Triple uptake inhibitors for the treatment of atypical depression

Abstract

Provided herein is a method of treating atypical depression in a subject in need thereof by administering to the subject a composition comprising a triple reuptake inhibitor having the structure of Compound (1). TIFF2025508878000026.tif25128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Patent Application No. 63 / 314,753, filed February 28, 2022, and U.S. Patent Application No. 63 / 484,905, filed February 14, 2023, the contents of each of which are incorporated herein by reference. [Background technology]

[0002] background Atypical depression is a subtype of depression characterized by mood reactivity and atypical symptoms including weight gain or hypereating, hypersomnia, leaden numbness, and interpersonal rejection sensitivity that causes significant social or occupational impairment. Atypical depression is the most common form of depression seen in psychiatric outpatient care. Current literature identifies atypical depression as a subtype of depression with high morbidity, early onset in life, and a tendency to persist for a long time. Patients with atypical depression, with their chronic course, long-lasting rejection sensitivity, and constant malaise, very often have a primary diagnosis of personality disorder or simply neurosis. This can lead to antidepressants, which have proven to be very effective, not being considered, which can have serious adverse effects.

[0003] Approximately 30% of patients with unipolar depression meet the criteria for atypical depression. However, atypical depression has not been well studied, and patients who meet the criteria for this subtype are often excluded from major depression trials. Currently, there are no comprehensive treatment guidelines for atypical depression, despite the large number of clinical trials. Patients with atypical depression have shown preferential response to phenelzine sulfate compared with imipramine hydrochloride in placebo-controlled trials, so monoamine oxidase inhibitors (MAOIs) are recommended as standard treatment. Unfortunately, MAOIs have dietary restrictions, contraindications, and well-known side effects.

[0004] Thus, there is an unmet medical need for novel ways to address the treatment of people with atypical depression. Summary of the Invention

[0005] overview (a) (i) mood reactivity, (ii) increased sleep, (iii) hypersomnia, (iv) leaden palsy, (v) prolonged interpersonal sensitivity resulting in significant social or occupational impairment, (b) (i) binge eating not associated with the regular use of inappropriate compensatory behaviors, (ii) binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, (c) (i) recurrent inappropriate compensatory behaviors such as self-induced vomiting; abuse of laxatives, diuretics, or other drugs to prevent weight gain, (ii) binge eating and inappropriate compensatory behaviors, (iii) self-evaluation that is inappropriately influenced by body shape and weight, (iv) anxiety that does not occur exclusively during episodes of anorexia nervosa, (v) recurrent compensatory behaviors of the purging type, and (vi) recurrent compensatory behaviors of the non-purging type, (d) (i) recurrent episodes of binge eating, (ii) eating an amount of food in a specific period of time that is significantly greater than most people would eat in a similar period of time under similar circumstances, (iii) inability to control eating during the episode 16. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of: (i) increased appetite, (ii) binge eating, (iii) a marked lack of impulse control followed by feelings of guilt, (f) a sense of being unable to stop eating or to control what or how much one eats, (v) eating much faster than usual, (vi) eating until one feels uncomfortably full, (vii) eating large amounts of food when one is not physically hungry, (viii) eating alone because one feels embarrassed by how much one is eating, (ix) feeling disgusted with oneself, depressed or with strong guilt after overeating, (x) significant distress regarding overeating, (e) (i) increased appetite, (ii) binge eating, (iii) a marked lack of impulse control followed by feelings of guilt, (f) (i) restriction of energy intake relative to needs leading to a marked underweight, (ii) a marked fear of gaining weight or becoming fat despite being underweight, and (iii) anxiety in the way one feels about one's weight or body shape, Compound 1 sufficient to improve at least one of the behaviors: Provided in part herein is a method comprising administering a composition comprising TIFF2025508878000002.tif25128 or a pharma- ceutically acceptable salt thereof.

[0006] Compound 1: Also provided herein is a method of treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising TIFF2025508878000003.tif25128 or a pharma- ceutically acceptable salt thereof.

[0007] In another aspect, Compound 1: 1. A method of treating a patient who has been diagnosed with atypical depression, comprising administering a pharmaceutical composition comprising TIFF2025508878000004.tif25128 or a pharma- ceutically acceptable salt thereof, wherein the subject is experiencing symptoms of hypersomnia, binge eating, mood reactivity, leaden paralysis, depressed mood, interpersonal sensitivity, rapid eating, recurrent episodes of binge eating, inability to control eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed about how much one is eating, feeling guilty about eating after overeating, feeling guilty about eating ... Also provided are methods in which the patient exhibits one or more behaviors selected from the group consisting of: feelings of disgust, depression or strong guilt about themselves, significant distress about overeating, overeating not associated with compensatory behaviors, recurrent compensatory behaviors, overeating with compensatory behaviors, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above a minimally normal weight, strong fears of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and a continuing lack of awareness of the seriousness of being underweight.

[0008] Other aspects include hypersomnia, binge eating, mood reactivity, leaden numbness, depressed mood, interpersonal sensitivity, rapid eating, recurrent episodes of binge eating, inability to control eating, eating much faster than usual, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, feeling disgusted with oneself, depressed or very guilty after overeating, marked distress about the binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, and compensatory behaviors. 1. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of overeating, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above a minimally normal weight, intense fear of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and a continuing lack of awareness of the seriousness of being underweight, comprising administering to a subject a compound 1: Also provided herein are methods comprising administering a unit dose comprising TIFF2025508878000005.tif26128, or a pharma- ceutically acceptable salt thereof.

[0009] Compound 1: Also provided herein is a method of treating Prader-Willi syndrome in a subject in need thereof, comprising administering a composition comprising TIFF2025508878000006.tif26128 or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0010] [Figure 1] 1 shows an exemplary X-ray powder diffraction pattern for (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride salt tetrahydrate. [Diagram 2]1 shows an exemplary X-ray powder diffraction pattern for the hydrochloride salt of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone. [Diagram 3] Shown are the mean (±SEM) food intake (in grams) by adult male Sprague-Dawley rats (n=31) over a 30-minute session, where **p<0.001: significant between-treatment effect on food consumption between Compound 1 and vehicle (VEH). [Figure 4] Shown are the mean (±SEM) total lever presses by adult male Sprague-Dawley rats (n=31) over a 30-min session, where **p<0.001: significant difference in lever presses between Compound 1 treatment and vehicle (VEH). [Diagram 5] Shown are the mean (±SEM) total lever presses by adult male Sprague-Dawley rats (n=31) during a 30-min operant session, where **p<0.001: significant difference in lever presses between Compound 1-treated (n=16) and vehicle (VEH) (n=15). [Figure 6] The mean (±SEM) of latencies to the first six consecutive epochs of non-REM sleep (NR) are shown. [Figure 7] The mean (±SEM) of latencies to the first three consecutive epochs of rapid eye movement (REM) sleep is shown. [Figure 8] 1 shows the effect of Compound 1 on chocolate intake, demonstrating that Compound 1 is effective in controlling overeating in an animal model. [Figure 9] 1 shows the effect of Compound 1 on chocolate intake, demonstrating that Compound 1 is effective in controlling overeating in an animal model. [Figure 10]Figures 10A and 10B show the 5-choice serial reaction time task (5CSRTT) test in rats to study impulsive behavior in rats. Figures 10A and 10B show that Compound 1 reduces impulsive behavior in rats, and that Compound 1 dose-dependently reduces premature and perseverative responses without adversely affecting response accuracy or speed. [Figure 11] SRTM model of plasma concentration of Compound 1 in the raphe nucleus versus SERT occupancy as a result of PET studies in HV. Figure 11 shows that 30 mg to 60 mg of Compound 1 resulted in 70% to 90% SERT occupancy. [Figure 12] 2TCM model of plasma concentration vs. DAT occupancy of Compound 1 in the striatum. Figure 12 shows that 30 mg to 60 mg of Compound 1 results in 25% to 40% DAT occupancy. [Figure 13] 1 shows the mean (±SEM) intake of chocolate across twelve 1-hour training sessions in the chocolate intake experiment described in Example 7. [Figure 14] The effect of Compound 1 on lever pressing and food consumption in high (n=15) and low (n=16) responder groups in the PROG / food choice task is shown in Figure 14. The mean (±SEM) number of total lever presses in a 30-minute session is shown, where **p<0.001: significant difference in lever presses between Compound 1 treatment and VEH. [Figure 15] The effect of Compound 1 on lever pressing and food consumption in high (n=15) and low (n=16) responder groups in the PROG / food choice task is shown. Figure 15 shows the mean (±SEM) food intake (in grams) over the 30 min session, where **p<0.001, *p<0.01: significant difference in treatment group effects on food consumption between Compound 1 and VEH administered. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description As generally described herein, the present disclosure provides a method for treating atypical depression in a subject in need thereof.The method comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of compound 1 or its pharmaceutically acceptable salt.Furthermore, the present disclosure provides a method for treating atypical depression with any crystalline form of compound 1 or its pharmaceutically acceptable salt.

[0012] Methods of Use and Treatment In one aspect, provided herein is a method of treating atypical depression in a subject in need thereof. In another aspect, provided herein is a method of treating a medical condition associated with atypical depression in a subject in need thereof.

[0013] In one aspect, (a) (i) mood reactivity, (ii) increased sleep, (iii) hypersomnia, (iv) leaden palsy, (v) prolonged interpersonal sensitivity resulting in significant social or occupational impairment, (b) (i) binge eating not associated with regular use of inappropriate compensatory behaviors, (ii) binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa, (c) (i) recurrent inappropriate compensatory behaviors such as self-induced vomiting; abuse of laxatives, diuretics, or other drugs to prevent weight gain, (ii) binge eating and inappropriate compensatory behaviors, (iii) self-evaluation inappropriately influenced by body shape and weight, (iv) anxiety not occurring exclusively during episodes of anorexia nervosa, (v) recurrent compensatory behaviors of the purging type, and (vi) recurrent compensatory behaviors of the non-purging type, (d) (i) recurrent episodes of binge eating, (ii) eating in a specific period of time significantly more food than most people would eat in a similar period of time under similar circumstances, (iii) inability to control eating during the episode 16. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of: (i) increased appetite, (ii) binge eating, (iii) a marked lack of impulse control followed by feelings of guilt, (f) a sense of being unable to stop eating or to control what or how much one eats, (v) eating much faster than usual, (vi) eating until one feels uncomfortably full, (vii) eating large amounts of food when one is not physically hungry, (viii) eating alone because one feels embarrassed by how much one is eating, (ix) feeling disgusted with oneself, depressed or with strong guilt after overeating, (x) significant distress regarding overeating, (e) (i) increased appetite, (ii) binge eating disorder, (iii) a marked lack of impulse control followed by feelings of guilt, (f) (i) restriction of energy intake relative to needs leading to a marked underweight, (ii) a marked fear of gaining weight or becoming fat despite being underweight, and (iii) anxiety in the way one feels about one's weight or body shape, Compound 1 sufficient to improve at least one of the behaviors: Provided herein is a method comprising administering a composition comprising TIFF2025508878000007.tif26128 or a pharma- ceutically acceptable salt thereof. Each of the behaviors described herein is described in the Diagnostic and Statistical Manual of Mental Disorders, e.g., the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

[0014] In some embodiments, the composition is a pharmaceutical composition.

[0015] In some embodiments, the pharmaceutical composition is a tablet.

[0016] In some embodiments, the pharmaceutical composition is in sustained release form.

[0017] In some embodiments, the pharmaceutical composition is a unit dose.

