FR3012142A1 - NOVEL AGOMELATIN AND SULFONIC ACID COMPLEXES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

New complexes of agomelatine and sulphonic acids of formula (I):

Description

The present invention relates to novel complexes of agomelatine and sulfonic acids, their method of preparation as well as pharmaceutical compositions containing them.

Agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide has the structure of formula (II): MeO NIICONIe Agomelatine is marketed under the brand name Valdoxan® or Thymanax® by the French group Servier as an agonist on the receptors of the melatoninergic system and antagonist of the 5-HT2c receptor. It is the first melatoninergic antidepressant, useful in the treatment of major depression, improving sleep and sexual function. Agomelatine, its preparation and its therapeutic use have been described in European patents EP 0 447 285 and EP1564202.

The object of the present invention is to elaborate complexes of agomelatine and sulphonic acids having the particular stoichiometry of 2 molar equivalents of agomelatine per 1 molar equivalent of sulphonic acids. These complexes have excellent properties in terms of solubility, stability and purity, making it possible to envisage their use for the manufacture of pharmaceutical compositions containing agomelatine. Moreover, the stoichiometry of the complexes according to the present invention confers a weight advantage in favor of the active ingredient of the i.e. Pagomelatin complex, making it possible to develop pharmaceutical formulations containing smaller amounts of complex.

