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

Abstract

The present disclosure relates to a compound of Formula (I): Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prophylaxis of pathological desert.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480045093.1 (22) Application Date 2024.07.05 (30) Priority Data 23183833.5 2023.07.06 EP (85) PCT International Application Entering National Phase Date 2025.12.31 (86) PCT International Application Application Data PCT / EP2024 / 069001 2024.07.05 (87) PCT International Application Publication Data WO2025 / 008506 EN 2025.01.09 (71) Applicant Comprehensive Research Laboratory Swedish AG Address Gothenburg, Sweden (72) Inventor Nicolas Waters (74) Patent Agency Beijing Sanju Sunshine Intellectual Property Agency Co., Ltd. 11250 Patent Attorney Qin Jie (51) Int.Cl. A61K 31 / 397 (2006.01) A61P 25 / 00 (2006.01) A61P 25 / 28 (2006.01) (54) Invention Title 3-(2,3-difluorophenoxy)azacyclobutane or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of pathological apathy (57) Abstract This disclosure relates to a compound of formula (I): Formula I or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of pathological apathy. Claims 5 pages Description 7 pages Drawings 1 page CN 121511082 A 2026.02.10 CN 1 21 51 10 82 A 1. A compound of formula I: Formula I or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of pathological apathy. 2. The compound of formula I according to claim 1, used for the treatment and / or prevention of pathological apathy. 3. A pharmaceutically acceptable salt of the compound of formula I according to claim 1, used for the treatment and / or prevention of pathological apathy. 4. The pharmaceutically acceptable salt used according to claim 1 or 3, wherein the pharmaceutically acceptable salt is an acid addition salt. 5. The pharmaceutically acceptable salt used 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, embosate, heptanoate, 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 as claimed in any one of claims 1 to 5, wherein the pharmaceutically acceptable salt is not a succinate or tartrate. 7. A compound as claimed in claim 1 or 2, or a pharmaceutically acceptable salt as claimed in any one of claims 1 to 6, wherein one or more hydrogen atoms in the compound of formula I are replaced by deuterium. 8. A compound as claimed in any one of claims 1, 2, or 7, or a pharmaceutically acceptable salt as claimed in any one of claims 1 to 7, administered to a patient suffering from pathological apathy for one month or longer. 9. A compound as claimed in any one of claims 1, 2, 7, or 8, or a pharmaceutically acceptable salt as claimed in any one of claims 1 to 8, wherein the pathological apathy includes apathy as defined according to an apathy measurement scale. 10. The compound used according to claim 9 or the pharmaceutically acceptable salt used according to claim 9, wherein the apathy measurement scale is one or more of the following: apathy assessment scale, apathy motivation index, dimensional apathy scale, Lille apathy rating scale. 11. The compound used according to any one of claims 1, 2, or 7 to 10 or the pharmaceutically acceptable salt used according to any one of claims 1, 3, or 10, wherein the pathological apathy is associated with a disease, condition, and / or symptom that responds to the regulation of monoamines in the cerebral cortex. 12. The compound used according to claim 11 or the pharmaceutically acceptable salt used according to claim 11, wherein the disease, condition, and / or symptom 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 instability. 13. The compound used according to claim 11 or 12, or the pharmaceutically acceptable salt used according to claim 11 or 12, wherein the disease, condition, and / or symptom includes a neurodegenerative disease or condition. 14. The compound used according to claim 13, or the pharmaceutically acceptable salt used according to claim 13, wherein the neurodegenerative disease or condition 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 used according to claim 13 or 14, or the pharmaceutically acceptable salt used according to claim 13 or 14, wherein the neurodegenerative disease or condition is selected from the group consisting of: dementia, Alzheimer's disease, and Parkinson's disease.16. The compound or pharmaceutically acceptable salt used according to any one of claims 13 to 15, wherein the neurodegenerative disease or condition is Parkinson's disease. 17. Administration of the compound or pharmaceutically acceptable salt used according to any one of claims 1, 2, or 7 to 16 to a patient suffering from the disease, condition, and / or symptom according to any one of claims 11 to 16. 18. Administration of the compound or pharmaceutically acceptable salt used according to any one of claims 1, 2, or 7 to 17 to a patient suffering from Parkinson's disease. 19. A pharmaceutical composition comprising a compound of formula I according to claim 1 or a pharmaceutically acceptable salt according to any one of claims 4 to 7, and an admixture of a pharmaceutically acceptable excipient, carrier, and / or diluent for the treatment and / or prevention of pathological apathy according to any one of claims 1 to 18. 20. Use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating and / or preventing pathological apathy. 21. The use of claim 20, wherein a compound of formula I is provided for the manufacture of a medicament for treating and / or preventing pathological apathy. 