Use of macvalerian in reducing use of cocaine or preventing reuse of cocaine

Abstract

The present invention relates to the use of macvalerian, or a pharmaceutically acceptable salt thereof, in the following; application in reducing the use of cocaine by patients with cocaine use disorder; the application is used for preventing a patient suffering from cocaine use disorder from reusing cocaine; the application is used for promoting cocaine quitting of a patient suffering from cocaine use disorder; use in the treatment of depression or anxiety symptoms associated with cocaine use disorders.

Description

[0001] The present invention relates to the use of mGluR5 antagonists. Technical Field

[0002] The present invention relates to an mGluR5 antagonist named mavoglurant or a pharmaceutically acceptable salt thereof, and its use in reducing the use of cocaine by patients with cocaine use disorder; preventing cocaine re-use by patients with cocaine use disorder; promoting abstinence from cocaine by patients with cocaine use disorder; and treating depression or anxiety symptoms associated with cocaine use disorder. In particular, the present invention relates to the use of mavoglurant or a pharmaceutically acceptable salt thereof in reducing the use of cocaine by patients with cocaine use disorder / preventing cocaine re-use by patients with cocaine use disorder. Background Art

[0003] Cocaine use disorder is a complex psychiatric disorder, defined by reference to DSM-5 criteria (i.e., according to the Diagnostic and Statistical Manual of Mental Disorders, 5th ed., Washington, DC: American Psychiatric Association, 2013), that continues to develop into a serious global health problem with adverse medical, social, and economic impacts (D. Shorter et al., Expert Opin. Emerging Drugs, 20(1), 2015). Socioeconomic risks associated with cocaine use include increased crime and violence. Adverse medical consequences derived from cocaine use include, but are not limited to, cardiovascular disorders (e.g., hypertension, stroke, heart attack, arrhythmias, cardiomyopathy), gastrointestinal disorders, respiratory disorders (e.g., bronchitis, chest pain), seizures, psychomotor agitation, sleep disorders, and psychosis. Cocaine use also affects brain regions associated with cognition (e.g., memory, learning, attention). Further associated health risks include infectious diseases (such as hepatitis B and C or HIV), and virtually any route of administration of cocaine can lead to serious medical events that can ultimately result in death. In addition, it is common for patients with cocaine use disorder to have concurrent psychiatric disorders.

[0004] The complete biological mechanisms of cocaine dependence are still not fully understood. Therefore, pharmacotherapy for cocaine use disorder focuses on the various stages that patients with cocaine use disorder may go through, and therefore targets different aspects, such as: i) attenuating the rewarding effects of cocaine use (e.g., euphoric effects); ii) acting as a "replacement therapy" for cocaine; iii) relieving cocaine withdrawal symptoms (e.g., cocaine craving, anxiety, or depression), D. Shorter et al., Expert Opin. Emerging Drugs, 20(1), 2015. The most promising results have been obtained with desipramine and amantadine, which have been shown to relieve cocaine withdrawal symptoms. In particular, desipramine has been shown to reduce both cocaine use and cocaine craving, although the reduction in craving develops only slowly (i.e., over 7 to 14 days), which allows for frequent reuse of cocaine. Other pharmacological agents that have been tested include GABA agents (e.g., topiramate, tiagabine, baclofen, and vigabatrin), agonist replacement agents (e.g., modafinil, methylphenidate, methadone, buprenorphine), dopamine agents (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole, and dextroamphetamine), D3 receptor ligands (e.g., CJB090), corticotropin-releasing factor (CRF) receptor antagonists (e.g., CP154,526), ​​dual dopamine-serotonin releasers (e.g., PAL-287), noradregenic agents (e.g., doxazosin, disulfiram, nepicastat), 5-HT 1A Receptor partial agonists (e.g., buspirone), MU opioid agonists (buprenorphine), desipramine, and amantadine. However, despite numerous research efforts in this area, including more than one hundred clinical trials, there are currently no drugs approved by regulatory agencies for treatment (Pharmacol Rev [Pharmacology Review] 68:533-562, July 2016; International Journal of Neuropsychopharmacology [International Journal of Neuropsychopharmacology], 11, 425-438, 2008). In addition, clinical treatment of patients with cocaine use disorder is complicated by the high tendency of these patients to fail to complete treatment and relapse.

[0005] Because cocaine has an immediate and powerful rewarding effect (e.g., feeling euphoric and increased energy), it is the most addictive substance of abuse. Cocaine users often increase their dosage in an effort to increase and prolong the rewarding effect of cocaine. Withdrawal from cocaine use is associated with adverse symptoms (e.g., anxiety, depression, pain (e.g., headaches), in particular) and cocaine cravings. Typically, the severe discomfort caused by quitting cocaine may prompt patients to relapse into cocaine use in an attempt to alleviate withdrawal symptoms. Finding a pharmacotherapy for the treatment of cocaine use disorder is a huge challenge and a high medical need, particularly finding a drug that can help achieve or maintain abstinence from cocaine use.

[0006] Preclinical models have shown that other mGluR5 antagonists (e.g., MPEP [i.e., 2-methyl-6-(2-phenylethynyl)pyridine] and MTEP [i.e., 3-[2-(2-methylthiazol-4-yl)ethynyl]pyridine]) reduce cocaine self-administration in mice (e.g., in Chiamulera, C. et al., Nat. Neurosci. 2001, 4, 873-874) or in rats (e.g., in Kenny, PJ et al., Behav. Pharmacol. 14, S55; Martin-Fardon R., et al., J. Pharmacol Exp Ther. 2009, 329(3):1084). However, neither MTEP nor MPEP has been further developed due to their shortcomings as therapeutic agents (Keck et al., 2013, Psychopharmacology, 229(2):253-65): for example, MTEP demonstrated potent inhibition of cytochrome P450 1A2 and rapid metabolism (Smith et al., 2004, Bioorg Med Chem Lett 14:5481-5484) and for example, MPEP demonstrated off-target effects on NMDA receptors, monoamine oxidase, and norepinephrine transporter (Cosford et al., J. Med. Chem., 2003, 46(2), pp. 204-206; O'Leary et al., 2000, Br J Chem Pharmacol., 46(2), pp. 204-206). Pharmacol [British Journal of Pharmacology] 131: 1429-1437; Heidbreder et al., 2003, Synapse [Synapse] 50: 269-276; Lea and Faden, 2006 CNS Drug Rev [Central Nervous System Drug Review] 12: 149-166).

[0007] It has been discovered that mavogulan may be an ideal candidate for the treatment of patients diagnosed with cocaine use disorder, providing therapeutic advantages to this patient population, such as one or more of the following:

[0008] i) it promotes cocaine abstinence, e.g., compared to placebo, e.g., by maintaining abstinence or reducing the amount or frequency of cocaine use, e.g., as assessed by urinalysis (e.g., by measuring metabolites of cocaine in urine, such as benzoylecgonine) or by using self-reported cocaine use and a standardized tool such as the timeline followback self-report [Sobell, LC, Sobell, MB (1996) Timeline Followback User's Guide: A Calendar Method for Assessing Alcohol and Drug Use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo, 2002, 26:393-400];

[0009] ii) it reduces relapse to cocaine use, for example, compared to placebo, e.g., in a treatment program (e.g., a clinical trial) where it increases the time to relapse or the rate of relapse in patients;

[0010] iii) which reduces (e.g., by elimination or by reduction in intensity, duration, or frequency) one or more symptoms associated with cocaine use disorder selected from the group consisting of:

[0011] a. Depressive symptoms, such as assessed from the Beck Depression Inventory [Beck, AT et al., (1961) An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571; Beck, AT et al., (1988) Psychometric properties of the Beck Depression Inventory: Twenty-five years of evaluation. Clinical Psychology Review, 8(1), 77-100]; and

[0012] b. Anxiety symptoms, such as assessed from the State-Trait Anxiety Inventory [Spielberger, CD (1989). State-Trait Anxiety Inventory: Bibliography (2nd ed.). Palo Alto, CA: Consulting Psychologists Press; Spielberger, CD et al., (1983). Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press].

[0013] iv) it increases retention of patients in treatment, e.g., it increases retention of patients in a treatment program (e.g., a clinical trial) (e.g., as measured by patient attendance at scheduled clinic visits and / or time to dropout from the clinical protocol), e.g., compared to placebo;

[0014] v) It improves overall functioning, as assessed by the Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) scales (Psychiatry, 2007, 4(7):28-37)

[0015] vi) it has a favorable therapeutic profile, such as a favorable safety profile or metabolic profile, such as a favorable profile with respect to psychiatric adverse events, genotoxicity, or cardiovascular adverse events (e.g., blood pressure, heart rate, electrocardiogram parameters); for example, it has a better therapeutic profile (e.g., fewer side effects, reduced off-target effects, or reduced toxicity, such as reduced genotoxicity) than one or more known therapeutic agents that have been shown to be effective in the treatment of cocaine use disorder; or

[0016] vii) as listed above, which has one or more of the therapeutic advantages of i) to vi), and which also reduces alcohol use, e.g., compared to placebo, e.g., by reducing the amount or frequency of alcohol use, e.g., as assessed by urinalysis (e.g., measuring metabolites of alcohol, such as ethyl glucuronide) or by using self-reported alcohol use and standardized tools such as timeline tracking self-report (J. Anal. Toxicolo [Journal of Analytical Toxicology] 2002, 26: 393-400). Summary of the invention

[0017] The present invention relates to the use of Mawogulan or a pharmaceutically acceptable salt thereof in the following:

[0018] - Use in reducing cocaine use in patients with cocaine use disorder;

[0019] - Use in preventing relapse to cocaine in patients with cocaine use disorder;

[0020] - Use in promoting abstinence from cocaine in patients with cocaine use disorder;

[0021] - Use in the treatment of depressive or anxiety symptoms associated with cocaine use disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : Cocaine (0.3 mg / kg / infusion, FR5) self-administration learning curve in Phase I. Rats achieved stable levels of cocaine self-administration over 15 days of acquisition training. Data represent mean + SEM. N = 12 per treatment group. 1) Subgroup Ia, active lever; 2) Subgroup II-b; active lever; 3) Subgroup II-a, inactive lever; 4) Subgroup II-b, inactive lever.

