Triple uptake inhibitors for treatment of atypical depression

Abstract

Provided herein are methods 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). # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to USSN 63 / 314,753, filed on February 28, 2022, and USSN 63 / 484,905, filed on February 14, 2023, the contents of each of which are incorporated herein by reference. Background Art

[0003] Atypical depression is a subtype of depression characterized by emotional reactivity and atypical symptoms, including weight gain or excessive eating, excessive sleeping, leaden paralysis, and interpersonal rejection sensitivity that leads to significant social or occupational impairment. Atypical depression is the most common form of depression seen in psychiatric outpatient clinics. Current literature supports atypical depression as a subtype of depression with a high prevalence, early onset in life, and a tendency to persist for a longer period of time. Patients with atypical depression with a chronic course, a long-standing rejection sensitivity pattern, and ever-present fatigue may easily end up with a preliminary diagnosis of a personality disorder or simple neurosis. This may have far-reaching negative consequences if this leads to the refusal to accept trials of highly effective antidepressants.

[0004] Approximately 30% of patients with unipolar depression meet criteria for atypical depression. However, atypical depression has been poorly studied, and patients who meet criteria for this subtype are often excluded from major depressive disorder trials. Currently, despite numerous drug trials, there are no comprehensive treatment guidelines for atypical depression. In placebo-controlled trials, patients with atypical depression have been shown to respond preferentially to phenelzine sulfate compared with imipramine hydrochloride, prompting the recommendation of monoamine oxidase inhibitors (MAOIs) as standard of care. Unfortunately, MAOIs have dietary restrictions, contraindications, and well-known side effects.

[0005] Therefore, there is an unmet medical need for new approaches to treating individuals with atypical depression. Summary of the invention

[0006] Provided herein, in part, are methods of treating a subject who exhibits at least one or more behaviors selected from the group consisting of: (a) (i) emotional reactivity, (ii) increased sleep, (iii) excessive sleep, (iv) leaden paralysis, (v) a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment, (b) (i) binge eating that is not associated with frequent 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 medications to prevent weight gain, (ii) binge eating and inappropriate compensatory behaviors, (iii) inappropriate influence of body shape and weight on self-evaluation, (iv) disturbances that do not occur exclusively during an episode 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 significantly more in discrete time periods than most people would eat in similar circumstances The method comprises administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to improve at least one of the behaviors, wherein the composition comprises:

[0007]

[0008] Also provided herein is a method of treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

[0009]

[0010] In another aspect, also provided herein is a method of treating a subject diagnosed with atypical depression, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is: The subject exhibits one or more behaviors selected from the group consisting of: excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, sensitivity to interpersonal rejection, rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, depression or intense guilt, marked distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating associated with compensatory behaviors, self-evaluation influenced by body shape and weight, vomiting-type recurrent compensatory behaviors, non-vomiting-type recurrent compensatory behaviors, refusal to maintain weight at or above minimum normal weight, intense fear of weight gain or becoming fat, distress about one's weight or body shape, self-worth influenced by weight or body shape, and persistent lack of awareness of the seriousness of low body weight.

[0011] In another aspect, the present invention also provides a method of treating a subject who exhibits at least one or more behaviors selected from the group consisting of: excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, interpersonal rejection sensitivity, rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortable full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, depression or excessive guilt, marked distress about binge eating, inconsistent compensatory behaviors, and / or inability to control eating. binge eating, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation influenced by body shape and weight, recurrent compensatory behaviors of the vomiting type, recurrent compensatory behaviors of the non-vomiting type, refusal to maintain weight at or above the minimum normal weight, intense fear of weight gain or becoming fat, distress due to one's own weight or body shape, self-worth influenced by weight or body shape, and persistent lack of awareness of the severity of low body weight; the method comprising administering a unit dose comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to alleviate at least the behavior, wherein Compound 1 is:

[0012]

[0013] Also provided herein are methods of treating Prader-Willi syndrome in a subject in need thereof, comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

[0014] BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1Depicted is an exemplary X-ray powder diffraction pattern of the hydrochloride salt quarter hydrate of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone.

[0016] Figure 2 Depicted is an exemplary X-ray powder diffraction pattern of the hydrochloride salt of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone.

[0017] Figure 3 Depicted are mean values ​​(± SEM) of food intake (in grams) during a 30 min period in adult male Sprague-Dawley rats (n=31), where **p<0.001: significant between-group effect of treatment on food consumption between Compound 1 and vehicle (VEH).

[0018] Figure 4 Depicted are the mean (± SEM) of total lever presses during a 30 min period in adult male Sprague-Dawley rats (n=31), where **p<0.001: significant difference in lever presses between Compound 1 treatment and vehicle (VEH).

[0019] Figure 5 Depicted are the mean (±SEM) of total lever presses during a 30 min operant session in adult male Sprague-Dawley rats (n=31), where **p<0.001: significant difference in lever presses between Compound 1 treatment (n=16) and vehicle (VEH) (n=15).

[0020] Figure 6 Depicted are the means (±SEM) of the first 6 consecutive recording epochs for latency to non-REM sleep (NR).

[0021] Figure 7 Depicted are the mean values ​​(± SEM) of the first 3 consecutive recording frames of latency to rapid eye movement sleep (REM).

[0022] Figure 8 and Fig. 9 The effect of Compound 1 on chocolate intake is depicted. Figure 8 and Fig. 9 This indicates that compound 1 is effective in controlling binge eating in animal models.

[0023] Fig. 10A and Fig. 10B A five-choice serial-reaction time task (5CSRTT) test in rats is depicted to study impulsive behavior in rats. Fig. 10A and 10B It was shown that compound 1 reduced the impulsive behavior of rats and compound 1 dose-dependently reduced premature and perseverative responses without negatively affecting the accuracy or speed of responses.

[0024] Fig.11 Depicted is the SRTM model of Compound 1 plasma concentration versus SERT occupancy in the raphe nucleus as a result of PET studies in HV. Fig.11 This indicates that at 30 mg to 60 mg of Compound 1 there was 70% to 90% SERT occupancy.

[0025] Fig.12 The 2TCM model of Compound 1 plasma concentration versus DAT occupancy in the striatum is depicted. Fig.12 This indicates that at 30 mg to 60 mg of Compound 1 there was 25% to 40% DAT occupancy.

[0026] Fig.13 Depicted are the mean (± SEM) intake of chocolate over 12 1-hour training sessions during the chocolate intake experiment described in Example 7.

[0027] Fig.14 and Fig.15 Depicted are the effects of Compound 1 on lever pressing and food consumption in high (n=15) and low (n=16) responding groups in the PROG / food-feeding choice task. Fig.14 Depicted are the mean (± SEM) number of total lever presses during the 30 minute period, where **p<0.001: significant differences in lever presses between Compound 1 dose treatments and VEH. Fig.15 Means (±SE M) of food intake (in grams) during a 30-min period are depicted, where **p<0.001, *p<0.01: significant between-group effect of treatment on food consumption between Compound 1 and VEH. DETAILED DESCRIPTION

[0028] 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 a pharmaceutically acceptable salt thereof. In addition, the present disclosure provides a method for treating atypical depression with a crystalline form of Compound 1 or a pharmaceutically acceptable salt thereof.

[0029] Methods of use and treatment

[0030] In one aspect, provided herein are methods of treating atypical depression in a subject in need thereof. In another aspect, provided herein are methods of treating a medical condition associated with atypical depression in a subject in need thereof.

[0031] In one aspect, provided herein are methods of treating a subject who exhibits at least one or more behaviors selected from the group consisting of: (a) (i) emotional reactivity, (ii) increased sleep, (iii) excessive sleep, (iv) leaden paralysis, (v) a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment, (b) (i) binge eating that is not associated with frequent 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 medications to prevent weight gain, (ii) binge eating and inappropriate compensatory behaviors, (iii) body shape and weight that unreasonably affect self-evaluation, (iv) disturbances that do not occur exclusively during an episode of anorexia nervosa, (v) recurrent compensatory behaviors of the vomiting type, and (vi) recurrent compensatory behaviors of the non-vomiting type, (d) (i) recurrent episodes of binge eating, (ii) eating significantly more in discrete time periods than most people would eat in similar circumstances in a similar manner; The method comprises administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to improve at least one of the behaviors, wherein the composition comprises: Each of the behaviors described herein is described in the Diagnostic and Statistical Manual of Mental Disorder, such as in the Diagnostic and Statistical Manual of Mental Disorder, 5th Edition.

[0032] In some embodiments, the composition is a pharmaceutical composition.

[0033] In some embodiments, the pharmaceutical composition is a tablet.

[0034] In some embodiments, the pharmaceutical composition is in sustained release form.

[0035] In some embodiments, the pharmaceutical composition is a unit dose.

[0036] In some embodiments, the composition comprises about 1 mg to about 70 mg of compound 1 or a pharmaceutically 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.

[0037] In some embodiments, the composition comprises about 1 mg / kg to about 70 mg / kg of compound 1 or a pharmaceutically 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.

[0038] In some embodiments, the composition is administered orally.

[0039] In some embodiments, the composition is administered once daily.

[0040] In some embodiments, the subject exhibits emotional reactivity; and at least two behaviors selected from the group consisting of increased appetite, excessive eating, increased sleep, hypersomnia, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment. In embodiments, the subject does not meet criteria for melancholic depression or catatonia.

