HK1177897B - Use of agomelatine for the preparation of drugs for treating obsessive compulsive disorder (ocd) - Google Patents

Description

Use of agomelatine for obtaining a medicament intended for the treatment of Obsessive Compulsive Disorder (OCD)

The invention relates to agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I):

and also the use of hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases thereof, for obtaining a medicament intended for the treatment of obsessive-compulsive disorder (OCD).

Agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide has the dual property that, on the one hand, it is an agonist of receptors of the melatoninergic system and, on the other hand, it is 5-HT_2CAn antagonist of the receptor. These properties provide for its activity in the central nervous system, more specifically in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular disease, digestive disease, insomnia and fatigue due to jetlag, appetite disorders and obesity.

Agomelatine, its preparation and its use in therapy are described in european patent specifications EP 0447285 and EP 1564202.

The applicant has now found that agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide-and also the hydrates, crystalline forms and addition salts thereof with pharmaceutically acceptable acids or bases-have valuable properties, which enable it to be used in the treatment of obsessive-compulsive disorders (OCD).

Obsessive Compulsive Disorder (OCD) is a pathological condition defined by the presence of obsessive compulsive and difficult to resist impulses. This pathological condition corresponds to a completely established standard and constitutes a completely separate pathologist entity (300-3, Disorder-DSM IV-Diagnostic and Statistical Manual of mental Disorders, 4 th edition, American Psychiatric Association).

Obsessive concepts are defined as repetitive thinking, impulsivity or mental construction, which at some time may be felt intrusive and uncomfortable and create a lot of distress. They are not only overly prejudice, but also carry real life problems. On the one hand, patients strive to ignore or suppress them, on the other hand, their origin is considered to be in their own psychological activities and they are excessive or irrational.

A difficult impulse to resist is repetitive behavioral or psychological activity intended to neutralize or reduce feelings of affliction or prevent a terrorist event or situation. There is no realistic correlation between hard-to-resist impulses and the pre-neutralization or prevention of them or their apparent overage.

The obsessive-compulsive and hard-to-withstand impulses create a significant distressing sensation and take a considerable amount of time. They interfere in particular with socio-occupational functions and daily activities of the patient.

Obsessive-compulsive disorder is not a chronic pathological condition resulting from the direct physiological effects of substances. Its lifetime is generally about 2-3% (Kaplan A et al, Psychiatric Services, 2003, 54 (8)).

Currently there is no exact satisfactory treatment for obsessive-compulsive disorder. More generally, patients are treated with the antidepressant clomipramine, a tricyclic antidepressant, or mainly with 5-hydroxytryptamine reuptake inhibitors (SSRIs) in combination with cognitive and behavioral therapy. However, SSRI treatment results in significant side effects, such as gastrointestinal disorders, e.g. nausea, anorexia, weight loss, sexual dysfunction or 5-hydroxytryptamine syndrome. Moreover, its efficacy is not direct, but appears after a treatment period of 15 days to 30 weeks, and only 20% of patients respond to these treatments.

Therefore, there remains a real need for new therapies that can improve the life of patients suffering from obsessive-compulsive disorder (OCD).

The applicant has now found that agomelatine can be used to treat obsessive-compulsive disorder (OCD) on the basis of its pharmacological profile and in particular its excellent tolerability observed in clinical trials carried out on approximately 3900 patients.

In particular, agomelatine does not have the side effects associated with usual psychotropic drugs. Among those effects, withdrawal syndrome observed when stopping the treatment with the usual psychotropic drugs is not present in the case of agomelatine, which makes it a therapeutic option in this indication.

The invention therefore relates to the use of agomelatine and its hydrates, crystalline forms and addition salts with a pharmaceutically acceptable acid or base, for obtaining a medicament intended for the treatment of obsessive-compulsive disorder (OCD).

The present invention relates in particular to the use of agomelatine obtained in form II as described in patent application EP 1564202, for obtaining pharmaceutical compositions destined to treat obsessive-compulsive disorder (OCD).

The pharmaceutical compositions are in a form suitable for administration by oral, parenteral, transdermal, nasal, rectal or lingual routes, especially in the form of injectable preparations, tablets, sublingual dosage forms, gelatin capsules, lozenges, suppositories, creams, ointments, epidermal gels and the like.

In addition to agomelatine, the pharmaceutical compositions of the invention also comprise one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, adsorbents, colorants, sweeteners, and the like.