The present invention relates to agomelatine and sulphonic acid complexes having the structure of formula (I): ## STR2 ## wherein 5-naphthalene disulfonic acid or benzene sulfonic acid The preferred compounds according to the invention are the following complexes of agomelatine and sulfonic acids: agomelatine complex / 1,5-naphthalene disulfonic acid (2/1), 113 agomelatine complex 1,5-naphthalene disulfonic acid (2/1) monohydrate, agomelatine complex / benzene sulfonic acid (2/1) The agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) is characterized by its diffraction pattern X on the powder represented in FIG. 1, measured on a Panalytical Xpert Pro MPD diffractometer (copper anticathode) The main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ° + 0.2), and of relative intensity e (expressed as a percentage of the most intense line) and are listed in Table 1: Table 1: Table of diffraction peaks of the agomelatine complex / 1,5-naphthalenesulphonic acid (2/1) 2-Theta (°) exp. cl (To) exp. Intensity (%) 6,3716 13,87229 18,97 11,3804 7,77552 17,98 11,9227 7,42299 36.06 12,5064 7,07784 100,00 12,6590 6,99288 13,75 14 , 5508 6.08767 44.17 15.5658 5.69292 11.96 16.2029 5.47051 42.63 16.9421 5.23346 25.85 17.6267 5.03171 18.67 19.4300 4.56857 49.04 20.2146 4.39301 22.77 21.4353 4.1550 17.80 21.6713 4.10090 22.84 22.2180 4.00121 64.19 22.4174 3.96607 10.83 24 0749 3,69664 29,61 24,5048 3,63275 13,33 25,1744 3,53763 20,58 25,7599 3,45853 23,59 When the complex of the present invention is characterized by ray diffraction measurement X, there may be measurement errors of identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about +0.2, and sometimes an error of about ± 0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex. The crystal structure of the agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) was determined and the following parameters were identified: Space group: P 1 21 / c 1 (14) Mesh parameters: a - 8.4970 (3) A, b 8.0873 (3) A, c 27.7107 (9) A; a - 90 °, p 93.059 (2) °, y - 90 ° Volume of the mesh: Vunit Ce = 1901,51100A3 The agomelatine / 1,5-naphthalenesulphonic acid (2/1) complex is also characterized by DSC ( differential scanning calorimetry) in the spectrum shown in Figure 2, which shows an endotherm corresponding to the melting of the complex at a temperature of about 237 ° C. The invention also relates to the complex agomelatine I acid 1,5-naphthalene disulfonic acid (2/1) monohydrate which is characterized by its powder X-ray diffraction pattern shown in Figure 3, measured on a diffractometer Panalytical Xpert Pro MPD (anticathode of copper). The main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ° + 0.2), and relative intensity (expressed as a percentage of the most intense line) and are listed in Table 2: Table 2: Table of diffraction peaks of the complex agomelatine I 1,5-naphthalene disulfonic acid (2/1) monohydrate 2-Theta (°) exp. d (To) exp. Intensity (%) 9,6680 9,14852 12,45 12,4885 7,08796 57,23 12,6164 7,01639 28,61 14,5042 6,10715 57,42 16,2684 5,44863 25.67 16 , 4624 5,38484 32,93 16,8967 5,24739 90,90 19,3772 4,58091 10,50 22,4767 3,95573 100.00 23,4111 3,79992 20.49 23,5330 3,78051 44.02 23.6735 3.75840 21.92 24.0477 3.70076 13.67 24.5716 3.62303 13.43 25.1240 3.54460 12.46 26.6602 3.34374 19.10 28, 1333 3,16930 12,07 28,2443 3,15971 22,49 When the complex of the present invention is characterized by the X-ray diffraction measurement, there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More specifically, the 2 theta values may have an error of about +0.2, and sometimes an error of about +0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex. The crystalline structure of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex was determined and the following parameters were identified: - Space group: P -1 (2) - Mesh parameters: a - 9.5673 (3) AT, b = 9.7223 (3) A, c = 11.4632 (3) A; a = 76.967 (2) °, J3 = 75.339 (1) °, y = 78.675 (2) ° Volume of the mesh: Vunit cen = 993.93800 À3 Agomelatine complex / 1,5-naphthalene disulfonic acid (2/1 ) monohydrate is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 4, which shows two endotherms: at about 116 ° C corresponding to the dehydration of the complex, the other at about 238 ° C corresponding to the fusion of the complex. The invention also relates to the agomelatine / benzene sulfonic acid complex (2/1) which is characterized by its powder X-ray diffraction pattern shown in FIG. 5, measured on a Panalytical Xpert Pro MPD diffractometer (copper anticathode). The main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ° + 0.2), and relative intensity (expressed as a percentage of the most intense line) and are listed in Table 3: Table 3: Table of diffraction peaks of agomelatine complex / benzene sulfonic acid (2/1) 2-Theta (°) exp. d (A) exp. Intensity (%) 8.0711 10.95469 35.25 12.6820 6.98026 68.37 -6 12.7706 6.93203 65.37 13.0114 6.80427 15.18 13.3054 6.65458 31 84 14.9475 5.92700 19.42 15.1121 5.86283 70.19 15.4873 5.72160 14.16 16.1644 5.48344 12.98 17.2360 5.1448 21.06 18.1046 4 , 89993 36.33 18.6255 4.76406 10.91 18.8009 4.72001 33.43 20.0908 4.41978 30.26 20.4742 4.33788 42.37 20.6921 4.29270 56.78 20.8640 4.25771 26.42 21.7142 4.09289 13.88 23.3683 3.80679 15.16 23.6410 3.76349 100.00 24.9314 3.57154 26.81 25.6543 3 47253 10.71 27.5599 3.23660 14.00 Where the complex of the present invention is characterized by X-ray diffraction measurement, there may be errors in the measurement of identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ± 0.2, and sometimes an error of about ± 0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex. The crystal structure of the agomelatine / benzene sulfonic acid complex (2/1) was determined and the following parameters were identified: - Space group: P -1 (2) - 7 - - Mesh parameters: a - 15, 5878 (8) Å, b = 15.7088 (6) Å, c = 7.2091 (3) Å; a - 100.445 (2) °, = 99.470 (2) °, y = 89.054 (3) ° - Volume of the mesh: Vunit cell 1712,18900 A The agomelatine / benzene sulfonic acid complex (2/1) is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 6, which shows an endotherm at about 116 ° C corresponding to the fusion of the complex. The invention also relates to a process for obtaining complexes of agomelatine and sulfonic acids, wherein: the two constituents are mixed in an organic or hydro-organic solvent in the desired proportions; the solution obtained is stirred and optionally heated to a temperature at most equal to the boiling point of the chosen solvent; the medium is cooled with stirring and the complex precipitates naturally or precipitates after being taken up in a second solvent; the precipitate obtained is filtered and dried. In the process according to the invention, the solvent used is preferably a ketone such as, for example, acetone; an ether such as, for example, diisopropyl ether, tetrahydrofuran or methyl t-butyl ether; an aromatic hydrocarbon such as toluene for example. When a second solvent is used to promote the precipitation of the complex, the solvent chosen is an alcohol such as, for example, methanol, ethanol or tert-butanol; an alkane such as, for example, n-hexane or n-heptane; or benzonitrile.