[0023] Figure 2 : Acute effects of mavogulan on cocaine self-administration in two subgroups of rats. Data represent mean + SEM. Asterisks (***: P < 0.001) indicate significant differences compared with saline or vehicle treatment. N = 12 per treatment group. 1) Vehicle; 2) mavogulan 1 mg / kg; 3) mavogulan 3 mg / kg; 4) mavogulan 10 mg / kg.

[0024] Figure 3 : Acquisition and extinction of cocaine self-administration responses in two subgroups of rats (Phase II). Rats achieved a stable level of cocaine self-administration during 15 days of acquisition training and then reduced responding on the active lever during a 9-day extinction learning paradigm. Data represent mean + SEM. N = 14-15 per group. 1) Subgroup II-a, active lever; 2) Subgroup II-b, active lever; 3) Subgroup II-a, inactive lever; 4) Subgroup II-b, inactive lever.

[0025] Figure 4 : Effect of mavogulan (10 mg / kg, PO, 1 hour pretreatment) on reinstatement of cocaine self-administration in rats. Data represent mean + SEM. Asterisks (***: P < 0.001) indicate significant differences. N = 14-15 per treatment group. 1) Last day of elimination; 2) Repeat, vehicle; 3) Last day of elimination; 4) Repeat, mavogulan 10 mg / kg.

[0026] Figure 5 :Research design plan 1. DETAILED DESCRIPTION

[0027] Embodiments of the present invention are:

[0028] Embodiment (a):

[0029] 1a. Mavogulan or a pharmaceutically acceptable salt thereof for use in reducing cocaine use in patients with cocaine use disorder.

[0030] 2a. Mavogulan or a pharmaceutically acceptable salt thereof for use in preventing cocaine relapse in patients with cocaine use disorder.

[0031] 3a. Mavogulan or a pharmaceutically acceptable salt thereof for use in promoting abstinence from cocaine in patients with cocaine use disorder.

[0032] 4a. Mavogulan or a pharmaceutically acceptable salt thereof for use in treating depression or anxiety symptoms associated with cocaine use disorder.

[0033] 5a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 4a, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting), or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0034] 6a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 5a, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder or bulimia.

[0035] 7a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 6a, wherein the use is combined with standardized psychological treatment, for example, on an individual or group level.

[0036] 8a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 7a, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0037] 9a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to embodiment 8a, wherein the psychosocial or behavioral therapy is computer-assisted.

[0038] 10a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 9a, wherein the use is concomitant with methadone or buprenorphine treatment.

[0039] 11a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 10a, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

[0040] 12a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to embodiment 11a, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0041] 13a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1a to 12a, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0042] 14a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 13a, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0043] 15a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 14a, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0044] 16a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to embodiment 15a, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0045] 17a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to embodiment 15a or 16a, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by an interval of 12 hours.

[0046] 18a. Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with alcoholism.

[0047] Embodiment (b):

[0048] 1b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in reducing cocaine use in patients with cocaine use disorder.

[0049] 2b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for preventing cocaine relapse in patients with cocaine use disorder.

[0050] 3b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for promoting abstinence from cocaine in patients with cocaine use disorder.

[0051] 4b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for use in treating depression or anxiety symptoms associated with cocaine use disorder.

[0052] 5b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 4b, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting), or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0053] 6b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 5b, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or bulimia.

[0054] 7b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 6b, wherein the use is combined with standardized psychotherapy, for example, on an individual or group level.

[0055] 8b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 7b, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0056] 9b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to embodiment 8b, wherein the psychosocial or behavioral therapy is computer-assisted.

[0057] 10b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 9b, wherein the use is concomitant with methadone or buprenorphine treatment.

[0058] 11b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 10b, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

[0059] 12b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to embodiment 11b, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0060] 13b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 12b, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0061] 14b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 13b, which is in an immediate release form or a modified release form.

[0062] 15b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any one of embodiments 1b to 14b, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0063] 16b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to embodiment 15b, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0064] 17b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to embodiment 15b or 16b, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by a 12-hour interval.

[0065] 18b. A pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with alcoholism.

[0066] Embodiment (c):

[0067] 1c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for use in reducing cocaine use in patients with cocaine use disorder.

[0068] 2c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for use in preventing cocaine relapse in patients with cocaine use disorder.

[0069] 3c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for use in promoting abstinence from cocaine in patients with cocaine use disorder.

[0070] 4c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for use in treating depression or anxiety symptoms associated with cocaine use disorder.

[0071] 5c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 4c, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting) or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0072] 6c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 5c, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder or bulimia.

[0073] 7c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 6c, wherein the use is combined with standardized psychological treatment, for example, on an individual or group level.

[0074] 8c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 7c, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0075] 9c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to embodiment 8c, wherein the psychosocial or behavioral therapy is computer-assisted.

[0076] 10c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 9c, wherein the use is concomitant with methadone or buprenorphine treatment.

[0077] 11c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 10c, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0078] 12c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 11c, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0079] 13c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 12c, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0080] 14c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any one of embodiments 1c to 13c, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bidmg / bid.

[0081] 15c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to embodiment 14c, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0082] 16c. A pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to embodiment 14c or 15c, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by a 12-hour interval.

[0083] 17c. A pharmaceutical combination comprising mavogulan, or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, for use according to any of the preceding embodiments, wherein the cocaine use disorder is associated with alcoholism.

[0084] Embodiment (d):

[0085] 1d. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reducing cocaine use in patients with cocaine use disorder.

[0086] 2d. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing cocaine use disorder patients from relapsing into cocaine.

[0087] 3d. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting abstinence from cocaine in patients with cocaine use disorder.

[0088] 4d. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating depression or anxiety symptoms associated with cocaine use disorder.

[0089] 5d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 4d, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting), or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0090] 6d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 5d, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or bulimia.

[0091] 7d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 6d, wherein the use is combined with standardized psychological treatment, for example, on an individual or group level.

[0092] 8d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 7d, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0093] 9d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to embodiment 8d, wherein the psychosocial or behavioral therapy is computer-assisted.

[0094] 10d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 9d, wherein the use is accompanied by methadone or buprenorphine treatment.

[0095] 11d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 10d, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

[0096] 12d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to embodiment 11d, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0097] 13d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 12d, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0098] 14d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 13d, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0099] 15d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 14d, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0100] 16d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to embodiment 15d, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0101] 17d. The use of Mavogulan or a pharmaceutically acceptable salt thereof according to embodiment 15d or 16d, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by an interval of 12 hours.

[0102] 18d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of the preceding embodiments, wherein cocaine use disorder is associated with alcoholism.

[0103] Embodiment (e):

[0104] 1e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for reducing cocaine use in patients with cocaine use disorder.

[0105] 2e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for preventing cocaine relapse in patients with cocaine use disorder.

[0106] 3e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for promoting abstinence from cocaine in patients with cocaine use disorder.

[0107] 4e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient for the manufacture of a medicament for treating depression or anxiety symptoms associated with cocaine use disorder.

[0108] 5e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 4e, wherein the cocaine use disorder is associated with inhaled cocaine (i.e., smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e., snorting), or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e., smoking).

[0109] 6e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 5e, wherein the cocaine use disorder is accompanied by a mental disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or bulimia.

[0110] 7e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 6e, wherein the use is combined with standardized psychotherapy, for example, on an individual or group level.

[0111] 8e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 7e, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0112] 9e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to embodiment 8e, wherein the psychosocial or behavioral therapy is computer-assisted.

[0113] 10e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 9e, wherein the use is concomitant with methadone or buprenorphine treatment.

[0114] 11e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 10e, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

[0115] 12e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to embodiment 11e, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0116] 13e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 12e, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0117] 14e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 13e, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0118] 15e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of embodiments 1e to 14e, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0119] 16e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to embodiment 15e, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0120] 17e. Use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to embodiment 15e or 16e, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by a 12-hour interval.

[0121] 18e. The use of a pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient according to any one of the preceding embodiments, wherein the cocaine use disorder is associated with alcoholism.

[0122] Embodiment (f):

[0123] 1f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for reducing cocaine use in patients with cocaine use disorder.

[0124] 2f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for preventing cocaine relapse in patients with cocaine use disorder.

[0125] 3f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for promoting abstinence from cocaine in patients with cocaine use disorder.

[0126] 4f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient for the manufacture of a medicament for treating depression or anxiety symptoms associated with cocaine use disorder.

[0127] 5f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 4f, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting) or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0128] 6f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 5f, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, or bulimia.

[0129] 7f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 6f, wherein the use is combined with standardized psychological treatment, for example, on an individual or group level.

[0130] 8f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 7f, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0131] 9f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to embodiment 8f, wherein the psychosocial or behavioral therapy is computer-assisted.

[0132] 10f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 9f, wherein the use is concomitant with methadone or buprenorphine treatment.

[0133] 11f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1f to 10f, and at least one additional pharmaceutically active ingredient, wherein the additional active agent is selected from a GABA agent (e.g., topiramate, baclofen or tiagabine) or a dopamine agent (e.g., a combination of bupropion, levodopa, and carbidopa).

[0134] 12f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 11f, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with a cocaine use disorder.

