Lille Apathy Rating Scale. Additionally or alternatively, the pathological apathy may be apathy associated with brain pathology in a neurodegenerative disease or disorder as known in the art.

[0033] The pathological apathy may include one of more of the following symptoms: absence of emotions, lack of motivation to do or complete activities, lack of sense or purpose, low energy levels, detachment form life and personal events. The pathological apathy may be apathy affecting the patient for one month or more such as two, three, four, five or sixth month or more.

[0034] In an example, the pathological apathy may be apathy taking place for a time of one month or more. Thus, there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy, which is administered to a patient suffering from pathological apathy for one month or more. The patient may be a human or an animal.

[0035] The pathological apathy may be associated with a disease, disorder and / or condition which is responsive to modulation of monoamines in the cerebral cortex. For example, the disease or disorder and / or condition may be selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), movement disorder, postural instability. The cognitive impairment may be age-related cognitive impairment or cognitive impairment associated with neurodegenerative disorder(s) and / or disease(s). The postural instability may comprise or consist of fall(s). In a further example, the disease, disorder and / or condition 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 still a further example, the disease, disorder and / or condition may be selected from the group consisting of dementia, Alzheimer's disease and Parkinson 's disease. The dementia may be frontotemporal dementia or Lewy body dementia. In still a further example, the disease, disorder and / or condition may comprise or consist of a neurodegenerative disease or disorder such as Alzheimer's disease or Parkinson 's disease. Moreover, the compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered to a patient suffering from a disease, disorder and / or condition as described herein such as one or more of the following: dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD) and movement disorder. In particular, the compound of Formula I, or pharmaceutically acceptable salt thereof, may be administered to a patient suffering from Parkinson 's disease.

[0036] There is also provided a pharmaceutical composition comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, as described herein, in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent, for use in the treatment and / or prevention of pathological apathy as described herein.

[0037] It will be appreciated that the compound of Formula I, or a pharmaceutically acceptable salt thereof, may be present in a therapeutically effective amount in the pharmaceutical composition described herein. The pharmaceutically acceptable dose may be form about 5 mg to about 80 mg one or twice daily. Further, the pharmaceutical composition may be a pharmaceutical composition for oral administration such as capsule, pill, tablet, lozenge or a liquid preparation such as a syrup, suspension or solution. For instance, the pharmaceutical composition may be a capsule or tablet such as a caplet.

[0038] Salts

[0039] In this document, the chemical structure of the salt of Formula II comprising a combination of the compound of Formula I and the acid has been drawn as a complex wherein the acidic proton(s) of the acid is attached to said acid. However, the skilled person understands that the acidic proton(s) of the acid may be attached to the nitrogen atom of the compound of Formula I and / or shared between the nitrogen atom of the compound of Formula I and the acid, and this is also intended to be encompassed by the salt described herein.

[0040] Labelled Compounds

[0041] Compounds of the present disclosure may be used in their labelled or unlabelled form. In the context of this present disclosure the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound. For instance, one or more hydrogen atoms of the compound of Formula I may be replaced with one or more isotopes such as one or more deuterium atoms

[0042] Labelled compounds of the present disclosure may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging. Labelled compounds of the present disclosure may contain at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this present disclosure the radionuclide may be selected from isotopes of hydrogen, carbon, nitrogen, fluorine and oxygen, such as2H (deuterium),3H (tritium),nC,13C,14C,18O,17O,19F and18F. It is known that substitution with heavier isotopes, such as substitution of one or more hydrogen atoms with deuterium (2H) might provide pharmacological advantages in some instances, such as increased metabolic stability.

[0043] The physical method for detecting a labelled compound of the present disclosure may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.