[0041] In some embodiments, the subject further exhibits one or more behaviors selected from the group consisting of: recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, feelings of lack of control over eating during an episode, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight unreasonably affecting self-evaluation, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0042] In one embodiment, the subject exhibits emotional reactivity, and the subject also exhibits one or more behaviors selected from the group consisting of: recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, feelings of lack of control over eating during an episode, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight inappropriately affecting self-evaluation, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0043] In one embodiment, the subject exhibits hyperphagia, and the subject further exhibits one or more behaviors selected from the group consisting of recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during episodes, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food without feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight unreasonably affecting self-evaluation, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0044] In one embodiment, the subject exhibits excessive sleep, and the subject also exhibits one or more behaviors selected from the group consisting of recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, feelings of lack of control over eating during an episode, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight unreasonably affecting self-evaluation, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0045] In one embodiment, the subject exhibits leaden paralysis, and the subject also exhibits one or more behaviors selected from the group consisting of recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during an episode, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food without feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight inappropriately affecting self-evaluation, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0046] In one embodiment, the subject exhibits a long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment, and the subject also exhibits one or more behaviors selected from the group consisting of recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during an episode, feeling that one cannot stop eating or control what or how much one eats, eating much faster than normal, eating until uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight unreasonably affecting self-esteem, disturbances that do not occur exclusively during an episode of anorexia nervosa, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0047] In some embodiments, the subject exhibits recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, a feeling of lack of control over eating during an episode, eating much faster than normal, feeling that one cannot stop eating or control what or how much one eats, obvious distress about binge eating, binge eating that is not associated with frequent use of inappropriate compensatory behaviors, and binge eating that does not occur only during the course of anorexia nervosa or bulimia nervosa; and three or more behaviors selected from the following: eating much faster than normal, eating until there is an uncomfortable feeling of fullness, eating a large amount of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression, or great guilt. In some embodiments, the subject exhibits distress about binge eating. In some embodiments, binge eating occurs at least once a week on average for 3 months. In some embodiments, binge eating is not associated with frequent use of inappropriate compensatory behaviors, and does not occur only during the course of anorexia nervosa or bulimia nervosa. Inappropriate compensatory behaviors include, but are not limited to, vomiting, diarrhea, fasting, and excessive exercise.

[0048] In some embodiments, the subject exhibits recurrent episodes of binge eating, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feeling unable to stop eating or control what or how much they eat, recurrent inappropriate compensatory behaviors to prevent weight gain, binge eating and inappropriate compensatory behaviors, body shape and weight that unreasonably influence self-evaluation, and disturbances that do not occur only during episodes of anorexia nervosa. In some embodiments, the discrete time periods are 2 hour periods, and the binge eating and inappropriate compensatory behaviors occur at least twice a week for 3 months.

[0049] In some embodiments, the subject is a subject diagnosed with atypical depression.

[0050] In some embodiments, the subject is a subject diagnosed with one or more behaviors selected from the group consisting of emotional reactivity, increased appetite, excessive eating, increased sleep, hypersomnia, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection resulting in significant social or occupational impairment.

[0051] In some embodiments, the subject is a subject diagnosed with a binge eating disorder. In some embodiments, the subject is a subject diagnosed with one or more behaviors selected from the following: recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, a sense of lack of control over eating during an episode, eating much faster than normal, feeling that one cannot stop eating or control what or how much one eats, significant distress about binge eating, binge eating that is not associated with frequent use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, eating much faster than normal, eating until one feels uncomfortable full, eating large amounts of food when one does not feel physically hungry, eating alone because of embarrassment about how much one eats, and feeling disgusted with oneself, depressed, or very guilty after overeating.

[0052] In some embodiments, the subject is a subject diagnosed with bulimia nervosa. In some embodiments, the subject is a subject diagnosed with one or more behaviors selected from the following: eating rapidly, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortable full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or extreme guilt, significant distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation influenced by body type and weight, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

[0053] In some embodiments, the subject is a subject diagnosed with anorexia nervosa. In some embodiments, the subject is a subject diagnosed with one or more behaviors selected from the following: restricting energy intake relative to needs in the context of age, sex, developmental trajectory, and physical health resulting in significantly low body weight, an intense fear of weight gain or becoming fat (even if underweight), a disorder in the way one experiences one's weight or shape, an inappropriate influence of weight or shape on self-evaluation, or a denial of the severity of current low body weight.

[0054] In some embodiments, the subject is a subject diagnosed with depression.

[0055] In some embodiments, the subject is a subject being treated for depression.

[0056] In some embodiments, the method comprises treating a subject diagnosed with depression and also exhibiting one or more atypical depression symptoms. In embodiments, the atypical depression symptoms are selected from emotional reactivity, increased appetite, excessive eating, increased sleep, excessive sleep, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection that leads to significant social or occupational impairment.

[0057] In some embodiments, performance of the behavior occurs at least once a day.

[0058] In some embodiments, the performance of the behavior lasts for at least one week. In some embodiments, the performance of the behavior lasts for at least two weeks. In some embodiments, the performance of the behavior lasts for at least three weeks.

[0059] In some embodiments, the performance of the behavior lasts for at least one month. In some embodiments, the performance of the behavior lasts for at least three months.

[0060] In some embodiments, the performance of the behavior occurs periodically.

[0061] Also provided herein is a method of treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

[0062] In certain embodiments, the impulsive behavior is characterized by a marked lack of impulse control followed by feelings of guilt.

[0063] In another aspect, also provided herein is a method of treating a subject diagnosed with atypical depression, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is: The subject exhibits one or more behaviors selected from the group consisting of excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, sensitivity to interpersonal rejection, rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, depression or intense guilt, marked distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating associated with compensatory behaviors, self-evaluation influenced by body shape and weight, vomiting-type recurrent compensatory behaviors, non-vomiting-type recurrent compensatory behaviors, refusal to maintain weight at or above minimum normal weight, intense fear of weight gain or becoming fat, distress about one's weight or body shape, self-worth influenced by weight or body shape, and persistent lack of awareness of the severity of low body weight.

[0064] In another aspect, the present invention also provides a method of treating a subject who exhibits at least one or more behaviors selected from the group consisting of: excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, interpersonal rejection sensitivity, rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, depression or excessive guilt, marked distress about binge eating, inconsistent compensatory behaviors, and so on. binge eating, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation influenced by body shape and weight, recurrent compensatory behaviors of the vomiting type, recurrent compensatory behaviors of the non-vomiting type, refusal to maintain weight at or above the minimum normal weight, intense fear of weight gain or becoming fat, distress due to one's own weight or body shape, self-worth influenced by weight or body shape, and persistent lack of awareness of the severity of low body weight; the method comprising administering a unit dose comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to alleviate at least the behavior, wherein Compound 1 is:

[0065]

[0066] Also provided herein are methods of treating Prader-Willi syndrome in a subject in need thereof, comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

[0067]

[0068] In one aspect, compound 1 is a therapeutic agent, and the method includes administering a composition comprising a therapeutically effective amount of a therapeutic agent to a subject in need thereof. In an embodiment, the therapeutic efficacy of treatment is determined by assessing improvement based on a depressive symptom scale (e.g., Inventory of Depressive Symptoms-Self-Reported (IDS-SR) or a modified version thereof). In an embodiment, the therapeutic efficacy of treatment is determined by assessing improvement based on a concise international neuropsychiatric interview (MiniInternational Neuropsychiatric Interview) (MINI-S). In an embodiment, the therapeutic efficacy of treatment is determined by assessing improvement based on a clinical global impression-severity (Clinicalglobal Impression-Severity) (CGI-S). In an embodiment, the therapeutic efficacy of treatment is determined by assessing improvement based on an Epworth Sleepiness Scale (Epworth Sleepiness Scale) (ESS) and total sleep time (TST; measured by an actigraph). In an embodiment, the therapeutic efficacy of treatment is determined by assessing improvement based on a clinical global impression-improvement (ClinicalglobalImpression-Improvement) (CGI-I). In embodiments, the therapeutic efficacy of treatment is determined by assessing improvement based on patient global impression of change (PGI-C). In embodiments, the therapeutic efficacy of treatment is determined by assessing improvement based on fatigue scales (e.g., Brief Fatigue Inventory (BFI), Fatigue Severity Scale (the Fatigue Severity Scale) (FSS), Fatigue Symptom Inventory (FSI) and Fatigue-Simple Table 10a (FACIT-Fatigue-10)). In various embodiments, it is determined that the subject improves a lot. In various embodiments, it is determined that the subject improves very much. In various embodiments, the subject shows a change from baseline.

[0069] Triple reuptake inhibitor

[0070] Triple reuptake inhibitors are serotonin-norepinephrine-dopamine reuptake inhibitors, which act as combined reuptake inhibitors of the monoamine neurotransmitters serotonin, norepinephrine and dopamine. Triple reuptake inhibitors simultaneously inhibit serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT), respectively. Inhibiting the reuptake of these neurotransmitters will increase their extracellular concentrations, and therefore lead to increased serotonergic, adrenergic and dopaminergic neurotransmission throughout the brain. A measure of the affinity of the compounds of the present disclosure can be the percentage inhibition from a radioligand binding assay using cells expressing human transporters and receptors. Related 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)

[0071] Atypical depression

[0072] Atypical depression is a subtype of major depressive disorder (MDD) characterized by emotional reactivity (extreme sensitivity to emotions and feelings that are highly reactive to environmental situations - this is a must-have feature), excessive sleep, craving for carbohydrates / increased appetite, leaden paralysis (deep fatigue) and chronic rejection sensitivity. Atypical depression causes more impairment than melancholic depression because individuals often have more interpersonal difficulties. The unique behavior of patients with atypical depression includes temporary improvement in mood and heaviness in the arms and legs after positive events or happy news. Patients with atypical depression are usually excluded from MDD development programs. Individuals with atypical depression account for 26% of MDD patients and have a prevalence of about 1-4% in the general population. The criteria are highly gender-specific (women are more likely to develop AD symptoms). Atypical depression is also associated with conduct disorder, social phobia, interpersonal dependence, low self-esteem and parental substance abuse. Atypical depression is also associated with a higher incidence of early childhood trauma, while melancholic depression is not.

[0073] Unique features and neurobiology of AD include early onset and low suicidality, a greater likelihood of a chronic course with multiple comorbidities, association with low HPA axis activity but not catecholaminergic abnormalities, phenotypic similarities to hypercortisolism (Cushing's disease) and hypothyroidism, and a near-normal appearance of sleep architecture despite hypersomnia and increased sleep duration (>10 h / day).