[0018] In some embodiments, the composition comprises about 1 mg to about 70 mg of compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 1 mg to about 60 mg of compound 1. In some embodiments, the composition comprises about 1 mg to about 45 mg of compound 1. In some embodiments, the composition comprises about 1 mg to about 30 mg of compound 1. In some embodiments, the composition comprises about 1 mg to about 15 mg of compound 1. In some embodiments, the composition comprises about 1 mg to about 5 mg of compound 1. In some embodiments, the composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, or about 70 mg of compound 1. In some embodiments, the composition comprises about 10 mg of compound 1. In some embodiments, the composition comprises about 15 mg of compound 1. In some embodiments, the composition comprises about 20 mg of compound 1. In some embodiments, the composition comprises about 30 mg of Compound 1. In some embodiments, the composition comprises about 35 mg of Compound 1.

[0019] In some embodiments, the composition comprises about 1 mg / kg to about 70 mg / kg of compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 1 mg / kg to about 60 mg / kg of compound 1. In some embodiments, the composition comprises about 1 mg / kg to about 45 mg / kg of compound 1. In some embodiments, the composition comprises about 1 mg / kg to about 30 mg / kg of compound 1. In some embodiments, the composition comprises about 1 mg / kg to about 15 mg / kg of compound 1. In some embodiments, the composition comprises about 1 mg / kg to about 5 mg / kg of compound 1. In some embodiments, the composition comprises about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, or about 70 mg / kg of Compound 1.

[0020] In some embodiments, the composition is administered orally.

[0021] In some embodiments, the composition is administered once a day.

[0022] In some embodiments, the subject exhibits mood reactivity and at least two behaviors selected from the group consisting of increased appetite, hyperphagia, increased sleepiness, hypersomnia, leaden dizziness, and long-term interpersonal rejection hypersensitivity that leads to significant social or occupational impairment.In some embodiments, the subject does not meet the criteria for melancholic depression or catatonia.

[0023] In some embodiments, the subject further exhibits one or more behaviors selected from the group consisting of recurrent episodes of binge eating, eating significantly more food in a particular period of time than most people would eat in a similar period of time under similar circumstances, a sense of not being able to control eating during the episode, feelings of being unable to stop eating or of being unable to control what or how much one eats, eating much faster than usual, eating until feeling uncomfortably full, eating large amounts of food when not physically feeling hungry, eating alone because one feels embarrassed by how much one is eating, feeling disgusted with oneself, depressed or extremely guilty after overeating, noticeable distress about the binge eating, binge eating not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively in the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0024] In embodiments, the subject exhibits mood reactivity and the subject experiences symptoms such as recurrent episodes of overeating, eating significantly more food in a particular period of time than most people would eat in a similar period under similar circumstances, a sense of being unable to control their eating during the episode, feelings that they cannot stop eating or that they cannot control what or how much they eat, eating much faster than normal, eating until they feel uncomfortably full, eating large amounts of food when they are not physically hungry, eating alone because they feel embarrassed by how much they are eating, or In some embodiments, the patient further exhibits one or more behaviors selected from the group consisting of: binge eating, feeling disgusted with oneself, depression or strong guilt after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-esteem that is inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0025] In embodiments, a subject exhibits binge eating disorder, and the subject experiences symptoms such as recurrent episodes of binge eating, eating significantly more food in a particular period of time than most people would eat in a similar period under similar circumstances, a sense of being unable to control their eating during the episode, feelings that they cannot stop eating or that they cannot control what or how much they eat, eating much faster than normal, eating until they feel uncomfortably full, eating large amounts of food when they are not physically hungry, eating alone because they feel embarrassed by how much they are eating, and / or In some embodiments, the patient further exhibits one or more behaviors selected from the group consisting of: feeling disgusted with oneself, feeling depressed or very guilty after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation that is inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0026] In embodiments, the subject exhibits hypersomnia and the subject is diagnosed with recurrent episodes of overeating, eating significantly more food in a given period of time than most people would eat in a similar period under similar circumstances, a sense of being unable to control their eating during the episode, feelings that they cannot stop eating or that they cannot control what or how much they eat, eating much faster than normal, eating until they feel uncomfortably full, eating large amounts of food when they are not physically hungry, eating alone because they feel embarrassed by how much they are eating, In some embodiments, the patient further exhibits one or more behaviors selected from the group consisting of: feeling disgusted with oneself, feeling depressed or very guilty after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation that is inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0027] In embodiments, the subject exhibits leaden paralysis and the subject has symptoms such as recurrent episodes of overeating, eating significantly more food in a given period of time than most people would eat in a similar period under similar circumstances, a sense of being unable to control their eating during the episode, feelings that they cannot stop eating or have no control over what or how much they eat, eating much faster than normal, eating until they feel uncomfortably full, eating large amounts of food when they are not physically hungry, eating alone because they feel embarrassed about how much they are eating, and / or feeling overwhelmed by the amount of food they are eating. In some embodiments, the patient further exhibits one or more behaviors selected from the group consisting of: feeling disgusted with oneself, feeling depressed or very guilty after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation that is inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0028] In embodiments, the subject exhibits long-term interpersonal sensitivity resulting in significant social or occupational impairment, and the subject has symptoms such as recurrent episodes of overeating, eating significantly more food in a given period of time than most people would eat in a similar period under similar circumstances, a sense of being unable to control eating during the episode, feelings that one cannot stop eating or that one cannot control what or how much one eats, eating much faster than normal, eating until one feels uncomfortably full, eating large amounts of food when one is not physically hungry, feeling embarrassed about how much one is eating, and / or feeling depressed. The patient further exhibits one or more behaviors selected from the group consisting of: eating alone because it makes them feel sad or upset, feeling disgusted with themselves, depression or strong guilt after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-esteem that is inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

[0029] In some embodiments, the subject exhibits three or more behaviors selected from the group consisting of recurrent episodes of overeating, eating in a certain period of time significantly more food than most people would eat in a similar period of time under similar circumstances, feeling that eating during the episode is not controlled, eating much faster than usual, feeling that they cannot stop eating or control what or how much they eat, significant distress related to overeating, overeating that is not associated with the regular use of inappropriate compensatory behaviors, and overeating that does not occur exclusively in the course of anorexia nervosa or bulimia nervosa; and eating much faster than usual, eating until they feel uncomfortably full, eating large amounts of food when they are not physically hungry, eating alone because they feel embarrassed by how much they eat, feeling disgusted with themselves, feeling depressed or feeling very guilty after overeating.In some embodiments, the subject exhibits distress related to overeating.In some embodiments, overeating occurs on average at least once a week for three months. In some embodiments, the binge eating is not associated with the regular use of inappropriate compensatory behaviors and does not occur exclusively during the course of anorexia nervosa or bulimia nervosa. Inappropriate compensatory behaviors include, but are not limited to, purging, fasting, and excessive exercise.

[0030] In some embodiments, the subject exhibits recurrent episodes of overeating, eating significantly more food in a specific period than most people would eat in a similar period under similar circumstances, feeling unable to stop eating or unable to control what or how much they eat, recurrent inappropriate compensatory behaviors to prevent weight gain, overeating and inappropriate compensatory behaviors, self-esteem is unduly affected by body shape and weight, and anxiety that does not occur only during anorexia nervosa episodes.In some embodiments, the specific period is a 2-hour period, and overeating and inappropriate compensatory behaviors occur at least twice a week for 3 months.

[0031] In some embodiments, the subject has been diagnosed with atypical depression.

[0032] In some embodiments, the subject has been diagnosed with one or more behaviors selected from the group consisting of mood reactivity, increased appetite, binge eating, increased sleep, hypersomnia, leaden dizziness, and long-term interpersonal hypersensitivity resulting in significant social or occupational impairment.

[0033] In some embodiments, the subject is the subject who has been diagnosed with binge eating disorder.In some embodiments, the subject is the subject who has been diagnosed with one or more behaviors selected from the group consisting of: recurrent episodes of binge eating; eating in a certain period of time, eating more food than most people would eat in a similar period of time under similar circumstances; feeling that eating during this episode is uncontrollable; eating much faster than usual; feeling that they cannot stop eating or cannot control what or how much they eat; significant distress about overeating; overeating that is not associated with regular use of inappropriate compensatory behaviors; overeating that is not exclusively occurring in the course of anorexia nervosa or bulimia nervosa; eating much faster than usual; eating until they feel uncomfortably full; eating large amounts of food when they are not physically hungry; eating alone because they feel embarrassed by how much they eat; and feeling disgusted with themselves, depressed or very guilty after overeating.

[0034] In some embodiments, the subject is the subject who has been diagnosed with bulimia nervosa.In some embodiments, the subject is the subject who has been diagnosed with one or more behaviors selected from the group consisting of: eating quickly, recurrent episodes of binge eating, being unable to control eating, eating much faster than usual, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because they feel embarrassed by how much they eat, feeling disgusted with themselves, depressed or very guilty after overeating, significant distress about overeating, overeating not associated with compensation behavior, recurrent compensation behavior, overeating with compensation behavior, self-evaluation influenced by body shape and weight, recurrent compensation behavior of purging type, and recurrent compensation behavior of non-purging type.

[0035] In some embodiments, the subject is the subject who has been diagnosed with anorexia nervosa.In some embodiments, the subject is the subject who has been diagnosed with one or more behaviors selected from the group consisting of: restricting energy intake to the need amount, which leads to significant underweight in the context of age, sex, developmental process and physical health, intense fear of gaining weight or becoming fat despite being underweight, and anxiety in the way they feel about their weight or body shape, excessive impact of weight or body shape on self-esteem, or denial of the seriousness of their current underweight.

[0036] In some embodiments, the subject has been diagnosed with depression.

[0037] In some embodiments, the subject has been treated for depression.

[0038] In some embodiments, the method comprises treating a subject who has been diagnosed with depression and also exhibits one or more atypical depression symptoms.In some embodiments, the atypical depression symptoms are selected from the group consisting of mood reactivity, increased appetite, hyperphagia, increased sleep, hypersomnia, leaden dizziness, and long-term interpersonal rejection hypersensitivity that causes significant social or occupational impairment.

[0039] In some embodiments, the behavioral manifestation occurs at least once per day.

[0040] In some embodiments, the behavioral manifestations persist for at least 1 week. In some embodiments, the behavioral manifestations persist for at least 2 weeks. In some embodiments, the behavioral manifestations persist for at least 3 weeks.

[0041] In some embodiments, the behavioral manifestations persist for at least one month. In some embodiments, the behavioral manifestations persist for at least three months.

[0042] In some embodiments, the manifestations of the behavior occur periodically.

[0043] Compound 1: Also provided herein is a method for treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising TIFF2025508878000008.tif26128 or a pharma- ceutically acceptable salt thereof. In certain embodiments, impulsive behavior is characterized by a marked lack of impulse control followed by feelings of guilt.

[0044] In another aspect, compound 1: 1. A method of treating a subject who has been diagnosed with atypical depression, comprising administering a pharmaceutical composition comprising TIFF2025508878000009.tif25128 or a pharma- ceutically acceptable salt thereof, wherein the subject is experiencing symptoms of hypersomnia, binge eating, mood reactivity, leaden numbness, depressed mood, interpersonal sensitivity, rapid eating, recurrent episodes of binge eating, inability to control eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed about how much one is eating, feeling disgusted with oneself after overeating, or Also provided herein are methods in which a patient exhibits one or more behaviors selected from the group consisting of feeling bad, depressed or extremely guilty, marked distress about overeating, overeating not associated with compensatory behaviors, recurrent compensatory behaviors, overeating accompanied by compensatory behaviors, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above a minimally normal weight, intense fear of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and a continuing lack of awareness of the seriousness of being underweight.