22. The use of claim 21, wherein a pharmaceutically acceptable salt of said compound of formula I is provided for the manufacture of a medicament for treating and / or preventing pathological apathy. 23. The use of claim 20 or 22, wherein said 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, embosate, heptanoate, 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. 25. The use according to any one of claims 20 or 22 to 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 hydrogen atoms in the compound of formula I are replaced by 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 one month or longer. 28. The use according to any one of claims 20 to 27, wherein the pathological apathy includes apathy as defined by 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 assessment scale, an apathy motivation index, a dimensional apathy scale, and a Riehl apathy rating scale. 30. The use according to any one of claims 20 to 29, wherein the pathological apathy is associated with a disease, condition, and / or symptom that responds to the regulation of monoamines in the cerebral cortex. 31. The use according to claim 30, wherein the disease, condition, and / or symptom is 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 instability. 32. The use according to claim 30 or 31, wherein the disease, condition, and / or symptom comprises a neurodegenerative disease or condition. 33. The use according to claim 31 or 32, wherein the neurodegenerative disease or condition 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 condition 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 condition 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 the disease, condition, and / or symptom according to 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 an admixture of the compound of formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier, and / or diluent. 39. A method for treating and / or preventing pathological apathy, the method comprising administering to a patient, such as a human or animal, an effective amount, such as a therapeutically effective amount, of a compound of formula I. (Claims 3 / 5, page 4, CN 121511082 A, Formula I or a pharmaceutically acceptable salt thereof)40. The method of 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 compound of formula I. 41. The method of 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 of claim 39 or 41, wherein the pharmaceutically acceptable salt is an acid addition salt. 43. The method of 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, embosate, heptanoate, 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. 44. The method of claim 39 or any one of 41 to 43, wherein the pharmaceutically acceptable salt is not a succinate or tartrate. 45. The method of any one of claims 39 to 44, wherein one or more hydrogen atoms in the compound of formula I are replaced by deuterium. 46. ​​The method of 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 longer. 47. The method of any one of claims 39 to 46, wherein the pathological apathy comprises apathy as defined by an apathy measurement scale. 48. The method of claim 47, wherein the apathy measurement scale is one or more of the following: an apathy assessment scale, an apathy motivation index, a dimensional apathy scale, or a Riehl apathy rating scale. 49. The method of any one of claims 39 to 48, wherein the pathological apathy is associated with a disease, condition, and / or symptom that responds to the regulation of monoamines in the cerebral cortex. 50. The method of claim 49, wherein the disease, condition, and / or symptom is 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 instability. 51. The method of claim 49 or 50, wherein the disease, condition and / or symptom includes neurodegenerative diseases or conditions.52. The method of claim 51, wherein the neurodegenerative disease or condition 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 of claim 52, wherein the neurodegenerative disease or condition is selected from the group consisting of: dementia, Alzheimer's disease, and Parkinson's disease. 54. The method of any one of claims 51 to 53, wherein the neurodegenerative disease or condition is Parkinson's disease. 55. The method of 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 the disease, condition, and / or symptom as described in any one of claims 50 to 56. 56. The method of 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 method according to any one of claims 39 to 56, wherein the method comprises administering a pharmaceutical composition to a patient, such as a human or animal, the pharmaceutical composition comprising an effective amount, such as a therapeutically effective amount, of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier, and / or diluent. Claims 5 / 5 Page 6 CN 121511082 A 3-(2,3-difluorophenoxy)azacyclobutane or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of pathological apathy Technical Field

[0001] This disclosure relates to pathological apathy. Specifically, this disclosure relates to the compound 3-(2,3-difluorophenoxy)azacyclobutane or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of pathological apathy, such as apathy associated with neurodegenerative diseases or conditions. Background Art

[0002] Apathy is a mental state of indifference in an individual, which may include, for example, a lack of interest and / or motivation. Many people experience apathy at some point in their lives, but this is usually a temporary experience that can be overcome without or with minimal medical intervention. For example, apathy may be felt during periods of stress or due to trauma.

