Pharmacologically acceptable salts of 3-(2,3-difluorophenoxy)azetidine and their use

Abstract

Salts of formula III in which n is 0.5 or 1, methods for producing the same, and uses thereof are disclosed. [Formula 1] JPEG2026522878000032.jpg27166

Description

[Technical Field]

[0001] This disclosure relates to pharmaceutically acceptable salts of compound 3-(2,3-difluorophenoxy)azetidine, methods for producing the same, and uses thereof. More specifically, this disclosure relates to succinate and tartrate salts of 3-(2,3-difluorophenoxy)azetidine. [Background technology]

[0002] The cerebral cortex encompasses several major brain regions involved in higher-order functions such as thinking, feeling, memory, and planning. Monoamines such as dopamine, norepinephrine, and serotonin are important neurotransmitters in mammalian cortical function. Ascending serotonergic and noradrenergic pathways innervate virtually all areas of the brain, including the cerebral cortex. Dopaminergic neurons in the CNS have more distinct projections and include numerous specific subcortical pathways in addition to mesocortical pathways that primarily innervate the frontal cortex. Primary or secondary dysfunction of the activity of monoamine pathways innervating the cerebral cortex leads to abnormalities in the activity of cortical dopamine, norepinephrine, and serotonin receptors, subsequently resulting in the manifestation of psychiatric and neurological symptoms.

[0003] Monoamines in the cerebral cortex modulate several aspects of cortical function that control emotion, anxiety, motivation, cognition, attention, arousal, and wakefulness. Thus, catecholamines, dopamine, and norepinephrine strongly influence areas of the prefrontal cortex, and the integrity of this area is essential for so-called executive cognitive functions, such as attention, behavioral planning, and impulse control. Norepinephrine is a major component of the circuits that modulate anxiety and fear, and therefore, in anxiety disorders such as panic disorder, generalized anxiety disorder (GAD), and specific phobias, norepinephrine dysregulation is thought to be present. Regarding mood and emotional function, the usefulness of compounds that promote the neurotransmission of norepinephrine and serotonin in particular in the treatment of depression and anxiety disorders has greatly contributed to the widely accepted concept that both of these neurotransmitters are involved in the regulation of emotional function.

[0004] Prog Neuro-Psychopharm&Bio Psych, 2013, 45, 54-63 discloses that compounds that specifically affect the transmission of monoamines, more precisely norepinephrine, dopamine, and serotonin, have been successfully used to alleviate emotional, cognitive, or attentional symptoms in patients suffering from, for example, 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 promote catecholamine transmission. Furthermore, Front Cell Neurosci, 2015, 9; 1-23 discloses that modulation of monoaminergic transmission is suggested to be a promising principle for the treatment of autism spectrum disorder.

[0005] Neurosci & Biobehav Rev, 2013, 37;1363-79 discloses that in Alzheimer's disease, progressive degeneration of the ascending monoamine system is associated with cognitive and non-dementia symptoms, and that pharmacological interventions leading to enhancement of monoamine transmission are suggested as strategies for both symptomatic and disease-modifying treatment of Alzheimer's disease.

[0006] Furthermore, the monoamine system of the cerebral cortex is known to be directly or indirectly involved in the core symptoms of schizophrenia. It has been proposed that this disorder arises from the convergence of various pathological etiologies on synaptic processes in the cerebral cortex, and that the resulting dysregulation of cortical microcircuits clinically manifests as the symptoms of schizophrenia (Harrison et al., Mol Psych, 2005, 1 O; 40-68). These cortical microcircuits are regulated by several neurotransmitters, including glutamate, GABA, and dopamine. Moreover, it has been proposed that pharmacologically enhancing dopamine transmission in the cerebral cortex can restore the function of these microcircuits and provide a useful strategy for improving the treatment of schizophrenia (Abi-Dargham et al., Eur Psych, 2005, 20; 15-27).

[0007] International Publication No. 2010 / 022055 discloses certain 3-phenoxy-azetidine derivatives as synthetic intermediates in the synthesis of voltage-gated sodium channel inhibitors. The unsalted compound 3-(2,3-difluorophenoxy)azetidine is one of the synthetic intermediates.

[0008] The database SciFinder discloses the compound 3-(2,3-difluorophenoxy)azetidine in its non-salt form as a commercially available chemical.

[0009] International Publication No. 2018 / 091687 discloses a 3-phenoxy-azetidine derivative that is useful for regulating the levels of monoamines such as dopamine, norepinephrine, and serotonin in the cerebral cortical regions of the mammalian brain, and more specifically for the treatment of central nervous system disorders. It is disclosed that the compound of formula I may be an isotopically labeled analog or a pharmaceutically acceptable salt of 3-(2,3-difluorophenoxy)azetidine. Example 1A discloses 3-(2,3-difluorophenoxy)azetidine hydrochloride. Example 1B discloses 3-(2,3-difluorophenoxy)azetidine fumarate.

[0010] Any list or discussion of previously published literature in this specification should not necessarily be construed as an endorsement that such documents are part of cutting-edge technology or common general knowledge.

[0011] Further investigation and development of 3-(2,3-difluorophenoxy)azetidine have revealed the need for a form of 3-(2,3-difluorophenoxy)azetidine that exhibits satisfactory pharmaceutical properties, handling properties, and drug properties, particularly on an industrial scale. Furthermore, there is a need for a form of 3-(2,3-difluorophenoxy)azetidine with high chemical stability, such as high chemical stability in solution. [Brief explanation of the drawing]

[0012] [Figure 1] The XRP diffraction pattern of the salt of equation IIIa11 is shown. [Figure 2] The XRP diffraction pattern of the salt of equation IIIb2 is shown.

[0013] The object of the present disclosure is to provide a form of 3-(2,3-difluorophenoxy)azetidine that exhibits satisfactory pharmaceutical properties as well as handling and drug properties, particularly on an industrial scale. The object of the present disclosure is also to provide a form of 3-(2,3-difluorophenoxy)azetidine that enables production at high purity on an industrial scale. Furthermore, the object of the present disclosure is to provide a form of 3-(2,3-difluorophenoxy)azetidine having high chemical stability such as high chemical stability in solution. Further, the object of the present disclosure is to provide aspects and / or advantages not provided by techniques known heretofore.

[0014] The present disclosure provides a salt of formula III [Chemical formula] wherein the salt is a combination of a compound of formula I and an acid of formula II [Chemical formula] and the ratio is 1:n wherein X is OH or H and n is 0.5 or 1.

[0015] The present disclosure also provides a pharmaceutical composition comprising the salt of formula III described herein in a mixture with a pharmaceutically acceptable excipient, carrier, and / or diluent.

[0016] Furthermore, the present disclosure provides the salt of formula III or the pharmaceutical composition described herein for use as a medicament.

