BRPI0710699A2 - use of a muscarinic agonist - Google Patents

Abstract

USE OF A MUSCARINIC AGONIST The invention relates to a new use of compounds and pharmaceutically acceptable salts thereof which are muscarinic agonists, in particular muscarinic-1 (Ml). These compounds are useful for the preparation of drugs for the treatment, relief or prevention of impulse control disorders. These include impulse control disorders Not Classified Elsewhere, such as intermittent explosive disorder, pyromania, kleptomania, pathological gambling mania and trichotillomania; and Otherwise Unspecified impulse control disorders, such as: compulsive shopping disorder, food hunger attacks and drink hunger attacks, self-injurious impulse behavior, such as pathologically pricking the skin, biting nails and stick your finger in the nose, ocular self-mutilation, head banging and self-biting; paraphilic sexual addictions, lack of control of a person's sexual impulses, including exhibitionism, fetishism, frotourism, pedophilia, masochism, sadism, transsexual fetishism and vouyerism, as well as compulsive use of the Internet and excessive use of cell phones.

Description

"USE OF A MUSCARINE AGONIST"

BACKGROUND OF THE INVENTION

An impulsive person is apt to move through a sudden impulse. This behavior is often associated with a lack of self-control. Impulsiveness, therefore, has a substantial impact on individuals as well as on society. Impulse control disorders (ICD's) are characterized by failure to resist an impulse, compulsion, or temptation to perform an act that is detrimental to the person or others. In most cases, the individual has a growing sense of detention or arousal before committing the act and then experiences pleasure, gratification or relief at the time of committing the act. After the act is performed, he may or may not feel remorse or guilt.

Impulse control disorders are a distinct group of psychiatric disorders, listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a residual category consisting of "Not Classified Elsewhere" (NEC) impulse control disorders. and "Not Otherwise Specified" (NOS) impulse control disorders. The first consist of: intermittent explosive disorder, pyromania, kleptomania, apostarpatological mania and trichotillomania. No specific disturbance is mentioned in the DSM-IV under the heading: "NOS impulse control disorders", but this group is defined as "a category of impulse control disorders that does not meet the criteria for any specific impulse control disorder or for any other mental disorder with characteristics involving impulse control (such as borderline, antisocial, histrionic and narcissistic personality disorders) ". In scientific and patent literacy, a number of such impulse control disorders, also referred to as "atypical impulse control disorders" are described, for example: compulsive buying disorder, food voracity attack and drink voracity attack, self-injurious impulse behavior, such as poking the skin pathologically, biting the nails and sticking the finger in the nose, self-mutilation, head banging and self-bite; paraphilic sexual addictions, lack of control of a person's sexual impulses, including exhibitionism, fetishism, fleet tourism, pedophilia, masochism, sadism, trans-fetishism and vouyerism, as well as compulsive Internet use and excessive cell phone use.

Patients suffering from impulse control disorder have been treated through psychotherapy, behavior modification, hypnosis, relaxation therapy, and administration of various pharmaceutical preparations, the latter with little or no success. Historically, impulse control disorders have been considered resistant to known pharmacological or psychotherapeutic treatments. Therefore, there is a continuing need for agents that will be effective in treating ICD-associated symptoms, either by eliminating or reducing them. In different patents and patent applications, a variety of molecular mechanisms are claimed to be of therapeutic value in impulse control disorders: opioid (US 5,780,479), anticonvulsant (WO 02/43731) antagonists; serotonin antagonists (US 2001023254), 5-HT1A agonists (WO 94/13659), serotonin reuptake inhibitors (WO 92/18005) and cannabinoid antagonists (US 2004/0077650).

Muscarinic agonists have been claimed as treatment for cognitive impairment, psychosis, affective disorders, mania and behavioral disorders (WO 2006/067494, WO 2006/017614 and EP 0525 879), as well as for the treatment of tics, tremors and related disorders (US2004 / 116505). These disorders are very distinct from impulse control disorders (DSM-IV).

DETAILED DESCRIPTION OF THE INVENTION The object of the present invention is to develop drugs for impulse control disorder atherapy which have a different donation mechanism than those currently on the market and which are likely to improve impulsivity control without negative effects on attention and concentration.