[0003] However, in a medical sense, pathological apathy is a long-term syndrome that may include symptoms such as loss of emotion, lack of motivation to perform or complete activities, lack of purpose, low energy levels, and / or a sense of detachment from life and personal events. Typically, pathological apathy is a symptom associated with an illness or condition, such as a neurodegenerative disease or condition. 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 cortex and cortical-limbic pathways.

[0004] Several measurement and assessment scales have been developed to diagnose apathy and determine whether it should be considered pathological apathy, such as the Apathy Assessment Scale (AES), the Apathy Motivation Index (AMI), the Dimensional Apathy Scale, and / or the Riehl Apathy Rating Scale.

[0005] With the increasing aging of the global population and the known increase in the prevalence of neurodegenerative diseases such as Parkinson's disease with age, the problem of pathological apathy is expected to become increasingly severe in the coming years.

[0006] WO 2018 / 091687 relates to 3-phenoxy-azacyclobutane derivatives that can be used to modulate the levels of monoamines such as dopamine, norepinephrine, and serotonin in the cortical regions of the mammalian brain, and more specifically for the treatment of central nervous system disorders. The compounds are described as being used to improve mental and motor function in Parkinson's disease. However, apathy is not mentioned.

[0007] BMJ Open 2020 10(9): e037632, pages 1-11 provide a literature review on apathy in Parkinson's disease. The compound 3-(2,3-difluorophenoxy)azacyclobutane is not mentioned.

[0008] It will be understood that the enumeration or discussion of obviously previously disclosed literature in this specification is not necessarily an admission that such literature is part of the prior art or common general knowledge.

[0009] Pathological apathy, especially persistent pathological apathy, has a very negative impact on quality of life because it affects many aspects of an individual, such as their interpersonal relationships, work capacity, overall health, etc. Currently, medications available for treating apathy include antidepressants, such as selective serotonin reuptake inhibitors (so-called SSRIs), antipsychotics, cholinesterase inhibitors, and medications that increase cerebral blood flow to treat apathy caused by stroke. Unfortunately, however, apathy has been found to be often difficult to treat, or even resistant to treatment. Therefore, there remains a need for a medicine capable of treating and / or preventing pathological apathy (such as pathological apathy associated with neurodegenerative diseases). In particular, there is a need for a medicine capable of treating and / or preventing pathological apathy associated with Parkinson's disease. Specification 1 / 7 pages 7 CN 121511082 A Summary of the Invention

[0010] One object of this disclosure is to overcome or at least alleviate the problems associated with the treatment and / or prevention of pathological apathy. Furthermore, one object of this disclosure is to provide aspects and / or advantages not provided by the technology known to date.

[0011] This disclosure provides a compound of formula I:

[0012] Formula I or a pharmaceutically acceptable salt thereof, for the treatment and / or prevention of pathological apathy.

[0013] This disclosure also provides a compound of formula I:

[0014] Formula I or a pharmaceutically acceptable salt thereof.

[0015] Use for manufacturing a medicine for the treatment and / or prevention of pathological apathy.

[0016] Furthermore, this disclosure provides a method for treating and / or preventing pathological apathy, the method comprising administering to a patient, such as a human or animal, an effective amount, such as a therapeutically effective amount, of a compound of formula I:

[0017] Formula I or a pharmaceutically acceptable salt thereof.

[0018] This disclosure describes providing a compound of formula I:

[0019] Formula I or a pharmaceutically acceptable salt thereof, for treating and / or preventing pathological apathy.