An alternative method is to co-grind the two components of the co-crystal. Preferably co-grinding is performed in a steel jar. A variant of this process consists of adding an organic solvent during grinding; in this case the co-crystal obtained is then dried. Among the solvents used, mention will be made more particularly of ketones, for example acetone; or ethers such as, for example, diisopropyl ether or methyl tert-butyl ether. Alcohols such as, for example, methanol, ethanol or tert-butanol can also be used. Advantageously, grinding is performed with stainless steel balls. The grinding is carried out by means of vibrations, preferably vibrations with a frequency ranging from 20 to 30 Hz. The vibrations are applied for a duration ranging from 5 minutes to 3 hours. Another alternative method consists in mixing two solutions containing each of the constituents and in rapidly freezing at a very low temperature the mixture obtained, then in drying at this same low temperature the co-crystal thus obtained. Advantageously, the two constituents are mixed in an organic or hydro-organic solvent. Preferably, the freezing and drying are carried out between -40 ° C and -60 ° C, and more preferably at -40 ° C. Another advantageous process according to the invention consists in mixing the agomelatine powders and the acid in question in a mixer, then extruding it by twin-screw extrusion without a die to obtain a solid grain directly at the extruder outlet. Preferably, the screw profile used is a high shear profile, optionally with the use of kneading elements to improve the contact surface between the constituents. The L / D parameter of the screw can vary between 10 and 40 and the speed of rotation between 10 and 200 rpm. The temperature used varies from 40 to 100 ° C.

The agomelatine and sulfonic acid complexes obtained have a significantly increased solubility compared to agomelatine per se, making them more suitable for the preparation of pharmaceutical formulations. The agomelatine and sulphonic acid complexes according to the invention also have excellent stability and very good purity. They are also obtained by a simple process, with no difficult step. The pharmaceutical forms containing the complexes according to the invention will be used for the treatment of disorders of the melatoninergic system, and more particularly in the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorder. , obsessive-compulsive disorders, mood disorders including bipolar disorder, major depression, seasonal depression, cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, anxiety, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia ,. various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as disorders of the cerebral circulation. In another field of activity, the co-crystals according to the invention can be used in sexual dysfunctions, as inhibitors of inummomodulators and in the treatment of cancers. The invention also extends to pharmaceutical compositions containing as active principle a complex of agomelatine and sulfonic acids according to the invention in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or sunscreen), nasal, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, skin gels, injectables, oral suspensions and chewables. The useful dosage is adaptable according to the stature and severity of the condition, the route of administration as well as the age and weight of the. patient. This dosage varies from 0.1 to 1 g per day of a; oinelatin in one or more doses. Representative examples of the present invention are illustrated with the corresponding Figures to better appreciate the purpose, features, and advantages thereof. FIG. 1: powder X-ray diffraction pattern of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex of Example 1. FIG. 2: DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) of Example 1.

3: powder X-ray diffraction pattern of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2. FIG. 4: DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid complex (2 1) monohydrate of Example 2. FIG. 5: powder X-ray diffraction diagram of the agomelatine / benzene sulphonic acid complex (2/1) of Example 3. FIG. 6: DSC thermogram of the agomelatine / benzene sulphonic acid complex (FIG. 2/1) of Example 3. Example 1: Agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) Method of operation 1 Agomelatine (5.00 g, 2 eq) and 1.5 acid anhydrous naphthalene disulfonic (2.96 g, 1 eq) are placed in a reactor. 20m1 of acetone are added. The suspension is stirred under reflux for 1 hour, then immediately filtered. The cake is washed twice with acetone and then dried for 1 hour. 25 g of a white solid corresponding to the title product are obtained.

