Pharmaceutically acceptable salts of 3-(2, 3-difluorophenoxy) azetidine and uses thereof

Abstract

Disclosed is a salt of formula (III) wherein n is 0.5 or 1, a process for the preparation thereof, and uses thereof.

Description

Technical Field

[0001] This disclosure relates to pharmaceutically acceptable salts of the compound 3-(2,3-difluorophenoxy)azacyclobutane, methods of their manufacture, and their uses. More specifically, this disclosure relates to succinate and tartrate salts of 3-(2,3-difluorophenoxy)azacyclobutane. Background Technology

[0002] The cerebral cortex encompasses several major areas of the brain involved in higher functions such as thinking, feeling, memory, and planning. Monoamines (such as dopamine, norepinephrine, and serotonin) are important neurotransmitters for cortical function in mammals. Ascending serotonergic and norepinephrine pathways innervate almost all areas of the brain, including the cerebral cortex. Dopaminergic neurons in the CNS have more distinctive projections, including, in addition to many specific subcortical pathways, mesocortical pathways that primarily innervate the frontal cortex. Primary or secondary dysfunction of the monoamine pathways innervating the cerebral cortex leads to abnormal activity at cortical dopamine, norepinephrine, and serotonin receptors, subsequently resulting in the manifestation of psychiatric and neurological symptoms.

[0003] Cortical monoamines regulate several aspects of cortical function, thereby modulating emotion, anxiety, motivation, cognition, attention, arousal, and wakefulness. Therefore, catecholamines, dopamine, and norepinephrine exert a strong influence on the frontal cortex, the integrity of which is essential for so-called executive cognitive functions related to, for example, attention, action planning, and impulse control. Norepinephrine is a major component of the circuitry regulating anxiety and fear and is therefore considered dysregulated in anxiety disorders such as panic disorder, generalized anxiety disorder (GAD), and specific phobias. Regarding mood and affective function, the effectiveness of compounds that particularly facilitate the neurotransmission of norepinephrine and serotonin in treating depression and anxiety has favorably contributed to the widely accepted concept that these neurotransmitters are involved in the regulation of affective function.

[0004] Prog Neuro-Psychopharm & Bio Psych, 2013, 45, 54-63 discloses 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 with conditions such as depression, anxiety disorders, and attention deficit hyperactivity disorder (ADHD). Additionally, 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 the regulation of monoaminergic transmission has been suggested as a promising mechanism for treating autism spectrum disorders.

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

[0006] Furthermore, the monoamine system in the cortex is known to be directly or indirectly involved in the core symptoms of schizophrenia. It has been proposed that this condition arises from the convergence of various pathological factors at the cortical synaptic processes, leading to dysregulation of cortical microcircuits, which clinically manifests as symptoms of schizophrenia (Harrison et al., Mol Psych, 2005, 10; 40-68). These cortical microcircuits are regulated by several neurotransmitters, including glutamate, GABA, and dopamine. It has been further proposed that pharmacological enhancement of cortical dopamine transmission could restore the function of these microcircuits, thus providing a useful strategy for improving the treatment of schizophrenia (Abi-Dargham et al., Eur Psych, 2005, 20; 15-27).

[0007] WO 2010 / 022055 discloses certain 3-phenoxy-azacyclobutane derivatives as synthetic intermediates in the synthesis of voltage-gated sodium channels as inhibitors. The non-salt form of 3-(2,3-difluorophenoxy)azacyclobutane is one such synthetic intermediate.

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

[0009] WO 2018 / 091687 discloses 3-phenoxy-aziridine derivatives that can be used to regulate the levels of monoamines such as dopamine, norepinephrine, and serotonin in the cerebral cortex of mammalian brains, and more specifically for the treatment of central nervous system disorders. It is disclosed that compounds of Formula I can be isotopically labeled analogs of 3-(2,3-difluorophenoxy)aziridine or pharmaceutically acceptable salts. Example 1A discloses 3-(2,3-difluorophenoxy)aziridine hydrochloride. Example 1B discloses 3-(2,3-difluorophenoxy)aziridine fumarate.

[0010] The enumeration or discussion of obviously previously disclosed documents in this specification is not necessarily an admission that such documents are part of the prior art or common general knowledge.

[0011] Further research and development of 3-(2,3-difluorophenoxy)azacyclobutane has revealed the need for a form of 3-(2,3-difluorophenoxy)azacyclobutane that exhibits satisfactory pharmaceutical properties as well as satisfactory handling and pharmacodynamic properties, particularly on an industrial scale. Furthermore, there is a need for a form of 3-(2,3-difluorophenoxy)azacyclobutane with high chemical stability, such as high chemical stability in solution. Attached Figure Description

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

[0013] Figure 2 The XRP diffraction pattern of the salt of formula IIIb2 is shown. Summary of the Invention

[0014] One object of this disclosure is to provide a form of 3-(2,3-difluorophenoxy)azacyclobutane that exhibits satisfactory pharmaceutical properties, as well as handling and pharmacodynamic properties, particularly on an industrial scale. Another object of this disclosure is to provide a form of 3-(2,3-difluorophenoxy)azacyclobutane that allows for high-purity manufacturing on an industrial scale. Furthermore, an object of this disclosure is to provide a form of 3-(2,3-difluorophenoxy)azacyclobutane with high chemical stability, such as high chemical stability in solution. Additionally, an object of this disclosure is to provide aspects and / or advantages not yet provided by techniques known to date.

[0015] This disclosure provides a salt of formula III:

[0016]

[0017] The salt is a combination of a compound of formula I and an acid of formula II:

[0018]

[0019] The ratio is 1:n.

[0020] in

[0021] X is OH or H; and

[0022] n is 0.5 or 1.

[0023] This disclosure also provides a pharmaceutical composition comprising a salt of Formula III as described herein and an admixture of a pharmaceutically acceptable excipient, carrier, and / or diluent.

[0024] In addition, this disclosure provides a salt or pharmaceutical composition of Formula III as described herein, which is used as a medicine.