[0020] Thus, a compound of formula I as described herein is provided for treating and / or preventing pathological apathy. Furthermore, a pharmaceutically acceptable salt of a compound of formula I as described herein is provided for treating and / or preventing pathological apathy.

[0021] This disclosure also provides a compound of formula I: Specification 2 / 7 pages 8 CN 121511082 A

[0022] Formula I or a pharmaceutically acceptable salt thereof.

[0023] Use for manufacturing a medicament for treating and / or preventing pathological apathy. Therefore, the use of a compound of formula I as described herein for manufacturing a medicament for treating and / or preventing pathological apathy is provided. Furthermore, the use of a pharmaceutically acceptable salt of a compound of formula I as described herein for manufacturing a medicament for treating and / or preventing pathological apathy is provided.

[0024] Furthermore, this disclosure provides a method for treating and / or preventing pathological apathy, the method comprising administering to a patient, such as a mammal or animal, an effective amount, such as a therapeutically effective amount, of a compound of formula I as described herein:

[0025] Formula I or a pharmaceutically acceptable salt thereof.

[0026] Therefore, a method for treating and / or preventing pathological apathy is provided, the 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 as described herein. Furthermore, a method for treating and / or preventing pathological apathy is provided, the method comprising 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 a compound of formula I as described herein.

[0027] The pharmaceutically acceptable salt of a compound of formula I may be an acid addition salt. Acid addition salts can be combinations of a compound of formula I and an acid in a 1:n ratio, where n can be 0.33, 0.5, or 1. Therefore, acid addition salts of formula II are provided:

[0028] The salt of formula II is a combination of a compound of formula I and an acid as described herein in a 1:n ratio, where n can be 0.33, 0.5, or 1. For example, n can be 0.5 or 1.

[0029] 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, embrittlement acid, heptanoic 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 instance, the acid is not succinic acid or tartaric acid. Therefore, the following groups can be freely selected: 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, embrittlement acid, heptanoic 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.

[0030] Thus, the acid addition salt may be selected from the group consisting of: hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, ascorbate, benzenesulfonate, benzoate, cinnamic acid salt, citrate, embosate, heptanoate, 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 instance, the acid addition salt is not a succinate or tartrate. Therefore, acid addition salts may be selected from the group consisting of: hydrochloride, hydrobromide, borate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embosate, heptanoate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, toluene-p-sulfonate, and any combination thereof.

[0031] As used herein, the term pathological apathy is understood to mean apathy that can be determined as pathological using apathy measurement scales known in the art. For example, one or more of the following may be used to determine that apathy is pathological: apathy assessment scale, apathy motivation index, dimensional apathy scale, Riehl apathy rating scale. Additionally or alternatively, pathological apathy may be apathy associated with neuropathology in neurodegenerative diseases or conditions known in the art.

[0032] Pathological apathy may include one or more of the following symptoms: loss of emotion, lack of motivation to perform or complete activities, lack of purpose, low energy levels, and detachment from life and personal events. Pathological apathy can be apathy affecting a patient for one month or longer, such as two months, three months, four months, five months, or six months or longer.

[0033] In one instance, pathological apathy can be apathy occurring for one month or longer. Therefore, a compound of formula I or a pharmaceutically acceptable salt thereof is provided for the treatment and / or prevention of pathological apathy, administered to a patient suffering from pathological apathy for one month or longer. The patient may be a human or an animal.

[0034] Pathological apathy may be associated with diseases, conditions, and / or symptoms that respond to the regulation of monoamines in the cerebral cortex. For example, the disease or condition and / or symptom may be selected from the group consisting of: dementia, cognitive impairment, autism spectrum disorder, affective disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), motor disorder, postural instability. Cognitive impairment may be age-related cognitive impairment or cognitive impairment associated with neurodegenerative conditions and / or diseases. Postural instability may include or consist of: falls. In a further example, the disease, condition and / or symptom 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 further example, the disease, condition and / or symptom 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 further example, a disease, condition, and / or symptom may include or consist of a neurodegenerative disease or condition, such as Alzheimer's disease or Parkinson's disease.

