# Patent

## Title
Crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it

## Abstract

Crystalline form V of the compound of formula (I):




characterised by its powder X-ray diffraction diagram.

Medicinal products containing the same which are useful in the treatment of melatoninergic disorders.

## Background
The present invention relates to a new crystalline form V 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 OF THE INVENTION
Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuable pharmacological properties.
Indeed it has the double feature of being, on the one hand, an agonist of melatoninergic system receptors and, on the other hand, an antagonist of the 5-HT2C receptor. Those properties confer activity in the central nervous system and, more especially, in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue resulting from jetlag, appetite disorders and obesity.
DESCRIPTION OF THE PRIOR ART
Agomelatine, its preparation and its therapeutic use have been described in European Patent Specification EP 0 447 285.
In view of the pharmaceutical value of this compound, it has been important to be able to obtain it with excellent purity, with well defined crystalline form, perfectly reproducible, which as a result exhibits valuable characteristics in terms of dissolution and formulation and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.
Patent Specification EP 0 447 285 describes the preparation of agomelatine in eight steps, starting from 7-methoxy-1-tetralone. However, that document does not specify the conditions for obtaining agomelatine in a form that exhibits those characteristics in a reproducible manner.


DETAILED DESCRIPTION OF THE INVENTION
The Applicant has now developed a new synthesis process that allows agomelatine to be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics for dissolution and formulation.
More specifically, the present invention relates to the crystalline form V of the compound of formula (I), characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):












2-Theta (°)
d (Å)
Intensité


exp.
exp.
(%)

















9.84
8.979
17


12.40
7.134
15


13.31
6.646
19


15.14
5.848
18


15.98
5.543
18


16.62
5.329
19


17.95
4.939
100


18.88
4.697
65


20.49
4.332
24


20.99
4.228
34


23.07
3.852
39


23.44
3.792
36


24.28
3.663
58


25.10
3.545
19


26.02
3.422
15


26.82
3.322
19


27.51
3.239
16









The invention relates also to a process for the preparation of the crystalline form V of the compound of formula (I), which process is characterised in that agomelatine is subjected to a mechanical grinding which is said to be “of high energy”.
In the crystallisation process according to the invention it is possible to use the compound of formula (I) obtained by any process.
The invention relates also to another process for the preparation of the crystalline form V of the compound of formula (I), which process is characterised in that agomelatine is heated until complete melting, then immediately put at room temperature and simultaneously a small quantity of crystalline form V of compound of formula (I) freshly prepared is added, and the mixture is cooled until crystallisation is complete.
Preferably, in that second crystallisation process according to the invention, agomelatine will be melted at 110° C.
The amount of crystalline form V added in that second process according to the invention will be preferably contained between 1/100 and 1/50 of agomelatine weight.
In that second crystallisation process according to the invention, it is possible to use the compound of formula (I) obtained by any process.
An advantage of obtaining that crystalline form is that it allows the preparation of pharmaceutical formulations having a consistent and reproducible composition, which as a result exhibits valuable characteristics in terms of dissolution which is especially advantageous when the formulations are to be used for oral administration.
A pharmacological study of the form V so obtained has demonstrated that it has substantial activity in respect of the central nervous system and in respect of microcirculation, enabling it to be established that the crystalline form V of agomelatine is useful in the treatment of stress, sleep disorders, anxiety, severe depression, seasonal affective disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, 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 ageing, migraine, memory loss, Alzheimer's disease, and in cerebral circulation disorders. In another field of activity, it appears that the crystalline V form of agomelatine can be used in the treatment of sexual dysfunction, that it has ovulation-inhibiting and immunomodulating properties and that it lends itself to use in the treatment of cancers.
The crystalline form V of agomelatine will preferably be used in the treatment of severe depression, seasonal affective disorders, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
The invention relates also to pharmaceutical compositions comprising as active ingredient the crystalline form V of agomelatine together with one or more appropriate inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned, more especially, those which are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and disintegrable pastes.
The useful dosage can be adapted according to the nature and the severity of the disorder, the administration route and the age and weight of the patient. The dosage varies from 0.1 mg to 1 g per day in one or more administrations.
The Examples below illustrate the invention but do not limit it in any way.
EXAMPLE 1
Crystalline form V of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide
100 g of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide are put in a mechanical grinder of the vario-planetary mill type for about 6 hours and the solid obtained is characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):