[0044] Combinations

[0045] It will be appreciated that the salt(s) of the present disclosure may be combined with a further pharmaceutical drug for use in the treatment and / or prevention of CNS disorder(s) and / or disease(s). The further pharmaceutical drug may be L-DOPA, a Selective Serotonin Reuptake Inhibitor, an antidepressant such as bupropion

[0046] (i.e. ( / ?S)-2-(tert-Butylamino)-l-(3-chlorophenyl)propan-l-one; CAS number 34911- 55-2), a CNS stimulant such as methylphenidate (i.e. methyl phenyl(piperidin-2-yl) acetate; CAS number 20748-11-2) and / or an antipsychotic. Thus, there is provided kit of parts comprising: (i) a salt of the present disclosure such as a salt of Formula II I as described herein, (ii) a pharmaceutical drug selected from the group consisting of

[0047] L-DOPA, a Selective Serotonin Reuptake Inhibitor, an antidepressant such as bupropi on (i.e. (RS)-2-(tert-Butylamino)-l-(3-chlorophenyl)propan-l-one; CAS number 349 11-55-2), a CNS stimulant such as methylphenidate (i.e. methyl phenyl(piperidin-2- yl)acetate; CAS number 20748-11-2) and an antipsychotic, and (iii) optionally instruc tions for separate, simultaneous or sequential administration of (i) and (ii).

[0048] As used herein, the term prevention includes references to the prophylaxis and / or preventing of the disease, disorder and / or condition. In particular, the term may refer to achieving a reduction in the likelihood of the patient (or healthy subject) developing the condition (for example, at least a 10% reduction, such as at least a 20%, 30% or 40% reduction, e.g. at least a 50% reduction).

[0049] Further, as used herein the term therapeutically effective amount refers to an amount of a compound that confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of and / or feels an effect).

[0050] The invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention.

[0051] Examples

[0052] Abbreviations

[0053] DA dopamine g gram(s) kg kilogram(s) mg milligram(s) mmol micromole(s)

[0054] NE norepinephrine s.c. subcutaneous

[0055] TBZ tetrabenazine

[0056] VMAT-2 vesicular monoamine transporter-2 w / v weight / volume

[0057] General

[0058] The compound 3-(2,3-difluorophenoxy)azetidine was provided by Integrative Research Laboratories Sweden AB, Gbteborg, Sweden in the form of a hydrochloric acid salt.

[0059] Male Sprague-Dawley rats weighing 280-320 g were used. Before the experiments the animals were housed in groups, maximum five animals in each cage, with free access to water and food. The animals were housed at least one week prior to surgery and use in the experiments.

[0060] Motility meters as known in the art were used to measure the locomotor activity. Example 1: Locomotor activity in rats pretreated with tetrabenazine Tetrabenazine (which has CAS number 58-46-8 and which is herein abbreviated TBZ) is a compound used for symptomatic treatment of hyperkinetic movement disorders. It is described in Movement Disorders, Vol. 37, No. 6, 2022, pages 1149-1163 that in rodent studies tetrabenazine biases behavior toward "low-effort" options, mirroring the phenotype apathy. Based on e.g. this information, TBZ treatment has been used as a model for pathological apathy in the present example. TBZ functions as a depleter of monoamines by binding selectively to the vesicular monoamine transporter-2 (VMAT- 2). VMAT-2 transports serotonin, dopamine (DA), norepinephrine (NE), and histamine into vesicles for storage. By high-affinity binding to VMAT-2, TBZ acts primarily as a reversible inhibitor of mono-amine uptake into granular vesicles of presynaptic neurons. This inhibition leads to a depletion of the monoamines, particularly dopamine resulting in a hypomonoaminergic state. The hypomonoaminergic state, which in this example was elicited by tetrabenazine, is associated with pathological apathy such as apathy linked to Parkinson 's disease and results in a decline in locomotor activity. Thus, reversing a decline in locomotor activity due to a hypomonoaminergic state indicates alleviation of pathological apathy (i.e. experience of less apathy) such as apathy linked to Parkinson 's disease.

[0061] The effects of 3-(2,3-difluorophenoxy)azetidine on locomotor activity were investigated in Male Sprague-Dawley rats pretreated with TBZ, at a dose known to produce a half-maximal reduction in locomotor activity.

[0062] The animals were allocated into four different treatment groups and treated as described below.