[0017] The present disclosure also provides the salts of formula III or pharmaceutical compositions described herein for use in the treatment and / or prevention of diseases, disorders, and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, mood disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), movement disorder, posture maintenance disorder, and pathological apathy.

[0018] The present disclosure also provides the use of the salts of formula III or pharmaceutical compositions described herein for the manufacture of a medicament for the treatment and / or prevention of diseases, disorders, and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, mood disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), movement disorder, posture maintenance disorder, and pathological apathy.

[0019] The present disclosure also provides a method for the treatment and / or prevention of diseases, disorders, and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, mood disorder, schizophrenia, anxiety disorder, attention deficit hyperactivity disorder (ADHD), movement disorder, posture maintenance disorder, and pathological apathy, the method comprising administering to a mammal such as a human or an animal in need thereof an effective amount, such as a therapeutically effective amount, of the salts of formula III or pharmaceutical compositions described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present disclosure provides a salt of formula III

CHEMICAL FORMULA

CHEMICAL FORMULA

[0021] Furthermore, the values ​​of X and n are explained below. It should be understood that such values ​​may be used in any of the definitions, examples, and / or claims described herein.

[0022] For example, if X is OH and n is 0.5 or 1, then the salt of formula IIIa is a combination of the compound of formula I and tartaric acid. [ka] It will be provided.

[0023] The tartaric acid described herein may be L-(+)-tartaric acid and / or D-(-)-tartaric acid. The tartaric acid may be provided as a racemic mixture. Alternatively, the tartaric acid of the salt of formula IIIa may be L-(+)-tartaric acid.

[0024] The value of n may be 0.5. Alternatively, the value of n may be 1.

[0025] For the salt of formula IIIa, if n is 0.5, then the salt of formula IIIa1 [ka] It will be provided.

[0026] For example, the tartaric acid in the salt of formula IIIa may be L-(+)-tartaric acid, and n may be 0.5. This salt may be called the salt of formula IIIa11.

[0027] For the salt of formula IIIa, if n is 1, then the salt of formula IIIa2 [ka] It will be provided.

[0028] Furthermore, X may be H, and n may be 0.5 or 1, thereby forming the salt of formula IIIb, which is a combination of the compound of formula I and succinic acid. [ka] It will be provided.

[0029] For the salt of formula IIIb, if n is 0.5, then the salt of formula IIIb1 [ka] It will be provided.

[0030] Furthermore, if n is 1 for the salt of equation IIIb, then the salt of equation IIIb2 [ka] It will be provided.

[0031] The salt of Formula III described herein is pharmaceutically acceptable and has been found to be unexpectedly crystalline and non-hygroscopic. Furthermore, it has been found to have a high melting point and high chemical purity, and in addition, to have acceptable, i.e., satisfactory water solubility. The high melting point is beneficial, for example, in tablet manufacturing. Satisfactory water solubility makes it suitable for all administrations to patients, such as humans, including oral administration.

[0032] Accordingly, the salt of formula III described herein is provided, characterized by being crystalline. The degree of crystallinity can be determined by XRPD or any other suitable method. The degree of crystallinity of the salt of formula III is well defined with respect to, for example, the melting point and / or XRPD, which is beneficial when manufacturing tablets, for example. It is also thought to enhance storage stability. The degree of crystallinity of the salt of formula III may be about 80% or more, for example, about 85% or more, about 90% or more, about 95% or more, about 99% or more, or about 100%, as measured by XRPD or any other suitable method. In particular, the degree of crystallinity of the salt of formula III may be 95% or more or 99% or more.

[0033] Salts of formula IIIa, for example, salt of formula IIIa11, may be characterized by XRP diffraction patterns as shown in Figure 1. Additionally or alternatively, salts of formula IIIa may be characterized by XRP diffraction patterns including a peak at approximately 27.4 degrees 2θ and one or more peaks selected from the following: approximately 17.8 degrees, approximately 19.5 degrees, approximately 19.9 degrees, and approximately 21.6 degrees 2θ.

[0034] Salts of formula IIIb, for example, salt of formula IIIb2, may be characterized by XRP diffraction patterns as shown in Figure 2. Additionally or alternatively, salts of formula IIIb may be characterized by XRP diffraction patterns including a peak at about 12.5 degrees 2θ and one or more peaks selected from the following 2θ degrees: about 13.3, about 16.5, about 19.3, about 22.4, about 23.3, about 24.1, about 24.9, about 25.9, and about 26.9 degrees 2θ.

[0035] The fact that the salt of formula III is non-hygroscopic is advantageous because it allows for storage that is unaffected, or substantially unaffected, by ambient humidity. Of course, this is important and useful when storing salt in situations such as the industrial production of pharmaceuticals. It has been found that the salt of formula III changes its weight by ±0.2% by weight or less at any humidity, such as any relative humidity described herein. Therefore, the salt of formula III is non-hygroscopic, or substantially non-hygroscopic. As an example, the salt of formula III changes its weight by ±0.2% or less at a relative humidity of about 80%. Relative humidity can be measured at room temperature, i.e., at a temperature of about 20°C to about 25°C, such as about 22°C.

[0036] In this book, relative humidity is defined as the ratio of the partial pressure of water vapor in the air to the equilibrium pressure of water at a given temperature and atmospheric pressure.

[0037] The salt of formula III has been found to have a high melting point. This is advantageous, for example, for enabling the manufacture of tablets. For example, the melting point may be in the range of approximately 135°C to approximately 190°C. In addition, the salt of formula III has been found to have satisfactory water solubility. For example, the water solubility may be in the range of approximately 15 mg / mL to approximately 75 mg / mL. Water solubility can be determined as described in this document.

[0038] Accordingly, salts of formula III described herein are provided, having a melting point in the range of about 135°C to about 190°C and / or water solubility in the range of about 15 mg / mL to about 75 mg / mL. For example, a salt of formula IIIa, such as the salt of formula IIIa11, may have a melting point of about 181.5°C and / or water solubility of about 53 mg / mL to about 106 mg / mL. In further examples, a salt of formula IIIb, such as the salt of formula IIIb2, may have a melting point of about 150.2°C and / or water solubility of about 20 mg / mL to about 40 mg / mL. Water solubility can be determined as described herein.

[0039] Furthermore, the salt of formula III has been found to have high chemical stability in solution. This is advantageous when processing the salt, such as when it is purified by recrystallization or manufactured and / or compounded by spray drying. In particular, the salt of formula III has been found to be chemically stable in methanol solution at room temperature (i.e., at a temperature of about 20°C to about 25°C, e.g., about 22°C), at a temperature of about 37°C and / or about 50°C for about 48 hours or more, e.g., about 168 hours or more.

[0040] This disclosure also provides pharmaceutical compositions comprising a salt of Formula III described herein in a mixture with pharmaceutically acceptable excipients, carriers, and / or diluents.