[0135] 13f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 12f, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0136] 14f. Use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of embodiments 1c to 13c, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0137] 15f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to embodiment 14f, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0138] 16f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to embodiment 14f or 15f, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered separately in the morning and evening by a 12-hour interval.

[0139] 17f. The use of a pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient according to any one of the preceding embodiments, wherein cocaine use disorder is associated with alcoholism.

[0140] Embodiment (g):

[0141] 1g. A method for reducing cocaine use in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient an effective amount of mavogulan or a pharmaceutically acceptable salt thereof.

[0142] 2g. A method for preventing relapse to cocaine in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient an effective amount of mavogulan or a pharmaceutically acceptable salt thereof.

[0143] 3g. A method for promoting abstinence from cocaine in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient an effective amount of mavogulan or a pharmaceutically acceptable salt thereof.

[0144] 4g. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient an effective amount of mavogulan or a pharmaceutically acceptable salt thereof.

[0145] 5g. The method of any one of embodiments 1g to 4g, wherein the cocaine use disorder is associated with inhalation of cocaine (i.e., smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e., snorting), or oral formulations of cocaine; in particular, associated with inhalation of cocaine (i.e., smoking).

[0146] 6g. The method of any one of embodiments 1g to 5g, wherein the cocaine use disorder is associated with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, or binge eating disorder.

[0147] 7g. The method of any one of embodiments 1g to 6g, wherein administration of mavogulan or a pharmaceutically acceptable salt thereof is combined with standardized psychological treatment, eg, on an individual or group level.

[0148] 8g. The method according to any one of embodiments 1g to 7g, wherein the administration of mavogulan or a pharmaceutically acceptable salt thereof is combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0149] 9g. The method of embodiment 8g, wherein the psychosocial or behavioral therapy is computer-assisted.

[0150] 10g. The method of any one of embodiments 1g to 9g, wherein administration of mavogulan or a pharmaceutically acceptable salt thereof is concomitant with methadone or buprenorphine treatment.

[0151] 11g. The method of any one of embodiments 1g to 10g, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with an additional active agent.

[0152] 12g. The method of embodiment 11g, wherein the additional active agent is selected from a GABA agent (eg, topiramate, baclofen, or tiagabine) or a dopamine agent (eg, a combination of bupropion, levodopa, and carbidopa).

[0153] 13g. The method of any one of embodiments 1g to 12g, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0154] 14g. The method of any one of embodiments 1g to 13g, wherein the mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0155] 15g. The method according to any one of embodiments 1g to 14g, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0156] 16g. The method of embodiment 15g, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0157] 17g. The method according to embodiment 15g or 16g, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in the morning and evening separated by 12 hours.

[0158] 18g. The method of any preceding embodiment, wherein the cocaine use disorder is associated with alcohol abuse.

[0159] Embodiment (h):

[0160] 1h. A method for reducing cocaine use in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0161] 2h. A method for preventing cocaine relapse in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0162] 3h. A method for promoting abstinence from cocaine in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0163] 4h. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0164] 5h. The method of any one of embodiments 1h to 4h, wherein the cocaine use disorder is associated with inhalation of cocaine (i.e., smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e., snorting), or oral formulations of cocaine; in particular, associated with inhalation of cocaine (i.e., smoking).

[0165] 6h. The method of any one of embodiments 1h to 5h, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, or binge eating disorder.

[0166] 7h. The method of any one of embodiments 1h to 6h, wherein administration of the pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is combined with standardized psychotherapy, e.g., at the individual or group level.

[0167] 8h. A method according to any one of embodiments 1h to 7h, wherein the administration of the pharmaceutical composition comprising an effective amount of Mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0168] 9h. The method of embodiment 8h, wherein the psychosocial or behavioral therapy is computer-assisted.

[0169] 10h. The method of any one of embodiments 1h to 9h, wherein the administration of the pharmaceutical composition comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is accompanied by concomitant treatment with methadone or buprenorphine.

[0170] 11h. The method of any one of embodiments 1h to 10h, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with an additional active agent.

[0171] 12h. The method of embodiment 11h, wherein the additional active agent is selected from a GABA agent (eg, topiramate, baclofen, or tiagabine) or a dopamine agent (eg, a combination of bupropion, levodopa, and carbidopa).

[0172] 13h. The method of any one of embodiments 1h to 12h, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0173] 14h. The method of any one of embodiments 1h to 13h, wherein the pharmaceutical composition comprising mavogulan or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is in an immediate release form or a modified release form.

[0174] 15h. The method according to any one of embodiments 1h to 14h, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0175] 16h. The method according to embodiment 15h, wherein the pharmaceutical composition comprising an effective amount of Mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is administered with food.

[0176] 17h. The method according to embodiment 15h or 16h, wherein the pharmaceutical composition comprising an effective amount of Mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient is administered separately in the morning and evening by a 12-hour interval.

[0177] 18h. The method of any preceding embodiment, wherein the cocaine use disorder is associated with alcohol abuse.

[0178] Embodiment (j):

[0179] 1j. A method for reducing cocaine use in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient.

[0180] 2j. A method for preventing cocaine relapse in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a drug combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient.

[0181] 3j. A method for promoting abstinence from cocaine in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient.

[0182] 4j. A method for treating depression or anxiety symptoms associated with cocaine use disorder in a cocaine use disorder patient in need thereof, the method comprising administering to the cocaine use disorder patient a pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient.

[0183] 5j. The method of any one of embodiments 1j to 4j, wherein the cocaine use disorder is associated with inhalation of cocaine (i.e., smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e., snorting), or oral formulations of cocaine; in particular, associated with inhalation of cocaine (i.e., smoking).

[0184] 6j. The method of any one of embodiments 1j to 5j, wherein the cocaine use disorder is associated with a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive compulsive disorder, or binge eating disorder.

[0185] 7j. The method of any one of embodiments 1j to 6j, wherein administration of the pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is combined with standardized psychotherapy, e.g., on an individual or group level.

[0186] 8j. A method according to any one of embodiments 1j to 7j, wherein the administration of the drug combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0187] 9j. The method of embodiment 8j, wherein the psychosocial or behavioral therapy is computer-assisted.

[0188] 10j. The method of any one of embodiments 1j to 9j, wherein the administration of the pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is accompanied by concomitant treatment with methadone or buprenorphine.

[0189] llj. The method of embodiment 10j, wherein the additional active agent is selected from a GABA agent (eg, topiramate, baclofen, or tiagabine) or a dopamine agent (eg, a combination of bupropion, levodopa, and carbidopa).

[0190] 12j. The method of any one of embodiments 1j to 11j, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0191] 13j. The method according to any one of embodiments 1j to 12j, wherein the pharmaceutical combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is in an immediate release form or a modified release form.

[0192] 14j. The method according to any one of embodiments 1j to 13j, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0193] 15j. The method according to embodiment 14j, wherein the pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is administered with food.

[0194] 16j. The method according to embodiment 14j or 15j, wherein the pharmaceutical combination comprising an effective amount of mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient is administered separately in the morning and evening by a 12-hour interval.

[0195] 17j. The method of any preceding embodiment, wherein the cocaine use disorder is associated with alcohol abuse.

[0196] Other examples:

[0197] Example 1: Mavogulan or a pharmaceutically acceptable salt thereof for use in reducing cocaine use in patients with cocaine use disorder.

[0198] Example 2: Mavogulan or a pharmaceutically acceptable salt thereof for use in preventing cocaine relapse in patients with cocaine use disorder.

[0199] Example 3: Mavogulan or a pharmaceutically acceptable salt thereof is used to promote cocaine abstinence in patients with cocaine use disorder.

[0200] Example 4: Mavogulan or a pharmaceutically acceptable salt thereof for use in treating depression or anxiety symptoms associated with cocaine use disorder.

[0201] Embodiment 5: Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 4, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous injection of cocaine, nasal inhalation of cocaine (i.e. snorting) or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

[0202] Embodiment 6: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 5, wherein the cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder or bulimia.

[0203] Embodiment 7: Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 1 to 6, wherein the use is combined with standardized psychological treatment, for example, on an individual or group level.

[0204] Embodiment 8: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 7, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

[0205] Embodiment 9: Mavogulan or a pharmaceutically acceptable salt thereof, for use according to embodiment 8, wherein the psychosocial or behavioral therapy is computer-assisted.

[0206] Embodiment 10: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 9, wherein the use is accompanied by methadone or buprenorphine treatment.

[0207] Embodiment 11: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1 to 10, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

[0208] Embodiment 12: Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of Embodiments 1 to 11, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

[0209] Embodiment 13. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 12, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

[0210] Embodiment 14: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1 to 13, wherein Mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

[0211] Embodiment 15: Mavogulan or a pharmaceutically acceptable salt thereof, for use according to any one of the preceding embodiments, wherein the cocaine use disorder is associated with alcoholism.

[0212] Embodiment 16: A combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional active agent or a pharmaceutically acceptable salt thereof selected from the group consisting of: a GABA agent (e.g., topiramate, tiagabine, baclofen or vigabatrin), an agonist replacement agent (e.g., modafinil, methylphenidate, methadone or buprenorphine), a dopamine agent (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole or dextroamphetamine), a D3 receptor ligand (e.g., CJB090), a corticotropin releasing factor (CRF) receptor antagonist (e.g., CP154,526), ​​a dopamine 5-hydroxytryptamine dual releaser (e.g., PAL-287), a noradrenergic agent (e.g., doxazosin, disulfiram, necastastat), a 5-HT 1A receptor partial agonists (e.g., buspirone), MU opioid agonists (e.g., buprenorphine), NET inhibitors (e.g., desipramine), and NMDA receptor antagonists (e.g., amantadine).