[0025] This disclosure also provides a salt or pharmaceutical composition of Formula III as described herein for the treatment and / or prevention of diseases, conditions and / or symptoms selected from the group consisting of: dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), movement disorders, postural instability and pathological apathy.

[0026] This disclosure also provides the use of salts or pharmaceutical compositions of Formula III as described herein for the manufacture of medicaments for the treatment and / or prevention of diseases, conditions and / or symptoms selected from the group consisting of: dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), movement disorders, postural instability and pathological apathy.

[0027] This disclosure also provides a method for treating and / or preventing diseases, conditions and / or symptoms selected from the group consisting of: dementia, cognitive impairment, autism spectrum disorder, affective disorders, schizophrenia, anxiety disorders, attention deficit hyperactivity disorder (ADHD), movement disorders, postural instability and pathological apathy, said method comprising administering to a mammal such as a human or animal in need an effective amount, such as a therapeutically effective amount, of a salt or pharmaceutical composition of Formula III as described herein.

[0028] describe

[0029] This disclosure provides a salt of formula III:

[0030]

[0031] The salt is a combination of a compound of formula I and an acid of formula II:

[0032]

[0033] The ratio is 1:n.

[0034] in

[0035] X is OH or H; and

[0036] n is 0.5 or 1.

[0037] Furthermore, the values ​​for X and n follow. It should be understood that such values ​​may be used in conjunction with any of the definitions, examples, and / or claims described herein.

[0038] For example, when X is OH and n is 0.5 or 1, a salt of formula IIIa is provided, which is a combination of a compound of formula I and tartaric acid:

[0039]

[0040] The tartaric acid described herein can be L-(+)-tartaric acid and / or D-(-)-tartaric acid. Tartaric acid can be provided as a racemic mixture. Alternatively, the tartaric acid of a salt of formula IIIa can be L-(+)-tartaric acid.

[0041] The value of n can be 0.5. Alternatively, the value of n can be 1.

[0042] When n is 0.5 for the salt of equation IIIa, the salt of equation IIIa1 is provided:

[0043]

[0044] In one instance, the tartaric acid in a salt of formula IIIa can be L-(+)-tartaric acid, and n can be 0.5. This salt can be named as a salt of formula IIIa11.

[0045] When n is 1 for the salt of equation IIIa, the salt of equation IIIa2 is provided:

[0046]

[0047] Furthermore, X can be H, and n can be 0.5 or 1, thus providing a salt of formula IIIb, which is a combination of the compound of formula I and succinic acid:

[0048]

[0049] When n is 0.5 for the salt of formula IIIb, the salt of formula IIIb1 is provided:

[0050]

[0051] Furthermore, when n is 1 for the salt of equation IIIb, it provides

[0052] Salts of formula IIIb2:

[0053]

[0054] The salt of Formula III as described herein is pharmaceutically acceptable and has been unexpectedly found to be crystalline and non-hygroscopic. Furthermore, this salt has been found to have a high melting point, high chemical purity, and acceptable, i.e., satisfactory, water solubility. The high melting point is an advantage, for example, in tablet manufacturing. The satisfactory water solubility makes this salt suitable for any administration to patients, such as humans, including oral administration.

[0055] Therefore, a salt of Formula III as described herein is provided, characterized by being crystalline. The degree of crystallinity can be determined by XRPD or any other suitable method. Having a well-defined degree of crystallinity in the salt of Formula III, for example, in terms of melting point and / or XRPD, is beneficial in the preparation of tablets, for example. Crystallinity is believed to enhance storage stability. The degree of crystallinity of the salt of Formula III, as measured by XRPD or any other suitable method, can be about 80% or higher, such as about 85% or higher, about 90% or higher, about 95% or higher, about 99% or higher, or about 100%. In particular, the degree of crystallinity of the salt of Formula III can be 95% or 99% or higher.

[0056] Salts of formula IIIa (such as salts of formula IIIa11) can be obtained by means of... Figure 1 The XRP diffraction pattern shown is used for characterization. Alternatively or alternatively, the salt of formula IIIa can be characterized by an XRP diffraction pattern containing a peak at about 27.4 degrees 2q and one or more peaks selected from the following: about 17.8, about 19.5, about 19.9, about 21.6 degrees 2q.

[0057] Salts of formula IIIb (such as salts of formula IIIb2) can be obtained by means of... Figure 2 The XRP diffraction pattern shown is used for characterization. Alternatively or alternatively, the salt of formula IIIb can be characterized by an XRP diffraction pattern containing a peak at about 12.5 degrees 2q and one or more peaks selected from the following: about 13.3, about 16.5, about 19.3, about 22.4, about 23.3, about 24.1, about 24.9, about 25.9, about 26.9 degrees 2q.

[0058] The fact that the salts of Formula III are non-hygroscopic is advantageous, as they allow for storage unaffected or substantially unaffected by ambient humidity. This is, of course, important and useful when storing salts in the context of industrial production, such as pharmaceuticals. It has been found that the salts of Formula III exhibit a weight change of 0.2% by weight or less at any humidity level (such as any relative humidity as described herein). Therefore, the salts of Formula III are non-hygroscopic or substantially non-hygroscopic. In one instance, the salts of Formula III exhibit a weight change of ±0.2% or less at approximately 80% relative humidity. Relative humidity can be measured at room temperature, i.e., at temperatures from approximately 20°C to approximately 25°C, such as approximately 22°C.

[0059] In this paper, relative humidity refers to 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.

[0060] Salts of Formula III have been found to have high melting points. This is an advantage because a high melting point allows for, for example, tablet manufacturing. For example, melting points can range from about 135°C to about 190°C. Additionally, salts of Formula III have been found to have satisfactory water solubility. For example, water solubility can range from about 15 mg / mL to about 75 mg / mL. Water solubility can be determined as described herein.

[0061] Therefore, salts of Formula III as 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, salts of Formula IIIa (such as salts 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 a further example, salts of Formula IIIb (such as salts 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.