[0074] The introduction of atypical depression as a separate diagnosis was primarily because drug trials clearly showed that such patients respond better to monoamine oxidase inhibitors (MAOIs) compared to tricyclic antidepressants (TCAs). Currently, both primary care providers and psychiatrists are involved in the MDD patient journey, however, psychiatrists are the only ones who can diagnose atypical depression.

[0075] When a major depressive episode is the most recent mood episode, the atypical features that are indicated can be applied to major depressive episode (MDD), dysthymia, nonbipolar disorder, and bipolar disorder. According to the Diagnostic and Statistical Manual of Mental Disorders V (DSM-5), the symptoms of MDD are five or more symptoms during the same 2-week period, at least one of which is: (1) depressed mood most of the day; and (2) decreased interest or pleasure in usual activities.

[0076] The following criteria are required to make a diagnosis of atypical depression according to DSM-5. In addition to meeting the criteria for major depressive disorder, the following indicative criteria may be required to make a diagnosis of atypical depression.

[0077] A. Emotional reactivity (i.e., an improvement in mood in response to actual or potential positive events)

[0078] B. 2 or more of the following:

[0079] (1) Significant weight gain or increased appetite

[0080] (2) Excessive sleep

[0081] (3) Leaden palsy (i.e., a heavy, leaden feeling in the arms or legs)

[0082] (4) a long-standing pattern of interpersonal rejection sensitivity (not limited to episodes of mood disturbance) that results in significant social or occupational impairment,

[0083] C. The criteria for "having melancholic features" or "having catatonia" are not met during the same episode.

[0084] The methods described herein treat, in part, subjects who exhibit at least one or more behaviors selected from the group consisting of: emotional reactivity, increased sleep, excessive sleep, leaden paralysis, and a long-standing pattern of interpersonal rejection sensitivity leading to severe social or occupational impairment, each of which is a term well known to those skilled in the art. Such behaviors may be referred to as atypical depressive symptoms. In an embodiment, the subject also exhibits one or more behaviors selected from the following: depressed mood - indicated by subjective report or by observation of others (in children and adolescents, this may be irritability), loss of interest or pleasure in almost all activities - indicated by subjective report or by observation of others, significant (more than 5 percent in a month) unintentional weight loss or decreased appetite (in children, failure to achieve expected weight gain), significant (more than 5 percent in a month) unintentional weight gain or increased appetite (in children, failure to achieve expected weight gain), sleep disturbance (insomnia or hypersomnia), psychomotor changes (agitation or sluggishness) severe enough to be observed by others, tiredness, fatigue or low energy or reduced efficiency in completing routine tasks, feelings of worthlessness or excessive, inappropriate or delusional guilt (not just self-blame or guilt about being ill), impaired ability to think, concentrate or make decisions - indicated by subjective report or by observation of others, recurrent thoughts about death (not just fear of death), and suicidal ideation or suicide attempt, each of which is a term well known to those skilled in the art.

[0085] Binge Eating Disorder (BED)

[0086] Binge eating disorder (BED) is an eating disorder characterized by recurrent episodes of binge eating, accompanied by feelings of lack of control and frequent negative feelings about oneself, but without intervals of compensatory behaviors such as self-induced vomiting, vomiting with laxatives, fasting, or prolonged exercise. The following criteria are required for a diagnosis of binge eating disorder according to DSM-5:

[0087] A. Recurrent binge eating episodes. A binge eating episode is characterized by both:

[0088] 1. Eating a clearly greater amount of food in a discrete period of time (e.g., in any 2-hour period) than most people would eat in a similar period of time under similar circumstances

[0089] 2. Feelings of lack of control over eating during an episode (e.g., feeling like you can't stop eating or control what or how much you eat).

[0090] B. Binge eating episodes are associated with three (or more) of the following:

[0091] 1. Eating much faster than normal

[0092] 2. Eat until you feel uncomfortably full

[0093] 3. Eating large amounts of food when you don’t feel physically hungry

[0094] 4. Eating alone because you are embarrassed about how much you eat

[0095] 5. Feeling disgusted with yourself, depressed, or extremely guilty after overeating

[0096] C. There is significant distress about binge eating

[0097] D. Binge eating occurs at least once a week on average for 3 months.

[0098] E. Binge eating is not associated with frequent use of inappropriate compensatory behaviors (e.g., vomiting, fasting, excessive exercise) and does not occur exclusively during the course of anorexia nervosa or bulimia nervosa.

[0099] Please specify, if any:

[0100] In partial remission: binge eating occurs at an average frequency of less than once a week over a sustained period of time after full criteria for binge eating disorder have previously been met.

[0101] In complete remission: After previously meeting all criteria for binge eating disorder, none of the criteria are met for a sustained period of time.

[0102] Indicate the current severity:

[0103] The diagnosis also notes the severity, from mild to extreme: Mild: 1-3 binge eating episodes per week. Moderate: 4-7 binge eating episodes per week. Severe: 8-13 binge eating episodes per week. Extreme: 14 or more binge eating episodes per week.

[0104] Bulimia Nervosa

[0105] Bulimia nervosa, also known simply as bulimia, is an eating disorder characterized by binge eating, followed by vomiting and an obsessive concern about body shape and weight. The following criteria are required to make a diagnosis of bulimia nervosa according to the DSM-5:

[0106] A. Recurrent binge eating episodes characterized by both of the following:

[0107] 1. Eating an amount of food in any 2-hour period that is clearly greater than the amount of food that most people would eat in a similar period of time under similar circumstances.

[0108] 2. Feeling like you can’t stop eating or control what or how much you eat.

[0109] B. Recurrent inappropriate compensatory behaviors to prevent weight gain, such as self-induced vomiting; abuse of laxatives, diuretics, or other medications; fasting or excessive exercise.

[0110] C. Binge eating and inappropriate compensatory behaviors occur at least once a week for 3 months.

[0111] D. Body shape and weight unreasonably affect self-evaluation.

[0112] E. The disturbance does not occur only during an episode of anorexia nervosa.

[0113] Please specify, if any:

[0114] Partial remission: Meeting some but not all criteria for a sustained period after all criteria were previously met.

[0115] Complete remission: No criteria are met during the duration period after all criteria were previously met.

[0116] Current severity (severity levels may increase to reflect additional symptoms and degree of functional impairment):

[0117] 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.

[0118] Anorexia nervosa

[0119] Anorexia nervosa is an eating disorder that causes a person to restrict their food intake. They may try to avoid eating completely, eat very small portions, and / or eliminate certain foods and eat only a select few. A common feature of anorexia is an extreme fear of being overweight (even if they are underweight). The following criteria are required to make a diagnosis of anorexia nervosa according to the DSM-5:

[0120] 1. Restriction of energy intake relative to requirements in the context of age, sex, developmental trajectory, and physical health resulting in significantly low body weight.

[0121] 2. An intense fear of gaining weight or becoming fat, even when underweight.

[0122] 3. Disturbances in the way one experiences one's weight or body shape, inappropriate influence of weight or body shape on self-evaluation, or denial of the severity of current low body weight.

[0123] Symptoms associated with anorexia may include:

[0124] Being underweight (sometimes severely)

[0125] Overeating and vomiting (through vomiting or taking laxatives)

[0126] Constipation, bloating and stomach pain

[0127] Dehydration

[0128] Distorted body image

[0129] ·Dizziness and fainting

[0130] Extreme tiredness (fatigue)

[0131] Extremely restrictive diet

[0132] Intense fear of gaining weight

[0133] Missing a period or failing to start a menstrual cycle

[0134] Loss or fluctuations in body fat and muscle

[0135] Poor circulation (often feeling cold)

[0136] Skin that is yellow, dry, or covered with soft hair (lanugo)

[0137] Taking weight loss pills or supplements

[0138] Talking about weight or food all the time

[0139] Suicidal thoughts or behaviors

[0140] Subtypes of anorexia include:

[0141] Restricted : The individual has not had recurrent episodes of binge eating or purgative behavior (i.e., self-induced vomiting or abuse of laxatives, diuretics, or enemas) during the past 3 months. This subtype describes presentations in which weight loss is achieved primarily through dieting, fasting, and / or excessive exercise.

[0142] Binge eating / vomiting and diarrhea type : The individual has had recurrent episodes of binge eating or purgative behavior (i.e., self-induced vomiting or abuse of laxatives, diuretics, or enemas) during the past 3 months.

[0143] Severity can include: mild (BMI>17 kg / m 2 ), moderate (BMI = 16-16.99 kg / m 2 ), severe (BMI = 15-15.99 kg / m 2 ) and extreme (BMI <15 kg / m 2 ).

[0144] Compound

[0145] Compound 1

[0146] Compound 1, as depicted below, is a triple reuptake inhibitor also known as (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone.

[0147]

[0148] 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 entirety.

[0149] In various embodiments, the methods described herein include administering Compound 1 or a pharmaceutically acceptable salt thereof. In various embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with a physiologically compatible inorganic acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid; or a salt of Compound 1 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.

[0150] In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt in the form of a hydrate or anhydrate (e.g., anhydrate, hemihydrate, monohydrate, or quarter hydrate). In certain embodiments, the pharmaceutically acceptable salt of Compound 1 is a hydrochloride salt in the form of a quarter hydrate.

[0151] In various embodiments, a pharmaceutically acceptable salt of Compound 1 is or a hydrate thereof.

[0152] In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof is an amorphous form. In certain embodiments, compound 1 or a pharmaceutically acceptable salt thereof is 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 quarter hydrate (Form 1). In some embodiments, the crystalline polymorph is (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (Form 2).

[0153] Form 1

[0154] In some embodiments, the compound is a crystalline quarter hydrate form of the hydrochloride salt of Compound 1 (Form 1), wherein Form 1 has Figure 1 In some embodiments, Form 1 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks, which are obtained by using Cu KαRadiation obtained at 2θ (2Theta): 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°.

[0155] Form 2

[0156] In some embodiments, the compound is a crystalline form of the hydrochloride salt of Compound 1 (Form 2), wherein Form 2 has Figure 2 In some embodiments, Form 2 is characterized by at least three peaks selected from the following X-ray powder diffraction peaks, which are obtained by using Cu Kα Radiation obtained at 2θ: 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°.