[0213] General terms

[0214] As used herein, the term "cocaine use disorder" or "CUD" is defined with reference to the DSM-5 criteria (i.e., according to the Diagnostic and Statistical Manual of Mental Disorders. [Diagnostic and Statistical Manual of Mental Disorders] 5th edition, Washington, DC: American Psychiatric Association, 2013), the entire contents of which are incorporated herein by reference. As used herein, the term "cocaine use disorder" is defined as a problematic pattern of cocaine use that occurs over a 12-month period that causes clinically significant impairment or distress, as manifested by at least two of the following:

[0215] 1) Cocaine is often taken in larger amounts or for longer than intended.

[0216] 2) The presence of a persistent desire to use cocaine or unsuccessful efforts to reduce or control cocaine use.

[0217] 3) Spending a significant amount of time in activities necessary to obtain cocaine, use cocaine, or recover from its effects.

[0218] 4) Craving or strong desire or wish to use cocaine.

[0219] 5) Repeated cocaine use leading to inability to fulfill major role obligations at work, school, or home.

[0220] 6) Continued cocaine use despite persistent or recurring social or interpersonal problems caused or exacerbated by the effects of cocaine.

[0221] 7) Important social, occupational, or recreational activities are abandoned or reduced because of cocaine use.

[0222] 8) Repeated use of cocaine under conditions that are harmful to the body.

[0223] 9) Continued cocaine use despite knowledge of persistent or recurring physical or psychological problems that may be caused or exacerbated by cocaine.

[0224] 10) Tolerance, defined by either: a) the need for significantly increasing amounts of cocaine to achieve intoxication or desired effects; or b) significantly diminished effects with continued use of the same amount of cocaine.

[0225] 11) Withdrawal symptoms, manifested by any of the following:

[0226] a) Typical withdrawal syndrome of cocaine:

[0227] i) cessation (or reduction) of prolonged cocaine use;

[0228] ii) Dysphoric mood and two (or more) of the following physiological changes within hours to days after cessation (or reduction) of cocaine use: fatigue; vivid, unpleasant dreams; insomnia or hypersomnia; increased appetite; psychomotor retardation or agitation.

[0229] b) Cocaine intake can relieve or avoid withdrawal symptoms.

[0230] "Cocaine use disorder" can be divided into the following three categories: mild (i.e., the presence of 2 to 3 symptoms, as defined by the DSM-5 standard), moderate (i.e., the presence of 4 to 5 symptoms, as defined by the DSM-5 standard), and severe (i.e., the presence of 6 or more symptoms, as defined by the DSM-5 standard). As used herein, in one embodiment, "cocaine use disorder" refers to "mild cocaine use disorder", "moderate cocaine use disorder", and "severe cocaine use disorder". As used herein, in another embodiment, "cocaine use disorder" refers to "mild cocaine use disorder", "moderate cocaine use disorder", or "severe cocaine use disorder".

[0231] The term "cocaine use disorder patient" refers to a patient diagnosed with CUD as defined herein. In one embodiment, the term "cocaine use disorder patient" refers to a patient diagnosed with CUD who abstains from cocaine, for example, for at least 1 day (e.g., 3 days or longer). The term "cocaine use disorder patient abstains from cocaine" refers to a patient diagnosed with CUD abstaining from cocaine for a period of time, for example, at least one day. The term "cocaine use disorder associated with alcohol abuse" refers to a patient diagnosed with cocaine use disorder and who abuses alcohol (i.e., a heavy drinker). As explained at http: / / drugabuse.com / library / alcohol-abuse / , an alcohol abuser may not drink on a consistent basis, for example, they only drink once a week, but when they drink, they may drink a lot, which can cause problems such as developing alcoholism. For clarity, herein, an alcohol abuser is not an alcohol use disorder patient (i.e., does not meet the criteria for alcohol use disorder defined with reference to the DSM-5 criteria). The term "heavy drinker" refers to a person who has a habit of using a lot of alcohol. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the Substance Abuse and Mental Health Services Administration (SAMHSA) defines "heavy alcohol use" as 5 or more consecutive days of drinking in the past month. NIAAA defines binge drinking as a drinking pattern that makes the blood alcohol concentration level (BAC) reach 0.08g / dL. Usually occurs after women take 4 alcoholic beverages and men take 5 alcoholic beverages within about 2 hours. The Substance Abuse and Mental Health Services Administration (SAMHSA) defines "binge drinking" as at least 1 day in the past month, on the same occasion (i.e., at the same time or a few hours apart from each other) men drink alcoholic beverages 5 times or more or women drink alcoholic beverages 4 times or more. As used herein, the term "alcohol", for example, relates to "beverage", "alcoholic beverage" or "drinking", refers to ethyl alcohol (i.e. ethanol (ethanol)). As used herein, the terms "drinking", "beverage" or "alcoholic beverage" are understood as "alcohol" in the context of a "standard drink", such as liquor or mixers for human consumption, where a "standard drink" is equal to 12g of ethanol.

[0232] As used herein, the term "cocaine" refers to cocaine itself (benzoylmethylecgonine free base), its salts (e.g., cocaine hydrochloride), or cocaine preparations (e.g., coca leaves, coca paste, and cocaine alkaloids (e.g., crack)), in all forms of which cocaine is the active ingredient. As used herein, the term "cocaine craving" refers to the conscious desire or strong desire to consume cocaine.

[0233] As used herein, the term "cocaine use" refers to cocaine consumption.

[0234] As used herein, the term "reduction in cocaine use" or "reduction in cocaine use" refers to a reduction in the amount or frequency of cocaine use, such as assessed by urinalysis (e.g., by measuring metabolites of cocaine in the urine, such as benzoylecgonine) or by using self-reported cocaine use and standardized tools such as the Timeline FollowBack self-report (Sobell LC, Sobell MB, 1996, Timeline FollowBack user's guide: A calendar method for assessing alcohol and drug use. Addiction Research Foundation, Toronto, Ontario, Canada; J. Anal. Toxicolo, 2002, 26:393-400).

[0235] As used herein, the term "cocaine abstinence" or "abstinence from cocaine" refers to the cessation of cocaine intake. As used herein, the term "promoting cocaine abstinence" or "promoting cocaine abstinence" refers to helping maintain abstinence from cocaine use, particularly after at least 1 day without cocaine intake, such as maintaining abstinence from cocaine use for a period of, for example, at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months or more, particularly at least 1 week or more, such as 2 weeks.

[0236] As used herein, the term "return to cocaine use" or "relapse to cocaine consumption" refers to cocaine intake (i.e., taking cocaine) after a period of abstinence from cocaine (e.g., after a period of abstinence from cocaine of at least 1 day or more, such as 3 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 6 months, or more).

[0237] As used herein, the term "preventing relapse to cocaine use" or "preventing relapse to cocaine consumption" refers to preventing a CUD patient from consuming cocaine after the patient has ceased consuming cocaine, particularly after 1 or more days without consuming cocaine. In some embodiments, the term encompasses permanent cessation of cocaine intake. In other embodiments, the term encompasses a delay in the time of relapse of cocaine intake compared to the time of relapse in a subject not administered a compound of the invention. The delay in relapse can be, for example, days (e.g., 2, 3, 4, 5, 6, 7 days), weeks (e.g., 1, 2, 3 weeks), months (e.g., 1, 2, 3, 4, 5, 6 months), or longer.

[0238] As used herein, the term "psychosocial or behavioral therapy" refers to, but is not limited to, cognitive behavioral therapy (e.g., as described in Arch. Gen. Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174), contingency management-based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1):168-174; J. Consul. Clin. Psychol. 2005; 73(2):354-59; or Case Reports in Psychiatry, Vol. 2012, Article No. 731638), community reinforcement approach-based therapy (e.g., as described in Drug Alcohol Depend [Drug Alcohol Depend] 2004; 74: 1-13), motivational interviewing-based therapy (e.g. as described in J. Consul. Clin. Psychol. [Clinical Psychology] 2001; 69 (5): 858-62), motivational reinforcement-based therapy (e.g. as described in Drug Alcohol Depend [Drug Alcohol Depend] 2007, 91: 97-101) or meditation-based therapy, such as transcendental meditation therapy (e.g. as described in Addiction [Addiction] 2004; 99 (7): 862-874 or J. Consul. Clin. Psychol. [Clinical Psychology] 2000; 68 (3): 515-52); in particular, contingency management-based therapy.

[0239] As used herein, the term "standardized psychotherapy" or "standardized psychological support" refers to standard counseling sessions, such as once a week, particularly counseling focused on cocaine consumption.

[0240] As used herein, the term "computer-assisted" in the expression "psychosocial or behavioral therapy is computer-assisted" refers to psychosocial or behavioral therapy (including the use of electronic tools (e.g., online tools, smartphones, wireless devices, or health apps)). As used herein, in one embodiment, the term "computer-assisted" in the expression "psychosocial or behavioral therapy is computer-assisted" is understood to mean "computer-implemented" (i.e., the psychosocial or behavioral therapy is computer-implemented).

[0241] The term "administered with food" refers to any solid or liquid food, for example, having a caloric content. The dose of mavogulan or a pharmaceutically acceptable salt thereof can be administered to the subject, for example, between thirty minutes before eating food and, for example, one hour after consumption. In particular, the administration of mavogulan or a pharmaceutically acceptable salt thereof is performed immediately after consumption of food until about thirty minutes after consumption.

[0242] The term "genetic variation" refers to a change in a gene sequence relative to a reference sequence (e.g., a common and / or wild-type sequence). A genetic variation can be a recombination event or a mutation, such as a substitution / deletion / insertion event (e.g., a point and splice site mutation). In one embodiment, the genetic variation is a genetic variation in mGluR5.

