Crystalline form of (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone

Abstract

The present invention relates to a crystalline form of (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone, a process for its preparation, pharmaceutical compositions comprising same and its use as an orexin receptor antagonist in the prevention and / or treatment of various orexin receptor-mediated disorders, such as Binge Eating Disorder (BED).

Description

[Technical field]

[0001] The present invention relates to a novel crystalline form of the active ingredient, (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone, which is also referred to herein as ACT-539313, its preparation, pharmaceutical compositions comprising said crystalline form, and its use as an orexin receptor antagonist in the prevention and / or treatment of various orexin receptor-mediated diseases, disorders and / or conditions, such as anxiety disorders, addictive disorders and eating disorders. [Background technology]

[0002] ACT-539313 (CAS RN 1435480-40-2) and its orexin receptor antagonist activity have been previously disclosed in WO2013068935. ACT-539313 is a potent and selective orexin-1 receptor antagonist that has been tested in clinical trials (NCT02702648, NCT03363984 and NCT04753164). Certain clinical aspects of this compound are discussed by Kaufmann P et al., Br J Clin Pharmacol. 2020;86(7):1377-1386; Berger, B et al., J Clin Pharmacol. 2020;60(7):931-941; and Kaufmann P et al., Prog Neuropsychopharmacol Biol Psychiatry. 2021;108:110166. Summary of the Invention

[0003] Summary of the Invention The crystalline forms of ACT-539313 disclosed herein will exhibit advantageous physical properties such as being non-hygroscopic, thus having a longer shelf life; less tendency to aggregate during storage; easier packaging / handling; and limited mass change during weighing / dispensing. The crystalline forms will be thermodynamically stable compared to other forms that are less thermodynamically stable or metastable. The crystalline forms will have advantageous bulk properties such as powder density and flowability. The polymorphs disclosed herein will have advantageous powder flow behavior such as a sufficiently high melting point and favorable compression properties, thus making them suitable for the manufacture of solid dosage forms such as tablets. Furthermore, certain pharmaceutical compositions having the crystalline forms of the present invention will have advantageous properties such as being particularly suitable for the manufacture of both capsules and tablets. The crystalline forms will also form easily in certain solvents, whereas in other solvents they will take substantially longer to crystallize. [Brief description of the drawings]

[0004] [Figure 1]FIG. 1 shows the powder X-ray diffraction diagram of ACT-539313 in crystalline form 1, which is shown for Cu Kα radiation. The X-ray diffraction diagram shows peaks with the following percentage relative intensities compared to the most intense peak in the diagram at the indicated refraction angles 2 theta (relative peak intensities are given in brackets) (selected peaks with a relative intensity of 10% or more from the 5-35° 2 theta range are reported): 7.8° (35%), 10.5° (37%), 12.5° (13%), 13.7° (22%), 14.2° (59%), 14.6° (17%), 15.6° (15%), 15.8° (13%), 18.4° (100%), 21.4° (18%), 21.8° (60%), 23.8° (19%), 24.1° (17%), 24.8° (14%), 25.1° (43%) and 25.5° (18%). In the X-ray diffraction diagram of Figure 1, the refraction angle 2 theta (2θ) is plotted on the horizontal axis and the counts are plotted on the vertical axis. For the avoidance of any doubt, the above peaks describe the experimental results of the powder X-ray diffraction shown in Figure 1. In contrast to the above list of peaks, it should be understood that only selected characteristic peaks are necessary to fully and unambiguously characterize each crystalline form of ACT-539313 of the present invention. [Diagram 2] 2 shows the powder X-ray diffraction diagram of ACT-539313 in the amorphous state, measured using XRPD method 1 and shown for Cu Kα radiation. In the diagram, the refraction angle 2θ is plotted on the horizontal axis and the counts are plotted on the vertical axis. [Diagram 3] Figure 3 shows a differential scanning calorimetry thermogram of ACT-539313 in crystalline form 1. Temperature [°C] is shown on the x-axis. Heat flow [mW] (endotherm endo down) is shown on the y-axis. [Figure 4] Figure 4 shows the gravimetric vapor sorption isotherm at 25°C for ACT-539313 in crystalline form 1. Relative humidity (25°C) in [%] is shown on the x-axis. Mass change in [% dry basis] is shown on the y-axis. [Diagram 5]Figure 5 shows the gravimetric vapor sorption isotherm of ACT-539313 in the amorphous state at 25°C. Relative humidity (25°C) in [%] is shown on the x-axis. Mass change in [% dry basis] is shown on the y-axis.

[0005] Description of the Embodiments 1) A first aspect of the present invention relates to a crystalline form of (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone (ACT-539313), characterized by the presence of peaks at the following refraction angles 2θ: 10.5°, 14.2° and 18.4° in the powder X-ray diffraction diagram.

[0006] The crystalline form according to embodiment 1) is understood to encompass the crystalline form of ACT-539313 in the free base (i.e., not in the form of a salt). Furthermore, the crystalline form may have non-coordinating and / or coordinating solvents. Coordinating solvents are used herein as the term for crystalline solvates. Similarly, non-coordinating solvents are used herein as the term for physically adsorbed or physically trapped solvents (Polymorphism in the Pharmaceutical Industry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: UJ Griesser: The Importance of Coordinating Solvents in the Pharmaceutical Industry). The crystalline forms of ACT-539313 disclosed herein do not have coordinated water, but may have non-coordinating water or another non-coordinating solvent.

[0007] 2) Another embodiment relates to a crystalline form of ACT-539313 according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 7.8°, 10.5°, 14.2°, 18.4° and 21.8°.

[0008] 3) Another embodiment relates to a crystalline form of ACT-539313 according to embodiment 1), characterized by the presence of peaks at the following refraction angles 2θ in the powder X-ray diffraction diagram: 7.8°, 10.5°, 12.5°, 13.7°, 14.2°, 14.6°, 18.4°, 21.4°, 21.8° and 25.1°.

[0009] 4) Another embodiment relates to a crystalline form of ACT-539313 according to embodiment 1), exhibiting an X-ray powder diffraction pattern essentially as shown in FIG.

[0010] 5) In another embodiment, the method described herein is carried out by differential scanning calorimetry (DSC). The present invention relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 4), characterized by a melting point of about 117.6°C as determined by

[0011] Another embodiment relates to a crystalline form of ACT-539313 characterized by a melting point of 117.6±2° C. as determined by differential scanning calorimetry (DSC) using the methods described herein.

[0012] 6) Another embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 5), exhibiting a differential scanning calorimetry profile essentially as shown in FIG.

[0013] 7) Another embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 6), which can be obtained by a process having the steps of: a. dissolving ACT-539313 in a solvent (particularly at a concentration of about 1 g of ACT-539313 in about 1 mL to about 20 mL of solvent), the solvent having one or more lower alcohols (particularly selected from 1-propanol, 2-propanol, ethanol or mixtures thereof; especially 2-propanol); b. waiting for the formation of a solid product (particularly for less than about 24 hours); and c. isolating said solid product.

[0014] The isolation step as defined herein may be carried out by any method known in the art for separating a solid precipitate from a liquid, preferably by filtration.

[0015] As used herein, the term "lower alcohol" refers to a mono-, di- or polyhydric (particularly mono- or dihydric; more particularly monohydric) alcohol, i.e., having one, two or three or more hydroxyl groups (particularly one or two; more particularly one hydroxyl group), which hydroxyl groups are converted to a C hydroxyl group by the replacement of one or more hydrogen atoms. 1-5 - means an alcohol bound to an alkane. 1-5 The term "-alkane" refers to a linear or branched saturated hydrocarbon chain consisting of 1 to 5 carbon atoms. Examples of lower alcohols as used herein are methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, 2-methyl-propan-2-ol, 2-methyl-propan-1-ol, 1-pentanol, 2-pentanol, 3-pentanol, ethylene glycol, propylene glycol, glycerol; in particular, methanol, ethanol, 1-propanol, 2-propanol; more particularly, ethanol, 1-propanol and 2-propanol. The solvent used to dissolve ACT-539313 as defined in embodiment 7) or any of the embodiments disclosed herein has at least 50% (particularly at least 75%; more particularly essentially 100%) of said one or more lower alcohols.