[0041] The pharmaceutical compositions described herein may be oral pharmaceutical compositions. For example, an oral pharmaceutical composition may be provided as a liquid formulation such as a syrup, suspension, or solution. Alternatively, an oral pharmaceutical composition may be provided as a solid such as a tablet, capsule, pill, or lozenge. In particular, an oral pharmaceutical formulation may be a capsule or tablet, such as a caplet.

[0042] Furthermore, salts or pharmaceutical compositions of Formula III described herein are provided for use as pharmaceuticals.

[0043] This disclosure also provides salts of Formula III described herein or pharmaceutical compositions for use in the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), motor disorders, postural disorders, and pathological apathy. For example, the diseases, disorders and / or conditions may be selected from the group consisting of dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, the diseases, disorders and / or conditions may include or consist of pathological apathy. Cognitive impairment may be age-related cognitive impairment, or cognitive impairment associated with neurodegenerative disorders and / or neurodegenerative diseases. Postural disorders may include or consist of falls. Pathological apathy may include, or consist of, apathy as defined according to known apathy measurement scales in the art, such as apathy rating scales, apathy motivation indicators, multidimensional apathy scales, and Reel apathy rating scales. Furthermore, pathological apathy may be associated with neurodegenerative diseases or neurodegenerative disorders such as dementia, Alzheimer's disease, and Parkinson's disease. In particular, pathological apathy may be associated with Parkinson's disease. The aforementioned diseases, disorders, and / or conditions may occur in association with neurological or psychiatric disorders such as schizophrenia, depression, dementia, and / or neurodegenerative disorders. In further examples, the aforementioned diseases, disorders, and / or conditions may occur in association with neurodegenerative diseases or neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or dementia associated with stroke. In yet another example, the aforementioned diseases, disorders, and / or conditions may occur in association with Parkinson's disease or Alzheimer's disease.

[0044] Furthermore, salts of Formula III or pharmaceutical compositions described herein are provided for use in the manufacture of pharmaceuticals for use in the treatment and / or prevention of diseases, disorders and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder(s), affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), motor disorders, postural disorders, and apathy. For example, the diseases, disorders and / or conditions may be selected from the group consisting of dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, the diseases, disorders and / or conditions may include or consist of pathological apathy. Cognitive impairment may be age-related cognitive impairment, or cognitive impairment associated with neurodegenerative disorders and / or neurodegenerative diseases. Postural disorders may include or consist of falls. Pathological apathy may include, or consist of, apathy as defined according to known apathy measurement scales in the art, such as apathy rating scales, apathy motivation indicators, multidimensional apathy scales, and Reel apathy rating scales. Furthermore, pathological apathy may be associated with neurodegenerative diseases or neurodegenerative disorders such as dementia, Alzheimer's disease, and Parkinson's disease. In particular, pathological apathy may be associated with Parkinson's disease. The aforementioned diseases, disorders, and / or conditions may occur in association with neurological or psychiatric disorders such as schizophrenia, depression, dementia, and / or neurodegenerative disorders. In further examples, the aforementioned diseases, disorders, and / or conditions may occur in association with neurodegenerative diseases or neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or dementia associated with stroke. In yet another example, the aforementioned diseases, disorders, and / or conditions may occur in association with Parkinson's disease or Alzheimer's disease.

[0045] This disclosure also provides methods for treating and / or preventing diseases, disorders, and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), motor disorders, postural disorders, and pathological apathy, the methods comprising administering to a mammal, such as a human or animal, in need of them, an effective amount, such as a therapeutically effective amount, of a salt or pharmaceutical composition of Formula III described in the specification. For example, the diseases, disorders, and / or conditions may be selected from the group consisting of dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, the diseases, disorders, and / or conditions may include or consist of pathological apathy. Cognitive impairment may be age-related cognitive impairment, or cognitive impairment associated with neurodegenerative disorders and / or neurodegenerative diseases. Postural disorders may include or consist of falls. Pathological apathy may include, or consist of, apathy as defined according to known apathy measurement scales in the art, such as apathy rating scales, apathy motivation indicators, multidimensional apathy scales, and Reel apathy rating scales. Furthermore, pathological apathy may be associated with neurodegenerative diseases or neurodegenerative disorders such as dementia, Alzheimer's disease, and Parkinson's disease. In particular, pathological apathy may be associated with Parkinson's disease. The aforementioned diseases, disorders, and / or conditions may occur in association with neurological or psychiatric disorders such as schizophrenia, depression, dementia, and / or neurodegenerative disorders. In further examples, the aforementioned diseases, disorders, and / or conditions may occur in association with neurodegenerative diseases or neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or dementia associated with stroke. In yet another example, the aforementioned diseases, disorders, and / or conditions may occur in association with Parkinson's disease or Alzheimer's disease.

[0046] As used herein, the term prevention includes references to preventive measures for diseases, disorders, and / or medical conditions and / or to preventing them. In particular, the term may mean achieving a reduction in the likelihood that a patient (or a healthy subject) will develop a medical condition (e.g., a reduction of at least 10%, e.g., a reduction of at least 20%, 30%, or 40%, e.g., a reduction of at least 50%).

[0047] Furthermore, as used herein, the term therapeutically effective amount refers to the amount of a compound that produces a therapeutic effect in the patient being treated. This effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of and / or feels the effect).

[0048] Salts of formula III can be prepared by combining the compound of formula I described herein with the acid of formula II described herein. Furthermore, the compound of formula I can be prepared as described in International Publication No. WO2018 / 091687 and / or by methods known in the art.

[0049] Therefore, this disclosure also provides a method for preparing the salt of Formula III described herein, the method being - A step of providing a compound of formula I described herein and an acid of formula II described herein in a ratio of 1:n, for example, 1:0.5 or 1:1, - A step of preparing a solution by combining the compound of formula I with the acid of formula II in a solvent such as THF, ethanol, or a mixture of ethanol and water, - A step that allows the salt of formula III to be precipitated, - The step of isolating a precipitate containing or consisting of a salt of formula III.

[0050] salt In this book, the chemical structure of the salt of formula III containing a combination of a compound of formula I and an acid of formula II is depicted as a complex in which the acidic proton(s) of the acid are attached to the acid. However, one skilled in the art understands that the acidic proton(s) of the acid of formula II can be attached to the nitrogen atom of the compound of formula I and / or can be shared between the nitrogen atom of the compound of formula I and the acid of formula II, and this is also intended to be encompassed by the salts described herein. For example, the salt of formula IIIa2 which is a 1:1 combination of a compound of formula I and tartaric acid is [Chemical Formula] also represented as follows.

[0051] Labeled compounds The compounds of the present disclosure can be used in their labeled or unlabeled forms. In the context of the present disclosure, a labeled compound has one or more atoms replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Such labeling enables the easy quantitative detection of the compound.

