HK1119055A - Use of agomelatine in obtaining medicaments intended for the treatment of smith-magenis syndrome - Google Patents

Description

Application of agomelatine in preparation of medicine for treating Smith-Magenis syndrome

Technical Field

The present invention relates to the use of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I) and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases for the preparation of a medicament for the treatment of Smith-Magenis syndrome.

Background

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 make it active in the central nervous system, more particularly in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

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

Disclosure of Invention

The applicant has now found that agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases have valuable properties, which make it useful in the treatment of Smith-Magenis syndrome.

E.g., Ann Smith et al, 1982 (Smith a.c.m. et al, 1986, am.j. med. genet., inc.24393-magenta 414) is a rare genetic disorder due to chromosomal microdeletions. This particularly severe disorder leads to the development of dysmorphic syndrome (dysmorphic syndrome), mental retardation (especially involving language acquisition), attention deficit hyperactivity disorder and self-attack (autoiggregation) associated with severe behavioral and sleep disorders in children (Smith a.c.m. et al, 1998, am.j.med.gene.,81，186-191)。

in addition to these factors, the family circle of children facing these obstacles is necessarily distressed not only by the handicap, but also by extreme living conditions (often disturbed nights, ever-high vigilance, child aggression requiring control, etc.), which in most cases results in complete breakdown of the household unit.

The incidence is one per 25,000 adult infants. Diagnosis is made on the basis of clinical signs, confirmed by confirmation of chromosomal 17 deletions using high-resolution karyotypes. Melatonin circadian rhythmReversal has recently been demonstrated and is likely to be the cause of sleep and behavioral disorders (De leisnyder h., 2006 Trends in endocrinology and Metabolism,17(7)，29-298)。

although there is no truly satisfactory and accepted treatment for SMS, the most commonly used drugs today are neuroleptics, hypnotics, psychostimulants, antidepressants, antipsychotics and carbamazepine to control behavioral disorders. These treatments are responsible for numerous secondary effects such as gastrointestinal disorders, weight gain, dyslipidemia, sexual dysfunction, tardive dyskinesia and cardiovascular effects (Richelson e. et al, 1999, j.clin.psychiatry,60(10) 5-14; trenton a.j. et al, 2003, CNS Drugs,17(5) 307-; freedman r. et al, 2003, New England Journal of Medicine,343,1738-1749). Furthermore, these treatments have no activity on the desynchronization of melatonin secretion, which is responsible for severe sleep disorders and certain behavioral disorders that have a devastating effect especially in children and children's families.

Currently, the strategy for treating desynchronization of melatonin secretion is to administer beta-adrenergic antagonists (acebutolol, propranolol) in the morning in order to block the endogenous secretion of melatonin, in combination with administration of exogenous melatonin in the evening (De leisnyder h. et al, 2003, j.med.gene.,40,74-78). However, melatonin is not active against behavioral disorders.

Therefore, it is important to have available new treatments for this rare lesion in children. In particular, perfecting the treatment to simultaneously alleviate severe sleep disturbance and behavioral disturbance will allow children and their families to regain a more reasonable quality of life.

The applicant has now found that agomelatine is particularly suitable for this indication, due to its pharmacological properties.

In fact, agomelatine can act simultaneously on the resynchronization of behavioural disorders and disturbed circadian rhythms. Moreover, agomelatine has no drug interactions and has the best acceptability: during the course of clinical trials which have been carried out, in more than 4000 patients agomelatine have been used, excellent clinical and biological resistance has been observed.

The invention therefore relates to the use of agomelatine and its hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases for the preparation of a pharmaceutical composition for the treatment of Smith-Magenis syndrome.

The present invention relates in particular to the use of agomelatine obtained in the form of crystalline form II as described in patent application EP 1564202 for the preparation of a pharmaceutical composition intended for the treatment of Smith-Magenis syndrome.

The pharmaceutical compositions will be in a form suitable for oral, parenteral, transdermal, nasal, rectal or lingual administration, especially in the form of injectable preparations, tablets, sublingual tablets, glossettes, gelatin capsules, lozenges, suppositories, creams, ointments, dermal 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, absorbents, colorants, sweeteners, and the like.

Mention may be made, as non-limiting examples, of:

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

lubricant: silicon dioxide, talcum powder, stearic acid and its magnesium salt and calcium salt, polyethylene glycol,

binder: aluminum and magnesium silicates, starch, gelatin, gum tragacanth, methyl cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone,

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

The effective dose varies according to the age and weight of the patient, the route of administration, the nature of the disease and any combination therapy, and is between 1mg and 50mg agomelatine per 24 hours.

The daily dose of agomelatine is preferably 25mg per day, and can be increased to 50mg per day.

Detailed Description

The pharmaceutical composition comprises:

a formulation for making 1000 tablets, each tablet containing 25mg of active ingredient:

… … … … … … … … … … 25g of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide

Lactose monohydrate … … … … … … … … … … … … … … … … … … … … 62g

Magnesium stearate … … … … … … … … … … … … … … … … … … … … … 1.3.3 g

Povidone … … … … … … … … … … … … … … … … … … … … … … … 9g

Anhydrous colloidal silica … … … … … … … … … … … … … … … … … 0.3.3 g

… … … … 30g of sodium cellulose glycolate (cellulose sodium glycolate)

Stearic acid … … … … … … … … … … … … … … … … … … … … … … 2.6.6 g

Clinical study:

exploratory phase II studies were performed in children with Smith-Magenis syndrome. 1-5mg/kg agomelatine is co-administered with 10mg/kg acebutolol (a β 1 adrenergic antagonist). The main analytical criteria were the activity record examination (activity) parameters recorded over 5 consecutive 30-day cycles, 30 days of treatment and 3, 5 and 15 months after treatment, and the Achenbach questionnaire, which allowed assessment of the behavioral disorders.

The results obtained show that agomelatine can reduce the frequency and duration of nighttime awakenings, with a concomitant reduction in the duration of daytime sleepiness. The expert found that this lesion was of significant clinical improvement in those children treated with agomelatine: a calm deep sleep, less nighttime awakenings and less early awakenings were recorded for the first time.

Real progress in relation to behavior was also observed. These primary effects continue to be seen in the family, who will be required to continue treatment on a homeostatic basis after the treatment has had a very positive result on their own.

Claims (6)

1. Use of agomelatine or one of the N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamides or hydrates, crystalline forms and addition salts with pharmaceutically acceptable acids or bases for the preparation of a medicament for the treatment of Smith-Magenis syndrome.

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

3. Pharmaceutical composition for the preparation of a medicament for the treatment of Smith-Magenis syndrome, comprising agomelatine or one of its hydrates, crystalline forms and addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable excipients.

4. Pharmaceutical composition according to claim 3, characterized in that agomelatine is obtained in the form of crystalline form II.

5. Agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide or one of its hydrates, crystalline forms and addition salts with a pharmaceutically acceptable acid or base for the treatment of Smith-Magenis syndrome.

6. Crystalline form II of agomelatine for use in the treatment of Smith-Magenis syndrome.