[0016] 8) Another embodiment relates to a method for producing a crystalline form of ACT-539313 according to any one of embodiments 1) to 6), the method comprising recrystallization of ACT-539313 in a solvent (particularly at a concentration of about 1 g of ACT-539313 in about 1 mL to about 20 mL of solvent), the solvent comprising one or more lower alcohols (particularly selected from 1-propanol, 2-propanol, ethanol or mixtures thereof; more particularly 2-propanol); in particular the method comprises the steps of: a. dissolving ACT-539313 in a solvent (particularly at a concentration of about 1 g of ACT-539313 in about 1 mL to about 20 mL of solvent), the solvent having one or more lower alcohols (particularly 1-propanol, 2-propanol, ethanol; especially 2-propanol); b. waiting for the formation of a solid product (particularly for less than about 24 hours); and c. isolating said solid product.

[0017] For the avoidance of any doubt, whenever one of the above embodiments refers to "peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram", it is to be understood that the powder X-ray diffraction diagram was obtained using combined Cu Kα1 and Kα2 radiation without removing Kα2; and the accuracy of the 2θ values ​​provided herein is within the range of + / -0.1 to 0.2°. In particular, when specifying a refraction angle 2θ for a peak in the embodiments and claims of the present invention, the 2θ values ​​stated are to be understood as being between the value -0.2° and the value +0.2° (2θ+ / -0.2°); and preferably between the value -0.1° and the value +0.1° (2θ+ / -0.1°).

[0018] When the plural forms are used for compounds, solids, pharmaceutical compositions, diseases, etc., they are intended to refer to the singular compound, solid, pharmaceutical composition, disease, etc. as well.

[0019] The definitions set forth herein are uniformly applied to the subject matter defined in any one of aspects 1) to 8) and apply mutatis mutandis throughout the specification and claims unless a broader or narrower definition is given by a specific definition. It should be understood that a definition or preferred definition of a term or expression may independently (and together) define and replace the respective term or expression in any or preferred definition of any or all other terms or expressions defined herein.

[0020] For example, when defining the presence of a peak in an X-ray powder diffraction diagram, a common way is to do this in terms of the S / N ratio (S=signal, N=noise). According to this definition, when stating that a peak must be present in an X-ray powder diffraction diagram, it is understood that the peak in the X-ray powder diffraction diagram is defined by having a S / N ratio (S=signal, N=noise) greater than x (x being a number greater than 1), usually greater than 2, in particular greater than 3.

[0021] When it is stated in the present invention that a crystalline form essentially exhibits the X-ray powder diffraction pattern depicted in Figure 1, the term "essentially" means that at least the main peaks of the diagram depicted in said figure, i.e. peaks having a relative intensity of more than 20%, in particular more than 10%, compared to the most intense peak in the diagram, must be present. However, a person skilled in the art of X-ray powder diffraction should be aware that the relative intensities of X-ray powder diffraction diagrams can be subject to strong intensity variations due to preferred orientation effects.

[0022] When not used in reference to temperature, the term "about" placed before a numerical value "X" means in this application between 10% of XX and 10% of X+X, preferably between 5% of XX and 5% of X+X, most preferably X. In the specific case of temperature, the term "about" placed before a temperature "Y" means in this application between a temperature Y-10°C and Y+10°C, preferably between Y-5°C and Y+5°C. Room temperature means a temperature of about 25°C.

[0023] Whenever the words "between" or "to" are used to describe a numerical range, the endpoints of the stated range are expressly intended to be included in the range. For example: when a temperature range is described as being between 40° C. and 80° C. (or 40° C. to 80° C.), it is meant that the endpoints 40° C. and 80° C. are included in the range; or when a variable is defined as an integer between 1 and 4 (or 1 to 4), it is meant that the variable is the integer 1, 2, 3, or 4.

[0024] The crystalline form of ACT-539313 according to any one of the embodiments 1) to 7) can be used as a medicament, for example in the form of a pharmaceutical composition for enteral administration (e.g., in particular orally). Cut.

[0025] 9) Thus, another embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) for use as a medicament.

[0026] The crystalline solid of ACT-539313 according to any one of embodiments 1)-7) may be used as the sole component or in admixture with other crystalline or amorphous forms of ACT-539313.

[0027] 10) A further embodiment relates to a pharmaceutical composition having as active ingredient a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) and further comprising at least one pharma- ceutically acceptable carrier material. In particular, said composition is a solid pharmaceutical composition, in particular a solid pharmaceutical composition for oral use, especially a tablet (for oral use).

[0028] In a preferred embodiment, the crystalline form of ACT-539313 according to any one of the embodiments 1) to 7) is contained in a solid dosage form (for oral use). In particular, said solid dosage form is a tablet, a capsule, a sphere, a granule, a lyophilized agent, a thin film; more particularly, said solid dosage form is a tablet or a capsule (for oral use); in particular, a tablet (for oral use).

[0029] The preparation of pharmaceutical compositions can be carried out in a manner well known to any person skilled in the art (see, for example, Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by combining the crystalline form of the present invention, optionally with other therapeutically valuable substances, with suitable non-toxic, inert, pharma- ceutically acceptable solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, to form a pharmaceutical dosage form.

[0030] 11) A further aspect is - from about 3% w / w to about 40% w / w of the active ingredient; - about 30% w / w to about 70% w / w of microcrystalline cellulose; - about 15% w / w to about 60% w / w of mannitol; - from about 3% w / w to about 10% w / w of crospovidone; - from about 0.2% w / w to about 4% w / w of sodium stearyl fumarate; and - about 0.5% w / w to about 5% w / w of silica colloidal hydrate; [The sum of the above components of the composition (especially a tablet or capsule; especially a tablet) is 100%.]; having; Or, in particular, - about 4% w / w to about 35% w / w of the active ingredient; - about 35% w / w to about 60% w / w of microcrystalline cellulose; - about 20% w / w to about 40% w / w of mannitol; - about 3% w / w to about 8% w / w of crospovidone; - from about 0.5% w / w to about 3% w / w of sodium stearyl fumarate; and - about 1% w / w to about 3% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially the tablet) is 100%.]; having; Or, inter alia: - about 5% w / w to about 25% w / w of the active ingredient; - about 38% w / w to about 55% w / w of microcrystalline cellulose; - about 24% w / w to about 35% w / w of mannitol; - about 4% w / w to about 6% w / w of crospovidone; - from about 0.5% w / w to about 2% w / w of sodium stearyl fumarate; and - about 1% w / w to about 2.5% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially the tablet) is 100%.]; having; It relates to a pharmaceutical composition according to embodiment 10) (especially a tablet or capsule for oral use; especially a tablet for oral use).

[0031] 12) A further aspect is - 22% to 25% w / w of the active ingredient; - 39%-44% w / w microcrystalline cellulose; - 24%-30% w / w mannitol; - 4%-6% w / w crospovidone; - 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1.5%-2.5% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially a tablet or capsule; especially a tablet) is 100%.]; Or, - 10% to 13% w / w of the active ingredient; - 47%-52% w / w microcrystalline cellulose; - 29%-34% w / w mannitol; - 4%-6% w / w crospovidone; - 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1%-2% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially a tablet or capsule; especially a tablet) is 100%.]; Or, - 6% to 8% w / w of the active ingredient; - 48%-54% w / w microcrystalline cellulose; - 31%-35% w / w mannitol; - 4%-6% w / w crospovidone; - 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1%-2% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially a tablet or capsule; especially a tablet) is 100%.]; Or, - 5% to 7% w / w of the active ingredient; - 50%-55% w / w microcrystalline cellulose; - 30%-35% w / w mannitol; - 4%-6% w / w crospovidone; - 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 0.5%-2% w / w of hydrated colloidal silica; [The sum of the above components of the composition (especially a tablet or capsule; especially a tablet) is 100%.]; It also relates to a pharmaceutical composition (especially a tablet or capsule for oral use; especially a tablet for oral use) according to embodiment 10), which has:

[0032] The term "ingredients" as used herein shall mean the active ingredients, the respective excipients (e.g., microcrystalline cellulose, mannitol, etc.), and further ingredients that may be present but do not substantially affect the essential characteristics of the corresponding pharmaceutical composition (e.g., minor amounts of impurities, etc.). The term "comprising" as used in embodiments 11) and 12) and in each claim may be replaced by the term "essentially consisting of", depending on the context.