[0045] Other aspects include hypersomnia, binge eating, mood reactivity, leaden numbness, depressed mood, interpersonal sensitivity, rapid eating, recurrent episodes of binge eating, inability to control eating, eating much faster than usual, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, feeling disgusted with oneself, depressed or very guilty after overeating, marked distress about the binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, and compensatory behaviors. 1. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of overeating, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above a minimally normal weight, intense fear of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and a continuing lack of awareness of the seriousness of being underweight, comprising administering to a subject a compound 1: Also provided herein are methods comprising administering a unit dose comprising TIFF2025508878000010.tif26128, or a pharma- ceutically acceptable salt thereof.

[0046] Compound 1: Also provided herein is a method of treating Prader-Willi syndrome in a subject in need thereof, comprising administering a composition comprising TIFF2025508878000011.tif26128 or a pharma- ceutically acceptable salt thereof.

[0047] In one aspect, compound 1 is a therapeutic agent, and the method comprises administering a therapeutically effective amount of a composition comprising the therapeutic agent to a subject in need thereof. In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on a depression symptom scale (e.g., the IDS-SR or modified version thereof). In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on the Mini-Instrumented Mental Illness Interview (MINI-S). In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on the Clinical Global Impression-Severity (CGI-S). In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on the Epworth Sleepiness Scale (ESS) and total sleep time (TST, measured by actigraphy). In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on the Clinical Global Impression-Improvement (CGI-I). In an embodiment, the therapeutic effect of the treatment is determined by assessing improvement based on the Patient Global Impression-Change (PGI-C). In embodiments, the therapeutic effect of treatment is determined by assessing improvement based on a fatigue scale (e.g., Brief Fatigue Inventory (BFI), Fatigue Severity Scale (FSS), Fatigue Symptoms Inventory (FSI), Fatigue-Short Form 10a (FACIT-Fatigue-10)). In various embodiments, the subject is determined to be substantially improved. In various embodiments, the subject is determined to be very substantially improved. In various embodiments, the subject shows a change from baseline.

[0048] Triple reuptake inhibitors Triple reuptake inhibitors are serotonin-norepinephrine-dopamine reuptake inhibitors that act as combined reuptake inhibitors of the monoamine neurotransmitters serotonin, norepinephrine and dopamine. Triple reuptake inhibitors simultaneously inhibit the serotonin transporter (SERT), the norepinephrine transporter (NET) and the dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations, thus resulting in increased serotonergic, adrenergic and dopaminergic neurotransmission throughout the brain. One assay for measuring the affinity of the compounds of the present disclosure may be the % inhibition from radioligand binding assays using cells expressing human transporters and receptors. Relevant radioligand binding assays for determining affinity are well known in the art (see Pacholczyk, T. et. al., 1991, Nature 350, 350-354; Pristupa, Z. et al., 1994, Mol. Pharmacol. 45, 125-135; Tatsumi, M. et. al., 1999, Eur. J. Pharmacol. 368, 277-283).

[0049] Atypical depression Atypical depression is a subtype of major depressive disorder (MDD) characterized by mood reactivity (moods that react strongly to environmental situations and are extremely sensitive - this is an essential feature), hypersomnia, carbohydrate craving / increased appetite, leaden paralysis (severe fatigue), and chronic rejection sensitivity. Atypical depression causes more disability than melancholic depression because individuals often have more difficulties with interpersonal relationships. Behaviors characteristic of patients with atypical depression include a temporary lightening of mood after positive events or happy news, as well as a feeling of heaviness in the arms and legs. Patients with atypical depression are usually excluded from MDD development programs. Patients with atypical depression represent 26% of MDD patients, with a prevalence rate of about 1-4% in the general population. Criteria are highly gender-dependent (women are more likely to develop AD symptoms). Atypical depression is also associated with conduct disorder, social phobia, interpersonal dependency, low self-esteem, and parental substance abuse. Atypical depression is also associated with higher rates of childhood trauma, whereas melancholic depression is not.

[0050] Hallmarks and neurobiology of AD include early onset and low suicidality, a higher likelihood of a chronic course with multiple comorbidities, an association with low HPA axis activity but not with catecholaminergic abnormalities, a phenotype similar to hypercortisolism (Cushing's syndrome) and hypothyroidism, and a sleep architecture that appears near normal despite hypersomnia and increased sleep duration (>10 hours / day).

[0051] The main reason for the introduction of atypical depression as a separate diagnosis is that medication trials have clearly shown that such patients respond better to monoamine oxidase inhibitors (MAOIs) than to tricyclic antidepressants (TCAs). Currently, both primary care providers and psychiatrists are involved in the treatment of patients with MDD, but only psychiatrists can diagnose atypical depression.

[0052] Atypical features as specifiers can apply to major depressive episode (MDD), dysthymia, non-bipolar disorder, and bipolar disorder if the most recent mood episode is a major depressive episode. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), some symptoms of MDD include five or more symptoms within the same two-week period, at least one of which is: (1) depressed mood for most of the day; and (2) decreased interest and pleasure in usual activities.

[0053] According to the DSM-5, a diagnosis of atypical depression requires the following criteria: In addition to meeting criteria for major depressive disorder, a diagnosis of atypical depression may require the following specifier criteria: A. Mood reactivity (i.e., brightening of mood in response to actual or potential positive events) B. Two or more of the following: (1) Significant weight gain or increased appetite (2) Hypersomnia (3) leaden paralysis (i.e., arms or legs feel heavy and leaden) (4) Prolonged interpersonal sensitivity resulting in significant social or occupational impairment (not limited to episodes of a mood disorder) C. The criteria for "melancholic features" or "catatonic features" are not met during the same episode.

[0054] The method described herein is in part for treating the subject who exhibits at least one or more behaviors selected from the group consisting of mood reactivity, increased sleepiness, hypersomnia, leaden dizziness, and long-term interpersonal rejection hypersensitivity, which causes significant social or occupational impairment, all of which are terms well known to those skilled in the art.Such behaviors may be called the symptoms of atypical depression. In embodiments, subjects are diagnosed with: depressed mood - as indicated by subjective report or observation by others (in children and adolescents, may be irritable mood); loss of interest or pleasure in almost all activities; significant (more than 5% in 1 month) unintended weight loss or decreased appetite (in children, absence of expected weight gain); significant (more than 5% in 1 month) unintended weight gain or increased appetite (in children, absence of expected weight gain); sleep disturbances (insomnia or hypersomnia); psychomotor changes that are severe enough to be observable by others (agitation or mental retardation); fatigue, lethargy, or lack of energy; or decreased efficiency in completing everyday tasks; feelings of worthlessness or excessive, inappropriate, or delusional guilt (not simply self-blame or guilt for being ill); decreased ability to think, concentrate, or make decisions - as indicated by subjective report or observation by others. and further exhibiting one or more behaviors selected from the group consisting of recurrent thoughts about death (not simply a fear of dying), as indicated by subjective report or observation by others, and suicidal ideation or suicide attempts, all of which are terms well known to those skilled in the art.

[0055] Binge Eating Disorder (BED) Binge Eating Disorder (BED) is an eating disorder characterized by recurrent episodes of binge eating accompanied by a sense of loss of control and often negative feelings about oneself, but without intervening periods of compensatory behaviors (such as self-induced vomiting, laxative purging, fasting, or prolonged exercise). According to the DSM-5, the diagnosis of binge eating disorder requires the following criteria: A. Recurrent episodes of binge eating. Episodes of binge eating are characterized by both of the following: 1. Eating an amount of food in a particular period of time (e.g., within any 2-hour period) that is significantly more than most people would eat at a similar time under similar circumstances 2. A sense of being unable to control overeating during the episode (e.g., feeling that you cannot stop eating or that you have no control over what or how much you eat) B. The 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're eating 5. Feeling disgusted with yourself, depressed, or extremely guilty after overeating C. There is significant distress about overeating. D. Binge eating occurs, on average, at least once a week for a three-month period. E. The binge eating is not associated with the regular use of inappropriate compensatory behaviors (e.g., purging, fasting, excessive exercise) and does not occur exclusively during the course of anorexia nervosa or bulimia nervosa. Identify if: In partial remission: Binge eating occurs with an average frequency of less than one episode per week for a period of time after all criteria for binge eating disorder have previously been met. In complete remission: None of the criteria for binge eating disorder are met for a period of time after all of the criteria were previously met. Identify current severity: The diagnosis also indicates severity, ranging from mild to severe: mild: 1-3 binge eating episodes per week, moderate: 4-7 binge eating episodes per week, severe: 8-13 binge eating episodes per week, and extreme: 14 or more binge eating episodes per week.

[0056] Bulimia nervosa Bulimia nervosa, also known simply as binge eating, is an eating disorder characterized by excessive eating followed by purging and excessive concern about body shape and weight. According to the DSM-5, the diagnosis of bulimia nervosa requires the following criteria: A. Recurrent episodes of binge eating characterized by both of the following: 1. Eating a significantly larger amount of food within any two-hour period than most people would eat in a similar period under similar circumstances. 2. Feeling unable to stop eating or control what or how much you eat. B. Self-induced vomiting; abuse of laxatives, diuretics, or other drugs; recurrent inappropriate compensatory behaviors, such as fasting or excessive exercise, to prevent weight gain. C. Binge eating and inappropriate compensatory behaviors occur, on average, at least once a week for a 3-month period. D. Self-evaluation is unduly influenced by body shape and weight. E. Anxiety does not occur exclusively during episodes of anorexia nervosa. Identify if: In partial remission: Some but not all criteria are met for a period of time after all criteria were met in the past. In complete remission: No criteria are met for a period of time after all criteria were previously met. Current severity (severity may increase to reflect degree of other symptoms and impairment): Mild: an average of 1-3 episodes of inappropriate compensatory behavior per week; Moderate: an average of 4-7 episodes of inappropriate compensatory behavior per week; Severe: an average of 8-13 episodes of inappropriate compensatory behavior per week; Extreme: an average of 14 or more episodes of inappropriate compensatory behavior per week.

[0057] Anorexia nervosa Anorexia nervosa is an eating disorder that restricts food intake. They may avoid eating completely, eat very little, and / or eliminate certain foods and eat only a small variety. A common feature of anorexia is an extreme fear of being overweight (even if they are underweight). According to the DSM-5, the diagnosis of anorexia requires the following criteria: 1. Restriction of energy intake relative to requirements leading to significant underweight in the context of age, sex, developmental stage, and physical health. 2. An intense fear of gaining weight or becoming fat despite being underweight. 3. Concerns about how one feels about one's weight or shape, an undue impact of weight or shape on self-evaluation, or denial of the seriousness of current underweight.

[0058] Symptoms associated with anorexia include: Being underweight (may be severe) Binge eating and purging (by vomiting or taking laxatives) Constipation, bloating, and abdominal pain ·dehydration Distorted body image Dizziness and fainting Extreme fatigue (lethargy) Extreme dietary restrictions An intense fear of gaining weight Stopping of menstruation or failure to start menstrual cycle Loss or fluctuation of body fat and muscle mass Poor circulation (always feeling cold) The skin becomes yellow, dry, or covered with soft hairs (vellus hairs) Taking diet or supplemental medications Always talk about weight or food Suicidal thoughts or behavior may include.

[0059] Subtypes of anorexia include: Food intake restriction type: The individual has not engaged in recurrent episodes of binge eating or purging behaviors (i.e., self-induced vomiting, or overuse of laxatives, diuretics, or enemas) in the past 3 months. This subtype represents weight loss achieved primarily through dieting, fasting, and / or excessive exercise. Binge / Purge: During the past 3 months, the individual has engaged in recurrent episodes of binge eating or purging behaviors (i.e., self-induced vomiting, or overuse of laxatives, diuretics, or enemas). The severity level was mild (BMI > 17 kg / m 2 ), moderate (BMI = 16~16.99kg / m 2 ), severe (BMI = 15~15.99kg / m 2 ), extreme (BMI < 15kg / m 2 ).