Surprisingly, muscarinic agonists were found to be active in a predictive animal model of impulsive behavior in humans: the attenuation of MK801 induced an increase in early rat responses in the 5-choice reaction time task, an effect associated with impulsive behavior. (Cole, 1987; Ruotsaiainen, 2000). Muscarinic agonists are active at doses ranging from 0.1-100 mg / kg after oral administration and their unique pharmacological profile clearly indicates therapeutic potential in impulse control disorders.

In a preferred embodiment, the invention encompasses the following muscarinic agonists: AF-150, AF-151, alvamelin, ACP-104, CDD-34, CDD-98, CDD-0097, CDD-0102, CDD-190, CDD-0199- J, CDD-0235-J, CDD-0304, cevimeline, CPR-2006, CS-932, desmethylclozapine, FPL-14995, FPL-15467, KAD-193R, L-680648, L-687306, L-689660, MCNA- 343, milameline, nebracetam, NGX-267, PD-151832, sabcomelin, SDZ-210-086, SR-46559A, talsaclidine fumarate, tazomelin, xanomelin, YM-796 and YM-954.

Most preferred is the use of the xanomelin muscarinic agonist.

The compounds of the invention of the general formula (1), as well as pharmacologically acceptable bones thereof, have muscarinic doreceptor agonistic activity. They are useful in the treatment of impulse control disorders, including intermittent explosive disorder, pyromania, kleptomania, pathological gambling, trichotillomania, eating disorder, food voracity attacks and drink-raving attacks, self-injurious impulse behavior, such as pathologically scratching the skin, biting the nails and sticking the finger in the nose, eye self-mutilation, headbanging and self-bite; paraphilic sexual addictions, lack of control of a person's sexual impulses, including exhibitionism, fetishism, fleet tourism, pedophilia, masochism, sadism, transvestic fetishism, and vouyerism; compulsive use of the Internet and excessive use of mobile phones.

DEFINITIONS

DSM-IV: Impulse Control Disorders Classified Elsewhere (NEC)

Intermittent Explosive Disorder (IED) is a disease characterized by the occurrence of distinct episodes of failure to resist aggressive impulses that result in severe attacks or destruction of property. The degree of aggressiveness expressed during an episode is excessively out of proportion to any provocation or psychosocial precipitation. The diagnosis of FDI is made only after other mental disorders that could account for episodes of aggressive behavior have been excluded (eg, antisocial personality disorder, borderline personality disorder, a psychotic disorder, a manic episode, conduct disorder, or ADHD). . In FDI, aggressive episodes are not due to the direct physiological effects of a substance (eg, drug addiction or medication) or a general medical condition (eg, head trauma). Patients may describe aggressive episodes as "phases" of "attacks" in which explosive behavior is preceded by a feeling of tension or excitement and is immediately followed by a feeling of relief. Then the individual may feel distressed, remorseful, regretful or ashamed of aggressive behavior.

Pyromania, also referred to as arsonism, pyrophilia, or pathologically provoking fires, is characterized by the presence of multiple episodes of deliberate and deliberate fire provocation. Patients experience thrilling tension or arousal prior to igniting a fire and are characterized by fascination with interest in, curiosity for, or attraction to. fires and their situational contexts.

Individuals with this disorder are often regular bystanders of fire in their vicinity, can set off false alarms, and get pleasure from fire-related institutions, equipment, and personnel. Pyromaniac Experimental pleasure, gratification, and release of tension when they ignite, witness their effects, or share in their consequences. Approval of fire is not done for monetary gain, as an expression of socio-political ideology, to conceal criminal activity, to express anger or revenge, to improve the circumstances in which you live, or to respond to an illusion or hallucination, and the provocation of fire not the result of fire. poor judgment (eg dementia, mental retardation or substance abuse).