[0033] 13) A further embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) for use in the manufacture of a (solid) pharmaceutical composition comprising ACT-539313 as an active ingredient and at least one pharma- ceutically acceptable carrier material.

[0034] 14) A further aspect of the invention relates to a crystalline form of ACT-539313 according to any one of aspects 1) to 7) or a pharmaceutical composition (in particular a tablet for oral use) according to any one of aspects 10) to 12) for use in the prevention and / or treatment of diseases or disorders associated with orexinergic dysfunction; in particular diseases or disorders in which blockade of at least one orexin receptor (in particular blockade of the OX1 receptor) is required.

[0035] Disorders related to orexinergic dysfunction are diseases or disorders for which antagonists of human orexin receptors, particularly OX1 receptors, are required, and in particular are mental health diseases or disorders in which orexinergic dysfunction is involved.The above-mentioned disorders may be defined as including in particular anxiety disorders, addictive disorders, mood disorders or appetite disorders, and cognitive dysfunction or sleep disorders.In particular, the above-mentioned disorders include anxiety disorders, addictive disorders and mood disorders, in particular anxiety disorders and addictive disorders.

[0036] Anxiety disorders can be differentiated by the primary object or specificity of fear, ranging from rather vague, as in generalized anxiety disorder, to limited, as in phobic anxiety (PHOB) or post-traumatic stress disorder (PTSD).Thus, anxiety disorders may be defined as including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), panic anxiety disorder (PAD), including panic attacks, phobic anxiety (PHOB), single phobia, social phobia (social anxiety disorder), avoidance disorder, somatoform disorder, including hypochondriasis, separation anxiety disorder, anxiety disorder due to general physical illness, and substance-induced anxiety disorder.In a sub-embodiment, a specific example of limited fear-induced anxiety disorder is phobic anxiety or post-traumatic stress disorder.In particular, anxiety disorders include generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, panic attacks, phobic anxiety, and avoidance disorder.

[0037] Addiction disorders may be defined as a dependency on one or more rewarding stimuli, in particular a dependency on one rewarding stimulus. Such rewarding stimuli may be of natural or synthetic origin. Examples of such rewarding stimuli are substances / drugs (natural or synthetic, such as cocaine, amphetamines, opiates (natural or (semi)synthetic, such as morphine or heroin), cannabis, ethanol, mescaline, nicotine, etc.), consumed alone or in combination; or other rewarding stimuli of natural origin (such as food, sweets, fats or sex) or synthetic origin (such as gambling or Internet / IT (excessive gaming or inappropriate involvement in social networking sites or blogs)). In a sub-embodiment, addiction disorders related to the use, abuse, seeking and relapse of psychotropic substances are defined as all types of psychological or physical dependence and their associated tolerance and dependence factors. Substance-related addictive disorders specifically include substance use disorders, such as substance dependence, substance craving, and substance abuse; and substance-induced disorders, such as substance addiction, substance withdrawal, and substance-induced delirium. The term "prevention or treatment of addiction" (i.e., preventive or therapeutic treatment of patients diagnosed as being addicted or at risk of becoming addicted) refers to the prevention or treatment of addiction. "reducing the onset of addiction, promoting withdrawal, promoting abstinence, or reducing, reducing or preventing the occurrence of relapse to addiction, in particular reducing the onset of addiction, promoting withdrawal, or reducing, reducing or preventing the occurrence of relapse to addiction."

[0038] Mood disorders include major depressive episodes, manic episodes, mixed episodes and hypomanic episodes; depressive disorders including major depressive disorder, dysthymic disorder; bipolar disorders including bipolar disorder type I, bipolar disorder type II (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorders due to general medical illness (including subtypes with depressive features, with major depressive-like episodes, with manic features, and with mixed features), substance-induced mood disorders (including subtypes with depressive features, with manic features, and with mixed features). Such mood disorders are in particular major depressive episodes, major depressive disorder, mood disorders due to general medical illness; and substance-induced mood disorders.

[0039] Appetite disorders include eating disorders and drinking disorders. Eating disorders may be defined as including eating disorders related to excessive food intake and associated complications; anorexia; compulsive eating disorders; obesity (whether due to any cause, such as genetic or environmental); obesity-related disorders including overeating and obesity observed in type 2 (non-insulin dependent) diabetics; bulimia including bulimia nervosa; cachexia; especially binge eating disorder or bulimia nervosa. In particular, eating disorders include metabolic dysfunction; appetite dysregulation; compulsive obesity; binge eating or anorexia nervosa. In a subembodiment, eating disorders may be defined as including, in particular, anorexia nervosa, bulimia nervosa, cachexia, binge eating disorder or compulsive obesity, most preferably binge eating disorder and / or bulimia nervosa. Drinking disorders include polydipsia and all other types of excessive liquid intake in psychiatric disorders. This pathological modification of eating may result from appetite disorders (attraction or aversion to food); alterations in energy balance (ingestion vs. expenditure); perception disorders about food quality (high fat or high carbohydrate, good taste); food availability disorders (restrictive dieting or deprivation) or water balance disorders.

[0040] Cognitive impairment includes deficits in attention, learning and especially memory function that occur temporarily or chronically in psychiatric, neurological, neurodegenerative, cardiovascular and immune diseases, and also occur temporarily or chronically in normal, healthy, young, adult or especially elderly populations. Cognitive impairment is particularly relevant to enhancing or maintaining memory in patients diagnosed with a disease or disorder that has as a symptom a decrease in memory (especially declarative or procedural), or at risk of developing such a disease or disorder, particularly dementia such as frontotemporal dementia or dementia with Lewy bodies or (especially) Alzheimer's disease. In particular, the term "prevention or treatment of cognitive impairment" relates to enhancing or maintaining memory in patients with clinical symptoms of cognitive impairment that manifest as a deficit in declarative memory, particularly associated with dementia such as frontotemporal dementia or dementia with Lewy bodies or (especially) Alzheimer's disease. Furthermore, the term "prevention or treatment of cognitive impairment" also relates to improving memory consolidation in any of the above patient groups.

[0041] Sleep disorders include sleep disorders, parasomnias, sleep disorders associated with general medical conditions, and substance-induced sleep disorders. In particular, sleep disorders include intrinsic sleep disorders (particularly insomnia, breathing-related sleep disorder, periodic limb movement disorder, and restless legs syndrome), exogenous sleep disorders, and circadian rhythm sleep disorders. Sleep disorders include, inter alia, insomnia, primary insomnia, idiopathic insomnia, insomnia associated with depression, emotional / mood disorders, aging, Alzheimer's disease, or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless legs syndrome, circadian rhythm sleep disorders; shift work sleep disorder; and jet lag syndrome. Parasomnias include agitation disorders and sleep-wake transition disorders; in particular, parasomnias include nightmare disorder, sleep startle disorder. and sleepwalking. Sleep disorders associated with general physical illnesses are in particular sleep disorders associated with diseases such as psychiatric disorders, neurological disorders, neuropathic pain, and heart and lung diseases. Substance-induced sleep disorders in particular include the subtypes insomnia type, parasomnia type, and mixed type, and in particular include conditions caused by drugs that cause a decrease in REM sleep as a side effect. Sleep disorders in particular include all types of insomnia, sleep-related dystonia; restless legs syndrome; sleep apnea; jet lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnia associated with psychiatric disorders. In addition, sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; transient insomnia due to environment (new environment, noise) or stress; grief; pain or short-term insomnia due to illness.

[0042] 15) A further embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) or a pharmaceutical composition (in particular a tablet for oral use) according to any one of embodiments 10) to 12) for use in the prevention and / or treatment of a disease or disorder selected from addiction disorders, anxiety disorders, appetite disorders, cognitive dysfunction and mood disorders (in particular addiction disorders, anxiety disorders and appetite disorders; more particularly appetite disorders; especially binge eating disorders).

