Use of macvalerian for reducing alcohol use or for preventing reuse of alcohol

Abstract

The present invention relates to the use of macvalerian or a pharmaceutically acceptable salt thereof in reducing the use of alcohol in patients with alcohol use disorder; application in preventing alcohol reuse of a patient with alcohol use disorder; application in promoting alcohol abstinence of a patient with alcohol use disorder; use in the treatment of depression or anxiety symptoms associated with alcohol use disorders.

Description

[0001] This application is a divisional application of a Chinese patent application filed on July 30, 2018, with Chinese patent application number 201880046607.X and invention name “Use of Mavogulan in reducing alcohol use or preventing alcohol re-use”, and this application claims the priority of US62 / 539,008. Technical Field

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

[0003] Alcohol use disorder (AUD) is a complex mental disorder, 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), which continues to develop into a serious global health problem that has adverse effects on medicine, society and economy. To date, the U.S. Food and Drug Administration (FDA) has only approved three drugs for the treatment of AUD (i.e., disulfiram, naltrexone and acamprosate), and the European Medicines Agency (EMA) has also approved nalmefene. Due to the heterogeneity of AUD, the efficacy of these drugs is only moderate, so there is still a high medical need to find more effective and safer drugs for the treatment of AUD (Alcohol Clin Exp Res [Alcoholism-Clinical and Experimental Research], Vol. 40, No. 7, 2016, 1368-1379). Other pharmacological agents that have been tested include, for example, opioid antagonists (e.g., nalmefene), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., verucerfont, pexacerfont), NK1R antagonists (e.g., tradipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines), voltage-gated sodium channel inhibitors (e.g., oxacarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride) and α2 adrenergic receptor agonists (e.g. clonidine).

[0004] In 1995, English et al. published a review (The quantification of drug caused morbidity and mortality in Australia [In Australia, the quantification of drugs leads to morbidity and mortality]. Federal Department of Public Services and Department of Health, Canberra) to disclose the health problems caused by long-term or habitual alcohol consumption. Adverse medical consequences derived from the use of alcohol are, for example, (but not limited to) cardiovascular disorders (e.g., hypertension, stroke, arrhythmia, cardiomyopathy), gastrointestinal disorders (e.g., gastritis, pancreatitis, cirrhosis, gastric or duodenal ulcers) and cancers (e.g., oropharyngeal cancer, esophageal cancer, liver cancer, gastric cancer). Further associated health risks include infectious diseases (e.g., hepatitis C or HIV), and serious medical accidents that can ultimately lead to death. In addition, additional dangers associated with AUD include the risk of accidents, injuries and violence. In addition, it is common that patients with alcohol use disorders are accompanied by mental disorders, such as depression, anxiety, bipolar disorder and schizophrenia.

[0005] The complete biological mechanisms of alcohol dependence are still not fully understood. Therefore, pharmacotherapy for alcohol use disorder focuses on the various stages that patients with alcohol use disorder may go through, and therefore targets different aspects, such as: i) attenuating the reinforcing effects of alcohol consumption (e.g., pleasurable subjective effects such as mild euphoria), ii) acting as a "replacement therapy" for alcohol, iii) relieving alcohol withdrawal symptoms (e.g., alcohol craving and anxiety). Pharmacotherapy for AUD can also be divided into three stages: a) from withdrawal to abstinence, with the goal of guiding patients to give up alcohol consumption (e.g., such as providing treatment with benzodiazepines, gabapentin, pregabalin, and baclofen), b) abstinence and relapse prevention (e.g., such as providing treatment with acamprosate, naltrexone, or disulfiram), and c) reducing alcohol consumption (e.g., such as providing treatment with nalmefene).

[0006] The search for pharmacological treatments for patients with alcohol use disorder is complicated by the high propensity for relapse in these patients (Addiction, 2006, 101, 212-222), and the high rate of early discontinuation in clinical trials (Alcohol Clin Exp Res, 1996, 20, 16-20). Thus, the treatment of alcohol use disorder is a significant challenge and a high medical need, particularly the search for medications that can help achieve or maintain abstinence from alcohol use.