[0060] compound compound 1 Compound 1, shown below, is a triple reuptake inhibitor also known as (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone. TIFF2025508878000012.tif26128

[0061] Methods for chemically synthesizing compound 1 are described in US Pat. No. 8,084,623 and US Pat. No. 9,527,810, which are incorporated by reference in their entireties.

[0062] In various embodiments, the methods described herein include administering compound 1 or a pharma- ceutically acceptable salt thereof. In various embodiments, the pharma- ceutically acceptable salt of compound 1 can be a salt of compound 1 with a physiologically compatible mineral acid such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid, or with an organic acid such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid.

[0063] In certain embodiments, the pharma- ceutically acceptable salt of Compound 1 is the hydrochloride salt in a hydrate or anhydrous form (e.g., anhydrous, hemihydrate, monohydrate, or quarter-hydrate).In certain embodiments, the pharma- ceutically acceptable salt of Compound 1 is the hydrochloride salt in a quarter-hydrate form.

[0064] In various embodiments, a pharma- ceutically acceptable salt of Compound 1 is TIFF2025508878000013.tif25128 or its hydrate.

[0065] In certain embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is in an amorphous form. In certain embodiments, Compound 1 or a pharma- ceutically acceptable salt thereof is in a crystalline form. In certain embodiments, the crystalline form is a crystalline polymorph or a hydrate thereof. In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride tetrahydrate (form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (form 2).

[0066] Form 1 In some embodiments, the compound is a crystalline quart-hydrate form of the hydrochloride salt of Compound 1 (Form 1), wherein Form 1 has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 1. In some embodiments, Form 1 has a Cu 2θ (2 theta) Kα It is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained by radiation: 5.5±0.20°, 9.4±0.20°, 10.6±0.20°, 12.5±0.20°, 14.6±0.20°, 16.2±0.20°, 16.6±0.20°, 17.3±0.20°, 18.6±0.20°, 19.6±0.20°, 22.2±0.20°, 22.7±0.20°, 23.1±0.20°, 23.7±0.20° and 25.3±0.20°.

[0067] Form 2 In some embodiments, the compound is a crystalline form of the hydrochloride salt of Compound 1 (Form 2), wherein Form 2 has an X-ray powder diffraction (XRPD) pattern substantially as shown in Figure 2. In some embodiments, Form 2 has a 2θ (2 theta) Cu Kα It is characterized by at least three peaks selected from the following X-ray powder diffraction peaks obtained by radiation: 5.2±0.20°, 10.5±0.20°, 12.3±0.20°, 15.3±0.20°, 15.6±0.20°, 16.0±0.20°, 17.1±0.20°, 18.8±0.20°, 23.0±0.20°, 23.9±0.20°, 27.2±0.20°, 28.2±0.20° and 30.5±0.20°.

[0068] In one aspect, the present disclosure relates to a composition, such as a pharmaceutical composition, comprising Compound 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, for the treatment of atypical depression in a subject in need thereof. In another aspect, the present disclosure relates to a composition, such as a pharmaceutical composition, comprising Compound 1 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient, for the treatment of a medical condition associated with atypical depression in a subject in need thereof. In various embodiments, the composition is a solid pharmaceutical composition.

[0069] In various embodiments, the amount of Compound 1 or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 1 mg to about 70 mg of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 1 mg to about 60 mg. In some embodiments, the composition comprises about 1 mg to about 45 mg. In some embodiments, the composition comprises about 1 mg to about 30 mg. In some embodiments, the composition comprises about 1 mg to about 15 mg. In some embodiments, the composition comprises about 1 mg to about 5 mg. In some embodiments, the composition comprises about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, or about 70 mg.

[0070] In various embodiments, the amount of Compound 1 or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions described herein may be about 1 mg / kg to about 70 mg / kg of Compound 1 or a pharma- ceutically acceptable salt thereof. In some embodiments, the composition comprises about 1 mg / kg to about 60 mg / kg. In some embodiments, the composition comprises about 1 mg / kg to about 45 mg / kg. In some embodiments, the composition comprises about 1 mg / kg to about 30 mg / kg. In some embodiments, the composition comprises about 1 mg / kg to about 15 mg / kg. In some embodiments, the composition comprises about 1 mg / kg to about 5 mg / kg. In some embodiments, the composition comprises about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, or about 70 mg / kg.

[0071] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of the free base form of Compound 1.

[0072] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharma- ceutically acceptable salt of Compound 1. In some embodiments, the pharma- ceutically acceptable salt of Compound 1 can be a salt of Compound 1 with a physiologically compatible mineral acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid, or with an organic acid, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid, or salicylic acid.

[0073] The pharmaceutical compositions provided herein may be administered by various routes, including but not limited to oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0074] The pharmaceutical compositions provided herein may be administered chronically ("chronic administration").Chronic administration refers to administration of the compound or its pharmaceutical composition for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as for the lifetime of the subject.In certain embodiments, chronic administration is intended to maintain the concentration of the compound in the blood constant, such as within the therapeutic window for an extended period of time.

[0075] The pharmaceutical compositions provided herein may be provided in unit dosage form to facilitate accurate dosing.The term "unit dose" or "unit dosage form" refers to a physically separate unit suitable as a single dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with suitable pharmaceutical excipients.In various aspects, the pharmaceutical dosage forms described herein may be administered as unit dosages.Exemplary unit dosage forms include pre-measured and pre-filled ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc., in the case of solid compositions.

[0076] The pharmaceutical compositions provided herein may be provided in sustained release form.Sustained release form is a formulation designed to slowly release therapeutic agent in the body over a long period of time.Sustained release form can be formulated, for example, to sustain the action of compound over a long period of time.Sustained release form can be formulated to provide an effective dose (e.g., provide a physiologically effective blood profile) of any compound described herein for about 4 hours, about 8 hours, about 12 hours, about 16 hours or about 24 hours.

[0077] In various embodiments, the pharmaceutical compositions provided herein are administered to a patient in a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.

[0078] In various embodiments, the pharmaceutical compositions provided herein contain Compound 1 as the sole active agent or in combination with other active agents.

[0079] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make the compositions suitable for administration to various animals are well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with no more than routine experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005.

[0080] definition To facilitate the understanding of the present invention, several terms and expressions are defined below.

[0081] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those usually understood by those skilled in the art to which this invention belongs. The abbreviations used herein have their conventional meaning in the chemical and biological arts. The chemical structures and formulas described herein are constructed according to the standard rules of chemical valence known in the chemical arts.

[0082] Throughout the description, where compositions are described as having, including, or comprising particular components, or where processes and methods are described as having, including, or comprising particular steps, it is further contemplated that there are compositions of the invention that consist essentially of or consist of the recited components, and that there are processes and methods of the invention that consist essentially of or consist of the recited processing steps.

[0083] When an application refers to an element or component as being included in and / or selected from a list of described elements or components, it should be understood that the element or component can be any one of the described elements or components, or the element or component can be selected from a group consisting of two or more of the described elements or components.

[0084] Furthermore, it should be understood that the elements and / or features of the compositions or methods described herein, whether express or implied herein, can be combined in various ways without departing from the spirit and scope of the present invention.For example, when a specific compound is mentioned, that compound can be used in various aspects of the method of the present invention, unless the context indicates otherwise.In other words, although the embodiments have been described and illustrated in this application in a manner that allows a clear and concise application to be described and drawn, it is intended and will be recognized that the embodiments may be combined or separated in various ways without departing from the teachings and invention.For example, it will be recognized that all features described and illustrated herein may be applicable to all aspects of the invention described and illustrated herein.

[0085] The articles "a" and "an" are used in this disclosure, unless the context is inappropriate, to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0086] The term "and / or" is used in this disclosure to mean either "and" or "or," unless otherwise indicated.

[0087] The expression "and / or" in connection with three or more listed objects should be understood to have the same meaning, unless the context indicates otherwise.

[0088] "Comprise," "Comprises," "Comprising" Use of the terms "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be understood to be open-ended and open-ended, e.g., not excluding additional, unrecited elements or steps, unless otherwise specifically recited or understood from the context.

[0089] When the use of the term "about" precedes a quantitative value, the invention also includes the specific quantitative value itself, unless otherwise specifically stated. As used herein, the term "about" refers to a ±10% variation from the nominal value, unless otherwise indicated or inferred from the context.

[0090] At various places in this specification, variables or parameters are disclosed in groups or ranges. The description is specifically intended to include every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0091] The use of any examples or exemplary language herein, such as "such as" or "including," is intended only to better describe the invention and does not pose a limitation on the scope of the invention unless recited in the claims. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0092] As a general matter, percentages of compositions specified are by weight unless otherwise indicated. Further, in the absence of a definition for a variable, the preceding definition of the variable controls.

[0093] As used herein, a "composition" or "pharmaceutical composition" or "pharmaceutical formulation" refers to a combination of an active agent with an inert or active excipient or carrier that makes the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0094] "Pharmaceutically acceptable" refers to compounds, molecular entities, compositions, substances and / or dosage forms that do not produce adverse, allergic or other untoward reactions when administered to animals or humans, as appropriate, and / or that are approved or approvable by a federal or state government regulatory agency or a corresponding agency in a country other than the United States, or that are described in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more specifically, in humans.

[0095] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group which may be present in a compound of the present invention (e.g., Compound 1), which is compatible with pharmaceutical administration.

[0096] Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Other acids, such as oxalic acid, are not themselves pharma- ceutical acceptable, but may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharma- ceutical acceptable acid addition salts.

[0097] Examples of bases are alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and bases where W is C 1~4 Formula NW4 is an alkyl + and the like.

[0098] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, monosulfate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include Na + , K + , Ca 2+ , NH4 + , and NW4 + (Where W is C 1~4 and the anion of a compound of the present invention combined with a suitable cation, such as a cation group, which may be an alkyl group.

[0099] For therapeutic use, it is contemplated that the salts of the compounds of the invention are pharma-ceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may find use, for example, in the preparation or purification of a pharma-ceutically acceptable compound.

[0100] As used herein, "pharmaceutical acceptable excipient" refers to a substance that aids in the administration and / or absorption of an active agent to a subject and can be included in the composition of the present invention without causing significant adverse toxic effects to the patient.Non-limiting examples of pharmaceutical acceptable excipients include water, NaCl, normal saline such as phosphate buffered saline, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes.Such preparations are sterilized and, if desired, can be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, and / or flavorings that do not adversely react with the compounds of the invention. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0101] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0102] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalants and chewables.

[0103] As used herein, "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration, transmucosal administration (e.g., buccal, sublingual, nasal, or transdermal), or subcutaneous administration to a subject, or implantation of a sustained release device, e.g., a mini-osmotic pump. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous injections, transdermal patches, and the like.

[0104] The term "sustained" as used herein refers to the behavior that persists in the subject, and the behavior persists in the subject for a long period of time or a certain period of time.In some embodiments, the behavior persists in the subject for at least 3, 6 or 12 hours, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or 31 days.In some embodiments, the behavior persists in the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months.

[0105] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" include actions taken during a subject's illness with a specified disease, disorder or condition that reduce the severity of the disease, disorder or condition or slow or delay the progression of the disease, disorder or condition (e.g., "therapeutic treatment"). As used herein, "treat", "treating" and "treatment" can include any effect that results in the improvement of a condition, disease, disorder, etc. (including one or more symptoms thereof), such as reducing, decreasing, modulating, ameliorating, or eliminating. Treating can include curing, improving, or at least partially ameliorating a disorder.