[0043] 16) A further embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) or a pharmaceutical composition according to any one of embodiments 10) to 12) (in particular a tablet for oral use) for use in the prevention and / or treatment of an eating disorder, said eating disorder being an eating disorder involving compulsive, binge eating behavior.

[0044] The term "eating disorder involving compulsive overeating behavior" is intended to mean a disorder involving recurrent episodes of binge eating, i.e., when a subject eats significantly more food in a short period of time than most people would eat under similar circumstances, and the episodes are characterized by a feeling of lack of control. Eating disorders involving compulsive overeating behavior are characterized by eating large amounts of food, by eating quickly (often to the point of discomfort), and by eating even when no longer hungry.

[0045] 17) A further embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) or a pharmaceutical composition (in particular a tablet for oral use) according to any one of embodiments 10) to 12) for use in the prevention and / or treatment of an eating disorder, said eating disorder being Binge-Eating Disorder (BED); Bulimia Nervosa (BN); Anorexia Nervosa (AN) (in particular binge-eating / purging type anorexia nervosa; especially binge-eating type anorexia nervosa); Pica; Other Specified Feeding and Eating Disorders (OSFED) (in particular atypical bulimia nervosa, low frequency and / or limited duration eating disorders, in particular binge-eating type anorexia nervosa; Binge Eating Disorder (BED), Bulimia Nervosa (BME), Night Eating Syndrome (NES), Unspecified Feeding or Eating Disorder (UFED), Eating Disorder (Eating Disorder), and Compulsive Overeating (CO); the eating disorder is further selected from the group consisting of Loss of Control (LOC) Eating; and in particular hyperphagia and / or overeating associated with Prader-Willi Syndrome (PWS).

[0046] 18) A further embodiment relates to a crystalline form of ACT-539313 according to any one of embodiments 1) to 7) or a pharmaceutical composition according to any one of embodiments 10) to 12) (in particular a tablet for oral use) for use in the prevention and / or treatment of an eating disorder, said eating disorder being binge eating disorder (BED), bulimia nervosa (BN) or anorexia nervosa binge eating, in particular binge eating disorder (BED).

[0047] The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders The Statistical Manual of Mental Disorders (DSM-5®, or also referred to herein as DSM-5) provides diagnostic criteria for specific eating behaviors and eating disorders.

[0048] Binge Eating Disorder (BED) is defined as recurrent episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes characterized by a feeling of lack of control. People with binge eating disorder may eat very quickly, even when they are not hungry. They may feel guilt, shame, or disgust, and may binge eat in private to hide their behavior. BED is associated with significant distress and significant physical, emotional, and social health risks, most commonly obesity and excessive weight gain, and a wide range of related conditions, such as sleep apnea, cancer, heart disease, high blood pressure, type 2 diabetes, and arthritis.

[0049] According to DSM-5®, 307.51 (F50.8), the following diagnostic criteria are provided for binge eating disorder: A. Recurrent Episodes of Binge Eating. Binge eating episodes are characterized by both: 1. Eating a significantly larger amount of food during a distinct period of time (e.g., within a 2-hour period at any time of day) than most people would eat at a similar time under similar circumstances; 2. A feeling of lack of control over the overeating during the episode (e.g., feeling unable to stop eating or of being unable to control what or how much is being eaten).

[0050] B. This binge eating episode is associated with three (or more) of the following:1. eating much faster than usual;2. eating until you feel uncomfortably full;3. eating large amounts of food when you are not physically hungry;4. eating alone because you feel embarrassed about how much you are eating;5. feeling self-loathing, depressed, or very guilty afterwards;C. there is obvious distress about the binge eating;D. the binge eating has occurred, on average, at least once a week over a three-month period.

[0051] E. The binge eating is not associated with recurrent inappropriate compensatory behaviors, as in bulimia nervosa, and does not occur exclusively during the course of bulimia nervosa or anorexia nervosa.

[0052] In addition, DSM-5® identifies criteria for complete and partial remission of BED and its severity: Partial BED remission is defined as: Binge eating occurs with an average frequency of less than one episode per week for a sustained period of time after previously and fully meeting the criteria for Binge Eating Disorder (A-E); Complete remission: Binge eating occurs with an average frequency of less than one episode per week for a sustained period of time after previously and fully meeting the criteria for Binge Eating Disorder;

[0053] The minimum level of severity of BED is based on the frequency of binge eating episodes. The following severity levels have been defined: Mild: 1-3 binge eating episodes per week. Moderate: 4-7 binge eating episodes per week. Severe: 8-13 binge eating episodes per week. Extreme: 1-3 binge eating episodes per week. Four or more binge eating episodes.

[0054] Bulimia nervosa (BN), also known simply as binge eating, is an eating disorder characterized by binge eating followed by self-induced compensatory behaviors (purging) to avoid weight gain. Purging may be induced by vomiting or laxatives, use of diuretics, stimulants, water fasting, etc. Binge eating is often associated with other mental disorders such as depression, anxiety, drug or alcohol problems, and high risk of suicide and self-harm. The DSM-5® diagnostic criteria establish the frequency that people with bulimia nervosa should exhibit binge eating and compensatory behaviors (purging) at least once a week.

[0055] Anorexia nervosa (AN) primarily affects adolescent girls and young women and is characterised by excessive dieting leading to severe weight loss, accompanied by a distorted body image and a pathological fear of becoming fat. The illness can have life-threatening physiological effects and cause lasting psychological upset.

[0056] The diagnostic criteria for AN in the DSM-5 include: I) restriction of energy intake relative to requirements, resulting in a body weight that is significantly underweight in relation to age, sex, growth trajectory, and physical health; significantly underweight is defined as a body weight below the lower limit of normal and, in children and adolescents, below the minimum expected body weight; II) intense fear of gaining weight or becoming fat or persistent behaviors that prevent weight gain, even though the patient's weight is already significantly underweight; III) disturbance in perception of one's weight or shape, undue impact of weight or shape on self-evaluation, or consistent lack of awareness of the seriousness of the current underweight.

[0057] A subtype of anorexia nervosa (AN) is binge eating / purging type AN. According to the diagnostic criteria set forth in the Structured Clinical Interview for DSM-5 (SCID-RV, Version 1.0.0 for DSM-5®), patients suffering from AN also qualify for this subtype if they have recurrent episodes of binge eating or purging behaviors (i.e., self-induced vomiting or laxative, diuretic or enema abuse) over a 3-month period.

[0058] Other specified eating disorders or feeding disorders (OSFED) are eating disorders and disorders of clinical severity that do not meet the diagnostic criteria for AN, BN, BED or pica. These may include atypical AN, atypical BN, infrequent and / or short-term BED and nighttime eating disorder (NES). In particular, the group of other specified eating disorders or feeding disorders (OSFED) referred to herein includes atypical BN; infrequent and / or short-term BED; and nighttime eating disorder (NES).

[0059] Eating Disorder or Eating Disorder Not Otherwise Specified (UFED) applies when an individual's symptoms do not meet the criteria for symptoms of another disorder or when there is simply not enough information to determine a more specific diagnosis. UFED is considered to fall within the scope of Eating Disorder or Eating Disorder Not Otherwise Specified (OSFED), formerly known as Eating Disorder Not Otherwise Specified (EDNOS) in past editions of the DSM (predating DSM-5). Although considered a "catch-all" classification, OSFED / EDNOS is a serious, life-threatening, treatable eating disorder. This category has evolved to include individuals who do not meet the strict diagnostic criteria for AN or BN, but still have a significant eating disorder. Community clinics have historically diagnosed the majority of individuals with EDNOS.

[0060] In the DSM-5®, individuals with OSFED exhibit eating or eating behaviors that cause clinically significant distress and impairment but do not fully meet the criteria for any other disorder. Examples of OSFED include: Atypical AN: Significant weight loss but not an individual's Meets all criteria for AN except weight is within or above normal range;BED infrequent and / or brief duration: Meets all criteria for BED except low frequency and / or less than 3 months;BN infrequent and / or brief duration: Meets all criteria for BN except occurrence of binge eating and inappropriate compensatory behaviors is low frequency and / or less than 3 months;Purging Disorder: Recurrent purging behaviors affecting weight or body shape, in the absence of binge eating. Abnormal Nighttime Eating Syndrome: Recurrent episodes of nighttime eating. Eating after awakening from sleep or excessive food consumption after dinner. The behavior is not better explained by environmental influences or social norms. The behavior causes significant distress / impairment. The behavior is not better explained by another mental health disorder (e.g. BED).