Kleptomania is characterized by a recurring failure to resist impulses to steal things, even though they are not necessary for personal use or for their monetary value. The individual experiences a subjective elevation in the sense of tension before stealing and feels pleasure, gratification, or relief when he commits theft. Theft is not committed to express anger or revenge, is not done in response to an illusion or hallucination, and is not accounted for by a conduct disorder, a manic episode or an antisocial personality disorder. Objects are stolen in spite of the fact that they are typically of little value to the individual who could have paid for them and often give them away or throw them away. Although patients usually avoid theft when immediate interruption is likely, they usually do not. plan the robberies in advance or take into account the chances of being caught. Theft is done without assistance or collaboration from others. Pathological gambling, also known as "pathological gambling disorder" or "problematic pathological gambling" is characterized by persistent and recurrent maladaptive gambling behavior that breaks personal, family and professional ties. The individual may be concerned about the gambling craze. Most patients say they are looking for "excitement" rather than money, increasing bets or higher risks may be needed to continue to produce the desired level of arousal. The betting craze often continues despite repeated efforts to control, slow, or cease behavior. The individual can bet as a way of escaping problems or relieving a dysphoric mood. A pattern of losses by "persecution" may develop, with an urgent need to keep betting to undo losses. Individuals may lie to family members, therapists or others to hide the extent of involvement in the gambling craze. When your loan resources are restricted, the person may resort to antisocial behavior (fraud, theft) to obtain money. The individual may be at risk of or have lost a significant relationship, job or educational or professional opportunity due to the gambling mania.

Trichotillomania, pathologically plucking hair, is defined as "recurrent failure to resist impulses to pull their hair, resulting in noticeable hair loss." It is a common disorder characterized by hair pulling, eyelashes, eyebrows and other body parts. Atricotillomania is a frequently chronic and socially debilitating disorder.

DSM-IV: PUSH CONTROL DISORDERS

NOT OTHERWISE SPECIFIED (US)

Compulsive buying disorder, also referred to as compulsive shopping disorder, uncontrolled buying is generally recognized as an impulse control disorder since it shares many characteristics with kleptomania.

Food Voracity Attack Disorder (BED) is characterized by distinct periods of food voracity attacks during which large amounts of food are consumed over a different period of time. A sense of control over food is absent. Disturbance of food voracity attacks is distinguished from Nervous Bulimia by the lack of regular use of inappropriate compensatory behaviors, such as self-inducing vomiting, misuse of laxatives and other medications, fasting, and excessive exercise that are characteristic of the latter. The disorder of food voracity attacks is mutatis mutandis - the same as the disorder of drunken voracity attacks.

Impulsive self-injurious behavior (also referred to as repetitive self-harm) is an individual's inability to control the urge to scratch, cut, strike, or cause self-injury through repeated mechanical irritation of the damaged area. This behavior begins to manifest itself in different forms, for example, skin-pitting (PSP), a chronic dermatological and psychiatric problem, which can lead to significant suffering, dysfunction and disfigurement, for example, in the form of facial lesions; nail biting (onychophagia); sticking the nose into the nose pathologically (rhinothilexomania); eye self-mutilation (self-enucleation): the use of fingers to loosen their own eyes, a rare and severe form of orbital trauma; hit the head and self bite.

Paraphilic sexual addictions (erotomania, hypersexuality), lack of control of a person's sexual impulses, are characterized by recurrent, intense sexual surgeries, fantasies or behaviors involving unusual objects, activities or situations and causing clinically significant disturbance or impairment in social, occupational areas. or other important activities. Paraphilias include exhibitionism (degenerate exposure), fetishism (use of non-living objects), touring (touching and rubbing against a person without their consent), pedophilia (focus on pre-pubescent children), sexual masochism (receiving humiliation or suffering), sexual sadism ( inflict humiliation or suffering), transvestic fetishism (wearing clothes of the opposite sex), and vouyerism (observing sexual activity).

Spending many hours of the day in front of a computer screen, accessing the Internet, may be characteristic of a well-paid job, but may also cause clinically significant disruption or impairment in social, occupational or other important areas of activity, particularly when unrelated to work. work and restricts a person's time off. Some clinicians have already listed "Internet compulsive use" as an impulse control disorder.

In the eyes of many adults, most teenagers use excessive cell phones. Most young people perceive this as very normal in some individuals, however, this behavior reaches pathological proportions, so it can be predicted that "decellular overuse" will be recognized as an impulse control disorder and may well prove not to be resistant to treatment. pharmacological

To provide a more concise description, some of the quantitative expressions provided herein are not qualified by the term "about". It is understood that if the term "about" is used explicitly or not, each quantity provided herein is intended to refer to the actual value provided and is also intended to refer to the approximation of such a value that would reasonably be inferred from the common technical ability, including approximations due to experimental conditions and / or measurement to that given value.