[0052] As an example, there are provided salts of formula III described herein in which one or more hydrogen atoms of the compound of formula I are replaced by deuterium.

[0053] The labeled compounds of the present disclosure can be useful as diagnostic tools, radiotracers, or monitoring agents in various diagnostic methods and for in vivo receptor imaging. The labeled compounds of the present disclosure can contain at least one radionuclide as a label. All positron-emitting radionuclides are candidates for use. In the context of the present disclosure, the radionuclide is 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 18 O, 17 O, 19 F, and 18Deuterium can be selected from isotopes of hydrogen, carbon, nitrogen, fluorine, and oxygen, such as F. 2 Substitutions with heavier isotopes, such as the substitution of one or more hydrogen atoms by H), are known to offer pharmacological benefits, such as increased metabolic stability, in some cases.

[0054] Physical methods for detecting the labeled compounds of this disclosure may be selected from positron emission tomography (PET), single-photon emission tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial tomography (CAT), or a combination thereof.

[0055] combination It should be understood that the salts(s) of this disclosure may be combined with other pharmaceuticals for use in the treatment and / or prevention of CNS disorders(s) and / or diseases(s). Other pharmaceuticals may include L-DOPA, selective serotonin reuptake inhibitors, antidepressants such as bupropion (i.e., (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, CAS number 34911-55-2), CNS stimulants such as methylphenidate (i.e., methylphenyl(piperidine-2-yl)acetate, CAS number 20748-11-2), and / or antipsychotics. Accordingly, a kit of components is provided comprising (i) a salt of the present disclosure, for example, a salt of Formula III as described herein; (ii) a pharmaceutical agent selected from the group consisting of L-DOPA, selective serotonin reuptake inhibitors, antidepressants such as bupropion (i.e., (RS)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, CAS No. 34911-55-2), CNS stimulants such as methylphenidate (i.e., methylphenyl(piperidine-2-yl)acetate, CAS No. 20748-11-2), and antipsychotics; and (iii) instructions for use for administering (i) and (ii) individually, simultaneously, or sequentially, as optional.

[0056] The present invention will be further described by reference to the following embodiments, which are not intended to limit the scope of the invention. [Examples]

[0057] In this book, compound nomenclature was performed using ChemDraw Ultra, version 12.0.2.1076. If the chemical name and chemical structure do not match, the chemical structure will be considered the correct structure.

[0058] Abbreviation AAC Accelerated Maturation Conditions ACN Acetonitrile ADHD (Attention Deficit Hyperactivity Disorder) aq. Water CNS (Central Nervous System) CAT (Computed Axis Tomography) DCM Dichloromethane DMSO (Dimethyl Sulfoxide) DSC (Differential Scanning Calorimetry) DVS (Dynamic Vapor Adsorption) EtOH Ethanol Fig. Figure g (grams) (multiple grams allowed) GABA (gamma-aminobutyric acid) GAD (Generalized Anxiety Disorder) h hours (multiple hours possible) HOAc Acetic Acid kg (kilograms) (multiple kilograms allowed) L (liters) LC (Low Crystalline or Liquid Chromatography) LC MS (Liquid Chromatography Mass Spectrometry) mg (milligrams) (multiple milligrams allowed) min. (multiple minutes allowed) mL (milliliters) (multiple milliliters are possible) MRI (Magnetic Resonance Imaging) MRS Magnetic Resonance Spectroscopy MTBE methyl tert-butyl ether NMR nuclear magnetic resonance RH (Relative Humidity) PET Positron Emission Tomography RT room temperature SPECT single-photon emission fault imaging Thermogravimetric analysis combined with TGMS mass spectrometry THF (Tetrahydrofuran) w / w weight ratio XRP Powder X-ray XRPD (Powder X-ray Diffraction) HR-XRPD High-Resolution Powder X-ray Diffraction HT-XPRD (High-Throughput Powder X-ray Diffraction)

[0059] General matters The reagents and solvents were used in their original, unpurified state. Unless otherwise specified, NMR analysis was performed using an NMR spectrometer operating at 500 MHz. Solvent peaks were used as internal standards.

[0060] XRPD data was collected using HT-XRPD and / or HR-XRPD.

[0061] HT-XRPD HT-XRPD patterns were obtained using a high-throughput XRPD instrument. The plate was mounted on a Bruker general-purpose surface detection diffraction system (GADDS) equipped with a VÅNTEC-500 gas surface detector corrected for intensity and geometric variations. Measurement accuracy (peak position) was calibrated using the NIST SRM1976 standard (corundum).

[0062] Data was acquired at room temperature using monochromatic Cu Kα radiation in the 2θ region of 1.5° to 41.5°, which is the most characteristic part of the XRPD pattern. Diffraction patterns from each well were collected within two 2θ ranges (1.5° ≤ 2θ ≤ 21.5° in the first frame and 19.5° ≤ 2θ ≤ 41.5° in the second frame) with an exposure time of 90 seconds for each frame. No background removal or curve smoothing was applied to the XRPD patterns.

[0063] HR-XRPD HR-XRPD data were collected at room temperature using a D8 Advance diffractometer equipped with a germanium monochromator, with Cu Kα1 emission (1.54056 Å). Diffraction data were collected in the 2θ range of 2.15–41.5°. Detector scanning was performed using a solid-state LynxEye detector at a scan rate of 15 seconds / step, with 0.016° per step. The sample was measured using an 8 mm long glass capillary with an outer diameter of 0.3 mm.

[0064] Moisture absorption test Hygroscopicity was measured using Dynamic Vapor Sorption (DVS) collected with the DVS Adventure system from Surface Measurement Systems (London, UK). The sample size was approximately 10 mg of solid material. Relative humidity was varied in 10% increments from 40-95-0-40%, and a 1-hour equilibrium period was set at a constant temperature of 25°C to record complete adsorption and desorption isotherms. Subsequently, the sample was measured using HT-XRPD.

[0065] The materials were classified as shown in Table 1 below based on their water absorption rate at 25°C / 80%RH during the first adsorption cycle of the adsorption isotherm. [Table 1]

[0066] Water solubility test Water solubility was evaluated by adding a fixed amount of water to 4-8 mg of the salt at room temperature. Water solubility was considered acceptable if it was equivalent to or better than that of 3-(2,3-difluorophenoxy)azetidine, i.e., 5 mg / mL or higher.

