Search

EP-4739308-A1 - 3-(2,3-DIFLUOROPHENOXY)AZETIDINE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, FOR USE IN THE TREATMENT AND/OR PREVENTION OF PATHOLOGICAL APATHY

EP4739308A1EP 4739308 A1EP4739308 A1EP 4739308A1EP-4739308-A1

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.

Inventors

  • WATERS, NICHOLAS

Assignees

  • Integrative Research Laboratories Sweden AB

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. 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. 2. The compound of Formula I according to claim 1 for use in the treatment and/or prevention of pathological apathy.
  3. 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. 4. The pharmaceutically acceptable salt for use according to claim 1 or 3, wherein the pharmaceutically acceptable salt is an acid addition salt.
  5. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 20. Use of a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of pathological apathy.

Description

3-(2,3-DIFLUOROPHENOXY)AZETIDINE, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, FOR USE IN THE TREATMENT AND/OR PREVENTION OF PATHOLOGICAL APATHY Technical field 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. Background 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. 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. 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. 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. 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. 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. 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. Summary 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. The present disclosure provides a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of pathological apathy. The present disclosure also provides the use of a compound of Formula I: Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prevention of pathological apathy. 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: Formula I or a pharmaceutically acceptable salt thereof. Description The present discl