[0007] Preclinical models have shown that other mGluR5 antagonists (e.g. MPEP [i.e. 2-methyl-6-(2-phenylethynyl)pyridine] or MTEP [i.e. 3-[2-(2-methylthiazol-4-yl)ethynyl]pyridine]) reduce ethanol self-administration in mice (e.g. in Sharko, AC et al., Soc. Neurosci. Abstr. [Social Neuroscience. Abstract] 783.781, 2002; or in Olive, MF, et al., Mol. Pharmacol. [Molecular Pharmacology] 2005, 67:349-3550). However, due to their shortcomings as therapeutic agents, neither MTEP nor MPEP has been further developed (Keck et al., 2013, Psychopharmacology [Psychopharmacology], 229(2):253-65): for example, MTEP has been shown to effectively inhibit cytochrome P450 1A2 and rapid metabolism (Smith et al. 2004, Bioorg Med Chem Lett [Bioorganic and Medicinal Chemistry Letters] 14:5481-5484) and, for example, MPEP has shown off-target effects on the NMDA receptor, monoamine oxidase, and norepinephrine transporter (Cosford et al., J. Med. Chem. [Journal of Medicinal Chemistry], 2003, 46(2), pp. 204-206; O'Leary et al., 2000, Br J 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).

[0008] It has been discovered that mavogulan may be an ideal candidate for the treatment of patients diagnosed with alcohol use disorder, providing therapeutic advantages for this patient population, such as one or more of the following:

[0009] i) it promotes abstinence from alcohol, e.g., compared to placebo, e.g., by maintaining abstinence or reducing the amount or frequency of alcohol use, e.g., as assessed by urinalysis [e.g., by measuring metabolites of alcohol in urine, such as ethyl glucuronide (EtG)] or by using standardized instruments such as self-reported alcohol use and timeline follow-up 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];

[0010] ii) it reduces relapse to alcohol use, for example compared to placebo, e.g. in a treatment program (e.g. a clinical trial) where it increases time to relapse or the rate of relapse in patients;

[0011] iii) which reduces (e.g., by elimination or by reduction in intensity, duration, or frequency) one or more symptoms associated with alcohol use disorder selected from the group consisting of:

[0012] 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

[0013] 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].

[0014] 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;

[0015] 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);

[0016] vi) it has a favorable therapeutic profile, e.g., a favorable safety profile or metabolic profile, e.g., favorable profiles 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, e.g., reduced genotoxicity) than one or more known therapeutic agents that have been shown to be effective in the treatment of alcohol use disorder; or

[0017] 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

[0018] The present invention relates to the use of Mawogulan or a pharmaceutically acceptable salt thereof in the following:

[0019] - Use in reducing alcohol use in patients with alcohol use disorder;

[0020] - Use in preventing relapse in patients with alcohol use disorder;

[0021] - Use in promoting abstinence from alcohol in patients with alcohol use disorder;

[0022] - Use in the treatment of depressive or anxiety symptoms associated with alcohol use disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 : Cocaine (0.3 mg / kg / infusion, FR5) self-administration learning curve in Phase I. Data represent mean + SEM. N = 12 per treatment group.

[0024] Figure 2 : Acute effects of mavogulan on cocaine self-administration in two subgroups of rats. Data represent mean + SEM. Asterisks ( : P < 0.001) indicates significant difference compared with saline or vehicle treatment. N = 12 per treatment group.

[0025] Figure 3 : Acquisition and extinction of cocaine self-administration responding (Phase II) in two subgroups of rats. Data represent mean + SEM. n = 14-15 per group.

[0026] 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) indicates significant difference. N = 14-15 per treatment group. 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 alcohol use in patients with alcohol use disorder.

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

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

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

[0033] 5a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1a to 4a, wherein the alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[0034] 6a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1a to 5a, wherein the alcohol 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 or a 12-step facilitation therapy.

[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 accompanied by 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 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g. nalmefene, naltrexone), CB-1 antagonists (e.g. rimonabant), CRH1 receptor antagonists (e.g. reluxofene, pexaserfone), NK1R antagonists (e.g. trodipitant), OTR agonists (e.g. oxytocin), GABA agents (e.g. topiramate, baclofen, benzodiazepines (e.g. alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g. oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g. gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g. varenicline), 5-HT3 antagonists (e.g. ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 in the morning and evening separately by an interval of 12 hours.