[0157] In one aspect, the present disclosure relates to a composition, such as a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for treating 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 pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, for treating a medical condition associated with atypical depression in a subject in need thereof. In various embodiments, the composition is a solid pharmaceutical composition.

[0158] In various embodiments, the amount of Compound 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be from about 1 mg to about 70 mg of Compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition comprises from about 1 mg to about 60 mg. In some embodiments, the composition comprises from about 1 mg to about 45 mg. In some embodiments, the composition comprises from about 1 mg to about 30 mg. In some embodiments, the composition comprises from about 1 mg to about 15 mg. In some embodiments, the composition comprises from 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.

[0159] In various embodiments, the amount of compound 1 or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described herein can be about 1 mg / kg to about 70 mg / kg of compound 1 or a pharmaceutically 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.

[0160] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of Compound 1 in free base form.

[0161] In various embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a pharmaceutically acceptable salt of Compound 1. In some embodiments, the pharmaceutically acceptable salt of Compound 1 can be a salt of Compound 1 with a physiologically compatible inorganic acid, such as hydrochloric acid, sulfuric acid, sulfurous acid, or phosphoric acid; or a salt of Compound 1 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.

[0162] The pharmaceutical compositions provided herein can be administered by various routes, including, but not limited to, oral (enteral) administration, parenteral (by injection), rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, and intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In certain embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0163] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or a pharmaceutical composition thereof over an extended period of time, e.g., within 3 months, within 6 months, within 1 year, within 2 years, within 3 years, within 5 years, etc., or can continue indefinitely, e.g., for the remainder of the life of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window over an extended period of time.

[0164] The pharmaceutical compositions provided herein can be present in unit dosage form to facilitate accurate administration. The term "unit dose" or "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a pre-determined amount of active substance calculated to produce a desired therapeutic effect in combination with a suitable pharmaceutical excipient. In various embodiments, the pharmaceutical dosage forms described herein can be administered in unit doses. Typical unit dosage forms include ampules or syringes of pre-filled, pre-measured liquid compositions or pills, tablets, capsules, etc. in the case of solid compositions.

[0165] The pharmaceutical composition provided herein can exist in a sustained release form.Sustained release forms are formulations designed to slowly release therapeutic agents in vivo over an extended period of time.Sustained release forms can be formulated to maintain the effect of, for example, a compound over an extended period of time.Sustained release forms can be formulated to provide an effective dose (e.g., providing physiologically effective blood characteristics) of any compound described herein within about 4 hours, about 8 hours, about 12 hours, about 16 hours, or about 24 hours.

[0166] In various embodiments, the pharmaceutical compositions provided herein are administered to a patient as a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In certain embodiments, the solid dosage form is a tablet.

[0167] In various embodiments, the pharmaceutical compositions provided herein comprise Compound 1 as the sole active agent or in combination with other active agents.

[0168] Although the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be appreciated by the skilled artisan that such compositions are generally suitable for administration to animals of all kinds. It is well known that pharmaceutical compositions suitable for administration to humans are modified so as to make the compositions suitable for administration to various animals, and ordinary skilled veterinary pharmacologists can design and / or perform such modifications using ordinary experiments. General considerations in the preparation and / or manufacture of pharmaceutical compositions can be found in, for example, Remington: The Science and Practice of Pharmacy 21st edition, Lippincott Williams & Wilkins, 2005.

[0169] definition

[0170] To facilitate understanding of the present invention, a number of terms and phrases are defined below.

[0171] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in the chemical and biological fields. Chemical structures and formulae shown herein are constructed according to standard rules of chemical valence known in the chemical art.

[0172] Throughout the description, where compositions are described as having, including or comprising specific components, or where processes and methods are described as having, including or comprising specific steps, it should be considered that, in addition, there are compositions of the invention consisting essentially of or consisting of the components, as well as there are processes and methods according to the invention consisting essentially of or consisting of the process steps.

[0173] In the present application, where an element or component is said to be included in a list of elements or components and / or selected from a list of elements or components, it should be understood that the element or component may be any one of the elements or components, or the element or component may be selected from two or more of the elements or components.

[0174] In addition, it should be understood that without departing from the spirit and scope of the present invention, the elements and / or features of the compositions or methods described herein can be combined in various ways, whether it is clear or implicit herein. For example, in the case of referring to a specific compound, the compound can be used for various embodiments of the method of the present invention, unless otherwise understood from the context. In other words, in the present application, embodiments are described and depicted in a manner that enables writing and drawing clear and concise applications, but it is expected and should be understood that, without departing from the present teachings and inventions, embodiments can be variously combined or separated. For example, it should be understood that all features described and depicted herein can be used for all aspects of the present invention described and depicted herein.

[0175] Unless the context is inappropriate, the articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" means one element or a plurality of elements.

[0176] The term "and / or" used in this disclosure means "and" or "or" unless stated otherwise.

[0177] Unless otherwise understood from the context, the expression "and / or" in connection with three or more objects described should be understood to have the same meaning.

[0178] The use of the terms "comprise," "comprises," "comprising," "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should generally be construed as open-ended and non-limiting, e.g., not excluding additional, unrecited elements or steps, unless clearly stated or understood otherwise from the context.

[0179] Where the term "about" is used before a quantitative value, unless specifically stated otherwise, the invention also includes the specific quantitative value itself. As used herein, the term "about" refers to a variation of ±10% from the nominal value, unless otherwise stated or inferred from the context.

[0180] At various locations in this specification, variables or parameters are disclosed in groups or in ranges. It is specifically intended to describe each and every individual subcombination of members including such groups and ranges. For example, integers in the range of 0 to 40 are specifically intended to 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 integers in the range of 1 to 20 are specifically intended to disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20 individually.

[0181] The use of any and all examples or exemplary language herein, such as "for example" or "including", is intended only to better illustrate the invention and will not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element is essential to the practice of the invention.

[0182] Generally, compositions specifying percentages are by weight unless otherwise indicated. Furthermore, if a variable is not accompanied by a definition, the preceding definition of the variable controls.

[0183] As used herein, a "composition" or "pharmaceutical composition" or "pharmaceutical preparation" refers to the combination of an active agent with an inert or active excipient or carrier, making the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0184] "Pharmaceutically acceptable" refers to compounds, molecular entities, compositions, materials, and / or dosage forms that do not produce adverse, allergic or other untoward reactions when administered to animals or humans as appropriate, and / or which are or may be approved by regulatory agencies of the Federal or state governments or corresponding agencies in countries outside the United States, or which are listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and, more specifically, in humans.

[0185] As used herein, "pharmaceutically acceptable salt" refers to any salt of an acidic or basic group that may be present in a compound of the invention (eg, Compound 1) that is compatible with pharmaceutical administration.

[0186] 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, p-toluenesulfonic 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, while not pharmaceutically acceptable in themselves, may be used to prepare salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0187] Examples of bases include, but are not limited to, alkali metal (eg, sodium and potassium) hydroxides, alkaline earth metal (eg, magnesium and calcium) hydroxides, ammonia, and compounds of formula NW4 + The compound wherein W is C 1-4 Alkyl, etc.

[0188] 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, palmitate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate. Thiocyanate, toluenesulfonate, undecanoate, etc. Other examples of salts include thiocyanate, toluenesulfonate, undecanoate, etc. with suitable cations such as Na + , K + , Ca 2+ NH4 + and NW4 + (W can be C 1-4 The anion of the compound of the present invention complexed with an alkyl group) or the like.

[0189] For therapeutic use, salts of the compounds of the invention are considered pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0190] As used herein, "pharmaceutically acceptable excipients" refer to substances that assist in administering active agents to subjects and / or absorption by subjects, and can be included in the compositions of the present invention without causing significant negative toxicological effects on patients. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, physiological saline solutions, such as phosphate buffered saline solutions, emulsions (e.g., oil / water or water / oil emulsions), lactated Ringer's solution, physiological sucrose, physiological glucose, adhesives, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, saline solutions (e.g., Ringer's solution), alcohols, oils, gelatin, carbohydrates, such as lactose, straight-chain starch or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and pigments, etc. Such preparations can be sterilized and, if necessary, can be mixed with adjuvants that do not react harmfully with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, colorants, and / or aromatic substances, etc. For examples of excipients, see Martin, Remington's Pharmaceutical Sciences, 15th ed., Mack Publ. Co., Easton, PA (1975).

[0191] "Subjects" contemplated for administration include, but are not limited to, humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly people)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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.

[0192] As used herein, "solid dosage form" refers to a pharmaceutical dosage form in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewable tablets.

[0193] As used herein, "administering" means 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 or implantation of a sustained-release device, such as a miniature osmotic pump, into a subject. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, ventricular / cerebroventricular and intracranial. Other delivery modes include, but are not limited to, the use of liposome preparations, intravenous infusions, transdermal patches, etc.

[0194] As used herein, the term "continue" refers to a behavior that continues in a subject, wherein the behavior continues to exist for an extended period of time or a predetermined time in the subject's body. In some embodiments, the behavior continues 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 a subject. In some embodiments, the behavior continues for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months in a subject.

[0195] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" include actions that occur when a subject has a specified disease, disorder, or condition that lessen the severity of the disease, disorder, or condition or that hinder or slow the progression of the disease, disorder, or condition (e.g., "therapeutic treatment"). As used herein, "treat," "treating," and "treatment" may include any effect, such as reduction, alleviation, modulation, improvement, or elimination, that results in an improvement in a disease, disorder, or condition, etc., including one or more symptoms of a disease, disorder, or condition, etc. Treatment may cure, ameliorate, or at least partially improve a condition.

[0196] As used herein, the phrase "therapeutically effective amount" refers to the amount of a compound (e.g., Compound 1) or a pharmaceutically acceptable salt thereof that will elicit a biological or medical response of a tissue, system, animal, or human being sought by a researcher, veterinarian, physician, or other clinician. The compounds described in the present disclosure, or pharmaceutically acceptable salts thereof, can be administered in a therapeutically effective amount to treat a disease. A therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof can be the amount required to achieve the desired therapeutic and / or preventive effect, such as an amount that causes symptom relief of conditions such as atypical depression.