[0106] The term "therapeutically effective amount" as used herein refers to the amount of a compound (e.g., Compound 1) or its pharmaceutically acceptable salt that produces the biological or medical response of a tissue, system, animal or human that is sought by a researcher, veterinarian, physician or other clinician. The compound or its pharmaceutically acceptable salt described in this disclosure can be administered in a therapeutically effective amount to treat disease. The therapeutically effective amount of a compound or its pharmaceutically acceptable salt can be the amount required to achieve the desired therapeutic and / or prophylactic effect, such as the amount that reduces the symptoms of a disorder such as atypical depression.

[0107] As used herein, "impulsive behavior" refers to behavior characterized by a marked lack of impulse control followed by feelings of guilt. Impulsive behavior includes mood reactivity, increased sleepiness, hypersomnia, leaden paralysis, long-term interpersonal rejection sensitivity resulting in significant social or occupational impairment, binge eating not associated with regular use of inappropriate compensatory behaviors, binge eating not occurring exclusively during the course of anorexia nervosa or bulimia nervosa, self-induced vomiting to prevent weight gain, recurrent inappropriate compensatory behaviors such as abuse of laxatives, diuretics, or other drugs, binge eating and inappropriate compensatory behaviors, self-evaluation inappropriately influenced by body shape and weight, anxiety not occurring exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type, recurrent episodes of binge eating, most people experiencing binge eating within a specific period of time, These include eating significantly more food than a person would eat under similar circumstances and in a similar period of time, a feeling of being unable to control eating during the episode, feelings that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until one feels uncomfortably full, eating large amounts of food when one is not physically hungry, eating alone because one feels embarrassed by how much one is eating, feeling disgusted, depressed or extremely guilty about oneself after overeating, noticeable distress about overeating, increased appetite, binge eating, as well as a marked lack of impulse control followed by feelings of guilt. Each of the behaviors described herein are well known to those skilled in the art.

[0108] As used herein, "sufficient to improve at least one of the behaviors" means that the behavior of the subject is improved when comparing the behavior before administration of Compound 1 to the behavior after administration of Compound 1, as measured or diagnosed in the Diagnostic and Statistical Manual of Mental Disorders. For example, reducing the amount of food intake in the subject for a day or within any two hours, as compared to the food intake by the subject before administration of Compound 1. Another example is reducing the amount of heaviness and leaden sensation in the arms or legs in a day in the subject, as compared to the food intake by the subject before administration of Compound 1. EXAMPLES

[0109] The following examples are provided to provide a more detailed understanding of the invention described herein. The synthetic and biological examples described herein are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as limiting the scope thereof in any way.

[0110] In the examples provided below, the following abbreviations are used: "PROG" refers to progressive ratio; "FR1" refers to a fixed ratio of 1 or fixed ratio 1; "SEM" refers to standard error; "VEH" refers to vehicle; "ANOVA" refers to analysis of variance study; "NR" refers to non-REM sleep; "REM" refers to REM sleep; "po" or "per os" refers to oral; "CAF" refers to caffeine; "DAT" refers to dopamine transporter; "SERT" refers to serotonin transporter; "TRI" refers to triple reuptake inhibitor; "NR" refers to non-REM sleep; "REM" refers to REM sleep.

[0111] Example 1. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) tetrahydrate [see U.S. Pat. No. 9,527,810] TIFF2025508878000014.tif29128 (S)-(1-benzyl-3-propylpyrrolidin-3-yl)(3,4-dichlorophenyl)methanone (IX-1) (5 g, 13.3 mmol, equiv: 1.00, see U.S. Pat. No. 9,527,810 for synthesis) was dissolved in dichloromethane (30 mL). The light yellow solution was cooled to 0-5°C and N-ethyldiisopropylamine (172 mg, 226 μL, 1.33 mmol, equiv: 0.1) was added. 1-Chloroethyl chloroformate (2.28 g, 1.74 ml, 15.9 mmol, equiv: 1.2) was added dropwise while maintaining the temperature at 0-5°C. The reaction was allowed to warm to room temperature over 30 min and stirred at room temperature for 1 h. Methanol (25 mL) was added and the pale yellow solution was heated to 40 °C for 40 min. The reaction mixture was concentrated under reduced pressure (40 °C, 600-15 mbar) to give 5.48 g of crude product. Ethyl acetate (30.0 mL) was added and the suspension was heated to 50 °C. Aqueous solution (239 mg, 239 μL, 13.3 mmol, equiv: 1.0) in ethyl acetate (35 mL) was added over 10 min. The white suspension was stirred at 50 °C for 1 h and cooled to room temperature over 1.5 h. The suspension was filtered and the filter cake was washed twice with ethyl acetate (10 mL) and dried under reduced pressure (40 °C, 15 mbar) to give 4.02 g of (15) as a quartohydrate (93% yield).

[0112] Example 2. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) tetrahydrate [see U.S. Pat. No. 9,527,810] 1. Grignard formation (A') TIFF2025508878000015.tif171286.8 g (279 mmol, 1.3 equiv.) of magnesium was suspended in 60 mL of tetrahydrofuran. The suspension was heated to 40° C. and 70.5 g of a 2% solution of 3,4-dichlorobromobenzene (A) in 200 mL of tetrahydrofuran was added (Grignard reaction started within a few minutes). After the exotherm had ceased, the remaining aryl bromide solution was added over 2 h. The reaction mixture was stirred at 40° C. for 1 h, then the mixture was cooled to room temperature.

[0113] 2. Grignard Addition TIFF2025508878000016.tif32128 A solution of acid chloride (13) (for synthesis see US Pat. No. 9,527,810) was degassed three times and 55.8 g (322 mmol, 1.5 equiv.) of N,N,N',N',N''-pentamethyldiethylenetriamine (PMDTA) was added. The light-colored suspension was heated to 40-45 °C and Grignard solution (A') was added dropwise over 1.5 h. After 1 h additional reaction time, the reaction mixture was cooled to room temperature. 500 mL of 2 M HCl(aq), 300 mL of saturated NaCl(aq) and 300 mL of ethanol were added. The organic phase was separated and washed with a mixture of 500 mL of 2 M HCl(aq), 300 mL of saturated NaCl(aq) and 300 mL of ethanol. The organic phase was washed with 400 mL of 1 M NaOH (aq) and twice with 150 mL of 10% NaCl (aq). The organic phase was concentrated under reduced pressure to an oil, dissolved in 100 mL of toluene, and concentrated again to give 87 g of crude material (14) with a purity of 80%.

[0114] 3. (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) as the tetrahydrate TIFF2025508878000017.tif28128The crude material (14) was dissolved in 130 mL of toluene and the solution was added dropwise to a mixture of 140 mL of toluene and 70 mL of 37% HCl (aq) at 60-70 °C. After 1 h, the reaction mixture was azeotroped with toluene (Tr max = 70 °C, Tj max = 120 °C, reduced pressure) and the volume was adjusted to 350-400 mL. A mixture of 700 mL of ethyl acetate and 3.6 mL of water was added at 65 °C. The solution was cooled to room temperature over 1 h, during which time crystallization started (around 45 °C). After stirring overnight, the suspension was cooled to 0-5 °C for 2 h, filtered and washed twice with 200 mL of ethyl acetate. The crystals were resuspended in 250 mL of ethyl acetate and digested at 55 °C for 2 h, then cooled to room temperature. The suspension was filtered and the filter cake was washed with 200 mL of ethyl acetate. The crystals were dried under reduced pressure at 50° C. to give 54.4 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride 1 / 4 hydrate as a powder with a purity of 99%.

[0115] An alternative route to (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) as the quartohydrate The crude material (14) was dissolved in 63 mL of toluene and deprotected with 24 mL of 37% HCl (aq) at 60° C. After completion of the reaction, the reaction mixture was azeotropically dried with toluene at 50-60° C. The solution was cooled to room temperature and 100 mL of water was added. The aqueous phase was separated and washed with 50 mL of toluene. The aqueous phase was azeotropically dried with toluene and concentrated to dryness to give 22.5 g (90% yield) of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quartet-hydrate. (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quartet-hydrate may be obtained by digestion or recrystallization, for example, by the process described below.

[0116] Conversion of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride anhydrous to the 1 / 4 hydrate form: (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride anhydrous (40 g, 124 mmol, equiv: 1.00, see Example 3 or US Pat. No. 9,527,810 for synthesis) was suspended in a mixture of ethyl acetate (340 mL), ethanol (36 mL), and water (0.6 mL) at room temperature. The suspension was heated to 40° C. and a mixture of ethyl acetate (20 mL), ethanol (0.5 mL), and water (0.6 mL) was added over 1 h. The suspension was cooled to room temperature over 1 h. After stirring overnight at room temperature, the suspension was cooled at 0-5° C. over 2-3 h, filtered, and washed with a cold (0-5° C.) mixture of ethyl acetate (55 mL), ethanol (5 mL), and water (0.5 mL). The filter cake was dried under reduced pressure at 50° C. to give 38 g (water content 1.5%) of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride 1 / 4 hydrate.

[0117] Recrystallization of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quartohydrate: 54.4 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quartet-hydrate were dissolved in 550 mL of ethanol at room temperature. The solution was filtered and concentrated under reduced pressure at 60° C. until the volume was 140 mL. The volume was adjusted to 550 mL by addition of ethyl acetate. The remaining ethanol was solvent exchanged with ethyl acetate (60° C., reduced pressure) and 55 mL of ethanol was added to the resulting suspension at 60° C. Then 1.5 mL of water was added and the solution was cooled slowly to room temperature during which time crystallization occurred. After stirring overnight at room temperature, the suspension was cooled to 0-5° C. for 1 h and filtered. The filter cake was washed with a mixture of 50 mL of ethyl acetate and 5 mL of ethanol, followed by two more washes with 50 mL of ethyl acetate. The crystals were dried overnight at 50° C. under reduced pressure to give 48.9 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride 1 / 4 hydrate as a powder with a purity of 99%.

[0118] Example 3. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) anhydrous [see U.S. Pat. No. 9,527,810] 50 g of the sodium salt was converted to the corresponding acid chloride (13) (for synthesis see U.S. Pat. No. 9,527,810). The acid chloride (13) was reacted with 3,4-dichlorophenyl-MgBr(A') and then deprotected. After azeotropic drying, Karl Fischer titration of the crude material (15) gave an orange opaque toluene solution (300 g, water content <0.1%).

[0119] (i) 1 / 5 of the crude (15) solution (maximum theoretical content: 11.3 g of (15)) was cooled to room temperature. After overnight storage at room temperature, the resulting suspension was filtered. The filter cake was washed with ethyl acetate (Karl Fischer titration of wet filter cake 0.2%) and dried under reduced pressure at 50-60°C to obtain 5.9 g of crystals of (15).

[0120] (ii) 1 / 5 of the crude (15) solution (maximum theoretical content: 11.3 g of (15)) was cooled to room temperature. After storage at room temperature for 4 days, the resulting suspension was stirred at 0-2°C for 4 hours. The resulting suspension was filtered, and the filter cake was washed with ethyl acetate (Karl Fischer titration of wet filter cake 0.2%) and dried under reduced pressure at 50-60°C to obtain 8.8 g of crystals of (15).

[0121] Example 4. Crystalline forms of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride and (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride tetrahydrate [see U.S. Pat. No. 9,527,810] Characterization methods and data for the crystalline forms of Compound 1 are described in US Pat. No. 9,527,810, which is incorporated by reference in its entirety.