[0046] 18a. Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of the preceding embodiments, wherein the alcohol 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 alcohol use in patients with alcohol use disorder.

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

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

[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 alcohol use disorder.

[0052] 5b. A pharmaceutical composition for use according to any one of embodiments 1b to 4b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption of ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[0053] 6b. A pharmaceutical composition for use according to any one of Examples 1b to 5b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein alcohol 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.

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

[0055] 8b. A pharmaceutical composition for use according to any one of embodiments 1b to 7b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management or a 12-step facilitation therapy.

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

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

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

[0059] 12b. A pharmaceutical composition for use according to embodiment 11b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the additional active agent or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2AReceptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

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

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

[0062] 15b. A pharmaceutical composition for use according to any one of Examples 1b to 14b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, 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 for use according to embodiment 15b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

[0064] 17b. A pharmaceutical composition for use according to Example 15b or 16b, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, 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 for use according to any one of the preceding embodiments, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the alcohol 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 alcohol use in patients with alcohol 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 alcohol relapse in patients with alcohol 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 alcohol in patients with alcohol use disorders.

[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 alcohol use disorder.

[0071] 5c. A pharmaceutical combination for use according to any one of Examples 1c to 4c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, wherein the alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[0072] 6c. A drug combination for use according to any one of Examples 1c to 5c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, wherein the alcohol 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 for use according to any one of embodiments 1c to 6c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, wherein the use is combined with standardized psychotherapy, for example, at the individual or group level.

[0074] 8c. A pharmaceutical combination for use according to any one of Examples 1c to 7c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management or a 12-step facilitation therapy.

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

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

[0077] 11c. A drug combination for use according to any one of embodiments 1c to 10c, comprising mavogulan or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active ingredient, wherein the additional active agent or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluzofan, pexaserfon), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

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

[0079] 13c. A pharmaceutical combination for use according to any one of Examples 1c to 12c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, 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 for use according to any one of Examples 1c to 13c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, 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. The pharmaceutical combination for use according to embodiment 14c, comprising mavogulan or a pharmaceutically acceptable salt thereof, and at least one additional pharmaceutically active ingredient, wherein mavogulan or a pharmaceutically acceptable salt thereof is administered with food.

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

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

[0086] 2d. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing alcohol relapse in patients with alcohol use disorder.

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

[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 alcohol 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 alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[0090] 6d. The use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of embodiments 1d to 5d, wherein the alcohol 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 or a 12-step facilitation therapy.

[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 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 the alcohol use disorder is associated with alcoholism.

[0103] Embodiment (e):

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

[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 alcohol 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 alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[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 alcohol 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 or a 12-step facilitation therapy.

[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 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines such as alprazolam, diazepam, lorazepam), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2AReceptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol use disorder.

[0117] 14e. 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, which is 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 alcohol 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 alcohol use in patients with alcohol use disorders.

[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 alcohol relapse in patients with alcohol use disorders.

[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 alcohol in patients with alcohol use disorders.

[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 alcohol 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 alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[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 alcohol 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 a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management or a 12-step facilitation therapy.

[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 and at least one additional pharmaceutically active ingredient according to any one of embodiments 1f to 10f, wherein the additional active agent or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 the alcohol use disorder is associated with alcoholism.

[0140] Embodiment (g):

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

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

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

[0145] 5g. The method of any one of embodiments 1g to 4g, wherein the alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for males and ≥40 g / day of ethanol for females).

[0146] 6g. The method of any one of embodiments 1g to 5g, wherein the alcohol 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.

[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 or a 12-step facilitation therapy.

[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 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 alcohol use disorder is associated with alcohol abuse.

[0159] Embodiment (h):

[0160] 1h. A method for reducing alcohol use in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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 alcohol relapse in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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 alcohol in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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 alcohol use disorder in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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 alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for males and ≥40 g / day of ethanol for females).

[0165] 6h. The method of any one of embodiments 1h to 5h, wherein the alcohol 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.

[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. The 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 or a 12-step facilitation therapy.

[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 or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2AReceptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 alcohol use disorder is associated with alcohol abuse.

[0178] Embodiment (j):

[0179] 1j. A method for reducing alcohol use in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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.