[0197] As used herein, "impulsive behavior" refers to behavior characterized by a marked lack of impulse control followed by feelings of guilt. Impulsive behavior includes emotional reactivity, increased sleep, excessive sleep, leaden paralysis, a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment, binge eating that is not associated with frequent 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 (e.g., self-induced vomiting; abuse of laxatives, diuretics, or other medications to prevent weight gain), binge eating and inappropriate compensatory behaviors, body shape and weight that unreasonably affect self-evaluation, disorders that do not occur exclusively during an episode of anorexia nervosa, recurrent vomiting-type compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors. Compensatory behaviors, recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during episodes, feeling 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 does not feel physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or extreme guilt, marked distress about binge eating, increased appetite, excessive eating, and marked lack of impulse control followed by feelings of guilt. Each of the behaviors described herein is well known to those skilled in the art.

[0198] As used herein, "sufficient to improve at least one of the behaviors" means that when the behavior before administration of Compound 1 is compared to the behavior after administration of Compound 1, the behavior of the subject is improved, as measured or diagnosed in the Diagnostic and Statistical Manual of Mental Disorders. For example, compared to the food intake of the subject before administration of Compound 1, the amount of food intake of the subject in a day or in any 2-hour period is reduced. In another example, compared to the food intake of the subject before administration of Compound 1, the amount of heaviness and leaden feeling in the arms or legs of the subject in a day is reduced.

[0199] Example

[0200] In order to more fully understand the invention described herein, the following examples are set forth.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and should not be construed as limiting their scope in any way.

[0201] In the examples provided below, the following abbreviations are used: "PROG" means progressive ratio; "FR1" means fixed ration of one or fixed ratio 1; "SEM" means standard error of the mean; "VEH" means vehicle; "ANOVA" means analysis of variance; "NR" means non-rapid eye movement sleep; "REM" means rapid eye movement sleep; "po" or "per os" means oral; "CAF" means caffeine; "DAT" means dopamine transporter; "SERT" means serotonin transporter; "TRI" means triple reuptake inhibitor; "NR" means non-rapid eye movement sleep; "REM" means rapid eye movement sleep.

[0202] Example 1. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) quarter hydrate [see U.S. Pat. No. 9,527,810]

[0203]

[0204] (S)-(1-benzyl-3-propylpyrrolidin-3-yl)(3,4-dichlorophenyl)methanone (IX-1) (5 g, 13.3 mmol, eq.: 1.00, see U.S. Pat. No. 9,527,810 for synthesis) was dissolved in dichloromethane (30 mL). The pale yellow solution was cooled to 0-5 ° C, and N-ethyldiisopropylamine (172 mg, 226 μL, 1.33 mmol, eq.: 0.1) was added. While the temperature was maintained at 0-5 ° C, 1-chloroethyl chloroformate (2.28 g, 1.74 mL, 15.9 mmol, eq.: 1.2) was added dropwise. The reaction was allowed to warm to room temperature within 30 minutes and stirred at room temperature for 1 hour. Methanol (25 mL) was added and the pale yellow solution was heated to 40 ° C for 40 minutes. 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. A solution of water (239 mg, 239 μL, 13.3 mmol, Eq: 1.0) in ethyl acetate (35 mL) was added over 10 minutes. The white suspension was stirred at 50° C. for 1 hour and cooled to room temperature over 1.5 hours. 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) (93% yield) as a quarter hydrate.

[0205] Example 2. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) quarter hydrate [see U.S. Pat. No. 9,527,810]

[0206] 1. Grignard formation (A')

[0207]

[0208] 6.8 grams of magnesium (279 mmol, 1.3 equivalents) were suspended in 60 ml of tetrahydrofuran. The suspension was heated to 40 ° C, and 70.5 g of 3,4-dichlorobromobenzene (A) was added at 200 mL of tetrahydrofuran (the Grignard reaction started within a few minutes). After the exotherm stopped, the remaining aryl bromide solution was added within 2 hours. The reaction mixture was stirred at 40 ° C for 1 hour, and then the mixture was cooled to room temperature.

[0209] 2. Griya bonus

[0210]

[0211] A solution of the acid chloride (13) (for synthesis see U.S. Pat. No. 9,527,810) was degassed three times and 55.8 g of N,N,N',N',N"-pentamethyldiethylenetriamine (PMDTA) (322 mmol, 1.5 equiv) was added. The light suspension was heated to 40-45°C and the Grignard solution (A') was added dropwise over 1.5 hours. After an additional reaction time of 1 hour, the reaction mixture was cooled to room temperature. 500 mL of 2M 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 consisting of 500 mL of 2M HCl(aq), 300 mL of saturated NaCl(aq) and 300 mL of ethanol. The organic phase was washed with 400 mL of 1M NaOH(aq) and 150 mL of 10% The organic phase was concentrated under reduced pressure to an oil, dissolved in 100 mL toluene and concentrated again to give 87 g of crude product (14) with 80% purity.

[0212] 3. (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride as a quarter hydrate (15)

[0213]

[0214] The crude product (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 (aqueous solution) at 60-70 ° C. After 1 hour, 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 consisting of 700 mL of ethyl acetate and 3.6 mL of water was added at 65 ° C. The solution was cooled to room temperature within 1 hour, during which crystallization (approximately 45 ° C) began. After stirring overnight, the suspension was cooled to 0-5 ° C for 2 hours, filtered and washed twice with 200 mL of ethyl acetate. The crystals were resuspended in 250 mL of ethyl acetate, digested at 55 ° C for 2 hours, and 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 obtain 54.4 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate as powder with a purity of 99%.

[0215] (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) as an alternative route to the quarter hydrate

[0216] The crude product (14) is dissolved in 63 mL of toluene and deprotected with 24 mL of 37% HCl (aqueous solution) at 60 ° C. After the reaction is completed, the reaction mixture is azeotropically dried with toluene at 50-60 ° C. The solution is cooled to room temperature, and 100 mL of water is added. The aqueous phase is separated and washed with 50 mL of toluene. The aqueous phase is azeotropically dried with toluene and concentrated to dryness to obtain 22.5 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidine-3-yl)-methanone hydrochloride quarter hydrate (90% yield). (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidine-3-yl)-methanone hydrochloride quarter hydrate can be obtained by digestion or recrystallization, for example, by the method described below.

[0217] Conversion of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride anhydrate to quarter hydrate form:

[0218] (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride anhydrate (40 g, 124 mmol, eq.: 1.00, see Example 3 or U.S. 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 consisting of ethyl acetate (20 mL), ethanol (0.5 mL) and water (0.6 mL) was added over 1 hour. The suspension was cooled to room temperature over 1 hour. After stirring overnight at room temperature, the suspension was cooled at 0-5°C over 2-3 hours, 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 of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate (1.5% water).

[0219] Recrystallization of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate:

[0220] 54.4 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate was dissolved in 550 mL of ethanol at room temperature. The solution was filtered and concentrated to a volume of 140 mL at 60° C. under reduced pressure. The volume was adjusted to 550 mL by adding ethyl acetate. The remaining ethanol solvent was exchanged for ethyl acetate (60° C., reduced pressure), and 55 mL of ethanol was added to the resulting suspension at 60° C. 1.5 mL of water was then added, and the solution was slowly cooled to room temperature, during which crystallization occurred. After stirring overnight at room temperature, the suspension was cooled to 0-5° C. for 1 hour 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 under reduced pressure at 50° C. overnight to obtain 48.9 g of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate as a powder with a purity of 99%.

[0221] Example 3. Synthesis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (15) anhydrate [see U.S. Pat. No. 9,527,810]

[0222] 50 g of the sodium salt was converted into the corresponding acid chloride (13) (see U.S. Pat. No. 9,527,810 for synthesis). The acid chloride (13) was reacted with 3,4-dichlorophenyl-MgBr (A') and then deprotected. After azeotropic drying, an orange turbid toluene solution (300 g, water content <0.1%) was obtained by Karl Fischer titration of the crude product (15).

[0223] (i) 1 / 5 of the crude (15) solution (maximum theoretical content: 11.3 g of (15)) was cooled to room temperature. After being stored at room temperature overnight, the resulting suspension was filtered. The filter cake was washed with ethyl acetate (Karl Fischer titration of the wet filter cake 0.2%) and dried under reduced pressure at 50-60°C to obtain 5.9 g of (15) crystals.

[0224] (ii) 1 / 5 of the crude (15) solution (maximum theoretical content: 11.3 g of (15)) was cooled to room temperature. After being stored 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 the wet filter cake 0.2%) and dried under reduced pressure at 50-60°C to obtain 8.8 g of (15) crystals.

[0225] 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 quarter hydrate [see U.S. Pat. No. 9,527,810]

[0226] Characterization methods and data for the crystalline form of Compound 1 are described in U.S. Patent No. 9,527,810, which is incorporated by reference in its entirety.

[0227] X-ray powder diffraction (XRPD)

[0228] The STOE STADI P diffractometer (Cu Kα X-ray diffraction powder patterns were recorded in transmission geometry under ambient conditions (radiation, primary monochromator, position-sensitive detector, angular range 3° to 42° (2θ), about 60 min total measurement time). The samples were prepared and analyzed without further processing (e.g. grinding or sieving).

[0229] XRPD pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate (Form 1)

[0230] The hydrochloride quarter hydrate solid of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Form 1) can be prepared by Figure 1 The powder X-ray diffraction patterns shown are identified by as little as one characteristic peak. An exemplary X-ray powder diffraction pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Form 1) is expressed in 2θ as follows: 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±0.2 0°, 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°.

[0231] XRPD pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride (Form 2)

[0232] The solid hydrochloride salt of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone (Form 2) can be prepared by Figure 2 The exemplary X-ray powder diffraction pattern of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride solid (Form 2) is represented by 2θ as follows: 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°.