[0062] Furthermore, salts of Formula III have been found to exhibit high chemical stability in solution. This is beneficial when the salts are processed, for example, when they are purified by recrystallization, manufactured and / or formulated by, for example, spray drying. In particular, salts of Formula III have been found to be chemically stable in methanol solution for about 48 hours or longer, such as about 168 hours or longer, at room temperature (i.e., at a temperature of about 20°C to about 25°C, such as about 22°C), at a temperature of about 37°C, and / or at a temperature of about 50°C.

[0063] This disclosure also provides a pharmaceutical composition comprising a salt of Formula III as described herein and an admixture of a pharmaceutically acceptable excipient, carrier, and / or diluent.

[0064] The pharmaceutical compositions described herein may be oral pharmaceutical compositions. For example, oral pharmaceutical compositions may be provided as liquid preparations, such as syrups, suspensions, or solutions. Alternatively, oral pharmaceutical compositions may be provided as solids, such as tablets, capsules, pills, or lozenges. In particular, oral pharmaceutical formulations may be capsules or tablets, such as capsules or tablets.

[0065] In addition, a salt or pharmaceutical composition of Formula III as described herein is provided for use as a medicine.

[0066] This disclosure also provides a salt or pharmaceutical composition of Formula III as described herein for treating and / or preventing diseases, conditions, and / or symptoms 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 instability, and pathological apathy. For example, diseases, conditions, and / or symptoms may be selected from the group consisting of: dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, diseases, conditions, and / or symptoms may include or consist of: pathological apathy. 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. Pathological apathy may include or consist of: apathy as defined by a scale known in the art for measuring apathy (such as the Apathy Assessment Scale, the Apathy Motivation Index, the Dimensional Apathy Scale, and the Riehl Apathy Rating Scale). Furthermore, pathological apathy can be associated with neurodegenerative diseases or conditions such as dementia, Alzheimer's disease, or Parkinson's disease. In particular, pathological apathy can be associated with Parkinson's disease. The aforementioned diseases, conditions, and / or symptoms can occur in association with neurological or mental disorders such as schizophrenia, depression, dementia, and / or neurodegenerative diseases. In further examples, the aforementioned diseases, conditions, and / or symptoms can occur in association with neurodegenerative diseases or conditions such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or stroke-related dementia. In yet another further example, the aforementioned diseases, conditions, and / or symptoms can occur in association with Parkinson's disease or Alzheimer's disease.

[0067] In addition, salts or pharmaceutical compositions of Formula III as described herein are provided for the manufacture of medicines for the treatment and / or prevention of diseases, conditions, and / or symptoms 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 instability, and apathy. For example, diseases, conditions, and / or symptoms may be selected from the group consisting of: dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, diseases, conditions, and / or symptoms may include or consist of: pathological apathy. 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. Pathological apathy may include or consist of: apathy as defined by a scale of apathy known in the art (such as the Apathy Assessment Scale, the Apathy Motivation Index, the Dimensional Apathy Scale, the Lille Apathy Rating Scale). Furthermore, pathological apathy can be associated with neurodegenerative diseases or conditions such as dementia, Alzheimer's disease, or Parkinson's disease. In particular, pathological apathy can be associated with Parkinson's disease. The aforementioned diseases, conditions, and / or symptoms can occur in association with neurological or mental disorders such as schizophrenia, depression, dementia, and / or neurodegenerative diseases. In further examples, the aforementioned diseases, conditions, and / or symptoms can occur in association with neurodegenerative diseases or conditions such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or stroke-related dementia. In yet another further example, the aforementioned diseases, conditions, and / or symptoms can occur in association with Parkinson's disease or Alzheimer's disease.

[0068] This disclosure also provides a method for treating and / or preventing diseases, conditions, and / or symptoms 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 instability, and pathological apathy, said method comprising administering to a mammal, such as a human, or an animal in need, an effective amount, such as a therapeutically effective amount, of a salt or pharmaceutical composition of Formula III as described herein. For example, diseases, conditions, and / or symptoms may be selected from the group consisting of: dementia, cognitive impairment, schizophrenia, and pathological apathy. In further examples, diseases, conditions, and / or symptoms may include or consist of: pathological apathy. 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. Pathological apathy may include or consist of the following: apathy as defined by a scale known in the art for measuring apathy (such as the Apathy Assessment Scale, the Apathy Motivation Index, the Dimensional Apathy Scale, and the Riehl Apathy Rating Scale). Furthermore, pathological apathy may be associated with neurodegenerative diseases or conditions (such as dementia, Alzheimer's disease, or Parkinson's disease). In particular, pathological apathy may be associated with Parkinson's disease. The aforementioned diseases, conditions, and / or symptoms may occur in association with neurological or mental disorders (such as schizophrenia, depression, dementia, and / or neurodegenerative diseases). In a further example, the aforementioned diseases, conditions, and / or symptoms may occur in association with neurodegenerative diseases or conditions (such as Parkinson's disease, Alzheimer's disease, vascular dementia, Huntington's disease, or stroke-related dementia). In yet another further example, the aforementioned diseases, conditions, and / or symptoms may occur in association with Parkinson's disease or Alzheimer's disease.

[0069] As used herein, the term prevention includes preventive treatment and / or prevention of disease, symptom, and / or condition. Specifically, the term may refer to achieving a reduction in the likelihood of a patient (or healthy subject) developing a condition (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%).

[0070] Furthermore, as used herein, the term "therapeutic effective amount" refers to the amount of compound that imparts a therapeutic effect to the treated patient. The effect can be objective (i.e., measurable by some test or biomarker) or subjective (i.e., the subject gives indications of the effect and / or feels the effect).

[0071] Salts of Formula III can be prepared by combining a compound of Formula I as described herein with an acid of Formula II as described herein. Furthermore, compounds of Formula I can be prepared as described in WO 2018 / 091687 and / or using methods known in the art.