[0243] As used herein, the terms "treat," "treating," "treatment," or "therapy" mean obtaining a beneficial or desired result, such as a clinical result. The beneficial or desired result may include, but is not limited to, alleviating one or more symptoms of a patient with cocaine use disorder as defined herein, such as anxiety symptoms or depression symptoms associated with cocaine use disorder, particularly associated with abstinence from cocaine in a patient with cocaine use disorder, as defined herein. For example, one aspect of treatment is that the treatment should have minimal adverse effects on the patient, such as the agent used should have a high level of safety, such as not producing the side effects of previously known treatment regimens. As used herein, for example, with respect to a symptom of a disorder, the term "alleviate" refers to reducing at least one of the frequency and magnitude of the symptom of the disorder in a patient.

[0244] As used herein, the term "concomitantly," eg, with respect to "concomitantly with methadone or buprenorphine treatment," refers to both simultaneous and sequential administration.

[0245] As used herein, the term "subject" refers to a mammal, preferably a human (male or female).

[0246] As used herein, the term "patient" refers to a subject suffering from a disease and who would benefit from treatment.

[0247] As used herein, a subject is "in need of" a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.

[0248] The term "pharmaceutical composition" as used herein is defined to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject to treat a particular condition (i.e., a disease, disorder or condition or at least one clinical symptom thereof) affecting the subject.

[0249] As used herein, the term "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. and combinations thereof as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 22nd Edition Mack Printing Company, 2013, pp. 1049-1070). Unless any conventional carrier is incompatible with the active ingredient, it is contemplated for use in the therapeutic or pharmaceutical composition.

[0250] The terms "drug", "active substance", "active ingredient", "pharmaceutical active ingredient", "active agent" or "therapeutic agent" are understood to mean a compound, particularly a compound of the type specified herein, in free form or in pharmaceutically acceptable salt form. In particular, as used herein (e.g., in any of the above embodiments (a) to (j), or in any of the claims below), with respect to mavogulan or a pharmaceutically acceptable salt thereof in combination with another active agent, it is meant that mavogulan is combined with at least one active agent or a pharmaceutically acceptable salt thereof selected from the following: GABA agents (e.g., topiramate, tiagabine, baclofen or vigabatrin), agonist replacement agents (e.g., modafinil, methylphenidate, methadone or buprenorphine), dopamine agents (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole or dextroamphetamine), D3 receptor ligands (e.g., CJB090), corticotropin releasing factor (CRF) receptor antagonists (e.g., CP154,526), ​​dopamine 5-hydroxytryptamine dual releasers (e.g., PAL-287), noradrenergic agents (e.g., doxazosin, disulfiram, necastastat), 5-HT 1A receptor partial agonists (e.g., buspirone), MU opioid agonists (e.g., buprenorphine), NET inhibitors (e.g., desipramine), and NMDA receptor antagonists (e.g., amantadine).

[0251] The term "immediate release form" refers to a pharmaceutical composition designed to release the active substance immediately after administration in vivo.

[0252] The term "modified release form" refers to a pharmaceutical composition that does not release the active substance immediately, but rather provides a sustained, delayed, continuous, gradual, extended or pulsatile release, thereby specifically altering the drug plasma level compared to an immediate release form. The term "modified release form" encompasses forms described as: controlled release forms, sustained release forms, extended release forms and long-acting forms; in particular sustained release forms.

[0253] The term "combination" or "pharmaceutical combination" refers to a fixed combination in a unit dosage form (e.g., capsules, tablets, caplets or granules), a non-fixed combination or a kit of parts for combined administration, wherein the compound of the invention and one or more combination partners (e.g., another drug specified herein, also referred to as an additional "pharmaceutically active ingredient", "therapeutic agent" or "adjuvant") can be administered separately and simultaneously or at intervals, especially when these intervals allow the combination partners to show cooperation, such as synergistic effects. As used herein, the terms "co-administration" or "combined administration" and the like are intended to cover the administration of the selected combination partners to a single subject (e.g., patient) in need, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or are administered simultaneously. The term "fixed combination" means that the active ingredients (e.g., the compound of the invention and one or more combination partners) are all administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" refers to that the active ingredients (e.g., the compound of the invention and one or more combination partners) are all administered to the patient as separate entities simultaneously or sequentially without specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the patient.

[0254] The compounds of the present invention can be administered separately by the same or different routes of administration as other medicaments, or administered together in the same pharmaceutical composition. In the combination therapy of the present invention, the compounds of the present invention and other therapeutic agents can be produced and / or formulated by the same or different manufacturers. In addition, the compounds of the present invention and another therapeutic agent can be formed into a combination therapy together: (i) before issuing a combination product to a physician (e.g., in the case of a kit comprising a compound of the present invention and another therapeutic agent); (ii) performed by a physician himself (or under the guidance of a physician) shortly before administration; (iii) performed in the patient himself, for example, during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0255] As used herein, the terms "a", "an", "the" and similar terms used in the context of the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0256] The use of any and all examples, or exemplary language (eg, "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.

[0257] As used herein, as used herein above and below, the compound of the present invention having the following formula (alternatively referred to as Compound (I)) is the mGluR5 antagonist (-)-(3aR, 4S, 7aR)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-m-tolylethynyl-octahydro-indole, also known as (-)-(3aR, 4S, 7aR)-4-hydroxy-4-[2-(3-tolyl)ethynyl]perhydroindole-1-carboxylic acid methyl ester, also known as Mavogulan:

[0258]

[0259] It can be prepared as described, for example, in WO 2003 / 047581 (e.g. in Example 1), or as described in WO 2010 / 018154. WO 2003 / 047581 (which is incorporated herein by reference) also describes its in vitro biological data, according to page 7. As used herein, "Mavogulan" refers to the free form, and any reference to "its pharmaceutically acceptable salt" refers to its pharmaceutically acceptable acid addition salt. As used herein, the term "Mavogulan or a salt thereof, such as its pharmaceutically acceptable salt", unless otherwise stated, should therefore be interpreted in the context of the present invention (particularly in the context of any embodiment, and the claims) as covering its free form and its pharmaceutically acceptable salt.

[0260] In one embodiment, compound (I) is also intended to represent an isotope-labeled form. An isotope-labeled compound has the structure shown in the above formula, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present invention include, for example, isotopes of hydrogen, i.e., compounds with the following formula:

[0261]

[0262] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 and R 23 Each is independently selected from H or deuterium; provided that at least one deuterium is present in the compound. In other embodiments, multiple deuterium atoms are present in the compound.

[0263] In addition, the incorporation of certain isotopes, especially deuterium (i.e. 2 H or D) can provide certain therapeutic advantages caused by higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements or improvement of therapeutic index or tolerability. It should be understood that deuterium is considered to be a substituent of the compounds of the present invention in this article. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specific isotope. If a substituent in a compound of the invention is represented as deuterium, the isotopic enrichment factor of the compound for each designated deuterium atom is at least 3500 (52.5% deuterium incorporation per designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0264] Other examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen (except deuterium), carbon, nitrogen, oxygen and fluorine, for example 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. Thus, it will be understood that the present invention includes compounds incorporating one or more of any of the above isotopes, including, for example, radioactive isotopes, such as 3 H and 14 C, or into which non-radioactive isotopes such as 2 H and 13 C. Such isotope-labeled compounds can be used in metabolic studies (using 14 C) reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation therapy for patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to the preparation of the compounds of the invention described by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0265] As used herein, the term "free form" or "free forms" refers to a compound in non-salt form, such as a base free form or an acid free form of the corresponding compound (e.g., a compound indicated herein (e.g., Mavogulan or other pharmaceutically active ingredient, e.g., as defined herein)).

[0266] As used herein, the term "salt / salts" or "salt form" refers to an acid addition salt or base addition salt of the corresponding compound, such as a compound indicated herein (e.g., mavogulan or other pharmaceutically active ingredients, e.g., as defined herein). "Salts" specifically include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound, and these salts are typically not biologically or otherwise undesirable. The compounds specified herein (e.g., mavogulan or other pharmaceutically active ingredients, e.g., as defined herein) can form acid salts and / or base salts by the presence of amino and / or carboxyl groups or similar groups thereof. The compounds of the present invention are capable of forming acid addition salts, and therefore, as used herein, the term mavogulan pharmaceutically acceptable salt means a pharmaceutically acceptable acid addition salt of mavogulan.

[0267] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0268] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0269] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0270] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0271] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0272] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0273] Pharmaceutically acceptable salts can be synthesized by basic or acidic moieties by conventional chemical methods. Generally, the free acid form of the compound can be reacted with a stoichiometric amount of a suitable base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base form of the compound with a stoichiometric amount of a suitable acid to prepare these salts. Such reactions are generally carried out in water or an organic solvent or a mixture of the two. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. The list of other suitable salts can be found, for example: "Remington's Pharmaceutical Sciences", 22nd edition Mack Publishing Company (Mack Printing Company) (2013); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, 2011, 2nd edition) written by Stahl and Wermuth.

[0274] The compounds specified herein (e.g., mavogulan or another pharmaceutically active ingredient, e.g., as defined herein) can be administered by conventional routes, in particular orally, such as in the form of tablets, capsules, caplets or granules, which can be manufactured according to pharmaceutical techniques known in the art (e.g., "Remington Essentials of Pharmaceutics", 2013, 1st edition, edited by Linda Felton, published by Pharmaceutical Press in 2012, ISBN 978 0 85711105 0; in particular Chapter 30), wherein pharmaceutical excipients are, for example, as described in "Handbook of Pharmaceutical Excipients", 2012, 7th edition, edited by Raymond C. Rowe, Paul J. Sheskey, Walter G. Cook and Marian E. Fenton, ISBN 978 0 85711 027 5". In particular, WO 2014 / 199316 describes formulations comprising mavogulan, in particular a modified release form thereof, and is incorporated herein by reference (more particularly the examples, preferred embodiments and claims therein).