[0061] Compulsive eating (CO), also known as food addiction, is a term commonly used for people who have a strong urge or compulsive desire (impulsive behavior) to consume large amounts of food in a relatively short period of time. CO may be used synonymously with BED.

[0062] Pica may exist in combination with other eating behaviors and eating disorders. The DSM-5® criteria for pica are: 1) persistent eating of non-nutritional, non-food substances for at least one month; 2) the eating of such substances is inappropriate for the individual's developmental level; 3) the eating behavior is not part of culturally supported or socially normative practices; 4) if the behavior occurs within the context of another mental disorder or health condition (e.g., schizophrenia, autism, or pregnancy), it is sufficiently severe to warrant independent clinical involvement.

[0063] Out-of-control (LOC) eating: A feeling of LOC during a binge eating episode is an essential feature of BED. The term "out-of-control eating" is used to describe these episodes, but is also used more broadly throughout the literature to describe binge-like eating behaviors with a feeling of LOC that occur across a wide range of individuals. This range specifically includes individuals who exhibit some of the features of BED but do not meet the full diagnostic criteria for the disorder (i.e., subthreshold BED), as well as individuals who exhibit other eating disorders (bulimia nervosa, anorexia nervosa, These ranges described as exhibiting LOC eating also include individuals in whom the diagnosis of subthreshold BED is difficult for specific reasons, such as post-bariatric surgery patients and young children.

[0064] Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder due to the loss of function of a specific gene on chromosome 15. The disorder is specifically associated with hyperphagia leading to severe obesity, and other behavioral problems that may lead to disabling physical and developmental disabilities in adolescence and adulthood. Hyperphagia in PWS manifests as an intense and persistent feeling of hunger accompanied by an obsession with food, an extreme drive to eat, food-related behavioral problems, and a lack of normal satiety. PWS-associated hyperphagia has overlap with binge eating disorder and obsessive-compulsive features (preoccupation with food); (e.g., Heymsfield SB et al., Obesity. 2014;22(S1):S1-17.doi.org / 10.1002 / oby.20646; and Schwartz L et al., J Neurodev Disord.2021 Jun 21;13(1):25.doi:10.1186 / s11689-021-09373-2).

[0065] The term "treat" or "treatment" or "treating" when used in reference to a disease / disorder / condition means that either the disease / disorder / condition is cured in a subject; or that some or all of the symptoms of the condition are reduced or eliminated, although the subject continues to be adversely affected by the condition.

[0066] The term "prevention" as used herein refers to the maintenance of efficacy with long-term treatment of the disorders referred to in this application, for example, the term may refer to the reduction or prevention of future episodes of binge eating (and related behaviors). The term "prevention" as used herein may refer to the reduction or prevention of relapse / recurrence of the disorders disclosed herein. In particular, the term refers to the prevention of relapse of the disorders disclosed herein (such as eating disorders, e.g., BED, BN, and binge-eating anorexia nervosa). Such reduction or prevention of relapse / recurrence of disorders is common in the field of psychiatric illnesses such as depression (e.g., prevention of depressive relapse or psychotic relapse), as evidenced by studies showing that medications reduce or prevent relapse and maintain efficacy [e.g., Hudson et al., JAMA Psychiatry. 2017 Sep 1;74(9):903-910. (PMID: 28700805); Romano et al., Am J Psychiatry. 2002 Jan;159(1):96-102. doi:10.1176 / appi.ajp.159.1.96. (PMID:11772696); and Dobson et al., J Consult Clin Psychol.2008 Jun;76(3):468-77.(PMID:18540740)]. The term "relapse" is defined as a full return of once remitted (binge eating) symptoms - before recovery is sustained. The term "relapse" refers to another episode of (binge eating) behavior after recovery has been achieved. The term "prevention" may be understood to be synonymous with the term "prophylaxis".

[0067] The term "subject", and similarly "patient", means a mammal, especially a human.

[0068] For the avoidance of any doubt, where a crystalline form of ACT-539313 is described as being useful for the prevention and / or treatment of a disease, such crystalline form of ACT-539313 is similarly suitable for use in the manufacture of a medicament for the prevention or treatment of that disease.

[0069] 19) A further embodiment relates to a method for the prevention and / or treatment of a disease / disorder according to any one of embodiments 14) to 18), in particular according to embodiment 18), which comprises administering to a subject in need of said prevention and / or treatment an effective amount of said active ingredient, (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone, or a pharmaceutical composition (in particular a tablet for oral use) according to any one of embodiments 10) to 12); wherein said active ingredient is in a crystalline form according to any one of embodiments 1) to 7).

[0070] 20) A further embodiment relates to the method of claim 19), wherein the amount is about 20 mg / day to about 250 mg / day; about 20 mg / day to about 225 mg / day; about 20 mg / day to about 200 mg / day; about 20 mg / day to about 175 mg / day; about 20 mg / day to about 150 mg / day; about 20 mg / day to about 125 mg / day; about 20 mg / day to about 100 mg / day; about 20 mg / day to about 75 mg / day; about 20 mg / day to about 80 mg / day; about 20 mg / day to about 60 mg / day; or about 20 mg / day to about 50 mg / day. In particular, the amount is about 20 mg / day to about 150 mg / day; about 20 mg / day to about 100 mg / day; or about 20 mg / day to about 80 mg / day. In particular, the amount is from about 20 mg / day to about 200 mg / day.

[0071] 21) A further embodiment relates to the method according to embodiment 19), wherein said amount is equal to about 30 mg / day; equal to about 35 mg / day; equal to about 40 mg / day; equal to about 45 mg / day; equal to about 50 mg / day; equal to about 55 mg / day; equal to about 60 mg / day; equal to about 65 mg / day; equal to about 70 mg / day; equal to about 75 mg / day; equal to about 80 mg / day; equal to about 100 mg / day; equal to about 125 mg / day; or equal to about 150 mg / day. In particular, said amount is equal to about 60 mg / day.

[0072] 22) Another aspect of the invention relates to an active ingredient in a crystalline form according to any one of embodiments 1) to 7), (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone or a pharmaceutical composition (in particular a tablet for oral use) according to any one of embodiments 10) to 12) for use in the prevention and / or treatment of a disease / disorder according to any one of embodiments 14) to 18), in particular according to embodiment 18), wherein the crystalline form is administered to a subject in an amount according to embodiments 20) and 21).

[0073] 23) Another aspect of the invention relates to the use of an active ingredient in a crystalline form according to any one of embodiments 1) to 7), (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone or a pharmaceutical composition (in particular a tablet for oral use) according to any one of embodiments 10) to 12) for the prevention and / or treatment (in the manufacture of a medicament) of a disease / disorder according to any one of embodiments 14) to 18), in which the crystalline form is administered to a subject in an amount according to embodiments 20) and 21).

[0074] Another aspect of the present invention relates to a pharmaceutical composition according to any one of aspects 9) to 18), wherein the active ingredient is 4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone (ACT-539313) [in any crystalline form, amorphous state or mixtures thereof].

[0075] Another aspect of the present invention relates to a method for the prevention and / or treatment of a disease / disorder according to any one of aspects 14) to 18), in particular according to aspect 18), which comprises administering to a subject in need of said prevention and / or treatment an effective amount of a pharmaceutical composition according to any one of aspects 9) to 18), in particular a tablet for oral use; wherein the active ingredient is (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone (ACT-539313) [in any crystalline form, amorphous state or mixtures thereof].

[0076] Yet another aspect of the present invention relates to a pharmaceutical composition (particularly a tablet for oral use) according to any one of aspects 9) to 18) for use in the prevention and / or treatment of a disease / disorder according to any one of aspects 14) to 18) (particularly according to aspect 18)), wherein the active ingredient is (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone (ACT-539313) [in any crystalline form, amorphous state or mixtures thereof].