[0035] Furthermore, a compound of Formula I or a pharmaceutically acceptable salt thereof may be administered to a patient suffering from a disease, condition, and / or symptom 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 motor disorder. In particular, a compound of Formula I or a pharmaceutically acceptable salt thereof may be administered to a patient suffering from Parkinson's disease.

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

[0037] It will be understood that a compound of formula I or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical compositions described herein in a therapeutically effective amount. A pharmaceutically acceptable dose may be from about 5 mg to about 80 mg, once or twice daily.Furthermore, the pharmaceutical composition may be a pharmaceutical composition for oral administration, such as capsules, pills, tablets, lozenges, or liquid formulations, as described in the specification 4 / 7 pages 10 CN 121511082 A, such as syrups, suspensions, or solutions. For example, the pharmaceutical composition may be a capsule or tablet, such as a capsule tablet.

[0038] Salts herein, the chemical structure of a salt of Formula II comprising a combination of a compound of Formula I and an acid is drawn as a complex, wherein the acidic proton of the acid is linked to the acid. However, those skilled in the art will understand that the acidic proton of the acid may be linked to a nitrogen atom of a compound of Formula I and / or shared between a nitrogen atom of a compound of Formula I and an acid, and this is also intended to be covered by the salts described herein.

[0039] Labeled Compounds The compounds of this disclosure may be used in their labeled or unlabeled form. In the context of this disclosure, a labeled compound has one or more atoms replaced by atoms whose atomic mass or mass number differs from the atomic mass or mass number normally found in nature. Labeling will allow for simple quantitative detection of the compound.

[0040] For example, one or more hydrogen atoms in a compound of Formula I may be replaced by one or more isotopes such as one or more deuterium atoms.

[0041] The labeled compounds of this disclosure can be used as diagnostic tools, radiotracers, or monitors in various diagnostic methods and for in vivo receptor imaging. The labeled compounds of this disclosure may contain at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for use. In the context of this disclosure, the radionuclide may be selected from isotopes of hydrogen, carbon, nitrogen, fluorine, and oxygen, such as 2H (deuterium), 3H (tritium), 11C, 13C, 14C, 18O, 17O, 19F, and 18F. It is known that substitution with a heavier isotope, such as replacing one or more hydrogen atoms with deuterium (2H), may provide pharmacological advantages in certain situations, such as increased metabolic stability.

[0042] The physical methods used to detect the labeled compounds of this disclosure may be selected from positron emission tomography (PET), single-photon imaging computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial computed tomography (CAT), or combinations thereof.

[0043] It will be understood that the salts of this disclosure may be combined with other pharmaceuticals for the treatment and / or prevention of CNS symptoms and / or diseases. Other pharmaceuticals may be L-DOPA, selective serotonin reuptake inhibitors, antidepressants such as bupropion (i.e., (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)prop-1-one; CAS No.: 34911-55-2), CNS stimulants such as methylphenidate (i.e., methyl phenyl(piperidin-2-yl)acetate; CAS No.: 20748-11-2), and / or antipsychotics.Therefore, a complete pharmaceutical assembly is provided comprising: (i) a salt of the present disclosure, such as a salt of Formula III as described herein; (ii) a drug 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)prop-1-one; CAS No.: 34911-55-2), CNS stimulants such as methylphenidate (i.e., methyl phenyl(piperidin-2-yl)acetate; CAS No.: 20748-11-2), and antipsychotic drugs; and (iii) instructions for use, optionally for the individual, simultaneous, or sequential administration of (i) and (ii).

[0044] As used herein, the term prevention includes referring to preventive treatment and / or prevention of disease, symptom, and / or illness. Specifically, the term may refer to the likelihood of achieving a reduction in the development of symptoms in a patient (or healthy subject) (e.g., a reduction of at least 10%, such as a reduction of at least 20%, 30%, or 40%, such as a reduction of at least 50%).

[0045] Furthermore, as used herein, the term "therapeuticly effective amount" refers to the amount of compound that imparts a therapeutic effect to the treated patient. The effect may be objective (i.e., measurable by some test or biomarker) or subjective (i.e., the subject gives indication of the effect and / or feels the effect).