[0275] The pharmaceutical composition or combination of the present invention may be in a unit dosage form (e.g., tablets, capsules, caplets or granules) containing an amount of mavogulan ranging from 1 mg to 300 mg, particularly 50 mg to 200 mg, for example 50 mg to 100 mg, more particularly 200 mg (referring to the amount of the free form of mavogulan, and if its salt is used, the amount will be adjusted accordingly; in particular, mavogulan is in free form). For the above-mentioned uses / treatment methods, the appropriate dose may vary according to a variety of factors (e.g., age, body weight, sex, route of administration or salt used). In patients weighing, for example, 50-70 kg, the specified daily dose is, for example, 200 mg / bid (referring to the amount of the free form of mavogulan, and if its salt is used, the amount will be adjusted accordingly).

[0276] abbreviation

[0277] BE = Benzoylecgonine

[0278] EtG = ethyl glucuronide

[0279] CM = Contingency Management

[0280] DSM 5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

[0281] CUD = cocaine use disorder

[0282] PK = Pharmacokinetics

[0283] TLFB = Timeline Tracking

[0284] mg = milligrams

[0285] bid=bid=twice a day

[0286] mmHg = millimetres of mercury

[0287] msec = milliseconds

[0288] HIV = Human Immunodeficiency Virus

[0289] ELISA = enzyme-linked immunosorbent assay

[0290] ECG = electrocardiogram

[0291] QT = time from the beginning of the Q wave to the end of the T wave

[0292] T wave = positive deflection after each QRS complex

[0293] ST wave = the time from the beginning of the S wave to the end of the T wave

[0294] QRS = time from the beginning of the Q wave to the end of the T wave

[0295] QTcF = Fridericia QT correction formula

[0296] SoA = Standard of Care

[0297] SSRI = selective serotonin reuptake inhibitor

[0298] C-SSRS = Columbia-Suicidality Severity Rating Scale

[0299] hCG = human chorionic gonadotropin

[0300] AST = aspartate aminotransferase

[0301] ALT = alanine aminotransferase

[0302] ULN = Upper limit of normal

[0303] GGT = gamma-glutamyl transpeptidase

[0304] AV block = atrioventricular block

[0305] UDS = Urinary Drug Screen

[0306] MDMA = 3,4-methylenedioxy-methamphetamine

[0307] MDEA = 3,4-methylenedioxy-N-ethylamphetamine

[0308] MDA = 3,4-methylenedioxy-amphetamine

[0309] Examples

[0310] The following examples serve to illustrate the present invention without limiting its scope. As used in the context of these examples, the term "Mavogulan" refers to the free form.

[0311] Example 1:

[0312] Evaluation of the effects of mavogulan on cocaine dependence and cocaine relapse in the Sprague-Dawley rat using an intravenous self-administration model

[0313] animal

[0314] Adult male Sprague-Dawley rats (reaching 300-325 g) from Harlan Laboratories (Indiana, USA) were used. Upon arrival, a unique identification number (tail tag) was assigned to the rats. The animals were housed in a suspended polycarbonate rat cage with a filter top and adapted for up to 7 days. Before starting the study, all rats were inspected, handled and weighed to ensure adequate health and suitability. During the study, a 12 h / 12 ​​h light / dark cycle was maintained. The room temperature was 21 ° C-23 ° C, and the relative humidity was maintained at 30%-70%. Water was provided ad libitum during the study.

[0315] Test compound

[0316] Cocaine hydrochloride (Sigma-Aldrich, USA) (1.05 mg / ml, equivalent to 0.3 mg / kg / infusion at 350 g body weight and 0.1 ml / infusion rate) was dissolved in saline (0.9% NaCl). The formulation was a clear solution.

[0317] Mavogulan (free form) was formulated in 0.5% methylcellulose (MC) at 1, 3 and 10 mg / kg and orally administered at a dose of 1 ml / kg 60 minutes before testing.

[0318] equipment

[0319] Intravenous drug self-administration is carried out in a sound-reduced operating room equipped with an exhaust fan (Med Associates, VT). Each chamber contains two levers located on one wall of the chamber. Only one of the two levers is active (located on the left side). Pressing the active lever will result in the delivery of a reinforcement (food or cocaine). The other lever is "inactive", that is, pressing will not deliver any reinforcement. A stimulus light is located above each lever, but during the timeout period (timeout period) (defined below), only the stimulus light above the active lever is turned on. There is a room light (providing lighting) at the top of the opposite wall. For food training (see details below), a pellet container for delivering food pellets (Bio-Serv's dust-free precision pellets #F0165, 45 mg) is placed between the two levers. The infusion pump installed above each chamber delivers the drug solution through a polyethylene tube connected to a single-channel fluid swivel joint, which is installed on a balance arm above the operating chamber. The output end of the swivel joint is attached to the external end of the intravenous catheter.

[0320] method

[0321] Phase I: Acute effects of mavogulan on cocaine self-administration in rats

[0322] Food training and surgery

[0323] Before intravenous cannulation surgery, rats were trained to press the active lever to obtain food. After rat food restriction and reaching about 85% of free feeding body weight, food training was started. After obtaining the lever pressing response to obtain food, rats were implanted with jugular vein catheters (Access Technologies, USA). The catheter was flushed with 0.2 ml heparin-enrofloxacin solution every day to avoid blockage and ensure smooth drug infusion. The flushing solution was made in a unit of 50 ml volume, which contained 1500 U heparin and 320 mg enrofloxacin. The solution was stored in sterile vials in a refrigerator at 4° C. Rats were fed ad libitum two days before surgery and throughout the recovery period.

[0324] During the study period, methohexital sodium ( Henry Schein Animal Health (USA) was used to confirm proper infusion via the implanted catheter. Brevital is a short-acting barbiturate that, when infused through the catheter, produces significant sedation within seconds. Brevital testing (0.2 ml of a 1% solution) was performed after both acquisition phases and after the compound testing phase of Phase I. Animals that did not immediately develop sedation were removed from the experiment.

[0325] Acquisition of cocaine self-administration responses

[0326] One week after surgery, during the entire study, the food of the rats raised in a single cage was restricted and the body weight was maintained at about 85% of the free-feeding body weight matched with their age. Then, through a fixed ratio (FR) feeding plan, rats were allowed to press the active lever to self-administer cocaine. In this study, the FR5 schedule was used, i.e., five lever presses delivered a dose of cocaine. The dose of cocaine was 0.3mg / kg / infusion, which was equal to 0.105mg / rat (350g) per infusion (0.1ml solution). Each cocaine infusion lasted 1.0 seconds. Cocaine delivery had a 20-second timeout, during which no drug was delivered even if the active lever was pressed. During the timeout, the stimulus light above the active lever was turned on. After 15 days of training, all rats showed a high and stable number of cocaine presses. Each training or test phase lasted 1 hour.

[0327] Drug treatment of Mawogulan

[0328] After a stable baseline of cocaine self-administration was established, pharmacology studies were initiated (less than 20% variation in daily drug infusion for 3 consecutive days; at least 6 drug infusions per session). Pharmacology studies were conducted twice weekly (usually on Wednesdays and Fridays), with baseline cocaine training maintained on the other days.

[0329] N = 12

[0330] vehicle

[0331] Mawogulan 1mg / kg

[0332] Mawogulan 3mg / kg

[0333] Mawogulan 10mg / kg

[0334] Phase II: Effects of mavogulan on relapse of cue-induced self-administration responding

[0335] Food training and surgery

[0336] Methods for food training, catheterization, flushing, and infusion confirmation were the same as those in Phase I.

[0337] get

[0338] This phase of cocaine self-administration training was conducted in a separate group of rats (N=32). The training method was the same as that of Phase I, but the cue (flash plus tone) was presented simultaneously during the cocaine infusion, and the cue light remained on for a 20-second timeout. As in Phase I, the rats underwent 15 days of acquisition training.

[0339] Elimination and cue-induced relapse

[0340] After reaching a stable rate of cocaine self-administration, rats underwent a 9-day elimination procedure that was similar to acquisition training (except that pressing the active lever resulted in a saline infusion instead of a cocaine infusion). During the elimination phase, no prompts appeared after pressing the active lever. On the 9th (last day) of elimination training, all rats reached the criteria for elimination (number of infusions ≤ 5 times, i.e., the number of active lever press responses < 30 times within a 1-hour period).

[0341] During the relapse phase, which was conducted one day after the last elimination phase, rats were shown prompts (flash + tone) at the beginning of the phase, and their lever pressing responses were recorded. There was no cocaine infusion during this relapse phase, and subjects received saline only on a FR5 schedule. An independent group design was used in this study, i.e., before the relapse phase, about half of the rats (N=15 after infusion confirmation) were administered an optimal dose of Mavogulan, and about half of the rats (N=14 after infusion confirmation) were administered a vehicle. Based on the results of Phase I, the optimal dose of Mavogulan used in Phase II was 10 mg / kg.

[0342] result

[0343] Phase I: Acute effects of mavogulan on cocaine self-administration

[0344] Acquisition of cocaine dependence

[0345] Acquisition of cocaine self-administration in Phase I Figure 1 After confirmation of correct infusion of Brevital, the study included twelve rats per group. Cocaine self-administration increased steadily during the first week of training and stabilized during the second week of training. Learning was confirmed by two-way ANOVA (training day effect: F[14,330]=6.199; P<0.001). There was a significant group x day interaction (F[1,330]=4.850, P<0.05), however post hoc comparisons did not reveal any significant differences between the groups on each training day, confirming comparable self-administration performance between the groups (subgroups).