[0233] Crystal structure analysis

[0234] For single crystal structural analysis, single crystals were mounted in a ring on a goniometer and measurements were performed under ambient conditions. Data were collected on a GEMINI R Ultra diffractometer from Oxford Diffraction (Oxford). The copper radiation of wavelength was used for data collection. The data were processed with the software CRYSALIS. The crystal structure was solved and improved with standard crystallographic software. In this case, the program ShelXTL from Bruker AXS (Karlsruhe) was used.

[0235] Preparation of Single Crystal of (3,4-Dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone Hydrochloride Quarter Hydrate

[0236] 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 allowed to reach ambient temperature without stirring. After 24 hours, a single crystal was harvested and subjected to X-ray crystallographic structure analysis.

[0237] The structural data derived from single crystal X-ray analysis of (3,4-dichloro-phenyl)-((S)-3-propyl-pyrrolidin-3-yl)-methanone hydrochloride quarter hydrate are the following unit cell parameters:

[0238]

[0239] where a, b and c are each representative lengths of the lattice, and α, β and γ are unit cell angles. The salt crystallizes in space group P1, providing The unit cell volume.

[0240] Differential Scanning Calorimetry (DSC)

[0241] Using Mettler-Toledo with FRS05 sensor TM Differential scanning calorimeter DSC820, DSC821 or DSC1 was used to record differential scanning calorimetry curves. Indium was used as a reference material for system suitability testing, and indium, benzoic acid, biphenyl and zinc were used as reference materials for calibration.

[0242] For measurement, about 2-6 mg of sample is placed in an aluminum pan, accurately weighed and hermetically sealed with a perforated lid. Before measurement, the lid is automatically pierced to obtain a pinhole of about 1.5 mm. Then, the sample is heated at a heating rate of typically 10 K / min under a nitrogen flow of about 100 mL / min.

[0243] Thermogravimetric analysis (TGA)

[0244] In Mettler-Toledo TM Thermogravimetric analysis was performed on a thermogravimetric analyzer (TGA850 or TGA851). Hydranal was used as a reference material for system suitability testing, and aluminum and indium were used as reference materials for calibration.

[0245] For thermogravimetric analysis, about 5-10 mg of sample was placed in an aluminum pan, accurately weighed and hermetically sealed with a perforated lid. Before measurement, the lid was automatically pierced to obtain a pinhole of about 1.5 mm. The sample was then heated at a heating rate of 5 K / min under a nitrogen flow of about 50 mL / min.

[0246] Example 5. Evaluation of the appetite suppressant effect of Compound 1 using the progressive ratio / chow feeding choice task in rats

[0247] A study was conducted to evaluate the appetite suppressant effect of Compound 1. The PROG / chow feeding choice procedure was used as a test designed to assess the effort rats are willing to make to eat a palatable food by pressing a lever rather than eating freely available standard food.

[0248] Methods. Thirty-one (n=31) adult male Sprague-Dawley rats were used in this study. Animals were restricted to 85% of their free-feeding weight, with moderate growth allowed throughout the study period. Animals were assessed using operant conditioning chambers. Animals were first introduced to high carbohydrate pellets ("palatable food") and trained to perform lever pressing for one week using a continuous reinforcement schedule with a fixed ration of 1 (FR1 = one active lever press triggering the delivery of palatable food). After this, rats were individually trained for 9 weeks at a progressive ratio (gradually more lever pressure was required to trigger the delivery of palatable food), at which time feed ("standard food") was introduced (=PROG / feed feeding selection program), and the animals were trained for another 5 weeks to obtain a stable baseline. Each session lasted 30 minutes, and the rats were run in the operant chamber once a day, five days a week (Monday to Friday). After the training period, doses of 5.0, 10.0 and 20.0 mg / kg of vehicle (VEH) or Compound 1 were administered via oral gavage weekly (Thursday or Friday). Treatment conditions were randomly selected. Lever pressing and food consumption (including spillage) were recorded after each operant session.

[0249] Statistical Analysis. Data were evaluated overall using repeated measures analysis of variance test (ANOVA) and post hoc comparisons. Factorial ANOVA was used to evaluate group x treatment interaction effects. If a significant interaction effect was found, each group was evaluated individually using post hoc comparisons (using the overall error term). Dunnett's test was also used to analyze differences between drug treatments and VEH. For all analyses, p values ​​of <0.05 were considered statistically significant.

[0250] Results. All treatment conditions showed a significant decrease in standard chow intake when 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]). Figure 3 There was no significant difference between VEH and the 5.0 mg / kg dose [F(1,90)=0.391, p=not significant], and a significant decrease in lever pressing was observed at 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], as shown in Figure 2. Figure 4 as displayed.

[0251] The study showed that Compound 1 exhibited an appetite suppressant effect. The pattern of reduced lever pressing and food intake shown in this study as the PROG / food feeding choice task was also shown in studies of other drugs and conditions known to suppress appetite. Examples of such drugs include fenfluramine, pre-feeding, cannabinoid antagonists and inverse agonists, and fluoxetine.

[0252] High responders compared to low responders. A factorial ANOVA for lever pressing showed a significant group x treatment interaction effect [F(3,90) = 13.824, p < 0.001; ηp 2 =0.323] and a significant linear trend interaction effect (p<0.001). Due to this significant interaction effect, high and low responder level presses were analyzed separately. Significant treatment effects were found in both groups (high: p<0.001; low: p=0.01). High responder level lever presses showed a significant linear trend (p<0.001). A priori comparisons indicated that lever presses were significantly reduced at 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 the 5.0 mg / kg dose was compared to the VEH condition [F(1,42)=3.372, p=not significant] ( Fig.14 When any drug condition was compared to VEH, post hoc comparisons showed no significant differences (5.0 mg / kg: [F(1,45) = 0.319, p = not significant], 10.0 mg / kg: [F(1,45, p = 0.079, p = not significant], 20.0 mg / kg: [F(1,45) = 3.157, p = not significant]). However, as Fig.14As shown, a significant quadratic trend was found in the low responder group (p = 0.01). Factorial ANOVA was also used to assess concurrent feed intake. A significant group x treatment interaction effect was found [F(3,90) = 3.191, p < 0.05; ηp 2 =0.099], and an interaction effect with a linear trend (p<0.05). This significant interaction effect allowed separate analyses of high and low responders. A significant treatment effect (p<0.001) and a significant linear trend (p<0.001) were found in both high and low responders. In the high responder group, a priori comparisons revealed that feed intake was significantly reduced 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. Low responders also showed a significant decrease in lever pressing at all doses of treatment (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 determined by Dunnett's test ( Fig.15 ).

[0253] Example 6. Evaluation of the appetite suppressant effect of compound 1 using a fixed ratio in rats

[0254] Another study was conducted to evaluate the appetite suppressant effect of Compound 1. A fixed ratio 1 (FR1) schedule was used, and this task is the most food-intensive and appetite-dependent operant schedule, with high sensitivity to appetite-related manipulations such as pre-feeding agents and appetite suppressant drugs.

[0255] Methods. Adult male Sprague-Dawley rats (n=31) identical to those in Example 5 were used in this study. Animals were trained once daily on a PROG / feeding choice program from Monday to Thursday. On Friday, the test day, the animals were switched from the PROG / feeding choice program to FR1 without prior training. Each operating period lasted 30 minutes, and lever presses were recorded at the end of the run. Drug treatment and FR1 exploration occurred on the Friday after a two-week washout period from Example 5. A 20.0 mg / kg dose of compound 1 or vehicle was administered via oral gavage on the test day. Only the highest dose was tested in this study because it produced the strongest reduction in lever presses and feed intake compared to VEH in Example 5. Treatment conditions were randomly assigned. Treatment group differences were assessed by unpaired t-tests. p values ​​<0.05 were considered statistically significant.

[0256] Results. Compound 1 caused a significant decrease in lever presses in the FR1 probe study as measured by an unpaired t-test (t=9.74; p<0.001). Figure 5 As shown, there was a significant reduction at the 20.0 mg / kg dose when compared to the vehicle (VEH). Importantly, 6 of the 16 rats that received the high drug dose pressed the lever but avoided eating some of the pellets. After the 30-minute operating period was completed, about 5-10 uneaten pellets were left in the food tray of these animals, which is an additional sign of appetite suppression. Therefore, together with the results of the study in Example 5, the study emphasizes that Compound 1 exhibits an appetite suppressant effect.

[0257] Example 7. Evaluation of the appetite suppressant effect of compound 1 using chocolate binge-like eating

[0258] Another study was conducted to evaluate the appetite suppressant effect of Compound 1 on chocolate binge-like eating.

[0259] Methods. A new group of male Sprague-Dawley rats (n=8; initial body weight 300-325 g) were used for the binge-like eating experiment. They were housed in pairs under the same conditions described above, however they were not food restricted and allowed ad libitum access to food (laboratory chow) and water in the home cage. Binge-like eating that occurred over the course of 12 exposure periods was obtained. Before chocolate exposure, an empty home cage with a ceramic dish was habituated for 3 days and 1 hour. In the case of chocolate exposure, rats received chocolate (0.3 g fat, 0.57 g carbohydrates and 0.073 g protein, totaling 5.34 kcal / g) on ​​days 1, 2, 4, 6, 7, 9, 12, 14, 15, 18, 23 and 28. On the exposure day, the rats were placed in an empty home cage with a ceramic dish containing ground chocolate for 1 hour. The weight of chocolate was taken before and after each period to determine intake. These acquisition procedures resulted in increasing levels of chocolate intake over time (from 0.9 ± 0.3 g chocolate in period 1 to 5.5 ± 0.5 g in period 12 (see Fig.13 )).

[0260] Drug administration. After 12 acquisitions of binge-like eating periods were completed, rats continued to be exposed to chocolate periods twice a week for 1 hour in an empty cage with a ceramic dish containing chocolate. One period was used to maintain binge-like behavior, and then the second period was used for drug treatment. These periods occurred randomly throughout the week, with the maintenance period always occurring before the drug treatment period. Compound 1 was dissolved in 0.3% Tween 80 in dH2O. Vehicle (VEH) or 5.0, 10.0 and 20.0 mg / kg doses were administered via oral gavage once a week for testing. A 4-hour pre-treatment induction time was used. An intra-subject design was used in this study, in which each rat received treatment once a week for a total of four weeks. Treatment conditions were randomly selected.