[0122] X-ray powder diffraction (XRPD) X-ray diffraction powder patterns were obtained using a STOE STADI P diffractometer (Cu Kα The measurements were recorded at ambient conditions in transmission geometry using a line, primary monochromator, position-sensitive detector, angular range 3°-42° (2 theta), total measurement time approximately 60 min. Samples were prepared and analyzed without further processing of the material (e.g., grinding or sieving).

[0123] XRPD pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride tetrahydrate (form 1) Solid (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride salt quartohydrate (Form 1) can be identified by only one characteristic peak in its powder X-ray diffraction pattern, shown in Figure 1. Exemplary X-ray powder diffraction patterns for (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride salt quartohydrate (Form 1) in terms of 2θ (2 theta) are: 5.5±0.20°, 9.4±0.20°, 10.6±0.20°, 12.5±0.20°, 14.6±0.20°, 16.2±0.20°, 16.6±0.20°. , 17.3±0.20°, 18.6±0.20°, 19.6±0.20°, 22.2±0.20°, 22.7±0.20°, 23.1±0.20°, 23.7±0.20° and 25.3±0.20°; in particular, the characteristic peaks are 9.4±0.20°, 14.6±0.20°, 16.6±0.20°, 19.6±0.20° and 22.2±0.20°.

[0124] XRPD pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (form 2) (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone solid hydrochloride salt (Form 2) can be identified by only one characteristic peak in its powder X-ray diffraction pattern shown in FIG. Exemplary X-ray powder diffraction patterns for the solid hydrochloride salt of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Form 2), in terms of 2θ (two theta), are: 5.2±0.20°, 10.5±0.20°, 12.3±0.20°, 15.3±0.20°, 15.6±0.20°, 16.0±0.20°, 17.1±0.20°, 18.8±0.20°, 23.0±0.20°, 23.9±0.20°, 27.2±0.20°, 28.2±0.20°, and 30.5±0.20°.

[0125] Crystal structure analysis For single crystal structure analysis, single crystals were mounted on a loop on a goniometer and measured at ambient conditions. Data were collected on a GEMINI Ultra diffractometer from Oxford Diffraction. Cu radiation of 1.54 Å wavelength was used for data collection. Data were processed with the software CRYSALIS. Crystal structures were solved and refined with standard crystallographic software. In this case, the ShelXTL program from Bruker AXS (Karlsruhe) was used.

[0126] Preparation of single crystals of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone monohydrochloride tetrahydrate 10 mg of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride was dissolved in 0.226 mL of nitromethane at 60° C. The solution was left to reach ambient temperature without stirring. After 24 hours, single crystals were harvested and submitted for X-ray crystallography.

[0127] Structural data from single crystal X-ray analysis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride tetrahydrate with the following unit cell parameters: TIFF2025508878000018.tif46128 where a, b and c are the typical lengths of the crystal lattice, respectively, and alpha, beta and gamma are the unit cell angles. The salt crystallizes in space group P1, with an average diameter of 1623.82 Å. 3 The lattice volume is obtained.

[0128] Differential Scanning Calorimetry (DSC) Differential scanning calorimetry curves were recorded using a Mettler-Toledo™ Differential Scanning Calorimeter DSC820, DSC821 or DSC1 equipped with a FRS05 sensor. System suitability tests were performed with indium as the reference material and calibration was performed with indium, benzoic acid, biphenyl and zinc as the reference materials.

[0129] For the measurements, approximately 2-6 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to the measurements, a hole was automatically drilled in the lid to obtain a pinhole of approximately 1.5 mm. The sample was then heated under a nitrogen flow of approximately 100 mL / min, typically using a heating rate of 10 K / min.

[0130] Thermogravimetric analysis (TGA) Thermogravimetric analysis was performed on a Mettler-Toledo™ Thermogravimetric Analyzer (TGA850 or TGA851). System suitability tests were performed with Hydranal as the reference material, and calibration was performed with aluminum and indium as the reference materials.

[0131] For thermogravimetric analysis, approximately 5-10 mg of sample was placed in an aluminum pan, accurately weighed, and sealed with a perforated lid. Prior to the measurement, a hole was automatically drilled in the lid to obtain a pinhole of approximately 1.5 mm. The sample was then heated under a nitrogen flow of approximately 50 mL / min using a heating rate of 5 K / min.

[0132] Example 5. Evaluation of the appetite suppressant effect of compound 1 using a progressive ratio / food choice task in rats A study was conducted to evaluate the appetite suppressant effects of Compound 1. The PROG / food choice procedure was used as a test designed to assess the effort of rats to eat a highly palatable food by pressing a lever instead of eating a freely available standard chow.

[0133] Methods. Thirty-one (n=31) adult male Sprague-Dawley rats were used in this study. Animals were restricted to 85% of their free-feeding body weight and allowed for gradual growth throughout the study period. Animals were assessed using operant conditioning chambers. Animals were first fed high-carbohydrate pellets ("highly palatable food") and trained to lever press using a fixed ratio 1 (FR1=one active lever press delivers highly palatable food) continuous reinforcement schedule for 1 week. After this, rats were trained on a progressive ratio (progressively higher lever pressures are required to deliver highly palatable food) schedule alone for 9 weeks, at which point chow ("standard chow") was introduced (=PROG / food choice procedure) and animals were trained for a further 5 weeks to obtain a stable baseline. Each session lasted 30 min and rats performed a run in the operant chamber once per day, 5 days per week (Monday-Friday). After the training period, vehicle (VEH) or Compound 1 was orally administered at doses of 5.0, 10.0, and 20.0 mg / kg once a week (Thursday or Friday). Treatment conditions were randomly selected. Lever pressing and food consumption (including food waste) were recorded after each operant session.

[0134] Statistical analysis. Repeated measures analysis of variance test (ANOVA) and planned comparisons were used to evaluate the data overall. Multi-way ANOVA was used to evaluate group x treatment interactions. When significant cross-effects were found, groups were evaluated separately using planned comparisons (with an overall error term). Dunnett's test was also used to analyze differences between drug treatments and VEH. A p-value <0.05 for all analyses was considered statistically significant.

[0135] Results. As shown in Figure 3, all treatment conditions showed a significant decrease in standard chow intake compared to VEH (5.0 mg / kg: [F(1,90) = 15.589, p < 0.001], 10.0 mg / kg [F(1,90) = 159.881, p < 0.001], and 20.0 mg / kg: [F(1,90) = 236.567, p < 0.001]). As shown in Figure 4, there was no significant difference between VEH and the 5.0 mg / kg dose [F(1,90) = 0.391, p = ns], while a significant decrease in lever pressing was seen with both the 10.0 mg / kg dose [F(1,90) = 13.534, p < 0.001] and the 20.0 mg / kg dose [F(1,90) = 38.407, p < 0.001].

[0136] This study shows that Compound 1 exerts an appetite suppressant effect. The pattern of reduced lever pressing and food intake shown in this study of the PROG / food choice task has been shown in other studies using drugs and conditions known to suppress appetite. Examples of drugs include fenfluramine, prefeeding, cannabinoid antagonists and inverse agonists, and fluoxetine.

[0137] High vs. low responders. A multiway ANOVA on lever pressing revealed a significant group x treatment interaction [F(3,90)=13.824, p<0.001; ηp 2= 0.323] and a significant interaction for linear trend (p<0.001). Due to this significant interaction, lever pressing for high and low responders was analyzed separately. Significant treatment effects were found for both groups (high: p<0.001, low: p=0.01). Lever pressing for high responders showed a significant linear trend (p<0.001). Planned comparisons revealed significant decreases in lever pressing for both the 10.0 mg / kg [F(1,42)=26.735, p<0.001] and 20.0 mg / kg [F(1,42)=55.797, p<0.001] doses when compared to VEH. No significant differences were found when comparing the 5.0 mg / kg dose to the VEH condition [F(1,42)=3.372, p=ns] (Figure 14). Planned comparisons showed no significant differences for any drug condition compared to VEH (5.0 mg / kg: [F(1,45)=0.319, p=ns], 10.0 mg / kg: [F(1,45)=0.079, p=ns], 20.0 mg / kg: [F(1,45)=3.157, p=ns]). However, as shown in Figure 14, there was a significant quadratic trend (p=0.01) in the low-responder group. Multi-way ANOVA was also used to assess concurrent food intake. There was a significant group x treatment interaction [F(3,90)=3.191, p<0.05; ηp 2= 0.099] as well as a linear trend interaction (p<0.05). This significant interaction allowed for separate analysis of high and low responders. A significant treatment effect (p<0.001) and a significant linear trend (p<0.001) were found for both high and low responders. In the high responder group, there was a significant decrease in food intake in the 5.0 mg / kg [F(1,42)=13.450, p<0.010], 10.0 mg / kg [F(1,42)=70.714, p<0.001], and 20.0 mg / kg [F(1,42)=100.204, p<0.001] groups when compared to VEH through planned comparisons. Low responders also showed a significant decrease in lever pressing at all dose treatments (5.0 mg / kg [F(1,45)=16.976, p<0.001], 10.0 mg / kg [F(1,45)=156.918, p<0.001], 20.0 mg / kg [F(1,45)=226.122, p<0.001]) as judged by Dunnett's test (Figure 15).

[0138] Example 6. Evaluation of the appetite suppressant effect of compound 1 using a fixed ratio schedule in rats Another study was conducted to evaluate the appetite suppressant effects of Compound 1. A fixed ratio 1 (FR1) schedule was used, which is the most food-dense and appetite-dependent operant schedule and is highly sensitive to appetite-related manipulations such as prefeeding and appetite suppressants.

[0139] Methods. This study used the same adult male Sprague-Dawley rats (n=31) as in Example 5. Animals were trained once a day on the PROG / food choice regimen from Monday to Thursday. On Friday, the test day, animals were switched from the PROG / food choice regimen to FR1 without prior training. Each operant session lasted 30 minutes, and lever pressing was recorded at the end of the run. Drug treatment and FR1 studies were conducted on Fridays after a 2-week washout period from Example 5. Compound 1 or vehicle was orally administered at a dose of 20.0 mg / kg on the test day. In Example 5, the highest dose produced the greatest reduction in lever pressing and food intake compared to VEH, so only the highest dose was tested in this study. Treatment conditions were randomly assigned. Treatment group differences were assessed by unpaired t-tests. A p-value of <0.05 was considered statistically significant.

[0140] Results. Compound 1 caused a significant decrease in lever pressing in the FR1 research study as measured by an unpaired t-test (t=9.74; p<0.001). As shown in Figure 5, the 20.0 mg / kg dose shows a significant decrease compared to vehicle (VEH). Importantly, 6 of 16 rats administered the high drug dose pressed the lever but did not eat any of the pellets. After completion of the 30-minute operant session, approximately 5-10 untouched pellets remained in the food dishes of these animals, which is a further indication of appetite suppression. Thus, taken together with the results in the study in Example 5, this study highlights that Compound 1 demonstrates an appetite suppressant effect.

[0141] Example 7. Evaluation of the appetite suppressant effect of compound 1 using chocolate binge-like ingestion In another study evaluating Compound 1 for its appetite suppressant effects, a chocolate binge-like feeding experiment was conducted.