[0180] 2j. A method for preventing alcohol relapse in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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 alcohol in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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.

[0182] 4j. A method for treating depression or anxiety symptoms associated with alcohol use disorder in an alcohol use disorder patient in need thereof, the method comprising administering to the alcohol 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.

[0183] 5j. The method of any one of embodiments 1j to 4j, wherein the alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for males and ≥40 g / day of ethanol for females).

[0184] 6j. The method of any one of embodiments 1j to 5j, wherein the alcohol 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.

[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. The method according to any one of embodiments 1j to 7j, 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 combined with a psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management or a 12-step facilitation therapy.

[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] 11j. The method of embodiment 10j, wherein the additional active agent or a pharmaceutically acceptable salt thereof is selected from the group consisting of: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[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 an alcohol 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 alcohol use disorder is associated with alcohol abuse.

[0196] Other examples:

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

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

[0199] Example 3: Mavogulan or a pharmaceutically acceptable salt thereof for use in promoting abstinence from alcohol in patients with alcohol use disorders.

[0200] Example 4: Mavogulan or a pharmaceutically acceptable salt thereof for use in treating depression or anxiety symptoms associated with alcohol 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 alcohol use disorder is associated with acute problematic high-risk drinking (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

[0202] Embodiment 6: Mavogulan or a pharmaceutically acceptable salt thereof for use according to any one of Embodiments 1 to 5, wherein the alcohol 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.

[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 or a 12-step facilitation therapy.

[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 an alcohol 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 alcohol 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: opioid antagonists (e.g., nalmefene, naltrexone), CB-1 antagonists (e.g., rimonabant), CRH1 receptor antagonists (e.g., reluxofene, pexaserfone), NK1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[0213] General terms

[0214] As used herein, the term "alcohol use disorder" or "AUD" is defined with reference to 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 "alcohol use disorder" is defined as a problematic pattern of alcohol 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) Alcohol is often consumed in larger amounts or for longer than intended.

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

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

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

[0219] 5) Repeated alcohol use that results in an inability to fulfill major role obligations at work, school, or home.

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

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

[0222] 8) Repeated use of alcohol in situations that are harmful to the body.

[0223] 9) Continuing to use alcohol despite knowledge that the person has persistent or recurring physical or mental problems that may be caused or aggravated by alcohol.

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

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

[0226] a) Typical alcohol withdrawal syndrome:

[0227] i) Stopping (or reducing) alcohol use can be burdensome and long-lasting

[0228] ii) Two (or more) of the following within hours to days after cessation (or reduction) of alcohol use: autonomic hyperactivity (e.g., sweating or pulse greater than 100 bpm); increased hand tremor; insomnia; nausea or vomiting; transient visual, tactile, or auditory hallucinations or delusions; psychomotor agitation; anxiety; generalized tonic-clonic seizures.

[0229] b) Ingestion of alcohol (or closely related substances such as benzodiazepines) may alleviate or prevent withdrawal symptoms.

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

[0231] The term "alcohol use disorder patient" refers to a patient diagnosed with AUD as defined herein. In one embodiment, the term "alcohol use disorder patient" refers to a patient diagnosed with AUD, and the patient quits alcohol, for example, for at least 1 day (e.g., 3 days or longer). The term "alcohol use disorder patient quits cocaine" refers to a patient diagnosed with AUD quitting alcohol for a period of time, for example, at least 1 day. The term "alcohol abuse" refers to an alcohol abuser (i.e., a large number of drinkers). As explained by 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 drinking, they may drink a lot, which can cause problems such as suffering from alcohol poisoning. For clarity, herein, an alcohol abuser is not an alcohol use disorder patient (i.e., does not meet the drinking disorder standard defined with reference to the DSM-5 standard). The term "large number of drinkers" refers to a person with a large number of alcohol use habits. 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 binge drinking on 5 or more consecutive days in the past month. NIAAA defines binge drinking as a pattern of drinking that results in a blood alcohol concentration (BAC) level of 0.08 g / dL. This usually occurs after consuming 4 alcoholic drinks for women and 5 alcoholic drinks for men within approximately 2 hours. The Substance Abuse and Mental Health Services Administration (SAMHSA) defines "bind drinking" as consuming 5 or more alcoholic drinks for men or 4 or more alcoholic drinks for women on the same occasion (i.e., at the same time or within a few hours of each other) on at least 1 day in the past month.