[0067] Differential Scanning Calorimetry (DSC) Analysis The melting point was determined using DSC analysis performed as described below. Thermal events were obtained from DSC thermograms recorded using a heat flux DSC3+ STARe system (Mettler-Toledo GmbH, Switzerland). The DSC3+ was calibrated for temperature and enthalpy using small pieces of indium (melting point = 156.6°C, δHf = 28.45 J / g) and zinc (melting point = 419.6°C; δHf = 107.5 J / g). The sample (approximately 2 mg) was sealed in a standard 40 μL aluminum pan, a pinhole was made, and it was heated in the DSC from 25°C to 300°C at a heating rate of 10°C / min. During the measurement, the DSC instrument was purged with dry N2 gas at a flow rate of 50 mL / min.

[0068] Chemical stability test in solution The chemical stability in solution was evaluated for two different salts of 3-(2,3-difluorophenoxy)azetidine according to the present invention, and one salt of 3-(2,3-difluorophenoxy)azetidine according to the prior art. Tests were conducted in methanol solution at two different temperatures (37°C and 50°C) for up to one week. Samples were analyzed by liquid chromatography (LC) combined with mass spectrometry (MS). The levels of 3-(2,3-difluorophenoxy)azetidine and possible degradation products were measured by LC-MS / UV detection, using an LC / MSD iQ Singlequad (Agilent). The HPLC module included a binary pump system, vacuum degasser, thermostatic autosampler, and thermostatic column compartment. Column: Poroshell 120 EC C18 (2.7*100 mm, 4.6 μm) Mobile phase A: Milli-Q water, 0.03% HOAc Mobile phase B: 0.03% HOAc in acetonitrile Flow rate: 1.0ml / min Dissolution gradient: [Table 2] Mass spectrometry parameters: Polarity: Positive / Negative Mode, ESI+ / - Desolvent removal temperature: 325℃ Capillary voltage: 3.5kV Mass range (m / z): 100~1000m / z Injection volume: 2.0μL UV: (190~400nm) 250nm

[0069] Synthesis of the compound of formula II, i.e., the acid addition salt of 3-(2,3-difluorophenoxy)azetidine. Compound 3-(2,3-difluorophenoxy)azetidine, i.e., the compound of formula I described herein, was combined with a number of different acids using method A or method B described below.

[0070] Method A: A fixed amount of a 1M aqueous solution of the acid or a solvent-free solid acid was added to a saturated solution of the compound of formula I in either THF or acetonitrile. The mixture was then subjected to a temperature profile that involved one heating cycle up to 50°C, followed by cooling to 5°C for 4 hours, and finally aging at 5°C for approximately 72 hours.

[0071] Method B: A suspension of the compound of formula II with an acid was prepared in ethanol. The mixture was then subjected to a temperature profile of three heating-cooling cycles at 5–50°C, followed by aging at 25°C for 72 hours.

[0072] Following the procedures described in Method A and Method B, respectively, the resulting solids were separated by centrifugation, dried, and analyzed by high-throughput XRPD (HT-XRPD). If the solid did not precipitate, the solvent in the solution was evaporated overnight under ambient conditions, and then evaporated overnight under vacuum at 50°C. Subsequently, the solid was exposed to accelerated aging conditions (AAC), i.e., a temperature of 40°C and relative humidity (RH) of 75%, for 48 hours. The solid subjected to AAC was analyzed again by XRPD to assess its physical stability. If no change occurred, substantially no change occurred, or only a very slight change occurred, the solid was considered stable. The solid was also subjected to visual inspection to observe any changes, such as discoloration. If the XRPD spectrum differed significantly from that obtained before AAC treatment, and / or if a change in color or other changes were observed during visual inspection, the salt was considered unstable. Novel XRPD patterns distinct from those of 3-(2,3-difluorophenoxy)azetidine and the acid were considered candidates for crystalline salts. Candidate crystalline salts were named by adding a number after the salt abbreviation, as shown in Table 3.

[0073] The base / acid ratio of the resulting salt form was determined by a relaxation time of at least 10 seconds. 1 The determination was made by 1H NMR spectroscopy or elemental analysis.

[0074] The results are shown in Table 3. Different solvents were used for crystallization. For example, ethanol, tetrahydrofuran, and acetonitrile were tested separately as solvents for the preparation of hydrochloride salts. In the "Chemical Stability" column, it was found that most salt forms were chemically stable even when exposed to accelerated maturation conditions, as indicated by the XRPD and visual inspections described above. Table 3 [Table 3-1] [Table 3-2]

[0075] Of the salt forms shown in Table 3, those that were chemically stable in the AAC test, or those that were converted to a chemically stable form after exposure to the AAC test, were further investigated as follows.

[0076] Hydrochloride DVS analysis of the HCl salt form shown in Table 3 revealed that its hygroscopicity was approximately 6% at 80% RH, indicating that this HCl salt form has moderate hygroscopicity.

[0077] Therefore, we found that the hydrochloride salt form described above is hygroscopic. Furthermore, we found that its water solubility exceeds 180 mg / mL.

[0078] Fumarate The hygroscopicity of the fumarate form, as described in Example 1B of International Publication No. 2018 / 091687, was found to be 0.3% at 80% RH, indicating that the fumarate is slightly hygroscopic. Furthermore, the water solubility of the fumarate was found to be approximately 16 mg / mL.

[0079] p-toluenesulfonate We found that the hygroscopicity of TOS1 salt is 3% at 80% RH, meaning that the TOS1 salt form has moderate hygroscopicity. Therefore, we concluded that the TOS1 salt form is hygroscopic. Furthermore, we found that its qualitative water solubility is approximately 10 mg / mL.

[0080] L-tartrate The most common salt form of tartrate was the TAR1 salt. Thermal analysis of the TAR1 salt showed that this salt form is a sesquihydrate containing 1.5 equivalents of water and dehydrates between 30°C and 100°C. This thermal behavior was characterized by broad endothermic activity corresponding to water loss. No other thermal phenomena were detected after dehydration, indicating that the crystalline structure collapses after water loss. It was concluded that the TAR1 salt form is unsuitable for development due to the risk of dehydration and the possibility of amorphous formation.

[0081] The TAR3 and TAR5 salt forms became hygroscopic upon exposure to AAC.

[0082] The TAR2 salt form appeared to be an anhydrous hemi-L-tartrate. The melting point of the TAR2 salt form was 181.5°C. DVS analysis showed that TAR2 had a water absorption of less than 0.2% at 80% RH. Water solubility ranged from 53 to 106 mg / mL. Upon exposure to AAC, a very small amount of the TAR2 salt form was converted to the TAR4 salt form.

[0083] We concluded that the TAR2 salt form is non-hygroscopic. Furthermore, we concluded that the TAR2 salt form has satisfactory water solubility. In addition, because the TAR2 salt form has a high melting point of 181.5°C, it is suitable for the manufacture of pharmaceutical compositions such as tablets.

[0084] TAR2 salt 1 ¹H NMR analysis has shown that this salt is a combination of the compound of formula I and L-tartaric acid in a ratio of 1:0.5.