2-Theta (°)
d (Å)
Intensité


exp.
exp.
(%)

















9.84
8.979
17


12.40
7.134
15


13.31
6.646
19


15.14
5.848
18


15.98
5.543
18


16.62
5.329
19


17.95
4.939
100


18.88
4.697
65


20.49
4.332
24


20.99
4.228
34


23.07
3.852
39


23.44
3.792
36


24.28
3.663
58


25.10
3.545
19


26.02
3.422
15


26.82
3.322
19


27.51
3.239
16









EXAMPLE 2
Crystalline form V of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide
4 g of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide are put in a ventilated incubator at 110° C. After 1 hour at 110° C., the product is immediately placed at room temperature and seeded with 0.05 g of crystalline form V of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide structurally pure obtained by mechanical grinding of high energy. After 5 minutes, the crystallisation is complete and the solid obtained is characterised by the following powder X-ray diffraction diagram, measured using a Siemens D5005 diffractometer (copper anticathode) and expressed in terms of inter-planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):












2-Theta (°)
d (Å)
Intensité


exp.
exp.
(%)

















9.84
8.979
17


12.40
7.134
15


13.31
6.646
19


15.14
5.848
18


15.98
5.543
18


16.62
5.329
19


17.95
4.939
100


18.88
4.697
65


20.49
4.332
24


20.99
4.228
34


23.07
3.852
39


23.44
3.792
36


24.28
3.663
58


25.10
3.545
19


26.02
3.422
15


26.82
3.322
19


27.51
3.239
16









EXAMPLE 3
Pharmaceutical Composition










Formulation for the preparation of 1000 tablets each containing a


dose of 25 mg:



















Compound of Example 1 or 2
25
g



Lactose monohydrate
62
g



Magnesium stearate
1.3
g



Maize starch
26
g



Maltodextrines
9
g



Silica, colloidal anhydrous
0.3
g



Sodium starch glycolate type A
4
g



Stearic acid
2.6
g










EXAMPLE 4
Pharmaceutical Composition










Formulation for the preparation of 1000 tablets each containing a


dose of 25 mg:



















Compound of Example 1 or 2
25
g



Lactose monohydrate
62
g



Magnesium stearate
1.3
g



Povidone
9
g



Silica, colloidal anhydrous
0.3
g



Sodium cellulose glycolate
30
g



Stearic acid
2.6
g

## Claims

1. A crystalline form V of the compound of formula (I):



wherein the compound exhibits essentially the following powder X-ray diffraction diagram, measured using a diffractometer (copper anticathode) and expressed in terms of inter-planar distance d (expressed in Å), Bragg's angle 2 theta (expressed in degrees), intensity and relative intensity (expressed as a percentage with respect to the most intense ray):













2-Theta (°)
d (Å)
Intensité


exp.
exp.
(%)

















9.84
8.979
17


12.40
7.134
15


13.31
6.646
19


15.14
5.848
18


15.98
5.543
18


16.62
5.329
19


17.95
4.939
100


18.88
4.697
65


20.49
4.332
24


20.99
4.228
34


23.07
3.852
39


23.44
3.792
36


24.28
3.663
58


25.10
3.545
19


26.02
3.422
15


26.82
3.322
19


27.51
3.239
16.

2. A process for the preparation of the crystalline form V of the compound of formula (I) of claim 1, wherein agomelatine is subjected to high energy mechanical grinding.

3. A process for the preparation of the crystalline form V of the compound of formula (I) of claim 1, wherein agomelatine is heated until completely melted, then immediately placed at room temperature and simultaneously a small quantity of crystalline form V of compound of formula (I) is added, and the mixture is cooled until crystallisation is complete.

4. A pharmaceutical composition comprising as active ingredient an effective amount of crystalline form V of the compound of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.

5. A method for treating a living animal body, including a human, afflicted with disorders of the melatoninergic system comprising the step of administering to the living animal body, including a human, an amount of crystalline form V of the compound of claim 1, which is effective for the alleviation of the disorder.

6. A method for treating a living animal body, including a human, afflicted with sleep disorders, stress, anxiety, seasonal affective disorders or severe depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, migraine, memory loss, Alzheimer's disease, and cerebral circulation disorders, comprising the step of administering to the living animal body, including a human, an amount of crystalline form V of the compound of claim 1, which is effective for the alleviation of the disorder.