[0063] Group 1: Vehicle, n = 5. In this document vehicle intends saline (0.9% w / v). In this group, the rats were subjected to s.c. injection with the vehicle followed by recording of the locomotor activity. The number of rats herein is denoted n.

[0064] Group 2, which is also denominated Control Group: TBZ 0.64 mg / kg, n = 5. In this group, the rats were subjected to s.c. injection with a solution of TBZ in saline to provide a dosage of 0.64 mg / kg in the rats followed by recording of the locomotor activity.

[0065] Group 3: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azetidine 11 pmol / kg, n = 5. In this group, the rats were pretreated by s.c. injection with a solution of TBZ in saline to provide a dosage of 0.64 mg / kg in the rats which were then left for two hours. Following this the rats were subjected to s.c. injection with a solution of 3-(2,3- difluorophenoxy)azetidine in vehicle to provide 3-(2,3-difluorophenoxy)azetidine in a dosage of 11 pmol / kg in the rats and recording of the locomotor activity started 15 minutes after completion of the injection.

[0066] Group 4: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azetidine 33 pmol / kg, n = 5. In this group, the rats were pretreated by s.c. injection with a solution of TBZ in saline to provide a dosage of 0.64 mg / kg in the rats which were then left for two hours. Following this the rats were subjected to s.c. injection with a solution of 3-(2,3- difluorophenoxy)azetidine in vehicle to provide 3-(2,3-difluorophenoxy)azetidine in a dosage of 33 pmol / kg in the rats and recording of the locomotor activity started 15 minutes after completion of the injection.

[0067] It will be appreciated that the dosage of 11 pmol / kg of the hydrochloric acid salt of 3- (2,3-difluorophenoxy)azetidine corresponds to a dosage of 2.06 mg / kg of the corresponding base (i.e. pure 3-(2,3-difluorophenoxy)azetidine). Further, the dosage of 33 pmol / kg of the hydrochloric acid salt of 3-(2,3-difluorophenoxy)azetidine corresponds to a concentration dosage of 6.17 mg / kg of the corresponding base.

[0068] The results are shown in Figure 1. It was observed that the locomotor activity for the Control Group (i.e. Group 2) was lower than that of Group 1 which was the group of rats not being pretreated with TBZ. Thus, addition of TBZ lowered the locomotor activity. It was also observed that the locomotor activity for Group 3 was higher than that observed for the Control Group. Further, it was observed that the locomotor activity for Group 4 was significantly higher than the locomotor activity for the Control Group and Group 3. In particular, it was observed that the locomotor activity for Group 4 was much higher than the locomotor activity for Group 3.

[0069] Thus, the compound 3-(2,3-difluorophenoxy)azetidine increased the locomotor activity in subjects such as rats suffering from a hypo-monoaminergic state. Further, a higher dosage of 3-(2,3-difluorophenoxy)azetidine resulted in an increase of the locomotor activity compared to a lower dosage. Thus, there was a dose-dependent increase in the locomotor activity when rats suffering from a hypo-monoaminergic state were administered the compound 3-(2,3-difluorophenoxy)azetidine.

[0070] Further example

[0071] An experiment was made with locomotor activity for rats not being treated with TBZ which is reported in Table 1 on page 89 in WO 2018 / 091687 where the overall trend was a decrease in locomotor activity when the dosage of the compound of Example 1A was increased. This table shows that the compound of Example 1A, i.e. 3-(2,3- difluorophenoxy)azetidine hydrochloric acid salt, had a very modest effect on the locomotor activity when the dosage was increased from 11 pmol / kg to 33 pmol / kg. The locomotor activity only increased from 135% to 163%. Moreover, the table shows that increasing the dosage yet further of the compound of Example 1A from 33 pmol / kg to 100 pmol / kg caused a decrease in the locomotor activity from 163% to 121%. Thus, the conclusion for the compound of Example 1A on the locomotor activity in non-pre- treated rats is that there is no dose-dependent increase in the locomotor activity when rats were administered the compound. As a result, this compound has no or very little effect on the locomotor activity, the trend being that the locomotor activity actually decreases with an increase in the dosage of the compound of Example 1A. However, it is noted that this comparative example did not involve rats being pretreated with TBZ. Thus, this model with TBZ non-pretreated rats is not a model for apathy.