[0261] Data Analysis. Repeated measures ANOVA and post hoc comparisons were used to assess the effect of Compound 1 on chocolate binge-like eating.

[0262] result. Figure 8 , Fig. 9 and Fig.13 The results of the binge-like eating experiment are shown in . Fig.13 The acquisition of binge-like chocolate intake over 12 training sessions is depicted. Figure 8The inhibitory effect of Compound 1 administration on binge-like eating was shown. There was an overall significant effect of Compound 1 treatment [F(3,21)=17.3, p<0.001]. A priori comparisons showed that Compound 1 at a dose of 5.0 mg / kg did not significantly inhibit chocolate intake [F(1,21)=1.5, not significant], but there was a significant reduction in chocolate intake at doses of 10.0 [F(1.21)=20.4, p<0.001] and 20.0 [F(1,21)=4.09, p<0.001] mg / kg.

[0263] Example 8. Evaluation of Compound 1 for Sleep in Rats Using Repeated Measures

[0264] Using a balanced repeated measures design, three doses of Compound 1 (1-10 mg / kg, oral) were tested for their effects on sleep / wake parameters in adult male Sprague-Dawley rats (n=8). The results were compared to the effects of caffeine (10 mg / kg).

[0265] Methods. Eight (n=8) adult male Sprague-Dawley rats were used in this study. Each rat received 3 doses of Compound 1 (1, 3 and 10 mg / kg), vehicle (pure H2O-negative control) and caffeine (10 mg / kg-positive control). Dosing was oral administration at a minimum of 3 days interval in the middle of the rat's normal inactive period. Sleep parameters (non-rapid eye movement sleep, NR; rapid eye movement sleep, REM) were recorded and the first 6 hours of post-dose recordings were analyzed. Figure 6 and Figure 7 As shown, results were compared to vehicle.

[0266] Results. Compound 1 had a wakefulness-promoting effect in rats at 10 mg / kg oral, with complete suppression of REM sleep. 3 mg / kg oral also significantly increased wakefulness and decreased REM sleep, but to a lesser extent.

[0267] Example 9. Evaluation of Compound 1 in the 5-Choice Serial Reaction Time Task (5-CSRTT) in Rats

[0268] The 5-choice continuous reaction time task (5-CSRTT) is widely used to measure the attention performance and reaction control (motor impulsivity) of rodents. The advantage of the test lies in its applicability to task modification. Among others, changes in the frequency of stimulus duration and stimulus presentation, etc. have been commonly used to challenge performance in the context of attention and reaction control. The main purpose of these studies is to examine the effect of compound 1 on attention performance and reaction control, which are defined as premature response (PREM) and persistent response (PSV), impulsive behavior and compulsive behavior, respectively. Two experimental operations were performed to challenge performance differently. Specifically, (1) compound 1 (1, 3, 10 mg / kg) was tested under standard test conditions of 0.75 s SD, 5 s ITI, 100 trials, and (2) compound 1 (1, 3 mg / kg) was tested for long ITI challenge. Long ITI challenge is designed to improve PREM and PSV reactions, and therefore provides a means to examine the effect of these two test models on the measurement of impulse and compulsive behavior.

[0269] Material

[0270] Vehicle control

[0271] Dosage form: 0.3% Tween 80 in 0.9% saline

[0272] Pretreatment time: 180 minutes

[0273] Compound 1

[0274] Dosage form: Compound 1 was suspended in 0.3% Tween 80 in 0.9% saline and sonicated. The drug was administered in a volume of 5 mL / kg by oral (PO) route.

[0275] Pretreatment time: 180 minutes

[0276] Test dose: Phase 1: 1, 3, 10 mg / kg; Phase 2: 1, 3 mg / kg

[0277] Subjects: 24 male Long Evans rats

[0278] Test system placement and management:After being familiar with the one-week period of the test facility, animals were placed on a restricted diet regimen, wherein they were fed about 20 g of standard laboratory chow (corresponding to about 80% of normal food consumption) once a day after the study program was completed (16:00h to 18:00h). Therefore, overall food intake was based on the food obtained during the 5-choice training / test and the feed at the end of each research day. On days when no training / testing occurred, the laboratory chow allocated every day was increased to about 24 grams / animal. Except during the 5-choice training / test period, water was available at will. Animals were maintained in a 12-hour / 12-hour light / dark cycle, and all tests were performed during the light cycle of the animal.

[0279] 5-choice serial reaction time task: The 5-choice operant chamber is housed in a soundproof and ventilated enclosure. The chamber consists of an aluminum enclosure (25x30cm) containing a reward box and a house light attached to a food pellet dispenser on one side wall, and 5 square niches (2.5x2.5x2.5cm) arranged on a curved panel on the opposite side wall and raised 2.5cm from the grid floor. An LED is placed at the rear of each niche. Each niche and reward box also contain a photocell to detect head entry. The test chamber is controlled by Med PC software.

[0280] The 5-CSRTT schedule starts with the lighting of the indoor light and the delivery of food pellets. The nose poke into the tray starts the first trial, which consists of the random lighting of one of the 5 lights for a continuous fixed interval (stimulation duration, SD) followed by the inter-trial interval (ITI, 5s). If a nose poke is recorded in the illuminated niche before the end of the SD or before the fixed interval (limited maintenance, LH) after this period, an additional pellet is allocated and a correct trial is recorded. Incorrect nose pokes (incorrect trials) or failure to respond (missed trials) within the allocated time get a timeout (TO) period, in which the indoor light is turned off for 5s. Respond to one of the five niches (PREM response) during the ITI, then get another TO. PSV reactions are not punished by TO.

[0281] Each period runs for 100 trials or 60 minutes, depending on which period endpoint is reached first. Animals are trained to the final test conditions of 0.75sSD, 5s ITI, and 5s limited retention via a series of steps. Target performance is a period of at least two weeks in which the threshold is about 80% correct ([correct / (correct+incorrect)]×100) and a stable performance of <20% omission rate. At this time point, drug testing begins according to a repeated measurement design, in which animals are treated in repeated test periods. Test periods are run twice a week under standard (5s ITI) and long ITI time arrangements to allow drug clearance and reset baselines to subjects between cycles.

[0282] Phase 1: The effect of Compound 1 (1, 3, 10 mg / kg) or vehicle control on test performance was investigated under standard test conditions: 0.75 s SD, 5 s ITI, 5 s LH, for a total of 100 trials. Treatments were administered in a random order.

[0283] Phase 2: Effects of Compound 1 (1 and 3 mg / kg) or vehicle control were investigated in a 10s ITI 5-choice schedule (10s ITI, 0.3s SD, 5s LH, 100 trials). Treatments were administered in a randomized order.

[0284] Statistical analysis: The main measures of performance from the 5-CSRTT, namely accuracy measured as % correct ([#correct / #correct+#incorrect]*100) or % hits ([#correct / #correct+#incorrect+#omissions]*100), response speed (latency to correct), incomplete trials (omissions), and total #trials are expressed as mean and SEM.

[0285] result

[0286] Phase 1: Effects of Compound 1 on 5-item Choice Task Performance: Standard Conditions : Compound 1 was tested at doses of 1, 3 and 10 mg / kg in all rats at each dose according to a repeated measures design. The vehicle pretreated group was used as a control. The main effects of treatment were found on 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 the dose-related decrease in PREM and PSV responses relative to vehicle controls after compound 1 pretreatment. In addition, the number of trials was reduced at a dose of 10 mg / kg. There was no main effect of treatment on any other task measure, including accuracy. The 5-CSRTT results obtained under standard testing conditions (0.75 second stimulation duration, 5 second ITI, 100 trials) are shown in Fig. 10A and Fig. 10B middle.

[0287] Phase 2: Effects of Compound 1 on 5-item choice task performance: 10 s ITI:Compound 1 was tested at doses 1 and 3 mg / kg in all rats at each dose according to a repeated measures design under a 10s ITI schedule. The vehicle pre-treated group was used as a control. Increasing the ITI from 5s to 10s and the duration of the visual stimulus from 0.75s to 0.3s reduced the accuracy (correct %; 5s ITI: 83.9 ± 1.5%; 10s ITI: 68.5 ± 2.4%; P < 0.01) and increased both PREM (5s ITI: 6.0 ± 1.2; 10s ITI: 46.7 ± 10.2; P < 0.01) and PSV (5s ITI: 20.9 ± 3.4; 10s ITI: 33.8 ± 7.4; P < 0.05) reactions. The effect of compound 1 on task performance under a 10s ITI schedule was assessed for vehicle pre-treatment under the same conditions. When all N = 21 rats were included in the analysis, there was no main effect of treatment on any measure (F2,40 ≤ 2.5; NS), i.e., there was no effect of treatment on accuracy (% correct, % hits) or on PREM / PSV responses. Rats were then divided into low impulsivity (LI) and high impulsivity (HI) subgroups based on the level of PREM responses made after vehicle pretreatment at a 10 s ITI schedule, (i.e., PREM: LI: 16.7 ± 2.4; HI: 93.9 ± 21.6; P < 0.01). This subgroup division resulted in a main effect of subgroup 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 relative to their LI counterparts. With respect to the effects of Compound 1 on task performance in these subgroups, a main effect of treatment and a subgroup x treatment interaction effect were noted 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).

[0288] Example 10. A randomized, double-blind, placebo-controlled, crossover multicenter trial of compound 1 in adults with atypical depression

[0289] A randomized, double-blind, placebo-controlled, crossover trial in which the efficacy and safety of Compound 1 were examined using the DSM-5 diagnosis of atypical depression. The trial consisted of a screening period, a treatment period, and a follow-up period as described in detail below. Participants could record symptoms associated with atypical depression using an electronic diary and wear an actigraph watch every day during the treatment period and the washout period.