Yield: 78.5% Melting point: 237 ° C. Method of operation 2 Agomelatine (2.98 g, 2 eq) and 1,5-naphthalene disulfonic acid tetrahydrate (2.18 g, 1 eq) are introduced into a 250 ml balloon. 100 ml of acetone are added and the reaction mixture is refluxed for 3 hours (the crystallization occurs after about one hour). The suspension is cooled to room temperature and stirred for 1 hour. 4.03 g of a white solid corresponding to the title product are isolated by filtration and dried under vacuum (10 mbar) at 40 ° C. for 15 hours. Yield 85.0% Melting point: 237 ° C Method of Operation 3 Agomelatine (5, OOg, 2 eq) and anhydrous 1,5-naphthalenesulphonic acid (2.96 g, 1 eq) are placed in a reactor. 40 ml of methyl ether and tert-butyl are added. The suspension is stirred under reflux for 3 hours, then immediately filtered. The cake is washed twice with methyl tert-butyl ether and then dried for 1 hour. 5.28 g of a white solid corresponding to the title product are obtained. Yield: 66.3% Melting point: 237 ° C. Example 2: Agomelatine / 1,5-naphthalenesulphonic acid (2/1) monohydrate complex Operating mode 1 Agomelatine (5, OOg, 1 eq) and anhydrous 1,5-naphthalenesulphonic acid (5.92 g, 1 eq) are placed in a reactor. 10 ml of ethanol and 20 ml of water are added. The suspension is stirred under reflux for 0.5 hours to become clear. The medium is then cooled naturally with stirring for 0.5 hours, and the suspension is filtered. The cake is washed with ethanol and water and then dried for 1 hour. 5.15 g of a white solid are obtained. Yield: 63.2% Melting point: 116 ° C (dehydration endotherm), 238 ° C Method of Operation 2 Agomelatine (5.00 g, 1 eq) and 1,5-naphthalene disulfonic acid tetrahydrate (7) , 40 g, 1 eq) are introduced into a reactor. 10 ml of ethanol and 20 ml of water are added. The suspension is stirred under reflux for 0.5 hours to become clear. The medium is then cooled naturally with stirring for 0.5 hours, and the suspension is filtered. The cake is washed with ethanol and water and then dried for 1 hour. 4.90 g of a white solid are obtained. Yield: 60.2% Melting Point: 116 ° C (Dehydration Endotherm), 238 ° C Method of Operation 3 Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370) g) are placed in a non-oxidizable 50m1 jar. Two stainless steel balls 12 mm in diameter are added and the jar is closed. Vibrations having a frequency of 30 Hz are applied for 15 minutes to conduct, after a night of drying at room temperature, 0.805 g of solid. Melting point: 116 ° C (dehydration endotherm), 238 ° C Method of operation 4 Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) are placed in a 50 ml jar. not oxidizable. Two stainless steel balls 12 mm in diameter are added and the jar is closed. 1000 of methyl ether and tert-butyl are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to conduct, after a drying night at room temperature, 0.803g of solid. Melting point: 116 ° C. (dehydration endotherm), 238 ° C. Example 3: Agomelatine / benzene sulphonic acid complex (2/1) Agomelatine (5.00 g, 2 eq) and benzene sulphonic acid (1, 62 g, 1 eq) are introduced into a reactor. 10 ml of ethanol and 15 ml (10 ml) + 5 ml of toluene are added. The suspension is stirred under reflux for 0.5 hours so that it becomes clear (if the solution is not clear, we add ethanol until it becomes). The medium is then cooled naturally to 5 ° C. with stirring for 0.5 hours, and the suspension is filtered. The cake is dried for 1 hour. 4.31 g of a white solid corresponding to the title product are obtained.

Yield: 65.2% Melting point: 116 ° C. In the above examples, agomelatine commercially available or prepared according to one of the methods described in the prior art can be used. EXAMPLE 4 Pharmaceutical Compositions: Capsules Assayed at 25 mg Agomelatine Pharmaceutical Composition Containing the Compound of Example 1 Formulation for the Preparation of 1000 Capsules Each Containing 25 mg Agomelatine Compound of Example 1 39.8 g Lactose ( Spherolac 100) 85.2 g 1500 starch 25.5 g CMS-Na 8.5 g Ac-Di-Sol ® (FMC) 17 g Stearic acid 3.4 g Pharmaceutical composition containing the compound of Example 2 Formulation for preparation of 1000 capsules each containing 25 mg of agomelatine Compound of Example 2 40.7 g Lactose (Spherolac 100) 85.2 g Starch 1500 25.5 g CMS-Na 8.5 g Ac-Di-Sol ® ( FMC) 17g Stearic acid 3.4 g Pharmaceutical composition containing the compound of Example 3 Formulation for the preparation of 1000 capsules each containing 25 mg of agomelatine Compound of Example 3 33.1 g Lactose (Spherolac 100) 85, 2 g Starch 1500 25.5 g CMS-Na 8.5 g Ac-Di-Sol® (FMC) 17 g Stearic acid 3.4 g Example 14: Pharma Compositions coatings: agomelatine 25 mg tablets Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine: Compound of Example 1 39.8 g Lactose monohydrate 115 g Magnesium stearate 2 g Corn starch 33 g Maltodextrins 15 g Colloidal anhydrous silica 1 g Pregelatinized maize starch, Type A 9 g Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine: Compound of Example 2 40.7 g Lactose monohydrate 115 g Magnesium stearate 2 g Corn starch 33 g Maltodextrins 15 g Colloidal silica anhydrous I g 20 Pregelatinized maize starch, Type A 9 g Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine: Compound of Example 3 33.1 g Lactose monohydrate 115 g Magnesium stearate 2 g Corn starch 33 g Maltodextrins 15 g Anhydrous colloidal silica 1 g Pregelatinized maize starch Type A 9 g -15- Detection methods and results 1. Purity of s samples Chromatographic conditions: column C18; mobile phase: 10 mmol / L phosphate buffer (adjusted to pH 7.0 with NaOH): 2: 7 acetonitrile (v / v); column temperature: 40 ° C; detection wavelength: 220 nm; internal standard method used with the compound of Example 1. Solutions at 1 mg / ml of the compounds of the invention are prepared with the mobile phase. 10 μl of each solution are injected into the liquid chromatography system and the chromatograms are recorded.