Throughout the description and claims of the present specification, the word "comprises" and variations of the word, such as "comprising" and comprising ", are not intended to exclude other activities, components, integers or steps.

The term "composition" as used herein encompasses a product comprising specified ingredients in predetermined amounts or proportions, as well as any product that results, directly or indirectly, from the combination of specified ingredients in specified quantities. With respect to pharmaceutical compositions, this includes a product comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product that results, directly or indirectly, from the combination, complex formation or aggregation of any two or more of the ingredients or of decoupling one or more of the ingredients or other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and uniformly maintaining the active ingredient in association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation. The pharmaceutical composition includes enough of the active compound in question to produce the desired effect on disease progression or conditions. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention with a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

From the binding affinity measured for a agonistamuscarinic, the lowest theoretical effective dose can be estimated. At a compound concentration equal to twice the measured Ki value, approximately 100% of muscarinic receptors are likely to be occupied by the compound. Converting this concentration to decomposed mg per kg of patient yields the lowest theoretical effective dose, providing optimal bioavailability. Pharmacokinetics, pharmacodynamics and other considerations may change the actual dose administered to a lower or higher value. The dose of compound to be administered will depend on the relevant indication, age, weight and gender of the patient and may be determined by a physician. The dosage will preferably be in the range 0.01 mg / kg to 10 mg / kg. The typical daily dose of active ingredients varies within a wide range and will be dependent on a number of factors such as the relevant indication, route of administration, age, weight and gender of the patient and may be determined by a physician. In general, oral and parenteral dosages will be in the range of 0.1 to 1,000 mg per day of total active ingredients.

The term "therapeutically effective amount" as used herein refers to an amount of a therapeutic agent for treating or preventing a treatable condition by administering a composition of the invention. This amount is sufficient to exhibit a detectable therapeutic, preventive, or palliative response in a detained system, animal or human. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for an individual will depend on the size and health of the individual, the nature and extent of the condition being treated, recommendations of the treating physician (researcher, veterinarian, physician or other clinician) and therapeutic product, combination of selected therapeutic products for administration. . Thus, it is not useful to specify an effective amount in advance. The term "treatment" as used herein refers to any treatment of a condition or disease of a mammal, preferably a human, and includes: (1) preventing the occurrence of the disease or condition in an individual predisposed to the disease but not yet It has been diagnosed with it, (2) inhibition of the disease or condition, ie, interruption of its development, (3) relief of the disease or condition, that is, causing the condition to regress or (4) ceasing the symptoms of the disease. As used herein, the term "medical therapy" is intended to include prophylactic, diagnostic and therapeutic regimes performed in vivo and ex vivo on human or other mammalian surgeries. The term "individual" as used herein refers to an animal, preferably a mammal, more preferably a human being, which has been the subject of treatment, observation or experiment.

EXAMPLE 1: FORMULATIONS USED IN ANIMAL STUDIES

For subcutaneous (s.c.) administration: At the desired amount (0.05 mg / ml) of MK801 in a glass tube, a few glass beads were added and the substance was milled through vortexing for 20 sec. After addition of 2 ml of solvent (0.9% saline), the compound was dissolved by swirling for 20 sec. The solvent minus 1 ml was added to the solution and stirred for 20 sec. Then, the pH was measured (pH 5-8) and swirled (20 sec). The last volume was added to the solution, swirled for 20 sec. And a final pH check was made, the actual pH was noted.

For intraperitoneal (i.p.) administration: To the desired amount (5 mg / ml) of desmethylclozapine in a glass tube, a few glass beads were added and the substance was milled through vortexing for 20 sec. After the addition of 2 ml of 1% methylcellulose and 5% mannitol in water, the compound was suspended by swirling for 20 sec. The remainder of the solvent minus 1 ml was added to the suspension and blown for 20 sec. Then the pH was measured and adjusted with 1 drop of 1.0 M NaOH (pH 5-8) and vortexed (20sec.). The last volume was added to the suspension, blown for 20 sec. And a final pH check was made, the actual pH was noted.