[0232] As used herein, the term "alcohol", e.g., in relation to a "beverage", "alcoholic beverage" or "drinking", refers to ethyl alcohol (i.e., ethanol). As used herein, the term "alcohol craving" refers to a conscious desire or strong wish to consume alcohol.

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

[0234] As used herein, the term "reduced alcohol use" or "reduction in alcohol use" refers to a reduction in the amount or frequency of alcohol use, such as assessed by urinalysis [e.g., by measuring metabolites of alcohol in urine, such as ethyl glucuronide (EtG)] or by using self-reported alcohol use and standardized tools such as timeline tracking 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). In one embodiment, "reduced alcohol use" or "reduction in alcohol use" refers to a reduction in drinking per day, a reduction in drinking per drinking day, or a reduction in the frequency of drinking, such as a reduction in the percentage of drinking days or the percentage of heavy drinking days. In another embodiment, "reduced alcohol use" or "reduction in alcohol use" refers to an increase in the time to any drinking or the time to the first heavy drinking. As used herein, the terms "drinking", "beverage" or "alcoholic beverage" are understood as "alcohol" in the context of a "standard drink", such as a spirit or blend for human consumption, where a "standard drink" equals 12 g of ethanol. As used herein, the term "heavy drinking day" refers to a daily total alcohol consumption of ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women.

[0235] As used herein, the term "alcohol abstinence" or "abstinence from alcohol" refers to the cessation of alcohol intake. As used herein, the term "promoting alcohol abstinence" or "promotion of alcohol abstinence" refers to helping maintain abstinence from alcohol use, particularly after at least 1 day without alcohol intake, such as maintaining abstinence from alcohol 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 "relapse into alcohol use" or "relapse into alcohol consumption" refers to alcohol intake (i.e., taking alcohol) after a period of abstinence from alcohol, such as after a period of abstinence from alcohol 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 alcohol re-use" or "preventing relapse of alcohol consumption" refers to preventing AUD patients from consuming alcohol after the patient stops consuming alcohol, particularly after 1 day or more of no alcohol intake. In some embodiments, the term encompasses permanent cessation of alcohol intake. In other embodiments, the term encompasses a delay in the time of reuse of alcohol intake compared to the time of reuse of a subject to whom the compounds of the present invention are not administered. The delay in reuse can be, for example, a few days (e.g., 2, 3, 4, 5, 6, 7 days), a few weeks (e.g., 1, 2, 3 weeks), a few months (e.g., 1, 2, 3, 4, 5, 6 months), or longer.

[0238] As used herein, the term "AUD is associated with high-risk drinking for acute problems" refers to alcohol use disorder associated with daily alcohol consumption of ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women (International Guide for Monitoring Alcohol Consumption and Related Harm, WHO / MSD / MSB / 00.4; World Health Organization 2000, p. 51: http: / / www.who.int / iris / handle / 10665 / 66529).

[0239] As used herein, the term "impulsivity" refers to the tendency to react quickly and unplanned to internal or external stimuli with reduced consideration of the negative consequences of these reactions to the impulsive individual or others (Moeller FG et al., Am J Psychiatry. 2001; 158: 1783-1793).

[0240] As used herein, the term "psychosocial or behavioral therapy" refers to, but is not limited to, 12-step facilitation therapy [e.g., NIAAA, Project MATCH Monograph Series. Vol. 1, NIH Publication No. 94-3722, (1995) reprinted 1999], 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 2004; 74: 1-13), motivational interviewing-based therapy (e.g., as described in J. Consul. Clin. Psychol. 2001; 69(5): 858-62), motivational reinforcement-based therapy (e.g., as described in Drug Alcohol Depend 2007, 91: 97-101), or meditation-based therapy, such as transcendental meditation therapy (e.g., as described in Addiction 2004; 99(7): 862-874 or J. Consul. Clin. Psychol. 2000; 68(3): 515-52); in particular, therapy based on contingency management.

[0241] As used herein, the term "standardized psychotherapy" or "standardized psychological support" refers to standard counseling sessions, e.g., once a week, particularly counseling focused on alcohol consumption.

