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EP-4739654-A1 - PHARMACEUTICALLY ACCEPTABLE SALTS OF 3-(2,3-DIFLUOROPHENOXY)AZETIDINE AND USES THEREOF

EP4739654A1EP 4739654 A1EP4739654 A1EP 4739654A1EP-4739654-A1

Abstract

There is disclosed a salt of Formula (III), wherein n is 0.5 or 1, a method of manufacturing thereof as well as uses thereof.

Inventors

  • KAZA ONOKA, Galina
  • EKAWA, Bruno
  • FERNANDEZ, ANA
  • BUKSA, Maija
  • NGUYEN, LIEN
  • WATERS, NICHOLAS

Assignees

  • Integrative Research Laboratories Sweden AB

Dates

Publication Date
20260513
Application Date
20240705

Claims (20)

  1. 1. A salt of Formula Formula III said salt being a combination of a compound of Formula I and an acid of Formula II: Formula I Formula II in a ratio of l :n, wherein X is OH or H; and n is 0.5 or 1.
  2. 2. The salt of Formula III according to claim 1, wherein X is OH thereby providing a salt of Formula Illa being a combination of the compound of Formula I and tartaric acid : Formula Illa
  3. 3. The salt of Formula Illa according to claim 2, wherein the tartaric acid is !_-(+)- tartaric acid.
  4. 4. The salt of Formula Illa according to claim 2, wherein the tartaric acid is D-(-)- tartaric acid.
  5. 5. The salt of Formula Illa according to claim 2, wherein the tartaric acid is !_-(+)- tartaric acid and D-(-)-tartaric acid.
  6. 6. The salt of Formula III according to claim 1, wherein X is H thereby forming a salt of Formula Illb being a combination of the compound of Formula I and succinic acid: Formula Illb
  7. 7. The salt of Formula III according to any one of the preceding claims, wherein n is 0.5.
  8. 8. The salt of Formula III according to any one of claims 1-6, wherein n is 1.
  9. 9. The salt according to any one of the preceding claims, characterised by being crystalline.
  10. 10. The salt of Formula III according to any one of claims 1-5, 7 or 9, characterized by an XRP diffractogram comprising a peak at 27.4 degrees 20 and one or more peaks selected from the following: 17.8, 19.5, 19.9, 21.6 degrees 20.
  11. 11. The salt of Formula III according to any one of claims 1-5, 7 or 9, characterized by an XRP diffractogram as shown in Figure 1.
  12. 12. The salt of Formula III according to any one of claims 1, 6, 8 or 9 , characterized by an XRP diffractogram comprising a peak at 12.5 degrees 20 and one or more peaks selected from the following: 13.3, 16.5, 19.3, 22.4, 23.3, 24.1, 24.9, 25.9, 26.9 degrees 20.
  13. 13. The salt of Formula III according to any one of claims 1, 6, 8 or 9, characterized by an XRP diffractogram as shown in Figure 2.
  14. 14. The salt of Formula III according to any one of the preceding claims, wherein one or more of the hydrogen atoms of the compound of Formula I is/are replaced with deuterium.
  15. 15. The salt of Formula III according to any one of the preceding claims, wherein said salt changes its weight by about ± 0.2% by weight or less at any humidity, such as any relative humidity such as a relative humidity of 80% measured at a temperature from 20 °C to 25 °C.
  16. 16. The salt of Formula III according to any one of claims 1-5 or 7-11, which has a water solubility from 53 mg/mL to 106 mg/mL and/ or a melting point of 181.5 °C.
  17. 17. The salt of Formula III according to any one of claims 1, 6-9, 12 or 13, which has a water solubility from 20 mg/mL to 40 mg/mL and/ or a melting point of 150.2 °C.
  18. 18. The salt of Formula III according to any one of the preceding claims, wherein said salt is chemically stable in methanol solution at room temperature, at a temperature of 37 °C and/or at a temperature of 50 °C for 48 hours or more such as for 168 hours or more.
  19. 19. A pharmaceutical composition comprising the salt of Formula III according to any one of the preceding claims in admixture with a pharmaceutically acceptable excipient, carrier and/or diluent.
  20. 20. The salt of Formula III as defined in any one of claims 1-18, or the pharmaceutical composition according to claim 19 for use as a medicament.