[0077] Thus, based on the subordination of the different embodiments 1) to 23) disclosed above, the following embodiments are possible, contemplated, and specifically disclosed herein as individual embodiments: 2+1、3+1、4+1、5+1、6+1、6+2+1、6+3+1、6+4+1、6+5+1、7+1、7+2+1、7+3+1、7+4+1、7+5+1、7+6+1、7+6+2+1、7+6+3+1、7+6+4+1、7+6+5+1、8+1、8+2+1、8+3+1、8+4+1、8+5+1、8+6+1、8+6+2+1、8+6+3+1、8+6+4+1、8+6+5+1、9+1、9+2+1、9+3+1、9+4+1、9+5+1、9+6+1、9+6+2+1、9+6+3+1、9+6+4+1、9+6+5+1、9+7+1、9+7+2+1、9+7+3+1、9+7+4+1、9+7+5+1、9+7+6+1、9+7+6+2+1、9+7+6+3+1、9+7+6+4+1、9+ 7+6+5+1、10+1、10+2+1、10+3+1、10+4+1、10+5+1、10+6+1、10+6+2+1、10+6+3+1、10+6+4+1、10+6+5+1、10+7+1、10+7+2+1、10+7+3+1、10+7+4+1、10+7+5+1、10+7+6+1、10+7+6+2+1、10+7+6+3+1、10+7+6+4+1、10+7+6+5+1、5+2+1、5+3+1、5+4+1、6+1、6+2+1、6+3+1、6+4+1、6+5+1、6+5+2+1、6+5+3+1、6+5+4+1、7+1、7+2+1、7+3+1、7+4+1、7+5+1、7+5+2+1、7+5+3+1、7+5+4+1、7+6+1、7+6+2+1、7+6+3+1、7+6+4+1、7+6+5+1、7+6+5+2+1、7+6+5+3+1、7+6+5+4+1、8+1、8+2+1、8+3+1、8+4+1、8+5+1、8+5+2+1、8+5+3+1、8+5+4+1、8+6+1、8+6+2+1、8+6+3+1、8+6+4+1、8+6+5+1、8+6+5+2+1、8+6+5+3+1、8+6+5+4+1、9+1、9+2+1、9+3+1、9+4+1、9+5+1、9+5+2+1、9+5+3+1、9+5+4+1、9+6+1、9+6+2+1、9+6+3+1、9+6+4+1、9+6+5+1、9+6+5+2+1、9+6+5+3+1、9+6+5+4+1、9+7+1、9+7+2+1、9+7+3+1、9+7+4+1、9+7+5+1、9+7+5+2+1、9+7+5+3+1、9+7+5+4+1、9+7+6+1、9+7+6+2+1、9+7+6+3+1、9+7+6+4+1、9+7+6+5+1、9+7+6+5+2+1、9+7+6+5+3+1、9+7+6+5+4+1、10+1、10+2+1、10+3+1、10+4+1、10+5+1、10+5+2+1、10+5+3+1、10+5+4+1、10+6+1、10+6+2+1、10+6+3+1、10+6+4+1、10+6+5+1、10+6+5+2+1、10+6+5+3+1、10+6+5+4+1、10+7+1、10+7+2+1、10+7+3+1、10+7+4+1、10+7+5+1、10+7+5+2+1、10+7+5+3+1、10+7+5+4+1、10+7+6+1、10+7+6+2+1、10+7+6+3+1、10+7+6+4+1、10+7+6+5+1、10+7+6+5+2+1、10+7+6+5+3+1、10+7+6+5+4+1、11+10+1、11+10+2+1、11+10+3+1、11+10+4+1、11+10+5+1、11+10+5+2+1、11+10+5+3+1、11+10+5+4+1、11+10+6+1、11+10+6+2+1、11+10+6+3+1、11+10+6+4+1、11+10+6+5+1、11+10+6+5+2+1、11+10+6+5+3+1、11+10+6+5+4+1、11+10+7+1、11+10+7+2+1、11+10+7+3+1、11+10+7+4+1、11+10+7+5+1、11+10+7+5+2+1、11+10+7+5+3+1、11+10+7+5+4+1、11+10+7+6+1、11+10+7+6+2+1、11+10+7+6+3+1、11+10+7+6+4+1、11+10+7+6+5+1、11+10+7+6+5+2+1、11+10+7+6+5+3+1、11+10+7+6+5+4+1、12+10+1、12+10+2+1、12+10+3+1、12+10+4+1、12+10+5+1、12+10+5+2+1、12+10+5+3+1、12+10+5+4+1、12+10+6+1、12+10+6+2+1、12+10+6+3+1、12+10+6+4+1、12+10+6+5+1、12+10+6+5+2+1、12+10+6+5+3+1、12+10+6+5+4+1、12+10+7+1、12+10+7+2+1、12+10+7+3+1、12+10+7+4+1、12+10+7+5+1、12+10+7+5+2+1、12+10+7+5+3+1、12+10+7+5+4+1、12+10+7+6+1、12+10+7+6+2+1、12+10+7+6+3+1、12+10+7+6+4+1、12+10+7+6+5+1、12+10+7+6+5+2+1、12+10+7+6+5+3+1、12+10+7+6+5+4+1、 13+1、13+2+1、13+3+1、13+4+1、13+5+1、13+5+2+1、13+5+3+1、13+5+4+1、13+6+1、13+6+2+1、13+6+3+1、13+6+4+1、13+6+5+1、13+6+5+2+1、13+6+5 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4+1、16+12+10+6+1、16+12+10+6+2+1、16+12+10+6+3+1、16+12+10+6+4+1、16+12+10+6+5+1、16+12+10+6+5+2+1、16+12+10+6+5+3+1、16+12+10+6+5+4+1、16+12+10+7+1、16+12+10+7+2+1、16+12+10+7+3+1、16+12+10+7+4+1、16+12+10+7+5+1、16+12+10+7+5+2+1、16+12+10+7+5+3+1、16+12+10+7+5+4+1、16+12+10+7+6+1、16+12+10+7+6+2+1、16+12+10+7+6+3+1、16+12+10+7+6+4+1、16+12+10+7+6+5+1、16+12+10+7+6+5+2+1、16+12+10+7+6+5+3+1、16+12+10+7+6+5+4+1、 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7+2+1、18+10+7+3+1、18+10+7+4+1、18+10+7+5+1、18+10+7+5+2+1、18+10+7+5+3+1、18+10+7+5+4+1、18+10+7+6+1、18+10+7+6+2+1、18+10+7+6+3+1、18+10+7+6+4+1、18+10+7+6+5+1、18+10+7+6+5+2+1、18+10+7+6+5+3+1、18+10+7+6+5+4+1、18+11+10+1、18+11+10+2+1、18+11+10+3+1、18+11+10+4+1、18+11+10+5+1、18+11+10+5+2+1、18+11+10+5+3+1、18+11+10+5+4+1、18+11+10+6+1、18+11+10+6+2+1、18+11+10+6+3+1、18+11+10+6+4+1、18+11+10+6+5+1、18+11+10+6+5+2+1、18+11+10+6+5+3+1、18+11+10+6+5+4+1、18+11+10+7+1、18+11+10+7+2+1、18+11+10+7+3+1、18+11+10+7+4+1、18+11+10+7+5+1、18+11+10+7+5+2+1、18+11+10+7+5+3+1、18+11+10+7+5+4+1、18+11+10+7+6+1、18+11+10+7+6+2+1、18+11+10+7+6+3+1、18+11+10+7+6+4+1、18+11+10+7+6+5+1、18+11+10+7+6+5+2+1、18+11+10+7+6+5+3+1、18+11+10+7+6+5+4+1、18+12+10+1、18+12+10+2+1、18+12+10+3+1、18+12+10+4+1、18+12+10+5+1、18+12+10+5+2+1、18+12+10+5+3+1、18+12+10+5+4+1、18+12+10+6+1、18+12+10+6+2+1、18+12+10+6+3+1、18+12+10+6+4+1、18+12+10+6+5+1、18+12+10+6+5+2+1、18+12+10+6+5+3+1、18+12+10+6+5+4+1、18+12+10+7+1、18+12+10+7+2+1、18+12+10+7+3+1、18+12+10+7+4+1、18+12+10+7+5+1、18+12+10+7+5+2+1, 18+12+10+7+5+3+1, 18+12+10+7+5+4+1, 18+12+10+7+6+1, 18+12+10+7+6+2+1, 18+12+10+7+6+3+1, 18+12+10+7+6+4+1, 18+12+10+7+6+5+1, 18+12+10+7+6+5+2+1, 18+12+10+7+6+5+3+1 or 18+12+10+7+6+5+4+1.