[0046] The invention will be further described with reference to the following examples, but these examples are not intended to limit the scope of the invention.

[0047] Examples Specification 5 / 7 pages 11 CN 121511082 A Abbreviations

[0048] Basic Information Compound 3-(2,3-difluorophenoxy)azacyclobutane is provided by Integrative Research Laboratories Sweden AB, Göteborg, Sweden, in the form of hydrochloride.

[0049] Male Sprague-Dawley rats weighing 280 to 320 g were used. Prior to the experiment, the animals were housed in groups of up to five per cage, with free access to water and food. The animals were housed for at least one week prior to surgery and use in the experiment.

[0050] Spontaneous activity was measured using a kinesiometer known in the art.

[0051] Example 1: Spontaneous Activity in Rats Pretreated with Bubenazine Bubenazine (CAS No. 58-46-8, and abbreviated herein as TBZ) is a compound used for the symptomatic treatment of hyperkinetic dyskinesia. As described in Movement Disorders, Vol. 37, No. 6, 2022, pp. 1149-1163, in rodent studies, bubenazine has led to a bias in behavior towards “effortless” selection, reflecting phenotypic apathy. Based on this information, for example, TBZ treatment has been used as a model of pathological apathy in this example.TBZ acts as a monoamine depletor by selectively binding to vesicular monoamine transporter 2 (VMAT-2). VMAT-2 transports serotonin, dopamine (DA), norepinephrine (NE), and histamine into vesicles for storage. Through high-affinity binding to VMAT-2, TBZ primarily acts as a reversible inhibitor of monoamine uptake by granular vesicles in presynaptic neurons. This inhibition leads to the depletion of monoamines, particularly dopamine, resulting in a hypomonaminase state. In this instance, the hypomonaminase state induced by bubenazine is associated with pathological apathy, such as apathy associated with Parkinson's disease, and results in decreased spontaneous activity. Therefore, reversing the decrease in spontaneous activity due to the hypomonaminase state indicates a reduction in pathological apathy (i.e., the experience of apathy relief), such as apathy associated with Parkinson's disease.

[0052] The effect of 3-(2,3-difluorophenoxy)azacyclobutane on spontaneous activity was investigated in male Sprague-Dawley rats pretreated with a dose of TBZ known to cause a half-maximal reduction in spontaneous activity.

[0053] The animals were divided into four different treatment groups and treated as described below.

[0054] Group 1: Carrier, n=5. In this document, the carrier means physiological saline (0.9% w / v). In this group, rats were subjected to subcutaneous injection of the carrier, followed by recording of spontaneous activity. The number of rats in this document is expressed as n.

[0055] Group 2, also known as the control group: TBZ 0.64 mg / kg, n=5. In this group, rats were subjected to subcutaneous injection of a solution of TBZ in physiological saline to provide a dose of 0.64 mg / kg in the rats, followed by recording of spontaneous activity.

[0056] Group 3: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azacyclobutane 11 µmol / kg, n = 5. In this group, rats were pretreated by subcutaneous injection of a solution of TBZ in physiological saline to provide a dose of 0.64 mg / kg in the rats, and then these rats were left to rest for two hours. Thereafter, the rats were subjected to subcutaneous injection of a solution of 3-(2,3-difluorophenoxy)azacyclobutane in a medium to provide a dose of 11 μmol / kg of 3-(2,3-difluorophenoxy)azacyclobutane in the rats, and spontaneous activity was recorded 15 minutes after the injection.

[0057] Group 4: TBZ 0.64 mg / kg + compound 3-(2,3-difluorophenoxy)azacyclobutane 33 µmol / kg, n = 5. In this group, rats were pretreated by subcutaneous injection of a solution of TBZ in saline to provide a dose of 0.64 mg / kg in vivo, and then the rats were left to rest for two hours.Subsequently, rats were subjected to subcutaneous injection of a solution of 3-(2,3-difluorophenoxy)azacyclobutane in a medium to provide a dose of 33 μmol / kg of 3-(2,3-difluorophenoxy)azacyclobutane in vivo, and spontaneous activity was recorded 15 minutes after injection.