Description

PHARMACEUTICALLY ACCEPTABLE SALTS OF 3-(2,3-DIFLUOROPHENOXY)AZETIDINE AND USES THEREOF Technical field The present disclosure concerns pharmaceutically acceptable salts of the compound 3-(2,3-difluorophenoxy)azetidine, a method for manufacturing thereof and uses thereof. More specifically, the present disclosure concerns a succinic acid salt and a tartaric acid salt of 3-(2,3-difluorophenoxy)azetidine. Background The cerebral cortex encompasses several major regions of the brain that are involved in higher functions such as thought, feelings, memory and planning. Monoamines, such as dopamine, norepinephrine and serotonin, are important as neurotransmitters for mammalian cortical function. The ascending serotonergic and noradrenergic pathways innervate virtually all regions of the brain, including the cerebral cortex. The dopaminergic neurons of the CNS have more distinct projections, including the meso- cortical pathway primarily innervating the frontal cortex in addition to a number of specific subcortical pathways. Primary or secondary dysfunctions in the activity of the monoamine pathways innervating the cerebral cortex lead to aberrations of the activity at cortical dopamine, norepinephrine and serotonin receptors and subsequently to manifestations of psychiatric and neurological symptoms. The monoamines of the cortex modulate several aspects of cortical functions controlling affect, anxiety, motivation, cognition, attention, arousal and wakefulness. Thus, the catecholamines, dopamine and norepinephrine exert strong influence on the frontal cortical areas, the integrity of which is essential for the so-called executive cognitive functions related to e.g., attention, planning of actions and impulse control. Norepinephrine is a major part in the circuitry regulating anxiety and fear and is thus believed to be dysregulated in anxiety disorders such as panic disorders, generalized anxiety disorder (GAD) and specific phobias. Concerning mood and affective functions, the usefulness of compounds facilitating particularly norepinephrine and serotonin neurotransmission in the treatment of depression and anxiety has strongly contributed to the widely accepted concept that these neurotransmitters are both involved in the regulation of affective functions. Prog Neuro-Psychopharm & Bio Psych, 2013, 45, 54-63 discloses that compounds specifically affecting the transmission of monoamines, more precisely norepinephrine, dopamine and serotonin, are successfully used to alleviate the affective, cognitive, or attentional symptoms in patients suffering from e.g., depression, anxiety and attention deficit hyperactivity disorder (ADHD). In addition, Biol Psych, 2011, 69(12); 89-99 discloses that all current pharmacological treatments for ADHD facilitate catecholamine transmission. Furthermore, Front Cell Neurosci, 2015, 9; 1-23 discloses that modulation of monoaminergic transmission has been suggested as a promising principle for the treatment of autism spectrum disorders. Neurosci & Biobehav Rev, 2013, 37; 1363-79 discloses that in Alzheimer's disease, progressive degeneration of ascending monoamine systems has been linked to cognitive as well as non-cognitive symptoms, and pharmacological interventions leading to enhanced monoamine transmission have been suggested as a strategy both for symptomatic and disease-modifying treatments of Alzheimer's disease. Furthermore, the monoamine systems in the cortex are known to be directly or indirectly involved in the core symptoms of schizophrenia. It has been proposed that this disorder emerges as various pathological etiologies converge upon cortical synaptic processes leading to dysregulation of the cortical micro-circuitry, which is clinically manifested as the symptoms of schizophrenia (Harrison et al., Mol Psych, 2005, 1 O; 40-68). This cortical micro-circuitry is regulated by several neurotransmitters, including glutamate, GABA, and dopamine. It has further been proposed that pharmacological enhancement of cortical dopamine transmission could restore the function of this microcircuitry, providing a useful strategy for improved treatment of schizophrenia (Abi-Dargham et al., Eur Psych, 2005, 20; 15-27). WO 2010/022055 discloses certain 3-phenoxy-azetidine derivatives as synthetic intermediates in the synthesis of inhibitors of voltage-gated sodium channels. The compound 3-(2,3-difluorophenoxy)azetidine in non-salt form is one of the synthetic intermediates. The database SciFinder discloses the compound 3-(2,3-difluorophenoxy)azetidine in non-salt form as a chemical that is commercially available. WO 2018/091687 discloses 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 system disorders. It is disclosed that the compound of Formula I may be an isotope labelled analog of or a pharmaceutically ac