[0072] Reference

[0073] 1. WO 2018 / 091687 Al

[0074] 2. Movement Disorders, Vol. 37, No. 6, 2022, pages 1149-1163

[0075] 3. BMJ Open 2020 10(9): e037632, pages 1-11.

Claims

Claims1. A compound of Formula I:Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of pathological apathy.

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

3. The 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. The 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, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p- sulphonate, and any combination thereof.

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

7. The compound for use according to claim 1 or 2, or the pharmaceutically acceptable salt for use according to any one of claims 1 or 3-6, wherein one or more of the hydrogen atoms of the compound of Formula I is / are replaced with deuterium.

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

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

10. The compound for use according to claim 9, or the pharmaceutically acceptable salt for use according to claim 9, wherein the apathy measurement scale is one or more of the following: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Lille Apathy Rating Scale.

11. The compound for use according to any one of claims 1, 2 or 7-10, or the pharmaceutically acceptable salt for use according to any one of claims 1 or 3-10, wherein the pathological apathy is associated with a disease, disorder and / or condition which is responsive to modulation of monoamines in the cerebral cortex.

12. The compound for use according to claim 11, or the pharmaceutically acceptable salt for use according to claim 11, 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), movement disorder and postural instability.

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

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

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

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

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

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

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

20. Use of a compound of Formula I:Formula Ior a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and / or prevention of pathological apathy.

21. The use according to claim 20, wherein a compound of Formula I is provided for the manufacture of a medicament 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 medicament 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, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, 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 salt or a tartrate salt.

26. The use according to any one of claims 20-25, wherein one or more of the hydrogen atoms of the compound of Formula I is / are replaced with deuterium.

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

28. The use according to any one of claims 20-27, wherein the pathological apathy comprises 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: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Lille Apathy Rating Scale.

30. The use according to any one of claims 20-29, wherein the pathological apathy is associated with a disease, disorder and / or condition which is responsive to modulation 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), movement disorder and postural instability.

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

33. The use according to claim 31 or 32, wherein the neurodegenerative disease or 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 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 32-34, wherein the neurodegenerative disease or disorder is Parkinson 's disease.

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

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

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

39. A method for the treatment and / or prevention of pathological apathy, said method comprising administering to a patient, such as a human or an animal, an effective amount, such a therapeutically effective amount, of a compound of Formula IFormula I or a pharmaceutically acceptable salt thereof.

40. The method according to claim 39, wherein the method comprises administering to a patient, such as a human or an animal, an effective amount, such a therapeutically effective amount, of a compound of Formula IFormula I41. The method according to claim 39, wherein the method comprises administering to a patient, such as a human or an animal, an effective amount, such 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, sulphate, formate, acetate, aconate, ascorbate, benzenesulphonate, benzoate, cinnamate, citrate, embonate, enantate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulphonate, naphthalene-2-sulphonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulphonate, and any combination thereof.

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

45. The method according to any one of claims 39-44, wherein one or more of the hydrogen atoms of the compound of Formula I is / are replaced with deuterium.

46. The method according to any one of claims 39-45, wherein the compound of Formula I or 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 39-46, wherein the pathological apathy comprises 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: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Lille Apathy Rating Scale.

49. The method according to any one of claims 39-48, wherein the pathological apathy is associated with a disease, disorder and / or condition which is responsive to modulation 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), movement disorder and postural instability.

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

52. The method according to claim 51, wherein the neurodegenerative disease or 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 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 51-53, wherein the neurodegenerative disease or disorder is Parkinson 's disease.

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

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

57. The method according to any one of claims 39-56, wherein the method comprises administering to a patient, such as a human or an animal, a pharmaceutical composition comprising an effective amount, such a therapeutically effective amount, of a compound of Formula IFormula I or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent.

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