KR20070017019A - New crystalline form iii of agomelatine, a process for its preparation and pharmaceutical compositions containing it - Google Patents

Abstract

The present invention relates to crystalline Form III and a medicament of a compound of formula (I), characterized by a powder X-ray diffraction diagram:

Description

Crystalline form III of agomelatine, a preparation method thereof, and a pharmaceutical composition containing the same {NEW CRYSTALLINE FORM III OF AGOMELATINE, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT}

The present invention provides a novel crystalline form III of agomelatine of formula (I), or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide, a process for preparing the same and a pharmaceutical composition containing the same It is about:

.

.

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

Indeed it has the dual feature of being an agonist of melatoninic system receptors while an antagonist of 5-HT _2C receptors. These properties act on the central nervous system and, more specifically, are active in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathology, pathology of the digestive system, jet lag and fatigue, appetite disorders and obesity.

Agomelatine, a process for its preparation and its therapeutic use are disclosed in European patent specification EP 0 447 285.

Given the pharmaceutical value of the compounds, they have good purity, are well-defined crystalline forms, have an ideal reproducibility to exhibit advantageous properties in terms of formulation, and are prolonged without specific requirements for temperature, light, humidity or oxygen levels. It has become important to be able to obtain compounds with sufficient stability to be stored for a long time.

Patent specification EP 0 447 285 discloses a process for preparing agomelatine in eight steps, starting from 7-methoxy-1-tetraron. However, this document does not specify the conditions for reproducibly obtaining agomelatine in the form exhibiting these characteristics.

Applicants have developed a novel synthetic method in which agomelatine can be obtained very reproducibly in well-defined crystalline form, which is of particular value for formulation.

More specifically, the invention is measured using a Siemens D5005 diffractometer (copper large cathode), interplanar distance d, Bragg's angle 2 theta, strength and relative A crystalline Form III of a compound of formula (I), characterized by the following powder X-ray diffraction diagram, expressed by intensity (expressed as percentage of strongest ray):

The invention also relates to a process for preparing crystalline Form III of the compound of formula (I), characterized in that the agomelatine is heated at 110 ° C. until melting is complete and then slowly cooled until crystals are formed. will be.

The advantage of obtaining crystalline forms is that pharmaceutical formulations can be prepared having a consistent and reproducible composition which is particularly advantageous when the formulation is used for oral administration.

The pharmacological studies of the thus obtained form III demonstrate that it has substantial activity on the central nervous system and microcirculation, and that crystalline form III of agomelatine is stress, sleep disorder, anxiety, severe depression, seasonal affective disorder, cardiovascular pathology , Pathology of the digestive system, parallax insomnia and fatigue, schizophrenia, panic attacks, depression, appetite disorders, obesity, insomnia, pain, psychosis disorder, epilepsy, diabetes, Parkinson's disease, elderly dementia, normal or pathological aging associated It can be established that it is useful for the treatment of various diseases, migraine, memory loss, Alzheimer's disease and brain circulation disorders. In another active field, crystalline Form III of agomelatine has ovulation-inhibiting and immunomodulatory properties that can be used for the treatment of sexual dysfunction and is likely to be used for the treatment of cancer by itself. Preferably crystalline Form III of agomelatine will be used for the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathology, jet lag and fatigue, appetite disorders and obesity.

The present invention also relates to pharmaceutical compositions comprising crystalline Form III of agomelatine as the active ingredient together with one or more suitable inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, more particularly those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragases, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, Dermal gels, injectable preparations, drinking suspensions and disintegratable pastes may be mentioned.

Useful dosages can be adjusted depending on the nature and severity of the disease, the route of administration and the age and weight of the patient. Doses vary from 0.1 mg to 1 g in one or more administrations daily.

The following examples are intended to illustrate the invention and do not limit the invention in any way.

Example 1 : Crystalline Form III of N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide

100 g of N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide was heated at 110 ° C. in a ventilated incubator until melting was complete and then slowly cooled until crystals formed. The crystalline Form III obtained is measured using a Siemens D5005 diffractometer (copper large cathode) and is indicated by the interplanar distance d, Brax angle 2 theta, intensity and relative intensity (expressed as percentage of the strongest ray). The following powder X-ray diffraction diagram is characterized:

Example 2 Pharmaceutical Composition

Formulations for the preparation of 1000 tablets each containing a dose of 25 mg:

Compound of Example 1 ..................... 25 g

Lactose Monohydrate ... 62 g

Magnesium Stearate ......................... 1.3 g

Corn Starch ... .26 g

Maltodextrin ... .9 g

Silica, colloidal anhydride ..... 0.3 g

Sodium Starch Glycolate Type A ........................ 4 g

Stearic Acid ... .2.6 g

Example 3 Pharmaceutical Composition

Formulations for the preparation of 1000 tablets each containing a dose of 25 mg:

Compound of Example 1 ..................... 25 g

Lactose Monohydrate ... 62 g

Magnesium Stearate ......................... 1.3 g

Povidone ... ...... 9 g

Silica, colloidal anhydride ..... 0.3 g

Sodium Cellulose Glycolate ............... 30 g

Stearic Acid ... .2.6 g

The present invention provides a novel method of synthesis in which agomelatine can be obtained very reproducibly in well-defined crystalline form, which is of particular value for formulation.

Claims (5)

Measured using a diffractometer (copper large cathode), the interplanar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the strongest ray) Crystalline Form III of agomelatine of Formula (I), characterized by the following powder X-ray diffraction diagram represented by:

A process for preparing crystalline Form III of the compound of formula (I) according to claim 1, characterized in that agomelatine is heated at 110 ° C. until melting is complete and then cooled slowly until crystals are formed. A pharmaceutical composition comprising crystalline Form III of agomelatine according to claim 1 as an active ingredient with at least one pharmaceutically acceptable inert, non-toxic carrier. 4. The pharmaceutical composition according to claim 3, which is used for the manufacture of a medicament for the treatment of melatoninic disorders. The method of claim 3, further comprising sleep disorders, stress, anxiety, seasonal affective disorders or severe depression, cardiovascular pathology, pathology of the digestive system, jet lag, fatigue and schizophrenia, panic attacks, depression, appetite disorders, obesity, insomnia, Used in the manufacture of a medicament for the treatment of psychotic disorders, epilepsy, diabetes, Parkinson's disease, elderly dementia, various diseases associated with normal or pathological aging, migraine, memory loss, Alzheimer's disease, brain circulation disorders and sexual dysfunction, ovulation inhibitors and A pharmaceutical composition, which is used as an immunomodulator and is used in the manufacture of a medicament for treating cancer.