[0290] Goals and End Points

[0291]

[0292]

[0293] Equivalents and scope

[0294] In the claims, articles such as "a", "an", and "the" may mean one or more than one, unless otherwise specified or otherwise obvious from the context. Claims or descriptions including "or" between one or more members of a group are considered intended unless otherwise specified or otherwise obvious from the context if one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which exactly one member of a group is present in, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

[0295] In addition, the present invention encompasses all variations, combinations and arrangements in which one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim that is subordinate to another claim can be modified to include one or more limitations found in any other claim that is subordinate to the same basic claim. In the case where the element is presented in a list, for example, in the form of a Markush group, each subgroup of the element is also disclosed, and any element can be removed from the group. It should be understood that, in general, in the case where the present invention or aspects of the present invention are referred to as including specific elements and / or features, certain embodiments of the present invention or aspects of the present invention are composed of such elements and / or features or are substantially composed of such elements and / or features. For the purpose of simplicity, these embodiments are not specifically described in exact language herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow the inclusion of additional elements or steps. In the case of giving a range, the endpoints are included. In addition, unless otherwise indicated or otherwise apparent from the context and understanding of one of ordinary skill in the art, in various embodiments of the present invention, values ​​expressed as ranges may be assumed to be any specific value or sub-range within the stated range, up to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0296] This application relates to various granted patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any incorporated reference and the current specification, the specification shall prevail. In addition, any specific embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the present claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if they are not explicitly set forth herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not it is related to the existence of the prior art.

[0297] Those skilled in the art will recognize or be able to ascertain many equivalents to the specific embodiments described herein using no more than routine experimentation. The scope of the present embodiments described herein is not intended to be limited to the description above, but as shown in the appended claims. It will be appreciated by those of ordinary skill in the art that various changes and modifications may be made to this description, as defined in the appended claims, without departing from the spirit or scope of the present invention.

Claims

1. A method of treating a subject exhibiting at least one or more behaviors selected from: (a)(i) emotional reactivity, (ii) increased sleep, (iii) excessive sleep, (iv) leaden paralysis, (v) a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment, (b)(i) binge eating not associated with frequent 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 behaviours, such as self-induced vomiting; abuse of laxatives; diuretics or other medications to prevent weight gain, (ii) overeating and inappropriate compensatory behaviors, (iii) body shape and weight unreasonably influence self-evaluation, (iv) a disorder that does not occur only during an episode of anorexia nervosa, (v) vomiting and diarrhea-type recurrent compensatory behaviors, and (vi) non-vomiting and diarrheal recurrent compensatory behaviors, (d)(i) recurrent binge eating episodes, (ii) eating clearly more food in a discrete period of time than most people would eat in a similar period of time under similar circumstances, (iii) a feeling of lack of control over eating during an episode, (iv) Feeling that they cannot stop eating or control what or how much they eat, (v) eating much faster than normal, (vi) eating until you feel uncomfortably full, (vii) eating large amounts of food without feeling physically hungry, (viii) Eating alone because of embarrassment about how much they eat, (ix) Feeling disgusted with oneself, depressed, or extremely guilty after overeating, (x) Obvious distress about binge eating, (e)(i) Increased appetite, (ii) excessive food intake, (iii) a marked lack of impulse control and subsequent feelings of guilt, (f)(i) restriction of energy intake relative to requirements resulting in markedly low body weight, (ii) an intense fear of gaining weight or becoming fat, even when underweight, and (iii) disturbances in the way one experiences one's weight or body shape; The method comprises administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to improve at least one of the behaviors, wherein Compound 1 is:

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

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

7. The method according to any one of claims 1-6, wherein the composition is administered once a day.

8. The method of any one of claims 1-7, wherein the subject exhibits emotional reactivity; and At least two behaviors selected from the group consisting of increased appetite, excessive eating, increased sleeping, hypersomnia, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection resulting in significant social or occupational impairment.

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

10. The method according to any one of claims 1-9, wherein the subject exhibits: Recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during episodes, eating much faster than normal, feeling unable to stop eating or control what or how much one eats, marked distress about binge eating, binge eating that is not associated with frequent use of inappropriate compensatory behaviors, and binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa; and Select three or more of the following behaviors: eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, being depressed, or feeling very guilty.

11. The method of claim 1, wherein the subject exhibits: Recurrent episodes of binge eating; eating clearly larger amounts of food in discrete time periods than most people would eat in similar time periods under similar circumstances; feeling unable to stop eating or control what or how much they eat; recurrent inappropriate compensatory behaviors to prevent weight gain; binge eating and inappropriate compensatory behaviors; body shape and weight inappropriately affecting self-evaluation; and disturbances that do not occur exclusively during episodes of anorexia nervosa.

12. The method of claim 11, wherein the discrete time periods are 2-hour periods, and the binge eating and inappropriate compensatory behaviors occur at least twice a week for 3 months.

13. The method according to claim 8, wherein the subject also exhibits one or more behaviors selected from the following: Recurrent binge eating episodes, eating clearly more food in discrete time periods than most people would eat in similar time periods under similar circumstances, feelings of lack of control over eating during an episode, feeling 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 not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression, or intense guilt, marked distress about binge eating, binge eating that is not associated with 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, body shape and weight inappropriately affecting self-esteem, disturbances that do not occur exclusively during an episode of anorexia nervosa, recurrent vomiting compensatory behaviors and recurrent non-vomiting compensatory behaviors.

14. The method of any one of claims 1-13, wherein the subject is a subject diagnosed with atypical depression.

15. The method of any one of claims 1-14, wherein the subject is a subject diagnosed with one or more behaviors selected from the group consisting of emotional reactivity, increased appetite, excessive eating, increased sleep, hypersomnia, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment.

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

17. The method of any one of claims 1-16, wherein the subject is a subject diagnosed with one or more behaviors selected from the group consisting of: recurrent binge eating episodes, eating clearly more food in a discrete time period than most people would eat in a similar time period under similar circumstances, a sense of lack of control over eating during an episode, eating much faster than normal, feeling that one cannot stop eating or control what or how much one eats, significant distress about binge eating, binge eating that is not associated with frequent use of inappropriate compensatory behaviors, binge eating that does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, eating much faster than normal, eating until one feels uncomfortable full, eating large amounts of food when one does not feel physically hungry, eating alone because of embarrassment at how much one eats, and feeling disgusted with oneself, depression, or excessive guilt after overeating.

18. The method of any one of claims 1-17, wherein the subject is a subject diagnosed with bulimia nervosa.

19. The method of any one of claims 1-18, wherein the subject is a subject diagnosed with one or more behaviors selected from the group consisting of: rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or excessive guilt, marked distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation of body type and weight as affected, vomiting-type recurrent compensatory behaviors, and non-vomiting-type recurrent compensatory behaviors.

20. The method of any one of claims 1-19, wherein the subject is a subject diagnosed with anorexia nervosa.

21. The method of any one of claims 1-20, wherein the subject is a subject diagnosed with one or more behaviors selected from the following: restricting energy intake relative to needs in the context of age, sex, developmental trajectory, and physical health resulting in significantly low body weight, an intense fear of weight gain or becoming fat (even if underweight), a disturbance in the way one experiences one's own weight or body shape, an inappropriate influence of weight or body shape on self-evaluation, or a denial of the severity of current low body weight.

22. The method of claim 1, wherein the subject is a subject diagnosed with depression.

23. The method of any one of claims 1-22, wherein the subject is a subject being treated for depression.

24. The method of claim 1, wherein the method comprises treating a subject diagnosed with depression and also exhibiting one or more atypical symptoms of depression.

25. The method of claim 24, wherein the atypical depressive symptoms are selected from the group consisting of emotional reactivity, increased appetite, excessive eating, increased sleep, hypersomnia, leaden paralysis, and a long-standing pattern of sensitivity to interpersonal rejection that results in significant social or occupational impairment.

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

27. The method of any one of claims 1-25, wherein the behavior is performed for at least one week.

28. The method of any one of claims 1-25, wherein the behavior is performed for at least two weeks.

29. The method of any one of claims 1-25, wherein the performance of the behavior persists for at least one month.

30. The method of any one of claims 1-25, wherein the behavior is exhibited for at least three months.

31. The method of any one of claims 1-25, wherein the performance of the behavior occurs periodically.

32. A method of treating a subject exhibiting impulsive behavior, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

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

34. A method of treating a subject diagnosed with atypical depression, comprising administering a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is: The subject exhibits one or more behaviors selected from the following: Excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, sensitivity to interpersonal rejection, rapid eating, recurrent binge eating episodes, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much one eats, feeling disgusted with oneself after overeating, depression or intense guilt, marked distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation influenced by body shape and weight, recurrent compensatory behaviors of the vomiting type, recurrent compensatory behaviors of the non-vomiting type, refusal to maintain weight at or above minimum normal weight, intense fear of weight gain or becoming fat, obsession with own weight or shape, self-worth influenced by weight or shape, and persistent lack of awareness of the seriousness of low body weight.

35. A method of treating a subject exhibiting at least one or more behaviors selected from the group consisting of: Excessive sleeping, excessive eating, emotional reactivity, leaden paralysis, depressed mood, sensitivity to interpersonal rejection, rapid eating, recurrent episodes of binge eating, lack of control over eating, eating much faster than normal, eating until feeling uncomfortably full, eating large amounts of food when not feeling physically hungry, eating alone because of embarrassment about how much they eat, feeling disgusted with themselves after overeating, depression or intense guilt, marked distress about binge eating, binge eating not associated with compensatory behaviors, recurrent compensatory behaviors, binge eating with compensatory behaviors, self-evaluation influenced by body shape and weight, recurrent compensatory behaviors of the vomiting type, recurrent compensatory behaviors of the non-vomiting type, refusal to maintain weight at or above minimum normal weight, intense fear of weight gain or becoming fat, obsession with one's weight or body shape, self-worth influenced by weight or body shape, and persistent lack of awareness of the seriousness of low body weight; The method comprises administering a unit dose comprising Compound 1 or a pharmaceutically acceptable salt thereof sufficient to alleviate at least the behavior, wherein Compound 1 is:

36. A method of treating Prader-Willi syndrome in a subject in need thereof, comprising administering a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, wherein Compound 1 is:

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