Abstract:
Crystalline form III 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.

Description:
[0001]     The present invention relates to a new crystalline form III 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  
       [0002]     Agomelatine, or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has valuable pharmacological properties.  
         [0003]     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 2C  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  
       [0004]     Agomelatine, its preparation and its therapeutic use have been described in European Patent Specification EP 0 447 285.  
         [0005]     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 formulation and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.  
         [0006]     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  
       [0007]     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 formulation.  
         [0008]     More specifically, the present invention relates to the crystalline form III 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&#39;s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):  
                                                     2-Theta (°)   d (Å)   Intensity       exp.   exp.   (%)                                10.52   8.405   100       12.92   6.848   40       16.15   5.482   53       17.38   5.097   69       17.84   4.968   96       18.55   4.779   22       19.20   4.619   97       19.89   4.460   30       20.32   4.366   24       21.15   4.197   26       22.08   4.022   16       22.96   3.870   23       23.33   3.810   95       23.84   3.730   33       24.52   3.628   25       24.88   3.576   59       25.07   3.550   90       26.27   3.390   61       26.86   3.316   22       27.97   3.187   20       29.51   3.024   43                  
 
         [0009]     The invention relates also to a process for the preparation of the crystalline form III of the compound of formula (I), which process is characterised in that agomelatine is heated at 110° C. until the melting be completed, and is then slowly cooled until crystallisation.  
         [0010]     An advantage of obtaining that crystalline form is that it allows the preparation of pharmaceutical formulations having a consistent and reproducible composition, which is especially advantageous when the formulations are to be used for oral administration.  
         [0011]     A pharmacological study of the form III 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 III 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&#39;s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer&#39;s disease, and in cerebral circulation disorders. In another field of activity, it appears that the crystalline III 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 III 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.  
         [0012]     The invention relates also to pharmaceutical compositions comprising as active ingredient the crystalline form III 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 dragées, granules, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions and disintegrable pastes.  
         [0013]     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.  
         [0014]     The Examples below illustrate the invention but do not limit it in any way.  
       EXAMPLE 1  
     Crystalline form III of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide  
       [0015]     100 g of N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide are heated at 110° C. in a ventilated incubator until the melting be completed, and are then slowly cooled until crystallisation. The crystalline form III 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&#39;s angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense ray):  
                                                     2-Theta (°)   d (Å)   Intensity       exp.   exp.   (%)                                10.52   8.405   100       12.92   6.848   40       16.15   5.482   53       17.38   5.097   69       17.84   4.968   96       18.55   4.779   22       19.20   4.619   97       19.89   4.460   30       20.32   4.366   24       21.15   4.197   26       22.08   4.022   16       22.96   3.870   23       23.33   3.810   95       23.84   3.730   33       24.52   3.628   25       24.88   3.576   59       25.07   3.550   90       26.27   3.390   61       26.86   3.316   22       27.97   3.187   20       29.51   3.024   43                  
 
       EXAMPLE 2  
     Pharmaceutical Composition  
       [0016]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Formulation 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 
               
               
                   
                 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 3  
     Pharmaceutical Composition  
       [0017]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                   
               
               
                 Formulation 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 anhydrous 
                 0.3 
                 g 
               
               
                   
                 Sodium cellulose glycolate 
                 30 
                 g 
               
               
                   
                 Stearic acid 
                 2.6 
                 g