As non-limiting examples, mention may be made of:

as diluent: lactose, glucose, sucrose, mannitol, sorbitol, cellulose, glycerol;

as lubricant: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol;

as binder: magnesium aluminum silicate, starch, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone;

as disintegrant: agar, alginic acid and its sodium salt, effervescent mixture.

The useful dose varies according to the sex, age and weight of the patient, the route of administration, the nature of the disorder and any relevant treatments and ranges from 1mg to 50mg agomelatine per 24 hours.

The daily dose of agomelatine is preferably 25 mg/day, with the possibility of increasing to 50 mg/day.

The pharmaceutical composition comprises:

1000 tablets of each formulation containing 25mg of active ingredient were prepared:

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Preclinical study

Preclinical studies using an obsessive-compulsive disorder (OCD) model demonstrated the potential of agomelatine in treating this pathological condition. Spontaneous pin burial in mice is a repetitive behavior considered to be strongly associated with OCD, and its inhibition suggests therapeutic activity in its treatment (Witkin j.m., Current Protocols Neurosciences, 2008, Chapter 9, Unit 9.30). Agomelatine significantly reduced spontaneous pin burial in mice in a dose-dependent manner after intraperitoneal administration of 10, 40 and 80mg/kg doses, indicating the potential for treating OCD. The study was conducted as follows. Male mice of the NMRI strain (Iffa-Credo, L' Arbresle, France) weighing 20-25g were each placed in a modular cloning cassette (30X 18X 19cm) containing 5cm of sawdust and covered with a porous plexiglass on the day of the experiment. The 24 "cat-eye" glass marbles were evenly distributed on the sawdust on the periphery of the box. At the end of the free probing 30 minutes, the animals were removed from the box and the number of buried pins was counted. Agomelatine or vehicle (control) was injected for 30 minutes before the test was started.

The results given as the number of marble burial obtained are as follows:

carrier: 20.2 ± 0.6(n ═ 14)

Agomelatine 10 mg/kg: 19.2 ± 1.3(n ═ 6)

Agomelatine 40 mg/kg: 15.3 ± 3.0(n ═ 6)

80mg/kg of agomelatine: 4.6 ± 1.9(n ═ 5)

Analysis of variance: f (3.33) < 23.4P < 0.01. P < 0.05 compared to vehicle (dunnett test) at 40 and 80mg/kg agomelatine doses.

The results obtained show the statistically significant activity of agomelatine in a representative model of obsessive-compulsive disorder.

Clinical research

A comparative clinical study with agomelatine and placebo was performed in 80 out-patient patients aged 18 years and under 65 years with a preliminary diagnosis of obsessive-compulsive disorder according to DSM-IV-TR criteria. At the time of study entry, patients must have a score above 20 according to the Y-BOCS Scale (YaleBrown Obsessive comprehensive Scale) and have their Obsessive-Compulsive disorder previously treated with a 5-hydroxytryptamine reuptake inhibitor (SRI). Patients must have a depression severity score of less than 24 according to the MADRS depression rating.

The study was a double-blind placebo-controlled study lasting a 16-week treatment period. Patients were randomized into either the placebo or 25mg agomelatine groups, with the possibility of increasing the agomelatine dose from up to 50mg if there was no response after 8 weeks of treatment (non-response criteria: less than 20% reduction in total Y-BOCS score).

The primary criterion used to assess efficacy is a reduction in total score according to the Y-BOCS scale. Another evaluation criterion for evaluating the Severity of Obsessive-compulsive and/or difficult-to-resist impulse states is the Improvement of the state given by the scores according to NIMH-OC (National Institute of Mental Health-evident-comprehensive) and CGI-S (Clinical Global expression-preference) and CGI (Clinical Global expression-Improvement). The presence of depression symptoms and their progression over time were analyzed at the beginning of treatment and 16 weeks after treatment according to the MADRS depression rating.

Responses were defined as a 35% reduction in total score according to the Y-BOCS scale and a score of 1 or 2 according to CGI. The mitigation is defined to be less than or equal to a score of 10 according to the Y-BOCS rating and less than or equal to 2 according to CGI-S.

The results observed confirm the efficacy of agomelatine in the treatment of Obsessive Compulsive Disorder (OCD) and also its good acceptable characteristics.

Claims (2)

1. Use of agomelatine as the sole active ingredient for obtaining a medicament intended for the treatment of obsessive-compulsive disorders.

2. Use according to claim 1, characterized in that agomelatine is obtained in form II.