[0072] Therefore, this disclosure also provides a method for preparing a salt of formula III as described herein, the method comprising the following steps:

[0073] - Provide compounds of formula I as described herein and acids of formula II as described herein in a ratio of 1:n (such as a ratio of 1:0.5 or 1:1);

[0074] - The compound of formula I is mixed with the acid of formula II in a solvent (such as THF or ethanol or a mixture of ethanol and water) to form a solution; and

[0075] -To precipitate the salt of Formula III; and

[0076] - Separate the precipitate containing salts of Formula III or composed of salts of Formula III.

[0077] Salt

[0078] In this document, the chemical structures of salts of Formula III comprising a combination of a compound of Formula I and an acid of Formula II have been drawn as complexes, wherein the acidic proton of the acid is attached to the acid. However, those skilled in the art will understand that the acidic proton of the acid of Formula II may be attached 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 of Formula II, and this is also intended to be covered by the salts described herein. For example, a salt of Formula IIIa2 as a 1:1 combination of a compound of Formula I and tartaric acid may also be represented as:

[0079]

[0080] Labeled compounds

[0081] The compounds disclosed herein may be used in their labeled or unlabeled form. In the context of this disclosure, labeled compounds have one or more atoms replaced by atoms whose atomic masses or mass numbers differ from those normally found in nature. Labeling will allow for simple quantitative detection of the compounds.

[0082] In one instance, a salt of Formula III as described herein is provided, wherein one or more hydrogen atoms in the hydrogen atoms of the Formula I compound are replaced by deuterium.

[0083] 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 emission tomography (PET) radionuclides are 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... 2 H (deuterium) 3 H (tritium) 11 C13 C 14 C 18 O、 17 O、 19 F and 18 F. It is known that heavier isotopes have been substituted, such as deuterium ( 2 Replacing one or more hydrogen atoms with H may provide pharmacological advantages in certain situations, such as increased metabolic stability.

[0084] Physical methods for detecting 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 X-ray tomography (CAT), or combinations thereof.

[0085] combination

[0086] It should be understood that the salts disclosed herein can be combined with other medications for the treatment and / or prevention of CNS symptoms and / or diseases. Other medications may include 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 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 single, simultaneous or sequential administration of (i) and (ii).

[0087] 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.

[0088] Example

[0089] In this paper, the compounds were named using ChemDraw Ultra version 12.0.2.1076. If the chemical name and chemical structure are inconsistent, the chemical structure should be considered the correct one.

[0090] abbreviation

[0091] AAC accelerated aging conditions

[0092] ACN Acetonitrile

[0093] ADHD (Attention Deficit Hyperactivity Disorder)

[0094] aq. pirfenidone

[0095] CNS (Central Nervous System)

[0096] CAT computed tomography (CT) axial X-ray computed tomography

[0097] DCM dichloromethane

[0098] DMSO (dimethyl sulfoxide)

[0099] DSC Differential Scanning Calorimetry

[0100] DVS Dynamic Vapor Adsorption

[0101] EtOH (ethanol)

[0102] Fig.

[0103] g gram

[0104] GABA γ-aminobutyric acid

[0105] Generalized Anxiety Disorder (GAD)

[0106] h hours

[0107] HOAc acetic acid

[0108] kg

[0109] L rise

[0110] LC low crystallinity or liquid chromatography

[0111] LCMS (Liquid Chromatography-Mass Spectrometry)

[0112] mg

[0113] min. minutes

[0114] mL

[0115] MRI (Magnetic Resonance Imaging)

[0116] MRS nuclear magnetic resonance spectroscopy analysis

[0117] MTBE (methyl tert-butyl ether)

[0118] NMR (Nuclear Magnetic Resonance)

[0119] RH (Relative Humidity)

[0120] PET Positron Emission Tomography

[0121] RT room temperature

[0122] SPECT single-photon imaging computed tomography

[0123] TGMS thermogravimetric analysis coupled with mass spectrometry

[0124] THF Tetrahydrofuran

[0125] w / w weight / weight

[0126] XRP (X-ray Powder)

[0127] XRPD X-ray powder diffraction

[0128] HR-XRPD High-Resolution X-ray Powder Diffraction

[0129] HT-XPRD High-throughput X-ray Powder Diffraction

[0130] Basic Information

[0131] Reagents and solvents should be used as is, without purification.

[0132] Unless otherwise specified, NMR analyses were performed on an NMR instrument running at 500 MHz. Solvent peaks were used as internal standards.

[0133] Use HT-XRPD and / or HR-XRPD to collect XRPD data.

[0134] HT-XRPD:

[0135] High-throughput XRPD equipment was used to obtain HT-XRPD maps. The plate was mounted on a Bruker Universal Area Detector Diffraction System (GADDS), which is equipped with corrections for intensity and geometric variations. -500 gas area detector. Measurement accuracy (peak position) calibration was performed using the NIST SRM1976 standard (corundum).

[0136] Data collection was performed at room temperature using monochromatic Cu Kα radiation in the 2θ region between 1.5° and 41.5°, the most unique portion of the XRPD pattern. Diffraction patterns for each aperture were collected in two 2θ ranges (1.5°≤2θ≤21.5° for the first frame and 19.5°≤2θ≤41.5° for the second frame), with an exposure time of 90 seconds per frame. No background subtraction or curve smoothing was applied to the XRPD patterns.

[0137] HR-XRPD:

[0138] HR-XRPD data were obtained using Cu Kα1 radiation on a D8 Advance diffractometer. The diffraction data were collected at room temperature using a germanium monochromator. The diffraction data ranged from 2.15 to 41.5°. Collection was performed within the range. The solid-state LynxEye detector was scanned using a scan rate of 0.016° per step and 15 seconds per step. Samples were measured in an 8mm long glass capillary with an outer diameter of 0.3mm.