[0142] Methods: A new group of male Sprague-Dawley rats (n = 8, initial body weight 300-325 g) was used for the binge-like feeding experiment. They were pair-housed under the same conditions as described above, but were not food-restricted and had free access to food (laboratory chow) and water in their home cages. Acquisition of binge-like feeding behavior was performed over 12 exposure sessions. Prior to chocolate exposure, rats were exposed to an empty feeding cage containing a ceramic dish for 1 h for 3 days. For chocolate exposure, rats were given chocolate (0.3 g fat, 0.57 g carbohydrate, 0.073 g protein, total 5.34 kcal / g) on ​​days 1, 2, 4, 6, 7, 9, 12, 14, 15, 18, 23, and 28. On the exposure day, rats were placed in an empty feeding cage containing a ceramic dish containing crushed chocolate for 1 h. Chocolate was weighed before and after each session to determine intake. These acquisition procedures resulted in a gradual increase in chocolate intake over the sessions, from 0.9±0.3 g of chocolate in the first session to 5.5±0.5 g by the 12th session (see FIG. 13).

[0143] Drug Administration. After completion of 12 acquisition sessions of binge-like eating behavior, rats continued their exposure to two 1-h chocolate sessions per week in an empty feeding cage containing a ceramic dish containing chocolate. The first session was for maintenance of binge-like behavior, then the second session for drug treatment. These sessions were randomized throughout the week, with the maintenance session always occurring before the drug treatment session. Compound 1 was dissolved in 0.3% Tween 80 in dH2O. For testing, vehicle (VEH) or 5.0, 10.0, and 20.0 mg / kg doses were administered orally once per week. The lead time used prior to treatment was 4 hours. This study used a within-subject design, with each rat receiving treatment once per week for a total of 4 weeks. Treatment conditions were selected randomly.

[0144] Data Analysis. Repeated measures ANOVA and planned comparisons were used to assess the effect of Compound 1 on binge-like eating of chocolate.

[0145] Results. The results of the binge-like feeding experiment are shown in Figures 8, 9, and 13. Figure 13 shows the acquisition of binge-like chocolate intake over 12 training sessions. Figure 8 shows the inhibitory effect of administration of Compound 1 on binge-like eating. There was an overall significant effect of Compound 1 treatment [F(3,21) = 17.3, p<0.001]. Planned comparisons revealed that the 5.0 mg / kg dose of Compound 1 did not significantly inhibit chocolate intake [F(1,21) = 1.5, ns], but there was a significant reduction in chocolate intake at the 10.0 mg / kg dose [F(1,21) = 20.4, p <0.001] and 20.0 mg / kg doses [F(1,21) = 4.09, p<0.001].

[0146] Example 8. Evaluation of Compound 1 on sleep using repeated measures in rats Using a counterbalanced repeated measures design, three doses of compound 1 (1-10 mg / kg, orally) were tested for their effects on sleep / wake parameters in adult male Sprague-Dawley rats (n=8). Results were compared to the effects of caffeine (10 mg / kg).

[0147] Methods: Eight (n=8) adult male Sprague-Dawley rats were used in this study. Each rat received three doses (1, 3, 10 mg / kg) of compound 1, vehicle (purified HO - negative control) and caffeine (10 mg / kg - positive control). Doses were administered orally in the middle of the rat's normal inactivity period with a minimum of 3 days between doses. Sleep parameters (non-REM sleep, NR; REM sleep, REM) were recorded and the first 6 hours of recordings after dosing were analyzed. Results were compared to vehicle, as shown in Figure 6 and Figure 7.

[0148] Results: Compound 1 had a wake-promoting effect and completely suppressed REM sleep in rats at an oral dose of 10 mg / kg. An oral dose of 3 mg / kg also significantly increased wakefulness and decreased REM sleep, but to a lesser extent.

[0149] Example 9. Evaluation of Compound 1 in the 5-choice serial reaction time task (5-CSRTT) in rats The 5-choice serial reaction time task (5-CSRTT) is widely used to measure attention and response control (motor impulsivity) in rodents. A strength of this test is its adaptability to task modifications. Varying the duration of the stimulus and the frequency of stimulus presentation, among others, have been commonly used to assess performance in the context of attention and response control. The primary objective of these studies was to investigate the effects of compound 1 on attention and aspects of response control defined as premature responses (PREM), a measure of impulsive behavior, and perseverative responses (PSV), a measure of compulsive behavior. Two experimental manipulations were performed to differentially assess performance. Specifically, (1) compound 1 (1, 3, 10 mg / kg) was tested under standard test conditions of 0.75 s SD, 5 s ITI, and 100 trials, and (2) compound 1 (1, 3 mg / kg) was tested against a long-ITI challenge. The chronic ITI challenge was designed to enhance PREM and PSV responses, thus providing a means to examine the effects of both test substances on measures of impulsive and compulsive behavior.

[0150] material Vehicle Control Formulation: 0.3% Tween 80 in 0.9% saline Pretreatment time: 180 minutes

[0151] compound 1 Dosage Form: Compound 1 was suspended in 0.3% Tween 80 in 0.9% saline and sonicated. The drug was administered via oral (PO) route at a volume of 5 mL / kg. Pretreatment time: 180 minutes Doses tested: Phase 1: 1, 3, 10 mg / kg; Phase 2: 1, 3 mg / kg

[0152] subject: 24 male Long-Evans rats

[0153] Housing and testing system management: After a one-week period for acclimation to the testing facility, animals were placed on a restricted diet and were provided with approximately 20 g of standard laboratory chow (corresponding to approximately 80% of normal food intake) once per day following completion of study procedures (between 16:00 and 18:00). Overall food intake was therefore based on food acquired during five-choice training / testing and chow at the end of each study day. On days when training / testing was not performed, the daily allotment of laboratory chow was increased to approximately 24 g per animal. Water was available ad libitum, except during the five-choice training / testing sessions. Animals were maintained on a 12-h / 12-h light / dark cycle and all testing was performed during the animals' light cycle.

[0154] 5-choice serial reaction time task: The five-choice operant chambers were placed in a sound-attenuated and ventilated enclosure. The chambers consisted of an aluminium enclosure (25 x 30 cm) with one wall containing a reward box attached to a food pellet dispenser and a house light, and the opposite wall containing an array of five square niches (2.5 x 2.5 x 2.5 cm) mounted on a curved panel and elevated 2.5 cm above the grid floor. An LED was located at the rear of each niche. Each niche and reward box also contained a photocell to detect head ingress. The test chambers were controlled by Med PC software.

[0155] The 5-CSRTT schedule was initiated by illumination of the house light and delivery of a food pellet. A nose poke into the tray of the box initiated the first trial, which consisted of an intertrial interval (ITI, 5 s) followed by the illumination of one of the five lights randomly at a fixed interval (stimulus duration, SD). If a nose poke was recorded within the illuminated niche before either the end of the SD or a fixed interval after this period (limited retention, LH), an additional pellet was released and recorded as a correct trial. An incorrect nose poke (incorrect trial) or failure to respond within the allotted time (missed trial) led to a time-out (TO) period, in which the house light was turned off for 5 s. Responding in one of the five niches during the ITI (PREM response) led to a further TO. PSV responses were not punished with a TO.

[0156] Each session lasted for either 100 trials or 60 min, depending on which session endpoint was reached first. Animals were trained through a series of steps to the final test condition: 0.75 s SD, 5 s ITI, 5 s limited retention. The goal performance was stable performance near a threshold of 80% correct responses ([correct responses / (correct responses+incorrect responses)]*100) and <20% omissions over a period of at least 2 weeks. At this point, drug testing began according to a repeated measures design, with animals being treated with repeated test sessions. Test sessions were conducted twice weekly on a standard (5 s ITI) and extended ITI schedule, with drug washouts and subjects being allowed to revert to baseline between cycles.

[0157] Phase 1: The effects of Compound 1 (1, 3, 10 mg / kg) or vehicle control on test performance under standard test conditions (0.75 s SD, 5 s ITI, 5 s LH, 100 trials in total) were investigated. Treatments were administered in random order.

[0158] Phase 2: The effects of Compound 1 (1 and 3 mg / kg) or vehicle control on a 5-choice schedule (10 s ITI, 0.3 s SD, 5 s LH, 100 trials) with an ITI of 10 s were investigated. Treatments were administered in random order.

[0159] Statistical analysis: The main measures of performance from the 5-CSRTT, namely accuracy measured as either % correct ([correct responses / correct responses + incorrect responses]*100) or % hit rate ([correct responses / correct responses + incorrect responses + omissions]*100), response speed (latency to correct response), incomplete trials (omissions), and total number of trials, are expressed as means and SEM.

[0160] result Phase 1: Effects of Compound 1 on 5-choice task performance: Standard conditionsCompound 1 was tested at doses of 1, 3, and 10 mg / kg in all rats following a repeated measures design. The vehicle pretreatment group served as the control group. Main effects of treatment were seen for total trials (F3,69=4.4; P<0.01), PREM responses (F3,69=5.1; P<0.01), and PSV responses (F3,69=4.6; P<0.01). These main effects reflect a dose-dependent decrease in PREM and PSV responses after Compound 1 pretreatment compared to vehicle controls. In addition, the 10 mg / kg dose reduced the number of trials. There was no main effect of treatment on any other task measures, including accuracy. 5-CSRTT results obtained under standard test conditions (stimulus duration of 0.75 s, ITI of 5 s, number of trials of 100) are shown in Figure 10A and Figure 10B.

[0161] Phase 2: Effects of Compound 1 on 5-choice task performance: 10-second ITI:Compound 1 was tested at each dose of 1 and 3 mg / kg in all rats according to a repeated measures design under a 10-s ITI schedule. The vehicle pretreatment group served as the control group. Increasing the ITI from 5 to 10 s and the duration of the visual stimulus from 0.75 to 0.3 s decreased accuracy (% correct, 5 s ITI: 83.9 ± 1.5%; 10 s ITI: 68.5 ± 2.4%; P < 0.01) and increased PREM (5 s ITI: 6.0 ± 1.2; 10 s ITI: 46.7 ± 10.2; P < 0.01) and PSV (5 s ITI: 20.9 ± 3.4; 10 s ITI: 33.8 ± 7.4; P < 0.05) responses. The effect of Compound 1 on task performance under a 10-s ITI schedule was evaluated in comparison with vehicle pretreatment under the same conditions. There was no main effect of treatment on any of the measures (F2,40 ≤ 2.5; NS), i.e., treatment had no effect on accuracy (% correct, % hits) or on PREM / PSV responses when all N = 21 rats were included in the analysis. Rats were then divided into low-impulse (LI) and high-impulse (HI) subgroups based on their level of PREM responding after vehicle pretreatment under a 10-s ITI schedule (i.e., PREM: LI: 16.7 ± 2.4, HI: 93.9 ± 21.6, P < 0.01). This subgrouping resulted in a main effect of subgroup emerging for PREM (F1,12 = 8.0; P = 0.02) and PSV responses (F1,12 = 8.3; P = 0.01), reflecting that HI rats had significantly higher PREM and PSV responses compared to LI rats. Regarding the effect of Compound 1 on task performance in these subgroups, a main effect of treatment and a subgroup x treatment interaction were found for both PREM (treatment: F2,24 = 6.7; P < 0.01; subgroup x treatment: F2,24 = 10.2; P < 0.01) and PSV responses (treatment: F2,24 = 4.2; P = 0.02; subgroup x treatment: F2,24 = 7.7; P < 0.01).

[0162] Example 10. A Randomized, Double-Blind, Placebo-Controlled, Crossover, Multicenter Study of Compound 1 in Adults With Atypical Depression A randomized, double-blind, placebo-controlled, crossover study to test the efficacy and safety of Compound 1 with a diagnosis of DSM-5 atypical depression. The trial will consist of a screening period, a treatment period, and a follow-up period, as detailed below. Participants may record symptoms related to atypical depression using an eDiary and may wear an actigraphy watch daily during the treatment and washout periods.