For intraperitoneal (i.p) administration: At the desired amount (5 mg / ml) of xanomelin in a glass tube, a few glass beads were added and the substance was milled through vortexing for 20 sec. After addition of 2 ml of 1% methylcellulose and 5% mannitol in water, the compound was suspended by swirling for 20 sec. And the tube was placed in an ultrasonic bath for 15 min. Before the solvent was added, the suspension was subjected to tumble for 20 sec. The remaining solvent minus 1 ml was added to the suspension and swirled for 20 sec. Then the pH was measured and adjusted with 5 drops of 1.0 M NaOH (pH 5-8) swirled (20 sec). The last volume was added to the suspension, vortexed for 20 sec. And a final pH check was made, the actual pH was noted.

EXAMPLE 2: THE 5-CHOICE REACTION COMPLETE TASK PROTOCOL

Animals

Male Wistar rats weighing 330-450 g (Harlan, Netherlands) are housed in pairs under a 12 h light / dark cycle (lights off at 7:00 am) and have daily access to a limited amount of food that maintains their body weight. approximately 85% of the free feeding weight. Water is available ad libitum. All procedures are in accordance with the European Communities Council Directive of 24 November 1986 (86/609 EEC).

Device

Standard 5-CSRT enclosures from MED associates Inc. Georgia, Vermont, US are used. The curved chamber wall contains 1.6cm2 holes, a depth of 2.2cm, 2cm above floor level. Each bureau has an infrared photocell beam crossing the inlet and illuminating a photoelectric cell to detect head entry, in each bureau a yellow stimulus light may be present. A food dispenser is located on the opposite wall. The box is illuminated by a 28 Volt, 100 mA household light. The 5-CSRT speakers are placed in cubicles that attenuate the sound. Online device control and data collection are performed by a MED-PC experimental device programming system (Tatham, 1989) operating under a Dell Optiplex GX1 PC.

Training

Rats are first trained to collect food dispensing reinforcement pellets and to collect reinforcements that are placed in the 5 holes in order to habituate the animals to the 5-CSRT task apparatus. Then 5-CSRT task training begins. These sessions begin by lighting the light in one of the holes for 30 seconds (stimulus duration). A mouse response in the lighted hole or a response in this particular hole for a short time after lightening (60 sec. Limited maintenance) is rewarded with the distribution of a ration pack, termination of the experiment, and a correct response is recorded. Light stimulus is presented in each of the holes 20 times during a session (total of 100 presentations) and the order of the presentations is random. A response in any other hole (failed response) or a general response failure during stimulus presentation and limited maintenance (omission) results in a 5 sec period. darkness (interruption) and end of the experiment. Upon completion of the experiment, a variable inter-experiment interval is initiated (1, 3, 5, 7, or 9 sec), after which the next experiment is started. When a correct 75% performance level is reached, the illumination duration of the light stimulus is reduced to a display of 0.5 sec. (from 30 to 20, 10, 5, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5) and a limited maintenance of 5 sec. (in three steps from 30 to 20.10 and 5 sec.) are reached (Robbins, 1993). The following parameters were measured (Muir, 1996):

Accuracy: The percentage of correct answers divided by the total answers made.

Omission errors: The number of stimulus presentations in response.

Correct Answers: The number of correct answers.

Failed Answers: The number of answers in the wrong hole.

Anticipatory responses: The number of premature responses made preceding the presentation of the light stimulus.

Persevering answers: Answers issued after an incorrect or correct answer.

EXAMPLE 3: ACTIVITY IN THE 5-CHOICE REACT TIME TASK

MK801 was tested in a Latin hexagon design, meaning that each rat received all tested dosages (0.01, 0.025, and 0.05 mg / kg s.c.) in a random order. Results from two different series of experiments are provided in table 1.

MK-801 (dizocilpine), an uncompetitive NMDA receptor antagonist

Table 1: ANSWERS IN THE SERIAL 5-CHOICE REACTION TIME TASK

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From table 1, it is evident that MK801 does not influence the correct answer numbers and failed answers. Significant effects are on the number of anticipatory responses, persevering responses, omitted responses, and the total number of responses: these are reinforced, except for the omitted responses, which are diminished, an evident effect at 0.025 mg / kg and 0.05 mg / kg and highly significant (* = ρ <0.05). This indicates that animals show impulsive behavior.