[0139] Hygroscopicity test

[0140] Hygroscopicity was measured using dynamic vapor adsorption (DVS9, collected on a DVS Adventure system from Surface Measurement Systems, London, UK). Sample sizes were approximately 10 mg of solid material. Complete adsorption and desorption isotherms were recorded by varying the relative humidity from 40% to 95% to 0% to 40% in 10% steps at a constant temperature of 25°C over a 1-hour equilibrium period. Samples were then measured using HT-XRPD.

[0141] Based on the percentage of water absorbed at 25°C / 80% RH during the first adsorption cycle of the adsorption isotherm, the materials are classified as shown in Table 1 below.

[0142] Table 1

[0143] Classification Water absorption rate (w / w) at 25℃ / 80%RH Non-hygroscopic 0-0.2 Slightly absorbent 0.2-2.0 Medium moisture absorption 2.0-15.0 Highly absorbent ＞15.0

[0144] Water solubility test

[0145] Water solubility is assessed by adding equal parts of water to 4 to 8 mg of salt at room temperature. If the water solubility is found to be equal to or greater than that of 3-(2,3-difluorophenoxy)azacyclobutane, i.e., equal to or greater than 5 mg / mL, the water solubility is considered acceptable.

[0146] Differential scanning calorimetry (DSC) analysis

[0147] The melting point was determined using DSC analysis performed as follows. Thermal events were obtained from DSC thermograms and recorded using a heat flux DSC3+STARe system (Mettler-Toledo GmbH, Switzerland). The temperature and thermal function of DSC3+ were calibrated using a small sample of indium (mp = 156.6 °C; δHf = 28.45 J / g) and zinc (mp = 419.6 °C; δHf = 107.5 J / g). The sample (approximately 2 mg) was sealed in a standard 40 μL aluminum dish, pinned, and heated in the DSC from 25 °C to 300 °C at a heating rate of 10 °C / min. During the measurement, the DSC apparatus was purged with dry N2 gas at a flow rate of 50 mL / min.

[0148] Tests for chemical stability in solution

[0149] The chemical stability in solution was evaluated for two different salts of 3-(2,3-difluorophenoxy)azacyclobutane according to the present invention and one salt of 3-(2,3-difluorophenoxy)azacyclobutane according to the prior art. Tests were performed in methanol solution at two different temperatures (37°C and 50°C) for up to one week. Samples were analyzed by liquid chromatography-mass spectrometry (LC-MS). Levels of 3-(2,3-difluorophenoxy)azacyclobutane and possible degradation products were measured by LC-MS / UV detection and LC / MSD iQ single quadrupole (Agilent). The HPLC module included a binary pump system, a vacuum degasser, a temperature-controlled autosampler, and a temperature-controlled column oven. Column: Poroshell 120EC C18 (2.7 x 100 mm, 4.6 μm).

[0150] Mobile phase A: 0.03% HOAc solution in Milli-Q water

[0151] Mobile phase B: 0.03% HOAc solution in acetonitrile.

[0152] Flow rate: 1.0 ml / min

[0153] Elution gradient:

[0154] Time (minutes) 0 0.5 5.5 8.5 9.5 Solvent A (%) 95 95 5 5 95 Solvent B (%) 5 5 95 95 5

[0155] Mass spectrometry parameters:

[0156] Polarity: Positive / Negative mode, ESI+ / -

[0157] Desolvation temperature: 325℃

[0158] Capillary voltage: 3.5kV

[0159] Mass range (m / z): 100 to 1000 m / z

[0160] Injection volume: 2.0 μL

[0161] UV: (190 to 400 nm) 250 nm

[0162] Synthesis of the acid addition salt of compound II, namely 3-(2,3-difluorophenoxy)azacyclobutane

[0163] The compound 3-(2,3-difluorophenoxy)azacyclobutane, namely the compound of formula I described herein, is combined with a variety of different acids using either method A or method B described below.

[0164] Method A:

[0165] An equal part of a 1M aqueous solution of an acid or pure solid acid was added to a saturated solution of the compound of formula I in THF or acetonitrile. The mixture was then subjected to a temperature curve of heating to 50°C, followed by cooling to 5°C for four hours, and finally aged at 5°C for approximately 72 hours.

[0166] Method B:

[0167] A suspension of the compound of formula II and the acid in ethanol was prepared. Subsequently, the mixture was subjected to a temperature profile of three heating-cooling cycles between 5 and 50 °C, and finally aged at 25 °C for 72 hours.

[0168] Following the procedures described for Methods A and B, respectively, the resulting solids were separated by centrifugation, dried, and analyzed by high-throughput XRPD (HT-XRPD). If no solid precipitate was observed, the solvent in the solution was evaporated overnight under ambient conditions and subsequently incubated overnight under vacuum at 50°C. The solids were then exposed to accelerated aging conditions (AAC), i.e., exposure to a temperature of 40°C and 75% relative humidity (RH) for 48 hours. The solids that had undergone AAC were then reanalyzed by XRPD to assess their physical stability. Solids were considered stable if no, substantially no, or very minor changes occurred. The solids were also subjected to visual inspection to observe any changes, such as discoloration. Salts were considered unstable if the XRPD spectrum of the salt differed significantly from that before AAC treatment and / or if visual inspection showed changes such as color. Novel XRPD patterns different from those of 3-(2,3-difluorophenoxy)azacyclobutanes and acids were considered potential shocks for crystalline salts. Potential crystalline salts are named using the salt's abbreviation followed by a number, as shown in Table 1.

[0169] With a relaxation time of at least 10 seconds 1 The base / acid ratio of the obtained salt form can be determined by ¹H NMR spectroscopy or elemental analysis.

[0170] The results are shown in Table 2. Different solvents were tried for crystallization. For example, ethanol, tetrahydrofuran, and acetonitrile were tried to prepare the hydrochloride salt. In the "Chemical Stability" column, most salt forms were found to be chemically stable under accelerated aging conditions, if indicated by XRPD and visual inspection as described above.

[0171] Table 2

[0172]

[0173]

[0174]

[0175] The salt forms listed in Table 1 that are chemically stable in the AAC test or that transform into chemically stable forms after exposure to the AAC test are further investigated below.