[0242] 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).

[0243] 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.

[0244] 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 (such as a point and splice site mutation). In one embodiment, the genetic variation is a genetic variation in mGluR5.

[0245] As used herein, the term "treat", "treating", "treatment" or "therapy" means obtaining a beneficial or desired result, such as a clinical result. Beneficial or desired results may include, but are not limited to, alleviating one or more symptoms of an alcohol use disorder patient as defined herein, such as anxiety symptoms or depression symptoms associated with alcohol use disorder, particularly associated with abstinence from alcohol by an alcohol use disorder patient, as defined herein. For example, one aspect of treatment is that the treatment should have minimal adverse effects on the patient, such as the medicament 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 the symptoms of a disorder, the term "alleviate" refers to reducing at least one of the frequency and amplitude of the symptoms of the disorder in the patient.

[0246] As used herein, the term "concomitantly," eg, with respect to "concomitantly with methadone or buprenorphine treatment," refers to both simultaneous and sequential administration.

[0247] As used herein, the term "subject" refers to a mammal, preferably a human (male or female).

[0248] As used herein, the term "patient" refers to a subject suffering from a disease and who would benefit from treatment.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] The terms "drug", "active substance", "active ingredient", "pharmaceutical active ingredient", "active agent" or "therapeutic agent" should be understood to mean a compound in free form or in pharmaceutically acceptable salt form, in particular a compound of the type specified herein. In particular, as used herein (for example 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 refers to mavogulan in combination with at least one active agent or a pharmaceutically acceptable salt thereof selected from the group consisting of opioid antagonists (for example nalmefene, naltrexone), CB-1 antagonists (for example rimonabant), CRH1 receptor antagonists (for example reluserf, pexaserfon), NK 1R antagonists (e.g., trodipitant), OTR agonists (e.g., oxytocin), GABA agents (e.g., topiramate, baclofen, benzodiazepines (e.g., alprazolam, diazepam, lorazepam)), voltage-gated sodium channel inhibitors (e.g., oxcarbazepine, valproic acid, zonisamide), voltage-dependent calcium channel agonists (e.g., gabapentin, pregabalin), α7 nicotinic acetylcholine receptor agonists (e.g., varenicline), 5-HT3 antagonists (e.g., ondansetron), 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

[0253] The term "immediate release form" refers to a pharmaceutical composition designed to release the active substance immediately after administration in vivo.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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:

[0260] .

[0261] 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 a pharmaceutically acceptable salt thereof, unless otherwise indicated, 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.

[0262] 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:

[0263]

[0264] 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.

[0265] 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.

[0266] 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 3H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or for radiation therapy of patients. In particular, 18F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to the preparation of the described compounds of the present invention by using suitable isotope-labeled reagents instead of previously used non-labeled reagents.

[0267] 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)).

[0268] 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.

[0269] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids.

[0270] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0271] 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.

[0272] Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases.

[0273] 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.

[0274] 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.

[0275] 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 in, for example: "Remington's Pharmaceutical Sciences", 22nd edition, Mack Printing Company (2013); and Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH Press, Weinheim, 2011, 2nd edition).

[0276] 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 85711 105 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).

[0277] 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).

[0278] abbreviation

[0279] BE = Benzoylecgonine

[0280] EtG = ethyl glucuronide

[0281] CM = Contingency Management

[0282] DSM 5 = Diagnostic and Statistical Manual of Mental Disorders, 5th edition.

[0283] AUD = Alcohol Use Disorder

[0284] CUD = cocaine use disorder

[0285] PK = Pharmacokinetics

[0286] TLFB = Timeline Tracking

[0287] mg = milligrams

[0288] bid=bid=twice a day

[0289] mmHg = millimetres of mercury

[0290] msec = milliseconds

[0291] HIV = Human Immunodeficiency Virus

[0292] ELISA = enzyme-linked immunosorbent assay

[0293] ECG = electrocardiogram

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

[0295] T wave = positive deflection after each QRS complex

[0296] ST wave = the time from the beginning of the S wave to the end of the T wave