[0085] For XRPD analysis, the diffraction pattern is provided in Figure 1. The main characteristic peaks, along with their position and relative intensity, were extracted from the diffraction pattern in Figure 1 and are shown in the table below.

[0086] Summary table of peaks shown in Figure 1 [Table 4]

[0087] succinate The hygroscopicity of the SUC1 salt form was found to be less than 0.2% at 80% RH. Therefore, the SUC1 salt form was found to be non-hygroscopic. Furthermore, the qualitative water solubility was found to be 20-40 mg / mL. TGMS and 1As shown by 1H NMR, the SUC1 salt form is a monosuccinate anhydride with a melting point of 150.2°C determined by differential scanning calorimetry (DSC). When EtOH / THF or ACN was used as the solvent, the SUC1 salt form was produced with a small amount of the SUC2 salt form present.

[0088] We concluded that succinates such as SUC1 salt are non-hygroscopic. Furthermore, we concluded that succinates such as the SUC1 salt form described herein have satisfactory water solubility. Moreover, the high melting point of the SUC1 salt form (150.2°C) makes it suitable for the manufacture of pharmaceutical compositions such as tablets. Furthermore, we found that the fact that only two polymorphs have been identified, and that only the SUC1 salt form is readily produced, is beneficial in relation to manufacturing and control of drug properties.

[0089] SUC1 salt 1 ¹H NMR analysis has shown that this salt is a combination of the compound of formula I and succinic acid in a 1:1 ratio.

[0090] XRPD analysis yielded the diffraction pattern shown in Figure 2. The main characteristic peaks, along with their location and relative intensity, were extracted from the diffraction pattern in Figure 2 and are shown in the table below.

[0091] Summary table of peaks shown in Figure 2 [Table 5]

[0092] Maronate MAO1 was found to be the most relevant crystalline form based on its crystallinity and physical stability. MAO2 was converted to MAO1, while MAO3 became hygroscopic when exposed to AAC.

[0093] 1 ¹H NMR analysis showed salt formation with a 1:1 stoichiometric ratio of malonic acid to the free base (i.e., the compound of formula I).

[0094] Thermal analysis revealed that MAO1 is in an anhydrous phase, initiating decomposition at 120°C and melting / decomposing at 154.6°C. Its water solubility was found to be 40-80 mg / mL. DVS analysis showed that MAO1 is moderately hygroscopic, absorbing 3.4% water at 80% RH. Therefore, the malonate is hygroscopic. [Examples]

[0095] 3-(2,3-difluorophenoxy)azetidine succinate [ka]

[0096] A) 3-(2,3-difluorophenoxy)azetidine DMSO (20 L) was added to a 50 L reactor, followed by tert-butyl 3-{[(4-methylphenyl)sulfonyl]oxy}-1-azetidine carboxylate (3.03 kg, 9.2 mol), 2,3-difluorophenol (1.32 kg, 10.2 mol), and potassium carbonate (2.30 kg, 16.6 mol). The reaction mixture was heated for 16 hours until the internal temperature reached 70°C. An additional amount of potassium carbonate (230 g, 1.66 mol) was added, and stirring was continued at 70-75°C for 6 hours. The temperature was raised to 80°C, and the mixture was stirred for a further 16 hours. The mixture was diluted with MTBE (15 L), and then water (15 L) was added. The two layers were separated, and the organic layer was washed with 10% Na2CO3 aqueous solution (5 L), 10% NaCl (5 L x 3), and water (5 L). This solution was placed in a 50 L reactor, and then aqueous HCl solution (37%, 5.65 kg, 57 mol) was added. The reaction mixture was stirred at an internal temperature of 22°C for 16 hours, and then water (15 L) was added. Most of the MTBE was evaporated, and then the aqueous layer was extracted with a fresh amount of MTBE (15 L). The two layers were separated, and the organic phase was discarded. The aqueous solution was cooled to 10°C, and then the pH was adjusted to 14 with aqueous NaOH solution (50%, 3.95 kg), taking care not to let the internal temperature exceed 35°C during the addition. The solution was extracted twice with DCM (25 L and 13 L). The combined organic layers were washed with water (13 L) and then concentrated under reduced pressure until the remaining volume was approximately 13 L. THF (13 L) was added, and distillation was continued until the remaining volume was approximately 11 L. Water (25 L) was added, and the solution was concentrated under reduced pressure until the remaining volume was approximately 23 L. The resulting slurry was stirred at 20°C for 1 hour, then cooled to 10-15°C for 17 hours. The precipitate was isolated by filtration, the filter cake was washed with water (2 × 2.5 L), and then dried on the filter at room temperature for 70 hours by passing air through the filter. 1.51 kg (92%) of the title compound was obtained as a solid. LC MS m / z 186[M+H] + . LC purity: 99.8 area%.

[0097] B) 3-(2,3-difluorophenoxy)azetidine succinate EtOH (15 L) was added to a 50 L reactor, followed by succinic acid (954 g, 8.08 mol). The slurry was stirred at an internal temperature of 32°C for approximately 2 hours until the acid was completely dissolved. This solution was drained from the reactor and stored at room temperature for 1 day. The reactor was rinsed with EtOH, and then EtOH (15 L) and water (3 L) were added. 3-(2,3-difluorophenoxy)azetidine (1.5 kg, 8.10 mol) was added, and the mixture was stirred at an internal temperature of 55°C for 1 hour until the amine was completely dissolved. This solution was cooled to room temperature and drained from the reactor. The reactor was rinsed with EtOH, and then the amine solution and succinic acid solution were filtered and returned to the reactor. This mixture was heated to an internal temperature of 75°C for 51 minutes. The mixture was gradually cooled to an internal temperature of 5°C (5°C every 20 minutes), and the resulting slurry was stirred at 5°C for 15 hours. The product was isolated by filtration, the filter cake was washed twice with EtOH (2 × 1.5 L), and then dried on the filter at room temperature for approximately 3 days by passing air through the filter. 1.73 kg (71%) of 3-(2,3-difluorophenoxy)azetidine succinate was obtained as a white solid. LC MS m / z 186[M+H] + . LC purity: 99.8 area%. 1 ¹H NMR (300MHz, DMSO-d6): δ 2.33 (s,4H), 3.84 (m,2H), 4.14 (m,2H), 5.12 (m,1H), 6.78 (m,1H), 7.1-7.2 (m,2H), 10.18 (b,3H), 1.8-2.0 (m,5H), 1.73 (m,4H), 1.65 (m,2H), 1.55 (m,3H), 1.15 (m,1H), 0.89 (t,3H). The NMR spectrum showed that the azetidine derivative identified above and succinic acid were in a 1:1 ratio. Therefore, in this embodiment, the succinate of 3-(2,3-difluorophenoxy)azetidine is provided as a combination comprising 3-(2,3-difluorophenoxy)azetidine and succinic acid in a 1:1 ratio. [Examples]