[0058] It will be understood that a dose of 11 μmol / kg of 3-(2,3-difluorophenoxy)azacyclobutane hydrochloride corresponds to a dose of 2.06 mg / kg of the corresponding base (i.e., pure 3-(2,3-difluorophenoxy)azacyclobutane). Furthermore, a dose of 33 μmol / kg of 3-(2,3-difluorophenoxy)azacyclobutane hydrochloride corresponds to a concentration dose of 6.17 mg / kg of the corresponding base.

[0059] The results are shown in Figure 1. Spontaneous activity was observed in the control group (i.e., group 2) to be lower than in group 1 (which was the group of rats not pretreated with TBZ). Therefore, the addition of TBZ reduced spontaneous activity. It was also observed that spontaneous activity in Group 3 was higher than that observed in the control group. Furthermore, spontaneous activity in Group 4 was significantly higher than that in both the control and Group 3. In particular, spontaneous activity in Group 4 was much higher than that in Group 3.

[0060] Therefore, compound 3-(2,3-difluorophenoxy)azacyclobutane increases spontaneous activity in subjects (such as rats in a low monoaminergic state). Furthermore, higher doses of 3-(2,3-difluorophenoxy)azacyclobutane result in increased spontaneous activity compared to lower doses. Therefore, spontaneous activity increases in a dose-dependent manner when compound 3-(2,3-difluorophenoxy)azacyclobutane is administered to rats in a low monoaminergic state.

[0061] Further examples of spontaneous activity experiments were conducted on rats not treated with TBZ, as reported in Table 1 on page 89 of WO 2018 / 091687, where the overall trend was a decrease in spontaneous activity as the dose of the compound in Example 1A increased. The table shows that when the dose was increased from 11 μmol / kg to 33 μmol / kg, the compound of Example 1A, namely 3-(2,3-difluorophenoxy)azacyclobutane hydrochloride, had a very modest effect on spontaneous activity. Spontaneous activity increased only from 135% to 163%. Furthermore, the table shows that further increasing the dose of the compound of Example 1A from 33 μmol / kg to 100 μmol / kg reduced spontaneous activity from 163% to 121%. Therefore, the conclusion regarding the effect of the compound of Example 1A on the spontaneous activity of untreated rats is that there was no dose-dependent increase in spontaneous activity when the compound was administered to rats. As a result, the compound had little or no effect on spontaneous activity, and the trend was that spontaneous activity actually decreased with increasing doses of the compound of Example 1A. However, it is noteworthy that this comparative example did not involve rats pretreated with TBZ.Therefore, this rat model using TBZ without pretreatment is not a model of apathy.

[0062] References 1. WO 2018 / 091687 A1 2. Movement Disorders, Vol. 37, No. 6, 2022, pp. 1149-1163 3. BMJ Open 2020 10(9): e037632, pp. 1-11. Specification 7 / 7 pages 13 CN 121511082 A Figure 1 Specification Figure 1 / 1 page 14 CN 121511082 A.

Claims

1. A compound of formula I: Formula I Or its pharmaceutically acceptable salt. It is used to treat and / or prevent pathological apathy.

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

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

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

5. The pharmaceutically acceptable salt 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, embosate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene- right - Sulfonates and any combination thereof.

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

7. The compound used according to claim 1 or 2 or The pharmaceutically acceptable salt used according to any one of claims 1 to 6 In the compound of formula I, one or more hydrogen atoms are replaced by deuterium.

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

9. The compound used according to any one of claims 1, 2, 7 or 8 or The pharmaceutically acceptable salt used according to any one of claims 1 to 8 The pathological apathy mentioned therein includes apathy as defined according to the apathy measurement scale.

10. The compound used according to claim 9 or The pharmaceutically acceptable salt used according to claim 9 The apathy measurement scale mentioned therein is one or more of the following: apathy assessment scale, apathy motivation index, dimensional apathy scale, and Riehl apathy rating scale.

11. The compound used according to any one of claims 1, 2, or 7 to 10, or The pharmaceutically acceptable salt used according to any one of claims 1 to 10 The pathological apathy described therein is associated with diseases, conditions and / or symptoms that respond to the regulation of monoamines in the cerebral cortex.

