AU2006203342B2

AU2006203342B2 - New crystalline form V of agomelatine, a process for its preparation and pharmaceutical compositions containing it

Info

Publication number: AU2006203342B2
Application number: AU2006203342A
Authority: AU
Inventors: Gerard Coquerel; Julie Linol; Jean-Claude Souvie
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2005-08-03
Filing date: 2006-08-03
Publication date: 2012-07-19
Anticipated expiration: 2026-08-03
Also published as: IL177173A0; NO20063517L; PE20070365A1; EP1752443A1; BRPI0603059A; TWI359128B; CU20060153A7; TW200736199A; WO2007015004A3; EP2277857A3; RS52423B; CA2555115C; ZA200606453B; HRP20120779T1; IL177173A; MXPA06008789A; EA011030B1; NO336967B1; CR8529A; CY1113011T1

Abstract

NEW CRYSTALLINE FORM V OF AGOMELATINE, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT Crystalline form V of the compound of formula (I) : NHCOMe MeO (I) characterised by its powder X-ray diffraction diagram. Medicaments.

Description

Pool Section 29 Regulation 3.2(2) AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: Invention Title: New crystalline form of agomelatine, a process for its preparation and pharmaceutical compositions containing it The following statement is a full description of this invention, including the best method of performing it known to us: -1 The present invention relates to a new crystalline form V of agomelatine, or N-[2-(7 methoxy-1-naphthyl)ethyl]acetamide, of formula (I) : NHCOMe MeO (I) a process for its preparation and pharmaceutical compositions containing it. 5 Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuable pharmaco logical 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-HT 2 c receptor. Those properties confer activity in the central nervous system and, more especially, in the 10 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. Agomelatine, its preparation and its therapeutic use have been described in European Patent Specification EP 0 447 285. 15 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. 20 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.

-2 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 5 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 (A) Intensit6 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 10 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.

-3 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 5 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 11 0 0 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. 10 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 15 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 20 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 25 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, 30 insomnia and fatigue due to jetlag, appetite disorders and obesity.

4 Accordingly, in one embodiment the invention relates to a method for the treatment of melatoninergic disorders comprising administering to a patient requiring such treatment an effective amount of crystalline form V of agomelatine or a pharmaceutical composition thereof. 5 In another embodiment the invention relates to a method for the treatment of sleep disorders, stress, anxiety, seasonal affective disorders, severe depression, cardiovascular pathologies, pathologies of the digestive system, insomnia or fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various 10 disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, sexual dysfunction, or cancers, or for ovulation-inhibition, or immunomodulation, the method comprising administering to a patient requiring such treatment an effective amount of crystalline form V of agomelatine or a pharmaceutical composition thereof. 15 In a further embodiment the invention relates to the use of crystalline form V of agomelatine or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of melatoninergic disorders. In another embodiment the invention relates to the use of crystalline form V of agomelatine or a pharmaceutical composition thereof in the manufacture of a 20 medicament for the treatment of sleep disorders, stress, anxiety, seasonal affective disorders, severe depression, cardiovascular pathologies, pathologies of the digestive system, insomnia or fatigue due to jetlag, 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, 25 migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, sexual dysfunction, or cancers, or for ovulation-inhibition, or immunomodulation.

4a 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, 5 parenteral (intravenous or subcutaneous) or nasal administration, tablets or drag6es, 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 10 0.1 mg to I 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)ethyllacetamide 15 1 OOg 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 20 most intense ray): -5 2-Theta (*) d (A) Intensit6 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)ethyljacetamide 4 g of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide are put in a ventilated incubator at 1 10 C. After 1 hour at 1 10*C, the product is immediately placed at room temperature and seeded with 5 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 10 (expressed as a percentage of the most intense ray) : -6 2-Theta (*) d (A) Intensite 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 5 Lactose monohydrate............................................................................................... 62 g M agnesium stearate ................................................................................................. 1.3 g M aize starch............................................................................................................. 26 g M altodextrines......................................................................................................... 9 g Silica, colloidal anhydrous ...................................................................................... 0.3 g 10 Sodium starch glycolate type A............................................................................... 4 g Stearic acid .............................................................................................................. 2.6 g 7 Example 4: Pharmaceutical composition Formulation for the preparation of 1000 tables each containing a dose of 25 mg: Compound of Example 1 or 2 25 g Lactose monohydrate 62 g 5 Magnesium stearate 1.3 g Povidone 9 g Silica, colloidal anhydrous 0.3 g Sodium cellulose glycolate 30g Stearic acid 2.6 g 10 Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof. Any discussion of documents, acts, materials, devices, articles or the like which has 15 been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this specification.

Claims

1. Crystalline form V of agomelatine of formula (I: NIHCOMe MeO (I) characterised by the following powder X-ray diffraction diagram, measured using a 5 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 with respect to the most intense ray)

2-Theta (*) d (A) Intensit6 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 -9 2. Process for the preparation of the crystalline form V of the compound of formula (I) according to claim 1, characterised in that agomelatine is subjected to a mechanical grinding which is said to be "of high energy". 3. Process for the preparation of the crystalline form V of the compound of formula (I) 5 according to claim 1, 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. 4. Pharmaceutical compositions comprising as active ingredient crystalline form V of 10 agomelatine according to claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers. 5. Pharmaceutical compositions according to claim 4 for use in the manufacture of a medicament for the treatment of melatoninergic disorders. 6. Pharmaceutical compositions according to claim 4 for use in the manufacture of a 15 medicament for the treatment of 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, various disorders associated with normal or 20 pathological ageing, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, and also in sexual dysfunction, as ovulation inhibitors, immunomodulators and cancers. 10 7. A crystalline form V of agomelatine of formula I as described herein with reference to Example I or 2. 8. A pharmaceutical composition comprising as active ingredient crystalline form V of agomelatine as hereinbefore described with reference to Example 3 or 4. 5 9. A method for the treatment of melatoninergic disorders comprising administering to a patient requiring such treatment an effective amount of the crystalline form V of agomelatine according to claim 1 or 7, or a pharmaceutical composition according to claim 4 or 8. 10. A method for the treatment of sleep disorders, stress, anxiety, seasonal affective 10 disorders, severe depression, cardiovascular pathologies, pathologies of the digestive system, insomnia or fatigue due to jetlag, 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, 15 cerebral circulation disorders, sexual dysfunction, or cancers, or for ovulation inhibition, or immunomodulation, the method comprising administering to a patient requiring such treatment an effective amount of the crystalline form V of agomelatine according to claim I or 7, or a pharmaceutical composition according to claim 4 or 8. 20 11 Use of crystalline form V of agomelatine according to claim 1 or 7, or a pharmaceutical composition according to claim 4 or 8 in the manufacture of a medicament for the treatment of melatoninergic disorders. 12. Use of crystalline form V of agomelatine according to claim 1 or 7, or a pharmaceutical composition according to claim 4 or 8 in the manufacture of a 25 medicament for the treatment of sleep disorders, stress, anxiety, seasonal affective disorders, severe depression, cardiovascular pathologies, pathologies of the digestive system, insomnia or fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with 30 normal or pathological ageing, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, sexual dysfunction, or cancers, or for ovulation inhibition, or immunomodulation.