[0078] In the above table, the numbers refer to the embodiments according to the above numbers, and "+" indicates dependency on other embodiments. The various embodiments are individually separated by commas. In other words, for example, "6+2+1" means embodiment 6) which is dependent on embodiment 2) which is dependent on embodiment 1), i.e. embodiment "6+2+1" corresponds to embodiment 1) further characterized by the features of embodiments 2) and 6).

[0079] The term "amount" as used in the embodiments disclosed herein means "total amount" or "dose" or "total dose" or "dosage" or "total dose"; in particular, the term means total amount or total dose. As used herein, the terms "amount", "total amount", "dose", "total dose", "dosage", "total dose" are understood to be synonyms meaning the amount of active ingredient. The terms may be used interchangeably within the context of the present invention and may be replaced by each other depending on the situation.

[0080] In this application, the term "about" before a numerical value "X" means between 10% of XX and 10% of X+X, in particular between 5% of XX and 5% of X+X, and in particular the term means X. This also applies when the numerical value "X" is itself stated as a percentage (%) in this application, for example, when X is stated as "about 0.5%", it means between 0.45% and 0.55%; in particular between 0.475% and 0.525%; in particular 0.5%.

[0081] For the avoidance of doubt, amounts of active ingredient recited in "mg" in embodiments disclosed herein are intended to mean the total amount of the crystalline active ingredient administered to a patient within a 24 hour period (e.g., 60 mg / day means that a total of 60 mg of active ingredient is administered to a patient within a 24 hour period).

[0082] The term "mg / day" as used in embodiments herein means milligrams per day and may be replaced with any of the following terms: "mg within a twenty-four-hour period," "mg within twenty-four hours," "mg per twenty-four hours," "mg daily," or "mg per day," as appropriate.

[0083] The term "subject", and similarly "patient", means a mammal, especially a human.

[0084] Experimental Method Abbreviations (as used herein): DSC Differential Scanning Calorimetry DCM Dichloromethane DVS Dynamic Vapor Sorption 1 H-NMR Proton Nuclear Magnetic Resonance L Liter min mL Milliliters Ph.Eur. European Pharmacopeia RH Relative Humidity RT room temperature XRPD X-ray powder diffraction

[0085] All solvents and reagents are used as obtained from commercial sources unless otherwise noted. Temperatures are given in degrees Celsius (° C.). Reactions are conducted at room temperature (RT) unless otherwise noted.

[0086] X-ray powder diffraction analysis (XRPD) XRPD Method 1: Powder X-ray diffraction patterns were collected on a Bruker D8 Advance X-ray diffractometer equipped with a Lynxeye detector operating in reflection mode (coupled 2theta / theta). Typically, a Cu X-ray tube was scanned at 40 kV / 40 mA. A step size of 0.02° (2θ) and a step time of 76.8 s were applied over a scan range of 3-50° 2θ. Divergence and antiscatter slits were used. The slit was fixedly set at 0.3°. The powder was lightly pressed into a silicon single crystal sample holder with a depth of 0.5 mm, and the sample was rotated in its own plane during the measurement. Diffraction data are reported using Cu Kα (λ=1.5418 Å) radiation. The accuracy of the 2θ values ​​provided herein is within + / - 0.1 to 0.2°, as is typical for previously recorded powder X-ray diffraction patterns.

[0087] Dynamic Vapor Sorption (DVS) Moisture sorption isotherms were collected on a multisample instrument SPS-100n (Projekt Messtechnik, Ulm, Germany) operated in stepping mode at 25 °C. A predefined humidity program (40-0-95-0-95-40% RH, 5% R H steps and a maximum equilibration time of 24 hours for each step were applied. Samples were equilibrated at 40% RH before starting the sorption scan. Approximately 20-30 mg of each sample was used. The classification of hygroscopicity disclosed herein was done according to the European Pharmacopeia Technical Guide (1999, p. 86), i.e., if the mass increase measured by the DVS method disclosed herein is less than 0.2%, the material is classified as "not hygroscopic" or "non-hygroscopic"; if the mass increase is less than 2% and more than 0.2% mass / mass, the material is classified as slightly hygroscopic; and finally, if the mass increase is less than 15% and more than 2% mass / mass, the material is classified as hygroscopic. The mass change between 40% and 80% relative humidity in the first adsorption scan was considered. The data shown is from the first ramp cycle.

[0088] Differential Scanning Calorimetry (DSC) DSC data were collected on a Mettler Toledo STARe System (DSC822e module, measuring cell with ceramic sensor, and STAR software version 9.20) equipped with a 34-position autosampler. The instrument was calibrated for energy and temperature using indium standards. Typically, 1-5 mg of each sample (5-6 mg for Reference Example 1) was heated in automatically drilled aluminum pans from -20°C to 280°C for 10°C min, unless otherwise noted. -1 (For Reference Example 1, 20°C min -1 The sample was heated at 200 K. A nitrogen purge was applied over the sample at 20 mL min. -1 The melting point was maintained at 100° C. The peak temperature is reported for the melting point.

[0089] Bulk density and tapped density Bulk and tapped density were measured on a Matec Densi-tap tapping device using a 10 mL glass cylinder, using powders without any treatment. Tapped density is reported after 3750 taps. EXAMPLES

[0090] ACT-539313 may be prepared according to the procedure described in Example 27 of WO2013068935, which results in ACT-539313 in an amorphous state.

[0091] Example 1 0.05 mL of 1-propanol is added to 50 mg of amorphous ACT-539313 in a 4 mL standard glass vial. After storage at room temperature with the cap on for 1 day, the solid material is isolated, which shows the XRPD diagram of ACT-539313 in crystalline form 1 (Figure 1).

[0092] Example 2 0.05 mL of ethanol is added to 50 mg of amorphous ACT-539313 in a 4 mL standard glass vial. After storage at room temperature with the cap on for 1 day, the solid material is isolated, which shows the XRPD diagram of ACT-539313 in crystalline form 1 (Figure 1).

[0093] Example 3 0.3 mL of 2-propanol is added to 300 mg of amorphous ACT-539313 in a 4 mL standard glass vial. After storage at room temperature with the cap on for 1 day, the solid material is isolated, which shows the XRPD diagram of ACT-539313 in crystalline form 1 (Figure 1).

[0094] [Table 1]

[0095] Example 4 Approximately 450 g of ACT-539313 was dissolved in 4 L of 2-propanol at 70° C. Approximately 1 L of solvent was distilled off and the remaining solution was transferred into a 4 L vessel and stirred at 50° C. while seeding with approximately 113 g of ACT-539313 of crystalline form 1. The seed material can be prepared according to the procedures described in Examples 1-3 after appropriate scale-up. The solution was then stirred at 50° C. for approximately 1 h, during which time a solid product precipitated. Heating was removed and the suspension was allowed to cool to room temperature and stirred overnight to yield 506 g (90%) of ACT-539313 of crystalline form 1. The crystalline product had a bulk density of 0.31 g / mL and a tapped density of 0.46 g / mL, measured according to the methods described herein.

[0096] Example 5 Specific pharmaceutical compositions suitable for administration to humans (25, 30, 50, 100 mg API) are shown in Table 2.