[0098] 3-(2,3-difluorophenoxy)azetidine hemi-L-(+)-tartrate A mixture of EtOH and water (19:1, 600 mL) was placed in a 1 L round-bottom flask, followed by the addition of 3-(2,3-difluorophenoxy)azetidine (75.3 g, 0.40 mol). Then, L(+)-tartaric acid (33.6 g, 0.22 mol) dissolved in a mixture of EtOH and water (19:1, 150 mL) was added. This slurry was stirred at an internal temperature of 76 °C for 40 minutes until almost all solids were dissolved. Next, water (55 mL) was added in portions until a clear solution was obtained. This mixture was stirred at 76 °C for 5 minutes and then cooled to room temperature. The resulting white slurry was stirred at 0-5 °C for 2 hours. The precipitate was isolated by filtration, and the filter cake was washed twice with a mixture of EtOH and water (19:1, 2 × 75 mL). The product was dried on a filter by passing air through it, at room temperature for 16 hours, and then under reduced pressure at 40°C for 24 hours. 84.4 g (80%) of the title compound was obtained as a white solid. m / z 186[M+H] + . LC purity: 100 area%. 1 ¹H NMR (400 MHz, D2O): δ 4.28 (m, 3H), 4.55 (m, 2H), 5.21 (m, 1H), 6.65 (m, 1H), 6.93 (m, 1H), 7.06 (m, 1H). The NMR spectrum showed that the ratio of the azetidine derivative identified above to L-tartaric acid was 2:1. Therefore, in this example, the L-tartrate of 3-(2,3-difluorophenoxy)azetidine is provided as a combination containing 3-(2,3-difluorophenoxy)azetidine and L-tartaric acid in a ratio of 1:0.5.

[0099] Comparative example: 3-(2,3-difluorophenoxy)azetidine fumarate [ka] In this comparative example, the 3-(2,3-difluorophenoxy)azetidine fumarate from Example 1B of International Publication No. 2018 / 091687 was re-evaluated. A re-examination of the LC-MS chromatogram of the 3-(2,3-difluorophenoxy)azetidine fumarate from Example 1B of International Publication No. 2018 / 091687 revealed that the product contained 2-4% impurities with a negative mode of 300 m / z and a positive mode of 302 m / z. These impurities were concluded to be adducts of amine and fumaric acid, and their chemical structures are shown below. [ka]

[0100] The formation of this impurity is thought to be due to a Michael addition reaction between 3-(2,3-difluorophenoxy)azetidine and fumaric acid, according to the reaction scheme shown below. [ka]

[0101] Although the impurity content of the Michael adduct may appear small (2-4%), it is highly likely to cause problems during the scale-up of the reaction, such as when scaling up to industrial production. Additional steps, such as steps to remove the impurities, negatively impact the overall performance and feasibility of the scale-up. Furthermore, this side reaction leading to the Michael adduct impurities is more likely to occur at large scales, such as industrial scales, because such process conditions typically require longer reaction times, which promotes the formation of Michael adduct impurities. [Examples]

[0102] Chemical stability in methanol solution at 37°C and 50°C Three different salts of 3-(2,3-difluorophenoxy)azetidine were investigated in chemical stability tests: 1) succinate from Example 1, 2) hemi-L-(+)-tartrate from Example 2, and 3) fumarate from Example 1B of International Publication No. 2018 / 091687 (prior art compound). 2.0 mg of each test compound was weighed into separate vials, with one vial prepared for each temperature. These vials were diluted with 1 mL of methanol. At each time point, the sample was diluted with Milli-Q water, i.e., ultrapure water, to a final concentration of approximately 600-700 μM relative to 3-(2,3-difluorophenoxy)azetidine (Formula I). ​​The time points were 1 hour, 2 hours, 3 hours, 4 hours, 24 hours, 48 ​​hours, and 1 week.

[0103] Potential degradation products were detected and characterized by LC-MS. Therefore, the chemical structure of the main degradation product in solution of 3-(2,3-difluorophenoxy)azetidine fumarate was determined to be a Michael adduct according to formula A shown below. [ka]

[0104] The chemical structures of the second and third highest decomposition products in the same methanol solution were determined to be two positional isomers of the monomethyl ester of the Michael adduct according to formulas B and C. However, it was not possible to determine which of the two peaks in the chromatogram corresponded to which of the two positional isomers. [ka]

[0105] The retention time for 3-(2,3-difluorophenoxy)azetidine (Formula I) was 3.7–3.8 minutes, while the retention time for the degradation product according to Formula A was 4.0–4.1 minutes. The retention times for the two degradation products according to Formulas B and C were 4.2–4.3 minutes and 4.4–4.5 minutes, respectively. The LC area percentages of the three different degradation products increased over time. For example, after one week at 50°C, the LC area percentages were as follows: Formula A was 60.2%, Formula B (or Formula C) was 11.6%, and Formula C (or Formula B) was 3.5%.

[0106] Table 6 shows the results of stability tests at 37°C and 50°C for methanol solutions of succinate 3-(2,3-difluorophenoxy)azetidine. The detected compound that elutes in 3.7-3.8 minutes is the unsalted form of 3-(2,3-difluorophenoxy)azetidine, which is designated as Formula I in the table. The corresponding results from methanol solutions of hemi-L-(+)-tartrate and fumarate 3-(2,3-difluorophenoxy)azetidine are shown in Tables 7 and 8, respectively.

[0107] Table 6.3 Chemical stability of succinate of 3-(2,3-difluorophenoxy)azetidine in methanol solution (at 37°C and 50°C, respectively) [Table 6]

[0108] Table 7. Chemical stability of 3-(2,3-difluorophenoxy)azetidine hemi-L-(+)-tartrate in methanol solution (at 37°C and 50°C, respectively) [Table 7]

[0109] Table 8.3 Chemical stability of 3-(2,3-difluorophenoxy)azetidine fumarate in methanol solution (at 37°C and 50°C, respectively) [Table 8]

[0110] As shown in Table 8, 3-(2,3-difluorophenoxy)azetidine fumarate (prior art compound according to Example 1B of International Publication No. 2018 / 091687) decomposes significantly in methanol solution at 37°C. Decomposition at 50°C is even more pronounced, with nearly half of the drug decomposing after two days. In contrast, as shown in Tables 6 and 7, neither the corresponding succinate nor the corresponding hemi-L-(+)-tartrate decomposes in methanol solution at any of the test temperatures. Therefore, the two salts of the present invention exhibit very high stability in solution, even when present in methanol solution at 50°C for one week.

[0111] remarks As described above in this specification, both succinate and hemi-L-(+)-tartrate salts of the compound of formula I are non-hygroscopic, have high melting points, possess good water solubility, and are stable in solution, thus allowing them to be handled and / or stored, for example, without decomposition or substantially without decomposition. Therefore, both salts have properties suitable for use as pharmaceuticals or for processing into pharmaceutical compositions.