[0163] Objectives and Endpoints TIFF2025508878000019.tif234160TIFF2025508878000020.tif174160

[0164] Equivalents and Scope In the claims, articles such as "a," "an," and "the" may mean singular or plural, unless indicated otherwise or otherwise clear from the context. A claim or specification containing "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the members of the group are present in, used in, or otherwise relevant to a given product or process, unless indicated otherwise or otherwise clear from the context. The invention includes embodiments in which only one member of a group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all members of a group are present in, used in, or otherwise relevant to a given product or process.

[0165] Moreover, the invention includes all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same original claim. Where elements are presented as lists, e.g., in the form of a Markush group, each subgroup of elements is also disclosed, and any element may be deleted from the group. In general, where an invention or aspect of an invention is referred to as comprising certain elements and / or features, it should be understood that certain embodiments of the invention or aspect of an invention consist of or consist essentially of such elements and / or features. For the sake of brevity, those embodiments have not been specifically recited herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, the endpoints are included. Moreover, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges may contemplate in various aspects of the invention any specific value or subrange within the stated range to one tenth of the unit of the lower limit of the range, unless clearly contradicted by the context.

[0166] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, this specification shall control. Furthermore, any particular aspect of the invention encompassed by the prior art may be expressly excluded from any one or more claims. Such aspects may be excluded even if the exclusion is not expressly set forth herein, since such aspects are deemed to be known to those skilled in the art. Any particular aspect of the invention may be excluded from any claim for any reason, whether related to the existence of prior art or not.

[0167] Those skilled in the art will recognize, or be able to ascertain with no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above specification, but rather as set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications may be made to the description without departing from the spirit or scope of the invention as defined in the appended claims.

Claims

1. The group consisting of: (a) (i) mood reactivity, (ii) increased sleep; (iii) hypersomnia, (iv) leaden paralysis, (v) prolonged interpersonal hypersensitivity resulting in significant social or occupational impairment; (b) (i) overeating that is not associated with the regular use of inappropriate compensatory behaviors; (ii) Binge eating that does not occur exclusively in the course of anorexia nervosa or bulimia nervosa; (c) (i) recurrent inappropriate compensatory behaviors, such as self-induced vomiting; abuse of laxatives, diuretics, or other drugs to prevent weight gain; (ii) overeating and inappropriate compensatory behaviors; (iii) self-evaluation is unduly influenced by body shape and weight; (iv) anxiety that does not occur exclusively during episodes of anorexia nervosa; (v) recurrent compensatory behavior of the purging type, and (vi) non-purging recurrent compensatory behaviors; (d) (i) recurrent episodes of binge eating, (ii) Eating an amount of food within a particular period of time that is significantly greater than most people would eat within a similar period under similar circumstances; (iii) a feeling of being unable to control overeating during the episode; (iv) Feelings that one cannot stop eating or have no control over what or how much one eats, (v) Eating much faster than usual, (vi) Eating until you feel uncomfortably full; (vii) Eating large amounts of food when you are not physically hungry, (viii) eating alone because one feels embarrassed about how much one is eating; (ix) Feeling disgust, depression, or strong guilt about yourself after overeating; (x) significant distress about overeating, (e) (i) increased appetite, (ii) bulimia, (iii) a significant lack of impulse control followed by feelings of guilt; (f) (i) Restriction of energy intake relative to requirements, leading to severe underweight; (ii) An intense fear of gaining weight or becoming fat despite being underweight; and (iii) Concerns about how they feel about their weight or body shape 1. A method for treating a subject exhibiting at least one or more behaviors selected from the group consisting of: Compound 1 sufficient to improve at least one of the behaviors: or a pharma- ceutically acceptable salt thereof.

2. The method of claim 1 , wherein the composition is a pharmaceutical composition.

3. The method of claim 1, wherein the composition is in a sustained release form.

4. The method of claim 1 , wherein the composition is a unit dose.

5. 5. The method of any one of claims 1 to 4, wherein the composition comprises about 1 mg / kg to about 70 mg / kg of Compound 1 or a pharma- ceutically acceptable salt thereof.

6. The method of any one of claims 1 to 5, wherein the composition is administered orally.

7. The method of any one of claims 1 to 6, wherein the composition is administered once daily.

8. The object is Mood reactivity and At least two behaviors selected from the group consisting of increased appetite, binge eating, increased sleepiness, hypersomnia, leaden palsy, and prolonged interpersonal hypersensitivity resulting in significant social or occupational impairment; The method of any one of claims 1 to 7, wherein the

9. 9. The method of claim 8, wherein the subject does not meet criteria for melancholic depression or catatonia.

10. The object is recurrent episodes of binge eating, eating in a particular period of time significantly more food than most people would eat in a similar period under similar circumstances, a sense of not being able to control eating during the episode, eating much faster than usual, feelings that one cannot stop eating or that one cannot control what or how much one eats, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, and binge eating that does not occur exclusively in the course of anorexia nervosa or bulimia nervosa; Three or more behaviors selected from the group consisting of eating much faster than usual, eating until you feel uncomfortably full, eating large amounts of food when you are not physically hungry, eating alone because you feel embarrassed by how much you are eating, and feeling disgusted with yourself, depressed, or very guilty after overeating. The method of any one of claims 1 to 9, wherein the

11. The object is Recurrent episodes of binge eating, eating significantly more food in a given period of time than most people would eat in a similar period under similar circumstances, feelings of being unable to stop eating or to control what or how much one eats, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation that is inappropriately affected by body shape and weight, and anxiety that does not occur exclusively during episodes of anorexia nervosa The method of claim 1, wherein the

12. 12. The method of claim 11, wherein said specified period of time is a two hour period and said binge eating and inappropriate compensatory behaviors occur at least twice a week for three months.

13. The object is recurrent episodes of binge eating, eating significantly more food in a particular period of time than most people would eat in a similar period under similar circumstances, feeling of not being able to control eating during the episode, feelings of being unable to stop eating or of being unable to control what or how much you eat, eating much faster than usual, eating until you feel uncomfortably full, eating large amounts of food when you are not physically hungry, eating alone because you feel embarrassed by how much you have eaten, feeling disgusted with yourself, depressed or very guilty after overeating, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, self-evaluation inappropriately affected by body shape and weight, anxiety that does not occur exclusively during episodes of anorexia nervosa, recurrent compensatory behaviors of the purging type, and recurrent compensatory behaviors of the non-purging type.

9. The method of claim 8, further exhibiting one or more behaviors selected from the group consisting of:

14. The method of any one of claims 1 to 13, wherein the subject has been diagnosed with atypical depression.

15. The method of any one of claims 1 to 14, wherein the subject has been diagnosed with one or more behaviors selected from the group consisting of mood reactivity, increased appetite, hyperphagia, increased sleep, hypersomnia, leaden paralysis, and long-term interpersonal hypersensitivity resulting in significant social or occupational impairment.

16. The method of any one of claims 1 to 15, wherein the subject has been diagnosed with a binge eating disorder.

17. The object is recurrent episodes of binge eating, eating significantly more food in a particular period of time than most people would eat in a similar period under similar circumstances, a sense of not being able to control eating during the episode, eating much faster than usual, feelings of being unable to stop eating or to control what or how much you eat, marked distress about the binge eating, binge eating that is not associated with the regular use of inappropriate compensatory behaviors, binge eating that does not occur exclusively in the course of anorexia nervosa or bulimia nervosa, eating much faster than usual, eating to the point of feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, and feeling disgusted with oneself, depressed or very guilty after overeating The method of any one of claims 1 to 16, wherein the subject has been diagnosed with one or more behaviors selected from the group consisting of:

18. The method of any one of claims 1 to 17, wherein the subject has been diagnosed with bulimia nervosa.

19. The object is eating quickly, recurrent episodes of binge eating, inability to control eating, eating much faster than usual, eating until feeling uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, feeling disgusted with oneself, depressed or very guilty after overeating, noticeable distress about the binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation affected by body shape and weight, recurrent purging compensatory behaviors, and recurrent non-purging compensatory behaviors. The method of any one of claims 1 to 18, wherein the subject has been diagnosed with one or more behaviors selected from the group consisting of:

20. The method of any one of claims 1 to 19, wherein the subject has been diagnosed with anorexia nervosa.

21. The object is Restriction of energy intake relative to needs leading to significant underweight in the context of age, sex, developmental progress, and physical health; intense fear of gaining weight or becoming fat despite being underweight; and anxiety about how one feels about one's weight or shape, undue impact of weight or shape on self-evaluation, or denial of the seriousness of current underweight The method of any one of claims 1 to 20, wherein the subject has been diagnosed with one or more behaviors selected from the group consisting of:

22. The method of claim 1, wherein the subject has been diagnosed with depression.

23. The method of any one of claims 1 to 22, wherein the subject has undergone treatment for depression.

24. 13. The method of claim 1, comprising treating a subject who has been diagnosed with depression and who also exhibits one or more atypical depressive symptoms.

25. 25. The method of claim 24, wherein the atypical depressive symptoms are selected from the group consisting of mood reactivity, increased appetite, hyperphagia, increased sleep, hypersomnia, leaden dizziness, and prolonged interpersonal sensitivity resulting in significant social or occupational impairment.

26. 26. The method of any one of claims 1 to 25, wherein said manifestation of the behavior occurs at least once per day.

27. 26. The method of any one of claims 1 to 25, wherein the manifestation of the behavior persists for at least one week.

28. 26. The method of any one of claims 1 to 25, wherein the manifestation of the behavior persists for at least two weeks.

29. 26. The method of any one of claims 1 to 25, wherein the manifestation of the behavior persists for at least one month.

30. 26. The method of any one of claims 1 to 25, wherein the manifestation of the behavior persists for at least 3 months.

31. The method of any one of claims 1 to 25, wherein the manifestations of the behavior occur periodically.

32. Compound 1:

46. ​​A method of treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising:

33. 33. The method of claim 32, wherein the impulsive behavior is characterized by a significant lack of impulse control followed by feelings of guilt.

34. Compound 1: or a pharmaceutically acceptable salt thereof, comprising the steps of: administering to a subject who has been diagnosed with atypical depression a pharmaceutical composition comprising: The subject is hypersomnia, binge eating, mood reactivity, leaden numbness, depressed mood, interpersonal sensitivity, fast eating, recurrent episodes of binge eating, inability to control eating, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, feeling disgusted with oneself, depressed or very guilty after overeating, marked distress about overeating, overeating not associated with compensation, recurrent compensatory behaviors, overeating with compensation, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above minimally normal weight, intense fear of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and continuing lack of awareness of the seriousness of being underweight. exhibiting one or more behaviors selected from the group consisting of: method.

35. hypersomnia, binge eating, mood reactivity, leaden numbness, depressed mood, interpersonal sensitivity, fast eating, recurrent episodes of binge eating, inability to control eating, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not physically hungry, eating alone because one feels embarrassed by how much one has eaten, feeling disgusted with oneself, depressed or very guilty after overeating, marked distress about overeating, overeating not associated with compensation, recurrent compensatory behaviors, overeating with compensation, self-esteem affected by body shape and weight, recurrent compensatory behaviors of the purging type, recurrent compensatory behaviors of the non-purging type, refusal to maintain weight above minimally normal weight, intense fear of gaining weight or becoming obese, anxiety about one's weight or body shape, self-esteem affected by weight or body shape, and continuing lack of awareness of the seriousness of being underweight.

1. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of: Compound 1 sufficient to reduce at least one of the behaviors: or a pharma- ceutically acceptable salt thereof. A method comprising:

36. Compound 1:

46. ​​A method of treating Prader-Willi syndrome in a subject in need thereof, comprising the step of administering a composition comprising:

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