[0097] [Table 2]

[0098] Capsule manufacturing process: ACT-539313, microcrystalline cellulose, mannitol, crospovidone and sodium stearyl fumarate were mixed in a RRM-mixer at 37 rpm for 5 min; sieved (0.8 mm screen); further mixed at 37 rpm for 5 min. The resulting internal phase blend was dry granulated (7.5 kN / 5 rpm) and further mixed at 37 rpm for 10 min. Sieved (0.8 mm screen) and hydrated colloidal silica were added and the blend was further mixed at 37 rpm for 5 min, then sieved (0.8 mm screen) sodium stearyl fumarate was added and final mixing was done at 37 rpm for 5 min. The resulting final blend was encapsulated in No. 0 hard gelatin capsules using Modu-C LS machine. Tablet manufacturing process: Surprisingly, the final blends (25 mg, 50 mg and 100 mg API) used to manufacture the capsules could be successfully compressed into round and / or oval tablets of different sizes (e.g., 10, 12, 13 and 17 mm) without any substantial change in composition.

[0099] Reference Example Reference Example 1 50 mL of DCM was added to 10 g of ACT-539313 in a 2 L round bottom flask and the solvent was removed on a rotary evaporator operating at 55 °C and 5 mbar until the solid residue was completely dried. The XRPD diagram of the solid material is shown in Figure 2. The resulting amorphous ACT-539313 had a bulk density of 0.06 g / mL and a tapped density of 0.13 g / mL, measured according to the method described herein.

[0100] [Table 3]

[0101] Reference Example 2 Nineteen vials, each containing approximately 10 mg of ACT-539313, were prepared, and evaporation in the vials from a DCM stock solution resulted in the formation of a clear (i.e. amorphous) film in the vial. The effects of added volumes of 2-propanol (0.01, 0.02, 0.04, 0.08, 0.16, 0.30 and 0.5 mL) as well as 0.02 mL added volumes of different organic solvents commonly used for crystallization (methanol, ethanol, ethyl acetate, water, tert-butyl methyl ether, dioxane, acetone, methyl isobutyl ketone, tetrahydrofuran, toluene and dimethyl sulfoxide) were systematically investigated. Only within 30 min, samples from the smallest volumes of 2-propanol, ranging from 0.01 mL to 0.16 mL, showed signs of crystallization (observed under an optical stereomicroscope with crossed polars). In contrast, ethanol showed the first signs of crystallization only after 1.25 h. Other solvents showed no signs of crystallization at about 6 h, and crystallization was observed from water, tert-butyl methyl ether, and methyl isobutyl ketone only upon visual inspection after 3 days.

[0102] Crystalline Form 1 of ACT-539313 described herein is less hygroscopic than amorphous ACT-539313 (see Figures 4 and 5; and Tables 1 and 3). In addition, the crystalline form melts at about 118°C, compared to the amorphous material, which has a glass transition temperature in the range of 50-70°C. Also, the bulk density of amorphous ACT-539313 (0.06 g / mL) is significantly less than the bulk density of crystalline Form 1 ACT-539313 (0.31 g / ml). A material with a lower density is lighter and therefore more difficult to handle (e.g., larger processing vessels are required). Based on the measured tapped and bulk densities, the flowability of the bulk material can be calculated, expressed by its Hausner ratio (HR), which is the ratio between tapped and bulk densities. The HR for crystalline form 1 of ACT-539313 (Example 4) is 1.47, suggesting that the powder flow type of this material is classified as "poor" (HR of 1.46-1.59). However, the HR for the amorphous material (Reference Example 1) is about 150% higher, i.e., 2.26, suggesting that the flow type is classified as "very poor" (HR>1.60).

Claims

1. Crystals of (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone in a crystalline form characterized by the presence of peaks at the following refraction angles 2θ: 10.5°, 14.2° and 18.4° in the powder X-ray diffraction diagram.

2. 2. The crystal according to claim 1, characterized in its crystalline form by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram: 7.8°, 10.5°, 14.2°, 18.4° and 21.8°.

3. 2. The crystal of claim 1, characterized in that the crystal form is characterized by the presence of peaks at the following refraction angles 2θ in a powder X-ray diffraction diagram: 7.8°, 10.5°, 12.5°, 13.7°, 14.2°, 14.6°, 18.4°, 21.4°, 21.8° and 25.1°.

4. The crystal according to any one of claims 1 to 3, characterized by a melting point of 117.6 ± 5.0°C as determined by differential scanning calorimetry.

5. A method for producing the crystal according to any one of claims 1 to 4, comprising the steps of: a. dissolving (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone in a solvent, the solvent having one or more lower alcohols selected from methanol, ethanol, 1-propanol and 2-propanol; b. waiting for the formation of a solid product; and c) isolating the solid product.

6. A method for producing the crystal of any one of claims 1 to 4, comprising recrystallization of (4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone in a solvent, the solvent being methanol, ethanol, 1-propanol, The process further comprises one or more lower alcohols selected from the group consisting of 1-propanol and 2-propanol.

7. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 4 as an active ingredient, and further comprising at least one pharma- ceutically acceptable carrier.

8. A solid dosage form of a drug comprising the crystal according to any one of claims 1 to 4.

9. 8. A pharmaceutical composition according to claim 7 in the form of a tablet for oral use, comprising: - from 3% w / w to 40% w / w of the active ingredient; - from 30% w / w to 70% w / w of microcrystalline cellulose; - mannitol from 15% w / w to 60% w / w; - 3% w / w to 10% w / w of crospovidone; - 0.2% w / w to 4% w / w of sodium stearyl fumarate; and - 0.5% w / w to 5% w / w of hydrated colloidal silica; 1. A pharmaceutical composition comprising:

10. 8. A pharmaceutical composition according to claim 7 in the form of a tablet for oral use, comprising: - 22% to 25% w / w of the active ingredient; - from 39% to 44% w / w of microcrystalline cellulose; - 24% to 30% w / w of mannitol; - 4% to 6% w / w of crospovidone; - from 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1.5% to 2.5% w / w of hydrated colloidal silica; Or, - 10% to 13% w / w of the active ingredient; - 47% to 52% w / w of microcrystalline cellulose; - 29% to 34% w / w of mannitol; - 4% to 6% w / w of crospovidone; - from 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1% to 2% w / w of hydrated colloidal silica; Or, - 6% to 8% w / w of the active ingredient; - 48% to 54% w / w of microcrystalline cellulose; - 31% to 35% w / w of mannitol; - 4% to 6% w / w of crospovidone; - from 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 1% to 2% w / w of hydrated colloidal silica; Or, - 5% to 7% w / w of the active ingredient; - 50% to 55% w / w of microcrystalline cellulose; - 30% to 35% w / w of mannitol; - 4% to 6% w / w of crospovidone; - from 0.5% to 1.5% w / w of sodium stearyl fumarate; and - 0.5% to 2% w / w of hydrated colloidal silica; 1. A pharmaceutical composition comprising:

11. The crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 7, 9 or 10 for use as a medicament.

12. The crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 7, 9 or 10 for use in the prevention and / or treatment of anxiety disorder, addictive disorder, mood disorder, appetite disorder, cognitive dysfunction or sleep disorder.

13. The crystals according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 7, 9 or 10 for use in the prevention and / or treatment of an eating disorder selected from the group consisting of binge eating disorder (BED); bulimia nervosa (BN); anorexia nervosa (AN); pica; other specified eating or eating disorder (OSFED); eating or eating disorder not otherwise specified (UFED); eating disorder not otherwise specified (EDNOS); compulsive overeating (CO); locomotion-out-of-control (LOC) eating; and increased appetite and / or hyperphagia associated with Prader-Willi syndrome (PWS).

14. The crystal according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 7, 9 or 10 for use in the prevention and / or treatment of binge eating disorder (BED).

15. A pharmaceutical for the prevention and / or treatment of anxiety disorders, addictive disorders, mood disorders, appetite disorders, cognitive dysfunction or sleep disorders, comprising a crystal according to any one of claims 1 to 4 as an active ingredient.

16. A pharmaceutical for the prevention and / or treatment of an eating disorder selected from the group consisting of binge eating disorder (BED); bulimia nervosa (BN); anorexia nervosa (AN); pica; other specified eating disorder or eating disorder (OSFED); eating disorder or eating disorder not otherwise specified (UFED); eating disorder not otherwise specified (EDNOS); compulsive overeating (CO); eating out of control (LOC); and increased appetite and / or hyperphagia associated with Prader-Willi syndrome (PWS), comprising as an active ingredient a crystal described in any one of claims 1 to 4.

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