[0297] QRS = time from the beginning of the Q wave to the end of the T wave

[0298] QTcF = Fridericia QT correction formula

[0299] SoA = Standard of Care

[0300] SSRI = selective serotonin reuptake inhibitor

[0301] C-SSRS = Columbia-Suicidality Severity Rating Scale

[0302] hCG = human chorionic gonadotropin

[0303] AST = aspartate aminotransferase

[0304] ALT = alanine aminotransferase

[0305] ULN = Upper limit of normal

[0306] GGT = gamma-glutamyl transpeptidase

[0307] AV block = atrioventricular block

[0308] UDS = Urinary Drug Screen

[0309] MDMA = 3,4-methylenedioxy-methamphetamine

[0310] MDEA = 3,4-methylenedioxy-N-ethylamphetamine

[0311] MDA = 3,4-methylenedioxy-amphetamine

[0312] Examples

[0313] 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.

[0314] Example 1:

[0315] Evaluation of the effects of mavogulan on cocaine dependence and cocaine relapse in Sprague-Dawley rats using an intravenous self-administration model

[0316] animal

[0317] Adult male Sprague-Dawley rats (reaching 300-325 g) from Harlan Laboratories (Indiana, USA) were used. Upon arrival, rats were assigned unique identification numbers (tail tags). Animals were housed in single cages in suspended polycarbonate rat cages with filter tops 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. Room temperature was 21 ° C-23 ° C, and relative humidity was maintained at 30%-70%. Water was provided ad libitum during the study.

[0318] Test compound

[0319] 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.

[0320] 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 the test.

[0321] equipment

[0322] 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 fluid swivel joint is attached to the external end of the intravenous catheter.

[0323] method

[0324] Phase I: Acute effects of mavogulan on cocaine self-administration in rats

[0325] Food training and surgery

[0326] 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 0.2ml heparin-enrofloxacin solution every day to avoid blockage and ensure smooth drug infusion. The flushing solution was made in a unit of 50ml volume, containing 1500U heparin and 320mg enrofloxacin (Baytril®). The solution was stored in a sterilized bottle in a 4°C refrigerator. Two days before surgery and throughout the recovery process, rats were fed freely.

[0327] During the study, methohexital sodium (Brevital®, 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 tests (0.2 ml of a 1% solution) were performed after the acquisition phase of both phases and after the compound testing phase of Phase I. Animals that did not immediately develop sedation were removed from the experiment.

[0328] Acquisition of cocaine self-administration responses

[0329] 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.

[0330] Drug treatment of Mawogulan

[0331] 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.

[0332] N = 12

[0333] vehicle

[0334] Mawogulan 1mg / kg

[0335] Mawogulan 3mg / kg

[0336] Mawogulan 10mg / kg

[0337] Phase II: Effects of mavogulan on relapse of cue-induced self-administration responding

[0338] Food training and surgery

[0339] Methods for food training, catheterization, flushing, and infusion confirmation were the same as those in Phase I.

[0340] get

[0341] 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.

[0342] Elimination and cue-induced relapse

[0343] 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).

[0344] 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.

[0345] result

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

[0347] Acquisition of cocaine dependence

[0348] 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).

[0349] Acute effects of mavogulan on cocaine self-administration

[0350] 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).

[0351] Phase II: Effects of Mavogulan on Relapse to Cue-Induced Self-Administration

[0352] Acquisition and elimination of cocaine dependence

[0353] Acquisition of cocaine self-administration Figure 3 The 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.

[0354] 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.

[0355] Relapse of cue-induced self-administration responses

[0356] 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.

[0357] in conclusion:

[0358] 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.

[0359] 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.