12. The compound used according to claim 11 or The pharmaceutically acceptable salt used according to claim 11 The diseases, conditions and / or symptoms mentioned therein are 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 instability.

13. The compound used according to claim 11 or 12 or The pharmaceutically acceptable salt used according to claim 11 or 12 The diseases, conditions and / or symptoms mentioned include neurodegenerative diseases or conditions.

14. The compound used according to claim 13 or The pharmaceutically acceptable salt used according to claim 13 The neurodegenerative diseases or conditions mentioned therein are 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 used according to claim 13 or 14 or The pharmaceutically acceptable salt used according to claim 13 or 14 The neurodegenerative diseases or conditions mentioned therein are selected from the group consisting of: dementia, Alzheimer's disease, and Parkinson's disease.

16. The compound used according to any one of claims 13 to 15 or The pharmaceutically acceptable salt used according to any one of claims 13 to 15 The neurodegenerative disease or condition mentioned is Parkinson's disease.

17. The compound used according to any one of claims 1, 2, or 7 to 16 or The pharmaceutically acceptable salt used according to any one of claims 1 to 16 The compound or the pharmaceutically acceptable salt is administered to a patient suffering from any of the diseases, conditions and / or symptoms according to any one of claims 11 to 16.

18. The compound used according to any one of claims 1, 2, or 7 to 17 or The pharmaceutically acceptable salt used according to any one of claims 1 to 17 Administer the compound or the pharmaceutically acceptable salt to a patient with Parkinson's disease.

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

20. Compound of Formula I: Formula I The use of its pharmaceutically acceptable salts in the manufacture of medicines for the treatment and / or prevention of pathological apathy.

21. The use according to claim 20, wherein the provided compound of formula I is used to manufacture a medicament for treating and / or preventing 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, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embosate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene- right - Sulfonates and any combination thereof.

25. The use according to any one of claims 20 or 22 to 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 hydrogen atoms in the hydrogen atoms of the compound of formula I are replaced by 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 one month or longer.

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 assessment scale, an apathy motivation index, a dimensional apathy scale, or a Riehl apathy rating scale.

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

31. The use according to claim 30, wherein the disease, condition and / or symptom 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 instability.

32. The use according to claim 30 or 31, wherein the disease, condition and / or symptom includes neurodegenerative diseases or conditions.

33. The use according to claim 31 or 32, wherein the neurodegenerative disease or condition 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 condition 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 condition 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 the disease, condition and / or symptom according to 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 an admixture of the compound of formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipient, carrier and / or diluent.

39. A method for treating and / or preventing pathological apathy, the method comprising administering to a patient, such as a human or animal, an effective amount, such as a therapeutically effective amount, of a compound of formula I. Formula I Or its pharmaceutically acceptable salt.

40. The method of 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 compound of formula I. Formula I.

41. The method of 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 of 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, embosate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, propionate, salicylate, sorbate, stearate, succinate, tartrate, toluene- right - Sulfonates 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 hydrogen atoms in the hydrogen atoms of the compound of formula I are replaced by 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 longer.

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 of claim 47, wherein the apathy measurement scale is one or more of the following: an apathy assessment scale, an apathy motivation index, a dimensional apathy scale, or a Riehl apathy rating scale.

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

50. The method of claim 49, wherein the disease, condition and / or symptom 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 instability.

51. The method of claim 49 or 50, wherein the disease, condition and / or symptom includes neurodegenerative diseases or conditions.

52. The method of claim 51, wherein the neurodegenerative disease or condition 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 of claim 52, wherein the neurodegenerative disease or condition 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 condition 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 the disease, condition and / or symptom according to any one of claims 50 to 56.

56. The method of 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 method according to any one of claims 39 to 56, wherein the method comprises administering a pharmaceutical composition to a patient, such as a human or animal, the pharmaceutical composition comprising an effective amount, such as a therapeutically effective amount, of a compound of formula I. Formula I or its pharmaceutically acceptable salt Admixtures with pharmaceutically acceptable excipients, carriers and / or diluents.

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