The compounds of the invention all have purities greater than or equal to 99%. 2. Stability Samples of the compounds of Examples 1, 2 and 3 are placed in incubators under denaturing conditions and stability is determined by 2-month DSC measurements. The results are shown in Table 4: Table 4 25 ° C, 60% RH BO 50 ° C BF 70 ° C BF Compound of Example 1 stable stable stable Compound of Example 2 stable stable stable Compound of Example Stable stable stable RH = Relative humidity; BO = Open Bottle; BF - Closed Bottle The compounds of the invention are stable under strongly denaturing conditions, which is favorable for their use in pharmaceutical compositions. 3. Solubility Using an external standard method, the compounds of Examples 1, 2 and 3 are tested in HPLC, and compared with form II agomelatine. The results are presented in Table 5 in the form of% increase in solubility with respect to the solubility of agomelatin II: Table 5 Sample Solubility (increase versus Agomelatin Form II) In water In 1-1C10, 1N In pH6.8 buffer Compound of Example 1 + 18% + 25% + 48% Compound of Example 2 + 12% + 75% + 57% Compound of Example 3 + 22% + 32% + 46% The results show that the agomelatine and sulfonic acid complexes of the present invention have a higher solubility than agomelatine of form II per se in water, in 0.1N HCl, similar to These results show that the complexes have a much better potential in terms of bioavailability than agomelatine of IL-4 form. DSC analyzes Approximately 5-10 mg of the compounds of Examples 1 , 2 and 3 are weighed in a closed aluminum crucible with a drilled aluminum cover (non hermetic), except decision contrary. The sample is introduced into a TA Q1000 (equipped with a chiller), cooled and maintained at 25 ° C. After thermal stabilization, the sample and reference are heated from 200 ° C to 250 ° C at a rate of 10 ° C / min and the response to heat flow is recorded. Nitrogen is used as purge gas, at a flow rate of 100 3 CM / mi n.

The DSC thermograms obtained with the compounds of Examples 1, 2 and 3 are reported in FIGS. 2, 4 and 6. 5. Analysis of the crystalline structure The conditions for measuring X-ray powder diffraction diagrams of the products of Examples 1, 2 and 3 are as follows: About 50 mg of the compounds of Examples 1, 2 and 3 are placed between two Kapton® films and fixed on the sample support. The sample is then placed in a PANALYTICAL XPERT-PRO MPD diffractometer in transmission mode under the following conditions: Generator parameters: 45 kV / 40 mA, theta / theta configuration -17- Anode: Cu K-Alphal [A] 1, 54060 K-Alpha2 [At] 1.54443 K-Beta [A] 1.39225 K-A2 / K-Al Ratio 0.50000 Scanning mode: continuous from 3 ° to 55 ° (Bragg angle 2 theta) Step [ ° 2Th.] 0,0170 Step time [s] 35,5301 Start angle ['MI.] 3,0034 End angle [° 2Th.] 54,9894 Rotation: yes X-ray diffraction patterns obtained for Examples 1, 2 and 3 are shown in Figures 1, 3 and 5.