Xanomelin, a mixed muscarinic-Mi and muscarinic-M4 agonists and desmethylclozapine, a muscarinic-Mi agonist and muscarinic-M4 were each tested in a Latin hexagon design, meaning that each rat received all test dosages (0, 1, 3 and 10 mg / kg, ip) in a random order. Results are provided in table 2.

<formula> formula see original document page 16 </formula>

Table 2: RESPONSE TO THE 5 SERIAL CHOICE REACTION TIME TASK

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The data provided in table 2 show that, at 10 mg / kg, axanomelin and desmethylclozapine reduce the number of anticipatory responses: an effect associated with impulsive behavior (Cole, 1987; Ruotsaiainen.2000).

INTERACTION STUDIES

Xanomelin and desmethylclozapine were each tested in the same dose range against 0.05 mg / kg (s.c.) of MK801, a dose shown to stimulate unambiguous impulsive behavior (see Table 1). The results are given in table 3:

Table 3: RESPONSE TO THE 5 SERIAL CHOICE REACTION TIME TASK <table> table see original document page 17 </column> </row> <table>

The data in Table 3 clearly indicate that xanomelin and desmethylclozapine antagonize the increase in MK801-induced anticipatory and perverse responses. REFERENCES, PATENTS AND PATENT APPLICATIONS

Cole, BJ. and Robbins T.W., Psychopharmacology, 91, 458-466,1987

Muir J.L. and colleagues, Cerebral Cortex (6) 470-481,1996.Robbins, T.W., Muir, J.L., Kiiicross, A.S. and Pretsell, D.: "Methods for Assessing Attention and Stimulus Control in the Rat". In Behavioral Neuroscience: A Practical Approach, Shagal, A., Oxfort University press, New York, Vol. 1, pages 13-46,1993.

Ruotsaiainen et al., Psychopharmacology, 148,111-123, 2000.

Tatham, T.A. and Zurn, K.R. "The MED-PC experimental apparatus programming system", Behavioral Research Methods.Instrumental Computers. 21, 294-302,1989EP 0525 879 25

US 5,780,479; US 2001/023254; US 2004/0077650 and US 2004/0116505

WO 92/018005; WO 94/013659; WO 02/043731; WO 2006/017614 and WO 2006/067494.

Claims (8)

Use of a muscarinic agonist, characterized in that it is intended for the preparation of a pharmaceutical composition for the treatment, alleviation or prevention of impulse control disorders. Use according to claim 1, characterized in that said muscarinic agonist has agonistic-muscarinic activity-1 (M1). Use according to claim 2, characterized in that said muscarinic agonist is selected from the group consisting of: AF-150, AF-151, alvamelin, ACP-104, CDD-34, CDD-98, CDD-0097, CDD-0102, CDD-190, CDD-0199-J, CDD-0235-J, CDD-0304, Cevimeline, CPR-2006, CS-932, Desmethylclozapine, FPL-14995, FPL-15467, KAD-193R, L- 680648, L-687306, L-689660, MCNa-343, milameline, nebracetam, NGX-267, PD-151832, sabcomelin, SDZ-210-086, SR-46559A, talsaclidine fumarate, tazomelin, xanomelin, YM-796 and YM-954. Use according to claim 3, characterized in that said muscarinic agonist is xanomelin. Use according to any one of claims 1-4, characterized in that said impulse control disorders are impulse control disorders not elsewhere classified. Use according to claim 5, characterized in that said NEC impulse control disorders are: intermittent explosive disorder, pyromania, kleptomania, pathological gambling mania and electrothilomania. Use according to any one of claims 1-4, characterized in that said pulse control disorders are pulse control disorders not otherwise specified (NOS). Use according to claim 7, characterized in that said NOS impulse control disorders are: compulsive buying disorder, food voracity attack disorder and drink voracity attack, self-injurious impulsive behavior, including stinging. pathologically skin, biting nails and sticking finger in nose, eye self-mutilation, headbanging and self-bite; Paraphilic sexual addictions, lack of control of a person's sexual impulses, including exhibitionism, fetishism, fleet tourism, pedophilia, masochism, sadism, transvestic fetishism, and Vouyerism, as well as compulsive use of Internet overuse.