[0346] Acute effects of mavogulan on cocaine self-administration

[0347] For subgroup Ib, a one-way ANOVA with repeated measures confirmed the significant effect of mavogulan [treatment effect: F(3,33)=6.358; P<0.01]. Post hoc comparisons further confirmed that mavogulan tended to reduce responses on the active lever at 3 mg / kg (p<0.10), and significantly reduced responses at 10 mg / kg (p<0.001).

[0348] Phase II: Effects of Mavogulan on Relapse to Cue-Induced Self-Administration

[0349] Acquisition and elimination of cocaine dependence

[0350] Acquisition of cocaine self-administration Figure 3The two groups (subgroups) included 14 and 15 rats after confirmation of correct infusion of Brevital. Like Phase I, cocaine self-administration increased steadily during the first week of training and stabilized during the second week of training. Two-way ANOVA confirmed a significant effect of training day (F[14,405]=3.463; P<0.001) and no differences between subgroups (F[1,405]=1.538, ns), indicating comparable learning performance between the two groups.

[0351] During the extinction phase, responses on the active lever gradually and significantly decreased, as confirmed by two-way ANOVA (effect of day: F[8,243]=41.635; P<0.001). Although there was also a significant main effect of subgroup (F[1,243]=5.306, P<0.05), post hoc comparisons showed that performance was comparable between groups during each extinction phase. All rats reached extinction criterion by 9 days of training.

[0352] Relapse of cue-induced self-administration responses

[0353] Effects of vehicle and mavogulan (10 mg / kg, PO, 1 hour before testing) on ​​relapse of cue-induced self-administration responding Figure 4 Two-way ANOVA confirmed a significant effect of phase (extinction vs. relapse, F[1,54] = 12,690; P < 0.001), a significant effect of treatment (vehicle vs. mavogulin, F[1,54] = 8.194; P < 0.01), and a significant treatment x phase interaction (F[1,54] = 12,805; P < 0.001). Post hoc analyses indicated that the phase effect was attributable solely to vehicle treatment, i.e., when the cue induced a significant relapse of active lever pressing (P < 0.001), cue-induced relapse was inhibited in mavogulin-treated rats.

[0354] in conclusion:

[0355] This study investigated the efficacy of mavogulan in a rat model of cocaine self-administration and in a reintroduction model of cocaine re-administration (i.e., cue-induced relapse).Mavogulan (10 mg / kg, PO, 1 hour before testing) significantly reduced cocaine self-administration in rats.

[0356] Furthermore, after extinction of self-administration responding, mavogulan (10 mg / kg, PO, 1 hour before testing) completely prevented the relapse of cue-induced self-administration responding.

[0357] In conclusion, this study demonstrates that mavogulan is effective in a rat model of cocaine self-administration, as well as in a model of reuse.

[0358] Example 2:

[0359] Placebo-controlled study in patients with CUD

[0360] Study objectives and end points

[0361]

[0362]

[0363] Study Design

[0364] This was a randomized, subject- and investigator-blinded, parallel-group, placebo-controlled study in patients with CUD. The study consisted of a screening period of approximately 21 days, followed by a 7-day baseline; a 98-day outpatient treatment period (a 14-day up-titration dosing regimen, followed by 84 days of maintenance dosing) and a final end-of-study visit evaluation approximately 14 days after the last study drug administration. The total duration of each patient in the study was up to approximately 20 weeks. The study design is summarized in Protocol 1, as Figure 5 shown.

[0365] Study Visits: (Days 1-112) Study visits were conducted twice weekly in an ambulatory setting. During these visits, urine samples were collected for drug screening (cocaine BE and other drug metabolites) and safety / efficacy assessments.

[0366] Screening (Day -28 to Day -8): Includes safety screening and other clinical testing to determine initial patient eligibility. Patients who meet eligibility criteria at Screening will be admitted for baseline assessment.

[0367] Baseline (Day -7 to Day -1): In addition to safety assessments, patient self-assessments were included using various scales and questionnaires. During baseline, self-reported history of cocaine use (TLFB) and two urine samples were collected on two different days, with a second urine sample collected 3 days prior to randomization to demonstrate abstinence from cocaine use.

[0368] Treatment (Days 1-98): After baseline, eligible patients were randomized in a 1:1 ratio to either mavogulan (free form) or placebo on Day 1.

[0369] Group A - Mavogulan (free form): First two weeks of titration regimen: 50 mg bid from days 1 to 7, 100 mg bid from days 8 to 14, then 200 mg bid for 84 days

[0370] The dose selected for evaluation in this study (200 mg bid / modified release formulation) was selected based on safety, tolerability, and pharmacokinetic data from the full mavogulan study.

[0371] Group B: matching placebo.

[0372] Study medication was taken twice daily (bid) with food, in the morning and evening (separated by approximately 12 hours intervals). For all ambulatory morning visits involving any study assessments or PK / urine sample collections, study medication was self-administered by the patient at the study center and supervised by the study staff. On these days, a standard breakfast was provided by the study center and consumed by the patient during his / her medication intake.

[0373] During treatment, patients should also undergo assessments with various scales and questionnaires, as well as safety assessments and pharmacokinetic sampling prior to and 2 ± 1 h after dosing, according to the SoA dose.

[0374] Urine samples (Days 1-113): Samples were collected twice weekly at the study center with at least 48 hours of separation testing, e.g., Tuesday and Friday or Monday and Thursday or Tuesday morning and Thursday afternoon. Staff observed sample collection and analyzed quantitatively for the presence of cocaine and alcohol metabolites [benzoylecgonine (BE) and ethyl glucuronide (EtG)]. Urine samples were collected during the study: 28 samples from patients continuing treatment for 14 weeks (4 samples in weeks 1-2 of titration); 24 samples in weeks 3-14 (maintenance dosing); 4 samples were collected in weeks 15-16 (follow-up) and 1 final sample was collected at the end of the study visit. If a patient failed to attend the clinic or refused to provide a sample on the scheduled testing day, the sample was considered positive unless the absence was allowed (e.g., illness, other personal reasons). If a sample was missing or refused, it was collected on the next day whenever possible.

[0375] Clinical support to ensure medication and regimen adherence:

[0376] Contingency Management (CM) and Psychosocial Support: In addition to study treatment, all patients received weekly on-site contingency management (CM) therapy focused on patient adherence and retention to treatment. In addition, they received standardized psychosocial support at least once a week.

[0377] Medication compliance: Patients were dosed in the morning on study site PK collection days and all other days involving urine sampling assessments when study drug was administered. On these days, self-administration of study drug was supervised by the investigator, and compliance was ensured by oral verification after swallowing the drug. To monitor medication compliance, patients were provided with a personal medication diary (booklet) to record the administration of study drug. Medication compliance was monitored by the investigator and / or study staff using tablet counts at least once a week. Dosage compliance was verified by comparing the patient's medication diary self-reported data with the total number of tablets in the returned bottle or blister (depending on the packaging format). Compliance was calculated as the total number of tablets ingested during the treatment phase divided by the total planned intake. If the investigator deems it appropriate, the patient may be contacted during the clinic to confirm compliance.

[0378] group

[0379] Patients aged 18-65 years diagnosed with CUD who used intranasal cocaine were enrolled in the study.

[0380] People with CUD

[0381] The investigator ensures that all subjects considered for the study meet one or more of the following eligibility criteria. No additional criteria are applied by the investigator. Subject selection is established by checking all eligibility criteria at screening and baseline. Relevant records of the eligibility criteria (e.g., checklists) are stored with the source files at the research site.

[0382] Deviation from any of the participation criteria excluded the subject from the study.

[0383] Inclusion Criteria

[0384] 1. Understand the study procedures and provide written informed consent before any assessment.

[0385] 2. Male and female subjects aged 18 to 65 years (inclusive) diagnosed with cocaine use disorder according to DSM 5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition).

[0386] 3. Cocaine must be administered intranasally.

[0387] 4. Recent cocaine use confirmed by positive urine screening for 1 or more benzoylecgonines (BE)

[0388] 5. Must be seeking treatment for cocaine dependence and expect to reduce or stop cocaine use based on the goals of the baseline assessment.

[0389] 6. Must abstain from cocaine use for at least 3 days prior to first dose (Day 1), as assessed by self-reported TLFB and two* urinalysis samples at baseline.

[0390] *The difference in BE levels between the two baseline samples must be reduced

[0391] 7. Must be in good health, confirmed by medical history, physical examination and screening.

[0392] 8. At Screening and Baseline, vital signs (systolic and diastolic blood pressure and pulse rate) must be within acceptable ranges (accounting for the increasing effect of cocaine on pulse rate by the investigator) for the purpose of qualifying the subject. Investigators may be instructed to use the following ranges:

[0393] Systolic blood pressure 90-150 mmHg

[0394] Diastolic blood pressure 50-90 mmHg

[0395] Three readings are acceptable. At least one of the three readings must be within the acceptable range.

[0396] 9. The patient must be able to:

[0397] Communicate verbally with researchers and understand written instructions

[0398] · Express willingness to complete all study procedures

[0399] Verbally acknowledge that she / he is able to attend every scheduled visit and that she / he does not have any planned events or activities that could materially interfere with study participation

[0400] Exclusion criteria

[0401] 1. History of hypersensitivity to any study treatment or excipients or to drugs of similar chemical class.

[0402] 2. A current diagnosis of a substance use disorder (according to DSM 5) for alcohol or other stimulants (except cocaine).