[0112] References 1.Prog Neuro-Psychopharm&Bio Psych,2013,45,54-63. 2.Biol Psych,2011,69(12);89-99. 3.Front Cell Neurosci,2015,9;1-23. 4.Neurosci&Biobehav Rev,2013,37;1363-79. 5. Mol Psych, 2005, 1 O; 40-68. 6. Eur Psych, 2005, 20; 15-27. 7. International Publication No. 2010 / 022055 8. International Publication No. 2018 / 091687

Claims

1. A salt of formula III, 【Chemistry 1】 The salt is a combination of the compound of formula I and the acid of formula II. 【Chemistry 2】 The ratio is 1:n, During the ceremony, X is either OH or H, Salts of formula III, where n is 0.5 or 1.

2. The salt of formula III according to claim 1, wherein X is OH, thereby providing a salt of formula IIIa which is a combination of the compound of formula I and tartaric acid. 【Transformation 3】

3. The salt of formula IIIa according to claim 2, wherein the tartaric acid is L-(+)-tartaric acid.

4. The salt of formula IIIa according to claim 2, wherein the tartaric acid is D-(-)-tartaric acid.

5. The salt of formula IIIa according to claim 2, wherein the tartaric acid is L-(+)-tartaric acid and D-(-)-tartaric acid.

6. The salt of formula III according to claim 1, wherein X is H, thereby producing a salt of formula IIIb, which is a combination of the compound of formula I and succinic acid. 【Chemistry 4】

7. A salt of formula III according to any one of the claims, wherein n is 0.

5.

8. A salt of formula III according to any one of claims 1 to 6, wherein n is 1.

9. The salt according to any one of the above claims, characterized in that it is crystalline.

10. A salt of formula III according to any one of claims 1 to 5, 7, or 9, characterized in that the XRP diffraction pattern includes a peak at 27.4 degrees 2θ and one or more peaks selected from the following: 17.8, 19.5, 19.9, and 21.6 degrees 2θ.

11. A salt of formula III according to any one of claims 1 to 5, 7, or 9, characterized in that the XRP diffraction pattern is as shown in Figure 1.

12. A salt of formula III according to any one of claims 1, 6, 8, or 9, characterized in that the XRP diffraction pattern includes a peak at 12.5 degrees 2θ 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, and 26.9 degrees 2θ.

13. A salt of formula III according to any one of claims 1, 6, 8, or 9, characterized in that the XRP diffraction pattern is as shown in Figure 2.

14. A salt of formula III according to any one of the claims, wherein one or more hydrogen atoms of the compound of formula I are substituted with deuterium.

15. The salt of formula III according to any one of the claims, wherein the salt undergoes a weight change of approximately ±0.2% by weight or less at any humidity, for example, any relative humidity, for example, at a relative humidity of 80% measured at a temperature of 20°C to 25°C.

16. A salt of formula III according to any one of claims 1 to 5 or 7 to 11, having a water solubility of 53 mg / mL to 106 mg / mL and / or a melting point of 181.5°C.

17. A salt of formula III according to any one of claims 1, 6 to 9, 12, or 13, having a water solubility of 20 mg / mL to 40 mg / mL and / or a melting point of 150.2°C.

18. The salt of formula III according to any one of the claims, wherein the salt is chemically stable in methanol solution at room temperature, at a temperature of 37°C and / or 50°C for 48 hours or more, for example, 168 hours or more.

19. A pharmaceutical composition comprising a salt of formula III as described in any one of the preceding claims in a mixture with a pharmaceutically acceptable excipient, carrier, and / or diluent.

20. For use as a pharmaceutical product, A salt of formula III as defined in any one of claims 1 to 18, or The pharmaceutical composition according to claim 19.

21. For use in the treatment and / or prevention of diseases, disorders, and / or conditions selected from the group consisting of dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), motor disorders, postural disorders, and pathological apathy, A salt of formula III as defined in any one of claims 1 to 18, or The pharmaceutical composition according to claim 19.

22. The aforementioned disease, disorder, and / or condition is pathological apathy. A salt of formula III for use as described in claim 21, or A pharmaceutical composition for use according to claim 21.

23. The aforementioned pathological apathy is as defined in the apathy measurement scale. Salt of formula III for use according to claim 22, A pharmaceutical composition for use according to claim 22.

24. The apathy measurement scale is one or more of the following: apathy assessment scale, apathy motivation index, multidimensional apathy scale, or Reel apathy assessment scale. A salt of formula III for use as described in claim 23, or A pharmaceutical composition for use according to claim 23.

25. The aforementioned pathological apathy is associated with neurodegenerative diseases such as dementia, Alzheimer's disease, or Parkinson's disease. A salt of formula III for use according to any one of claims 21 to 24, or A pharmaceutical composition for use according to any one of claims 21 to 24.

26. The aforementioned neurodegenerative disease is Parkinson's disease. A salt of formula III for use as described in claim 25, or A pharmaceutical composition for use according to claim 25.

27. For the manufacture of a pharmaceutical product for the treatment and / or prevention of a disease, disorder, and / or condition 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 disorder, and pathological apathy, Use of a salt of formula III as defined in any one of claims 1 to 18 or the pharmaceutical composition according to claim 19.

28. The use according to claim 27, wherein the disease, disorder, and / or condition is pathological apathy.

29. The use according to claim 28, wherein the pathological apathy is as defined in the apathy measurement scale.

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

31. The use according to any one of claims 27 to 30, wherein the pathological apathy is related to a neurodegenerative disease such as dementia, Alzheimer's disease, or Parkinson's disease.

32. The use according to claim 31, wherein the neurodegenerative disease is Parkinson's disease.

33. A method for the treatment and / or prevention of a disease, disorder and / or condition 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 disorder, and pathological apathy, wherein the method comprises administering to a mammal such as a human or animal in need thereof an effective amount, such as a therapeutically effective amount, of a salt of formula III as defined in any one of claims 1 to 18, or a pharmaceutical composition as defined in claim 19.

34. The method according to claim 33, wherein the disease, disorder, and / or condition is pathological apathy.

35. The method according to claim 34, wherein the pathological apathy is as defined in the apathy measurement scale.

36. The method according to claim 35, wherein the apathy measurement scale is one or more of the following scales: an apathy evaluation scale, an apathy motivation index, a multidimensional apathy scale, and a Reel apathy evaluation scale.

37. The method according to any one of claims 33 to 36, wherein the pathological apathy is related to a neurodegenerative disease such as dementia, Alzheimer's disease, or Parkinson's disease.

38. The method according to claim 36, wherein the neurodegenerative disease is Parkinson's disease.

Images