HK1098129B - New crystalline form iv of agomelatine, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Description

New crystalline form IV of agomelatine, process for its preparation and pharmaceutical compositions containing it

Technical Field

The present invention relates to a new crystalline form IV of agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide of formula (I):

a process for its preparation and pharmaceutical compositions containing it.

Background

Agomelatine, or N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide, has valuable pharmacological properties.

It does have a dual profile, 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 (severe depression), seasonal affective disorder, sleep disorders, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and its therapeutic use are described in european patent specification EP 0447285.

In view of the pharmaceutical value of the compound, it is important to obtain the compound in good purity, in a well-defined crystalline form and with excellent reproducibility, as a result of which valuable properties are exhibited in terms of formulation and are sufficiently stable that it can be stored for a long time without specific requirements on temperature, light, humidity or oxygen level.

Patent specification EP 0447285 describes the eight-step preparation of agomelatine starting from 7-methoxy-1-tetralone. However, the document does not specify the conditions for obtaining agomelatine exhibiting these characteristics in a reproducible manner.

Disclosure of Invention

The applicant has now developed a new synthetic process which makes it possible to obtain agomelatine in a well-defined, highly reproducible crystalline form which exhibits, in particular, valuable characteristics in terms of formulation.

More specifically, the present invention relates to crystalline form IV of the compound of formula (I) characterized by the following powder X-ray diffraction diagram, measured using a siemens D5005 diffractometer (copper on cathode), expressed as interplanar spacing D, bragg 2 θ angle, intensity and relative intensity (expressed as a percentage of the most intense ray):

the invention also relates to a process for the preparation of the crystalline form IV of the compound of formula (I), characterized in that agomelatine is heated at 110 ℃ until complete melting, then rapidly cooled between 50 and 70 ℃ and maintained at 70 ℃ for about 5 hours until crystallization.

The advantage of obtaining such a crystalline form is that it allows the preparation of pharmaceutical formulations having a consistent and reproducible composition, which is particularly beneficial when the formulation is intended for oral administration.

Pharmacological studies of the crystalline form IV thus obtained have demonstrated its important activity in the central nervous system and in the microcirculation, which has led to the establishment of crystalline form IV of agomelatine useful for the treatment of the following disorders: stress, sleep disorders, anxiety, major depression, seasonal affective disorders, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss, alzheimer's disease and cerebral circulation disorders. In another field of activity, it is indicated that crystalline form IV of agomelatine is useful for the treatment of sexual dysfunction, has ovulation-inhibiting and immunomodulating properties and is useful in the treatment of cancer.

Crystalline form IV of agomelatine is preferably used for the treatment of major depressive disorder, seasonal affective disorder, sleep disorders, cardiovascular disease, insomnia and fatigue due to jet lag, appetite disorders and obesity.

The invention also relates to a pharmaceutical composition comprising crystalline form IV of agomelatine as active ingredient together with one or more suitable inert non-toxic excipients. Among the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, such as tablets or dragees, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and disintegratable pastes.

Useful dosages are adjusted according to the nature and severity of the disorder, the route of administration, and the age and weight of the patient. The dose varies between 0.1mg and 1g per day, administered one or more times.

Detailed Description

The following examples illustrate the invention but do not limit it in any way.

Example 1: crystalline form IV of N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide

100g N- [2- (7-methoxy-1-naphthyl) ethyl ] acetamide was heated at 110 ℃ until complete melting, then rapidly cooled between 50 and 70 ℃ and maintained at 70 ℃ for 5 hours until crystallization. The resulting form IV is characterized by the following powder X-ray diffraction pattern, measured using a siemens D5005 diffractometer (copper on cathode), expressed as interplanar spacing D, bragg 2 θ angle, intensity and relative intensity (expressed as a percentage of the most intense ray):

example 2: pharmaceutical composition

A formulation for making 1000 tablets, each tablet containing a 25mg dose:

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Example 3: pharmaceutical composition

A formulation for making 1000 tablets, each tablet containing a 25mg dose:

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Claims (5)

1. Crystalline form IV of agomelatine of formula (I):

characterized by the following powder X-ray diffraction pattern, measured using a diffractometer with copper on cathode, expressed as interplanar spacing d, bragg 2 theta angle, intensity and relative intensity, expressed as a percentage of the most intense ray:

2. process for the preparation of the crystalline form IV of the compound of formula (I) according to claim 1, characterized in that agomelatine is heated at 110 ℃ until complete melting, then rapidly cooled between 50 and 70 ℃ and maintained at 70 ℃ for about 5 hours until crystallization.

3. A pharmaceutical composition comprising as active ingredient the crystalline form IV of agomelatine according to claim 1 in association with one or more pharmaceutically acceptable inert non-toxic carriers.

4. Use of the crystalline form IV of the compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of melatoninergic disorders.

5. Use of crystalline form IV of a compound of formula (I) according to claim 1 in the manufacture of a medicament for the treatment of: sleep disorders, stress, anxiety, seasonal affective disorder or major depression, cardiovascular disease, digestive system disease, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, cerebral circulation disorders, sexual dysfunction, use as ovulation inhibitors and immunomodulators, and cancer.