[0403] 3. Current or lifetime DSM 5 criteria for schizophrenia or any psychotic or organic mental disorder.

[0404] Note: Subjects diagnosed with other psychiatric disorders may be included if treatment for the co-occurring psychiatric disorder does not interfere with the completion of the study or place the patient at higher risk by participating in the trial.

[0405] 4. Current treatment for substance use disorder (e.g., disulfiram, acamprosate, methylphenidate, modafinil, topiramate, immediate-release dexamethasone, or baclofen).

[0406] 5. Requires treatment with any psychotropic medication, including any anti-epileptic medication (except for short-term treatment of insomnia)

[0407] Notice:

[0408] SSRI's may be used if adequate stable doses have been achieved for at least 1 month prior to administration

[0409] 6. Use of other study drugs at screening, or within 5 half-lives or 30 days before enrollment, or longer as permitted by local regulations (whichever is longer).

[0410] 7. Pregnant or lactating (lactating) women, where pregnancy is defined as the state of a woman from conception until termination of pregnancy, as confirmed by a positive hCG laboratory test

[0411] 8. Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant unless they use effective contraception during the dosing period and for 30 days after the last dose of study drug*.

[0412] *Effective contraceptive methods include:

[0413] Total abstinence (when this is consistent with the subject's preference and usual lifestyle). NOTE: Cyclic abstinence (e.g., by calendar, by ovulation, by temperature, post-ovulation methods) and withdrawal are not acceptable methods of contraception

[0414] Female sterilization (bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks prior to study treatment. Note: In the case of oophorectomy alone, only if the female's reproductive status has been confirmed by subsequent hormone level assessment

[0415] Male sterilization (at least 6 months prior to screening). For female subjects in the study, the vasectomized male partner must be the subject's only partner

[0416] Barrier methods: condoms or occlusive caps (diaphragms or cervical / vault caps) with spermicidal foam / gel / film / cream / suppositories; intrauterine device (IUD); or

[0417] Intrauterine system (IUS)

[0418] Injectable or implantable or oral or transdermal hormonal contraceptives are not considered effective methods of contraception if taken with study medication.

[0419] Women are considered postmenopausal and of no reproductive potential if they have had 12 months of natural (spontaneous) amenorrhea and have appropriate clinical findings (eg, appropriate age, history of vasoconstrictive symptoms).

[0420] 9. History of porphyria.

[0421] 10. History of or presence of malignancy in any organ system (except localized basal cell carcinoma of the skin or in situ cervical cancer) that has been treated or untreated in the past 5 years (regardless of whether there is evidence of local recurrence or metastasis)

[0422] 11. Any disease, condition, or history of drug use that, in the opinion of the investigator or designated personnel, may confound the study results or bring additional risks when administering the study drug to the subject, or prevent the successful completion of the study

[0423] 12. Any surgical or medical condition that may significantly alter the absorption, distribution, metabolism, or excretion of the drug, or that may endanger the subject during study participation. The investigator will make this determination based on the subject's medical history and / or clinical or laboratory evidence of the following conditions during screening:

[0424] Clinical laboratory values ​​(including AST, ALT, total bilirubin, or creatinine) that were considered clinically unacceptable in the CUD population at screening by the investigator:

[0425] ALT and serum bilirubin should not exceed 2x ULN

[0426] GGT, AST, and alkaline phosphatase should not exceed 5x ULN.

[0427] If the safety laboratory assessment at screening is outside the above range, the assessment can be repeated once before randomization. If the repeated value remains outside the specified range, the subject will be excluded from the study.

[0428] 13. Current and / or previous concomitant treatment with drugs that are strong or moderate inducers / inhibitors of CYP3A4 (e.g., clarithromycin, ketoconazole, ritonavir, etc.)

[0429] 14. Concomitant use of drugs known to prolong the QT interval, unless these drugs can be permanently discontinued during the study.

[0430] 15. Current diagnosis of ECG abnormalities or history of ECG abnormalities at screening or baseline, indicating a significant safety risk for the subject participating in the study, such as:

[0431] Concomitant clinically significant arrhythmias, such as sustained ventricular tachycardia and clinically significant second- or third-degree AV block without a pacemaker

[0432] History of familial long QT syndrome or known family history of torsades de pointes

[0433] QTcF>450 milliseconds (male); QTcF>460 milliseconds (female)

[0434] Note: Sinus tachycardia, left axis deviation, and nonspecific ST or T wave changes are not excluded

[0435] 16. Known history or presence of cardiovascular or cerebrovascular diseases such as: angina pectoris, myocardial infarction, stroke, transient ischemic attack, peripheral vascular disease.

[0436] 17. History of immunodeficiency, including positive HIV (ELISA and Western blot) test results.

[0437] 18. Chronic infection with hepatitis B (HBV) or hepatitis C (HCV).

[0438] 19. Please mark “yes” on item 4 or 5 of the suicidal ideation section of the C-SSRS if suicidal ideation has occurred within the past 6 months, or “yes” on any item in the suicidal behavior section (except “non-suicidal self-injurious behavior” which is also included in the suicidal behavior section) if the behavior has occurred within the past 2 years.

[0439] 20. Patients cannot:

[0440] Any major problems with transportation arrangements or anticipated time availability to travel to the study site, and any plans to move to a location in the next few months that would make continued participation in the study impractical

[0441] Involvement in any unresolved legal issues that could jeopardize the continuation or completion of the research

[0442] Statistical models and analytical methods

[0443] The primary variable was the proportion of days of cocaine use during the treatment period (days 1-98).

[0444] For each patient, the proportion of days with cocaine use was calculated by dividing the number of days with cocaine use during the treatment period, i.e., the full 98 days, by the number of days between the first and last day of dosing (if study treatment was discontinued prematurely). was treated as a continuous variable. Cocaine consumption (yes / no) was recorded daily using the TLFB throughout the study.

[0445] A Bayesian analysis was performed on the proportion of days of cocaine use. It was assumed to be a continuous outcome with normally distributed errors. A linear model with treatment factors and past cocaine consumption as covariates was fitted. Uninformative priors were used for all parameters. Past cocaine consumption was the proportion of days of cocaine use in the 3 months prior to the screening visit, estimated using the TLFB. The model estimated the posterior probability that the difference in the proportion of days of cocaine use between mavogulan and placebo was <0 (i.e. <-10%). Based on the documentation of this indication, a 10% difference in days is considered to be a minimal clinically relevant effect, whereas a 20% difference is a very promising effect.

[0446] A study showed a positive signal for efficacy if both of the following criteria were met:

[0447] 1. There is at least 90% probability that the difference in the proportion of days of cocaine use between mavogulan and placebo is < 0

[0448] 2. There is at least a 50% probability that the difference in the proportion of days of cocaine use between mavogulan and placebo is <-10%

[0449] If the distribution of the data was not normal, sensitivity analyses were performed using alternative models (e.g., negative binomial regression). In addition, longitudinal data (weekly use) were analyzed using mixed models for repeated measures to compare consumption characteristics between treatment groups over time.

[0450] Secondary variables: include the proportion of negative UDS during treatment and will be analyzed in the same manner as the primary variable. Safety and PK are secondary endpoints of this study.

Claims

1. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating the reduction of cocaine use in patients with cocaine use disorder.

2. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing cocaine use disorder patients from relapsing into cocaine.

3. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for promoting abstinence from cocaine in patients with cocaine use disorder.

4. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating depression or anxiety symptoms associated with cocaine use disorder.

5. Use of mavogulan or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment according to any one of claims 1 to 4, wherein the cocaine use disorder is associated with inhaled cocaine (i.e. smoking), intravenous cocaine injection, nasal inhalation of cocaine (i.e. snorting) or oral formulations of cocaine; in particular, associated with inhaled cocaine (i.e. smoking).

6. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 5, wherein cocaine use disorder is accompanied by a psychiatric disorder, such as antisocial personality disorder, borderline personality disorder, depression, anxiety, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder or bulimia.

7. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treatment according to any one of claims 1 to 6, wherein the use is administered in conjunction with standardized psychological treatment, for example, on an individual or group level.

8. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 7, wherein the use is administered in combination with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management.

9. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to claim 8, wherein the psychosocial or behavioral therapy is computer-assisted.

10. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 9, wherein the use is concomitant with methadone or buprenorphine treatment.

11. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 10, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in combination with another active agent.

12. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of any one of claims 1 to 11, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with cocaine use disorder.

13. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 12, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an immediate release form or a modified release form.

14. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment according to any one of claims 1 to 13, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered in an amount from 50 mg / bid to 200 mg / bid, in particular 50 mg / bid, 100 mg / bid or 200 mg / bid, for example 200 mg / bid.

15. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment according to any one of the preceding claims, wherein the cocaine use disorder is associated with alcoholism.

16. A combination comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional active agent selected from the group consisting of a GABA agent (e.g., topiramate, tiagabine, baclofen or vigabatrin), an agonist replacement agent (e.g., modafinil, methylphenidate, methadone or buprenorphine), a dopamine agent (e.g., bupropion, a combination of levodopa and carbidopa, risperidone, olanzapine, aripiprazole or dextroamphetamine), a D3 receptor ligand (e.g., CJB090), a corticotropin releasing factor (CRF) receptor antagonist (e.g., CP154,526), ​​a dopamine 5-hydroxytryptamine dual releaser (e.g., PAL-287), a noradrenergic agent (e.g., doxazosin, disulfiram, necastastat), a 5-HT 1A receptor partial agonists (e.g., buspirone), MU opioid agonists (e.g., buprenorphine), NET inhibitors (e.g., desipramine), and NMDA receptor antagonists (e.g., amantadine).

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