[0176] hydrochloride

[0177] The hygroscopicity of the HCl salt form shown in Table 2 was evaluated by DVS analysis and found to be approximately 6% at 80% RH, indicating that this HCl salt form is moderately hygroscopic.

[0178] Therefore, the above-mentioned hydrochloride form was found to be hygroscopic. Furthermore, water solubility was found to be above 180 mg / mL.

[0179] Fumarate

[0180] The hygroscopicity of the fumarate form according to Example 1B in WO 2018 / 091687 was investigated and 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.

[0181] p-Toluenesulfonate

[0182] The hygroscopicity of the TOS1 salt form was found to be 3% at 80% RH, indicating that the TOS1 salt is moderately hygroscopic. Therefore, the TOS1 salt form is found to be hygroscopic. Furthermore, the qualitative water solubility was found to be approximately 10 mg / mL.

[0183] L-Tartrate

[0184] The TAR1 salt form is the most common salt form of tartrate. Thermal analysis of the TAR1 salt form indicates that it is a sesquihydrate containing 1.5 equivalents of water, which dehydrates between 30°C and 100°C. The thermal behavior is characterized by a broad endothermic peak corresponding to water loss. No other thermal events were detected after dehydration, indicating that the crystal structure collapses upon water loss. The conclusion is that the TAR1 salt form is unsuitable for development due to the risks of dehydration and potential amorphization.

[0185] The TAR3 and TAR5 salt forms become deliquescent when exposed to AAC.

[0186] The TAR2 salt form appears to be an anhydrous hemi-L-tartrate. The melting point of the TAR2 salt form is 181.5 °C. DVS analysis indicates that TAR2 has a water absorption rate of less than 0.2% at 80% RH. Water solubility ranges from 53 to 106 mg / mL. Very small amounts of the TAR2 salt form convert to the TAR4 salt form upon contact with AAC.

[0187] In conclusion, the TAR2 salt form is non-hygroscopic. Furthermore, the TAR2 salt form exhibits satisfactory water solubility. Additionally, the high melting point of 181.5°C in the TAR2 salt form makes it suitable for manufacturing pharmaceutical compositions, such as tablets.

[0188] TAR2 salt 1 1H NMR analysis indicated that the salt was a combination of compound I of formula and L-tartaric acid in a ratio of 1:0.5.

[0189] XRPD analysis provides Figure 1 The diffraction pattern in [the image / image]. [The image / image] has already been obtained from [the image / image]. Figure 1 The main characteristic peaks, their positions, and relative intensities were extracted from the diffraction pattern and are given in the table below.

[0190] Summary from Figure 1 The peak value table

[0191]

[0192] Succinate

[0193] 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 to 40 mg / mL. (This information is consistent with TGMS and...) 1 The SUC1 salt form, as indicated by HNMR, is an anhydrous monosuccinate, with a melting temperature of 150.2 °C, as determined by differential scanning calorimetry (DSC). When EtOH / THF or ACN is used as a solvent, a SUC1 salt containing a small amount of the SUC2 salt form is formed.

[0194] The conclusion is that succinates (such as SUC1 salts) are non-hygroscopic. Furthermore, it is concluded that succinates (such as the SUC1 salt form described herein) possess satisfactory water solubility. In addition, the high melting point of 150.2°C of the SUC1 salt form makes it suitable for manufacturing pharmaceutical compositions, such as tablets. Moreover, the discovery that only two polymorphs were identified and the ease of forming only the SUC1 salt form is beneficial for the manufacture and control of pharmaceutical properties.

[0195] SUC1 salt 1 1H NMR analysis showed that the salt was a combination of compound I of formula and succinic acid in a 1:1 ratio.

[0196] XRPD analysis provides Figure 2 The diffraction pattern in [the image / image]. [The image / image] has already been obtained from [the image / image]. Figure 2 The main characteristic peaks, their positions, and relative intensities were extracted from the diffraction pattern and are given in the table below.

[0197] Summary from Figure 2 The peak value table

[0198]

[0199] malonate

[0200] Based on crystallinity and physical stability, MAO1 was found to be the most relevant crystalline form. MAO2 transforms into MAO1, while MAO3 becomes deliquescent upon exposure to AAC.

[0201] 1 ¹H NMR analysis showed that a salt was formed in a stoichiometric ratio of free base (i.e., compound I):malonic acid of 1:1. Thermal analysis showed that MAO1 was an anhydrous phase, which began to decompose at 120 °C and melted / decomposed at 154.6 °C. Water solubility was found to be between 40 and 80 mg / mL. DVS analysis showed that MAO1 was moderately hygroscopic, with a water absorption rate of 3.4% at 80% RH. Therefore, malonate is hygroscopic.

[0202] Example 1

[0203] 3-(2,3-difluorophenoxy)azacyclobutane succinate

[0204]

[0205] A) 3-(2,3-difluorophenoxy)azacyclobutane

[0206] DMSO (20 L) was charged into a 50-L reactor, followed by tert-butyl 3-{[(4-methylphenyl)sulfonyl]oxy}-1-azacyclobutanecarboxylate (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 to an internal temperature of 70 °C for 16 hours. 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 another 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 a 10% aqueous solution of Na₂CO₃ (5 L), 10% NaCl (3 × 5 L), and water (5 L). The solution was loaded into a 50-L reactor, and then an 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 batch of MTBE (15 L). The two layers were separated, and the organic phase was discarded. The aqueous solution was cooled to 10°C, and the pH was adjusted with an aqueous NaOH solution (50%, 3.95 kg) until a pH of 14 was obtained, while maintaining an internal temperature below 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 and then cooled to 10-15°C for 17 hours. The precipitate was separated by filtration, and the filter cake was washed with water (2 × 2.5 L) and then dried on a filter for 70 hours by evacuating the filter cake through a vacuum at room temperature. 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.