[0360] In summary, this study shows that mavogulan is effective in a rat model of cocaine self-administration and a multiple use model. Based on these results and the known role of mGluR5 receptors in substance use disorders (e.g., in Glutamate-based therapies for psychiatric disorders, Springer 2000, ISBN 978-3-0346-0240-2, pp. 133-147: Metabotropic glutamate receptors as targets for the treatment of drug and alcohol dependence), it is expected that the mGluR5 antagonist mavogulan will be effective in the alcohol self-administration model and the alcohol multiple use model. Similarly, preclinical models have shown that other mGluR5 antagonists such as MPEP [i.e., 2-methyl-6-(2-phenylethynyl)pyridine], which reduces cocaine self-administration in mice (e.g., in Chiamulera, C. et al., Nat. Neurosci. [Nature Neuroscience] 2001, 4, 873-874), reduces cocaine self-administration in rats (e.g., in Kenny, PJ et al., Behav. Pharmacol [Behavioral Pharmacology] 14, S55) and also reduces ethanol self-administration in mice (e.g., in Sharko, AC et al., Soc. Neurosci. Abstr. [Social Neuroscience Abstracts] 783, 781, 2002) or such as MTEP [i.e., 3-[2-(2-methylthiazol-4-yl)ethynyl]pyridine], which reduces ethanol consumption in mice (e.g., in Olive, MF, et al., Mol. Pharmacol. [Behav ... . [Molecular Pharmacology] 2005, 67: 349-3550) and reducing cocaine self-administration in rats (Martin-Fardon R., et al., J. Pharmacol Exp Ther [Journal of Pharmacology and Experimental Therapeutics] 2009, 329 (3): 1084).

[0361] 2. Clinical testing:

[0362] Clinical testing of mavogulan can be conducted, for example, according to standard clinical practice (eg, placebo-controlled studies in patients with alcohol use disorders, such as those in Clinicaltrials.gov; in opentrials.net), for example, by dosing 200 mg bid of its modified release formulation (free form).

Claims

1. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating patients with alcohol use disorders to reduce alcohol use.

2. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating patients with alcohol use disorders to prevent alcohol relapse.

3. Use of mavogulan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating patients with alcohol use disorders to promote alcohol abstinence.

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

5. Use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 for the manufacture of a medicament for treatment, wherein the alcohol use disorder is associated with high-risk drinking for acute problems (i.e., wherein the alcohol use disorder is associated with daily alcohol consumption ≥60 g / day of ethanol for men and ≥40 g / day of ethanol for women).

6. Use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 for the manufacture of a medicament for treatment, wherein alcohol 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 according to any one of claims 1 to 6 for the manufacture of a medicament for treatment, 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 according to any one of claims 1 to 7 for the manufacture of a medicament for treatment, wherein the use is combined with psychosocial or behavioral therapy or a combination thereof, in particular a therapy based on contingency management or a 12-step facilitation therapy.

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

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

11. Use of mavogulan or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 for the manufacture of a medicament for treatment, 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 according to any one of claims 1 to 11 for the manufacture of a medicament for treatment, wherein the patient has a genetic variation associated with a substance use disorder, such as a genetic variation associated with an alcohol use disorder.

13. Use of Mavogulan or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 for the manufacture of a medicament for treatment, 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 according to any one of claims 1 to 13 for the manufacture of a medicament for treatment, 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 according to any one of the preceding claims for the manufacture of a medicament for use in the treatment of an alcohol use disorder 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 an opioid antagonist (e.g., nalmefene, naltrexone), a CB-1 antagonist (e.g., rimonabant), a CRH1 receptor antagonist (e.g., reluxofene, pexaserfone), a NK1R antagonist (e.g., trodipitant), an OTR agonist (e.g., oxytocin), a GABA agent (e.g., topiramate, baclofen, a benzodiazepine (e.g., alprazolam, diazepam, lorazepam)), a voltage-gated sodium channel inhibitor (e.g., oxcarbazepine, valproic acid, zonisamide), a voltage-dependent calcium channel agonist (e.g., gabapentin, pregabalin), an α7 nicotinic acetylcholine receptor agonist (e.g., varenicline), a 5-HT3 antagonist (e.g., ondansetron), a 5-HT 1A Partial receptor agonists (eg, aripiprazole), 5-HT 2A Receptor antagonists (e.g. quetiapine, olanzapine, mirtazapine), 5-HT reuptake inhibitors (e.g. trazodone), SERT inhibitors (e.g. duloxetine), α1 adrenergic receptor antagonists (e.g. doxazosin, prazosin), glucocorticoid receptor antagonists (e.g. mifepristone), α1 adrenergic receptor agonists (e.g. guanfacine), AChE inhibitors (e.g. citicoline), dopamine D2 receptor antagonists (e.g. tiapride), α2 adrenergic receptor agonists (e.g. clonidine), NMDA receptor antagonists (e.g. acamprosate), and aldehyde dehydrogenase inhibitors (e.g. disulfiram).

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