[0207] B) 3-(2,3-difluorophenoxy)azacyclobutane succinate

[0208] 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 nearly 2 hours until the acid was completely dissolved. The solution was drained from the reactor and stored at room temperature for one day. The reactor was rinsed with EtOH, and then EtOH (15 L) and water (3 L) were added. 3-(2,3-difluorophenoxy)azacyclobutane (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. The 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 returned to the reactor through a filter. The mixture was heated to an internal temperature of 75 °C for 51 minutes. After gradually cooling the mixture to an internal temperature of 5 °C (5 °C / 20 min), the resulting slurry was stirred at 5 °C for 15 hours. The product was separated by filtration, and the filter cake was washed twice with EtOH (2 × 1.5 L), and then dried on a filter for nearly three days by evacuating the filter cake through a vacuum at room temperature. 1.73 kg (71%) of succinate of 3-(2,3-difluorophenoxy)azacyclobutane 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 shows that the ratio of the identified azacyclic butane derivative to succinic acid is 1:1. Therefore, in this example, the succinate of 3-(2,3-difluorophenoxy)-azacyclic butane is provided as a combination of 3-(2,3-difluorophenoxy)azacyclic butane and succinic acid in a 1:1 ratio.

[0209] Example 2

[0210] 3-(2,3-difluorophenoxy)azacyclobutane hemi-L-(+)-tartrate

[0211] A mixture of EtOH and water (19:1, 600 mL) was added to a 1-L round-bottom flask, followed by the addition of 3-(2,3-difluorophenoxy)azacyclobutane (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. The slurry was stirred at an internal temperature of 76 °C for 40 minutes until almost all the solids were dissolved. Water was then added in portions (55 mL) until a clear solution was obtained. After stirring at 76 °C for 5 minutes, the mixture was cooled to room temperature. The resulting white slurry was stirred at 0–5 °C for 2 hours. The precipitate was separated 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 the product at room temperature for 16 hours, and then dried under vacuum 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 (400MHz, 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 spectra show that the ratio of the identified azacyclobutane derivative to L-tartaric acid is 2:1. Therefore, in this example, the L-tartaric acid salt of 3-(2,3-difluorophenoxy)-azacyclobutane is provided as a combination of 3-(2,3-difluorophenoxy)-azacyclobutane and L-tartaric acid in a ratio of 1:0.5.

[0212] Comparative example: 3-(2,3-difluorophenoxy)azacyclobutane fumarate

[0213]

[0214] In this comparative example, the 3-(2,3-difluorophenoxy)azicyclic butane fumarate from Example 1B of WO 2018 / 091687 was re-evaluated. Upon re-examination of the LC-MS chromatogram of the 3-(2,3-difluorophenoxy)azicyclic butane fumarate from Example 1B of WO 2018 / 091687, the product was observed to be contaminated with 2 to 4% of an impurity, with an m / z of 300 in negative mode and 302 in positive mode. The conclusion is that the impurity is an adduct of an amine and fumaric acid, with the chemical structure shown below.

[0215]

[0216] It is believed that the formation of this impurity is due to the Michael addition reaction between 3-(2,3-difluorophenoxy)azacyclobutane and fumaric acid according to the reaction scheme shown below.

[0217]

[0218] Although the concentration of Michael adduct impurities may appear low (2 to 4%), they can potentially cause problems during reaction scale-up (such as scale-up to industrial production), where additional steps (such as steps for impurity removal) negatively impact the overall performance and feasibility of the scale-up. Furthermore, when the reaction is carried out on a large scale, such as industrial scale, these side reactions leading to Michael adduct impurities may occur to a greater extent, where process conditions typically involve, for example, longer reaction times, which will favor the formation of Michael adduct impurities.

[0219] Example 3

[0220] Chemical stability in methanol solution at 37°C and 50°C

[0221] In chemical stability tests, three different salts of 3-(2,3-difluorophenoxy)azacyclobutane were investigated: 1) the succinate according to Example 1, 2) the hemi-L-(+)-tartrate according to Example 2, and 3) the fumarate (prior art compound) according to Example 1B of WO 2018 / 091687. 2.0 mg of each test compound was weighed and placed into one vial for each temperature. The 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 to 700 μM relative to 3-(2,3-difluorophenoxy)azacyclobutane (Formula I). ​​The time points were one, two, three, four, 24, 48 hours, and one week.

[0222] The possible degradation products formed were detected and characterized by LC MS. Therefore, the chemical structure of the major degradation product in the solution of 3-(2,3-difluorophenoxy)azacyclobutane fumarate was determined to be a Michael adduct according to formula A, as shown below.

[0223]

[0224] The chemical structures of the second and third highest degradation products in the same methanol solution were determined to be two positional isomers of the Michael adduct monomethyl ester according to formulas B and C. However, it is impossible to determine which of these two positional isomers corresponds to which of the two peaks in the chromatogram.

[0225]

[0226] The retention time of 3-(2,3-difluorophenoxy)azacyclobutane (Formula I) was 3.7 to 3.8 minutes. The retention time of the degradation product according to Formula A was 4.0 to 4.1 minutes. The retention times of the two degradation products according to Formulas B and C were 4.2 to 4.3 minutes and 4.4 to 4.5 minutes, respectively. The LC area % of the three different degradation products increased over time, and for example, the LC area % after one week at 50°C was as follows: Formula A was 60.2%, Formula B (or Formula C) was 11.6%, and Formula C (or Formula B) was 3.5%.

[0227] The results of stability studies of methanol solutions of 3-(2,3-difluorophenoxy)azacyclobutane succinate at 37 °C and 50 °C are shown in Table 3. The compound detected by elution at 3.7 to 3.8 min is the non-salt form of 3-(2,3-difluorophenoxy)azacyclobutane, and this compound is designated as Formula I in the table. Corresponding results for methanol solutions of hemi-L-(+)-tartrate and fumarate of 3-(2,3-difluorophenoxy)azacyclobutane are shown in Tables 4 and 5, respectively.

[0228] Table 3.3 shows the results of 3-(2,3-difluorophenoxy)azacyclobutane succinate in methanol solution at 37 °C and 50 °C, respectively. Chemical stability

[0229]

[0230] Table 4. Semi-L-(+)-tartrates of 3-(2,3-difluorophenoxy)azacyclobutane at 37 °C and 50 °C, respectively. Chemical stability in methanol solution

[0231]

[0232] Table 5. Fumarates of 3-(2,3-difluorophenoxy)azacyclobutane were dissolved in methanol at 37 °C and 50 °C, respectively. Chemical stability in liquid

[0233]

[0234] As shown in Table 5, the fumarate of 3-(2,3-difluorophenoxy)azacyclobutane (the prior art compound according to Example 1B of WO 2018 / 091687) degrades significantly in methanol solution at 37°C. The degradation is even more pronounced at 50°C, where almost half of the drug has degraded after two days. Conversely, and as shown in Tables 3 and 4, the corresponding succinate and the corresponding hemi-L-(+)-tartrate do not degrade in methanol solution at any test temperature. Therefore, both salts of the present invention exhibit very high stability in solution even after being placed in methanol solution at 50°C for one week.

[0235] Remark

[0236] As shown above, both the succinate and hemi-L-(+)-tartrate salts of Formula I are non-hygroscopic, have high melting points, good water solubility, and are stable in solution, which allows them to be used, for example, in solution handling and / or storage without or substantially without degradation. Therefore, both salts possess properties that make them suitable for use as pharmaceuticals or for processing into pharmaceutical compositions.

[0237] References

[0238] 1. Prog Neuro-Psychopharm&Bio Psych, 2013, 45, 54-63.

[0239] 2. Biol Psych, 2011, 69(12); 89-99.

[0240] 3. Front Cell Neurosci, 2015, 9; 1-23.

[0241] 4. Neurosci & Biobehav Rev, 2013, 37; 1363-79.

[0242] 5. Mol Psych, 2005, 1O; 40-68.

[0243] 6. Eur Psych, 2005, 20; 15-27.

[0244] 7.WO 2010 / 022055

[0245] 8.WO 2018 / 091687

Claims

1. A salt of Formula III: the salt being a combination of a compound of Formula I and an acid of Formula II: in a ratio of 1 :n, wherein X is OH or H; and 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 Ilia, which is a combination of the compound of Formula I and tartaric acid:

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

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

5. The salt of Formula Ilia 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 forming a salt of Formula IIIb, which is a combination of the compound of Formula I and succinic acid:

7. The salt of Formula III according to any one of the preceding claims, wherein n is 0.

5.

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

9. Salt according to any of the preceding claims, characterized in that is crystalline.

10. The salt of Formula III according to any one of claims 1 to 5, 7 or 9, which is characterized by an XRP diffraction pattern comprising a peak at 27.4 degrees 2q and one or more peaks selected from 17.8, 19.5, 19.9, 21.6 degrees 2q.

11. The salt of Formula III according to any one of claims 1 to 5, 7 or 9, which is characterized by an XRP diffraction pattern as shown in Figure 1.

12. The salt of Formula III according to any one of claims 1, 6, 8 or 9, which is characterized by an XRP diffraction pattern comprising a peak at 12.5 degrees 2q and one or more peaks selected from 13.3, 16.5, 19.3, 22.4, 23.3, 24.1, 24.9, 25.9, 26.9 degrees 2q.

13. The salt of Formula III according to any one of claims 1, 6, 8 or 9, which is characterized by an XRP diffraction pattern as shown in Figure 2.

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 are replaced by deuterium.

15. The salt of Formula III according to any one of the preceding claims, wherein the salt has a weight change of about ±0.2% by weight or less at any humidity, such as any relative humidity, such as at a relative humidity of 80% measured at a temperature of 20°C to 25°C.

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

17. The salt of Formula III according to any one of claims 1, 6 to 9, 12 or 13, which has 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 preceding claims, wherein the salt is chemically stable in methanolic solution for 48 hours or more, such as 168 hours or more, at room temperature, at a temperature of 37 °C and / or at a temperature of 50 °C.

19. A pharmaceutical composition comprising a salt of Formula III according to any one of the preceding claims in admixture with a pharmaceutically acceptable excipient, carrier and / or diluent.

20. A salt of Formula III according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use as a medicament.

21. A salt of Formula III according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for use in 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), movement disorder, postural instability and pathological apathy.

22. The salt of Formula III for use according to claim 21 or the pharmaceutical composition for use according to claim 21, wherein the disease, disorder and / or condition is pathological apathy.

23. The salt of Formula III for use according to claim 22, the pharmaceutical composition for use according to claim 22, wherein the pathological apathy is as defined in an apathy measurement scale.

24. The salt of Formula III for use according to claim 23 or the pharmaceutical composition for use according to claim 23, wherein the apathy measurement scale is one or more of the following: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Rier Apathy Rating Scale.

25. The salt of Formula III for use according to any one of claims 21 to 24 or the pharmaceutical composition for use according to any one of claims 21 to 24, wherein the pathological apathy is associated with a neurodegenerative disease such as dementia, Alzheimer’s disease or Parkinson’s disease.

26. The salt of Formula III for use according to claim 25 or the pharmaceutical composition for use according to claim 25, wherein the neurodegenerative disease is Parkinson’s disease.

27. Use of a salt of Formula III according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 for the manufacture of a medicament 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), movement disorder, postural instability and pathological apathy.

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 an apathy measurement scale.

30. The use according to claim 29, wherein the apathy measurement scale is one or more of the following: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Rier Apathy Rating Scale.

31. The use according to any one of claims 27 to 30, wherein the pathological apathy is associated with 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), movement disorder, postural instability and pathological apathy, 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 a salt of Formula III according to any one of claims 1 to 18 or a pharmaceutical composition according to 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: Apathy Evaluation Scale, Apathy Motivation Index, Dimensional Apathy Scale, Rier Apathy Rating Scale.

37. The method according to any one of claims 33 to 36, wherein the pathological apathy is associated with 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.

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