Claims (16)

REVENDICATIONS1. Agomelatine and sulfonic acid complexes of formula (I): NHCOMe 2 1 RSO 3 H, x H 2 O where x is 0 or 1, and RSO 3 H is 1,5-naphthalene disulfonic acid or benzene sulfonic acid. 2. Agomelatine complex of formula (1) according to claim 1 which is the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1). 3. agomelatine complex of formula (I) according to claim 2 characterized by its powder X-ray diffraction diagram expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2) , and of the following relative intensity: 2-Theta (°) exp. d (A) exp. Intensity (%) 6.3716 13.87229 18.97 11.3804 7.77552 17.98 11.9227 7.42299 36.06 12.5064 7.07784 100.00 12.6590 6.99288 13.75 14.5508 6.08767 44.17 15.5658 5.69292 11.96 16.2029 5.47051 42.63 16.9421 5.23346 25.85 17.6267 5.03171 18.67 19.4300 4.56857 49.04 20.2146 4.39301 22.77 MeO (I) -19- 21.4353 4.14550 17.80 21.6713 4.10090 22.84 22.2180 4.00121 64.19 22.4174 3.96607 10.83 24.0749 3.69664 29.61 24.5048 3.63275 13.33 25.1744 3.53763 20.58 25.7599 3.45853 23.59 Including shapes with diffraction angles within ± 0.2 ° . 4. agomelatine complex of formula (I) according to claim 1 which is the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate. 5. agomelatine complex of formula (I) according to claim 4, characterized by its powdery X-ray diffraction pattern expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed as 0 + 0, 2), and of the following relative intensity: 2-Theta (°) exp. d (To) exp. Intensity (%) 9.6680 9.14852 12.45 12.4885 7.08796 57.23 12.6164 7.01639 28.61 14.5042 6.10715 57.42 16.2684 5.44863 25.67 16.4624 5.38484 32.93 16.8967 5.24739 90.90 19.3772 4.58091 10.50 22.4767 3.95573 100.00 23.4111 3.79992 20.49 23.5330 3.78051 44.02 23.6735 3.75840 21.92 24.0477 3.70076 13.67- 20 - 24.5716 3.62303 13.43 25.1240 3.54460 12.46 26.6602 3.34374 19.10 28.1333 3.16930 12.07 28.2443 3.15971 22.49 Including Forms whose diffraction angles correspond to ± 0.2 °. 6. Agomelatine complex of formula (I) according to claim 1 which is the complex agomelatine / benzene sulfonic acid (2/1). 7. Agomelatine complex of formula (I) according to claim 6 characterized by its powder X-ray diffraction diagram expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2) , and of the following relative intensity: 2-Theta (°) exp. d (To) exp. Intensity (%) 8.0711 10.95469 35.25 12.6820 6.98026 68.37 12.7706 6.93203 65.37 13.0114 6.80427 15.18 13.3054 6.65458 31.84 14.9475 5.92700 19.42 15.1121 5.86283 70.19 15.4873 5.72160 14.16 16.1644 5.48344 12.98 17.2360 5.14486 21.06 18.1046 4.89993 36.33 18.6255 4.76406 10.91 18.8009 4.72001 33.43 20.0908 4.41978 30.26 20.4742 4.33788 42.37 20.6921 4.29270 56.78-21 - 20.8640 4.25771 26.42 21.7142 4.09289 13.88 23.3683 3.80679 15.16 23.6410 3.76349 100.00 24.9314 3.57154 26.81 25.6543 3.47253 10.71 27.5599 3.23660 14.00 Including shapes with diffraction angles within ± 0.2 °. 8. Process for obtaining complexes of agomelatine and sulfonic acids according to one of claims I to 7, characterized in that: agomelatine and sulphonic acids are mixed in an organic or hydro-organic solvent aqueous in the desired proportions; the solution obtained is stirred and optionally heated to a temperature at most equal to the boiling point of the chosen solvent; the medium is cooled with stirring and the ce-crystal precipitates naturally or precipitates after being taken up in a second solvent; the precipitate obtained is filtered and dried. 9. Process for preparing the agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the two constituents are co-milled. 10. A process for preparing the agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the two constituents are mixed in an organic or hydro-organic solvent and then frozen and dried to a very high temperature. low temperature. 11. A process for the preparation of agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the powders of agomelatine and the acid in question are mixed in a mixer, and the mixture is extruded. by twin-screw extrusion without die to obtain a solid grain directly at the extruder outlet. 12. Pharmaceutical compositions containing as active ingredient a complex of agomelatine and sulfonic acids according to one of claims 1 to 7, in combination with one or more inert, non-toxic and pharmaceutically acceptable vehicles. 13. Pharmaceutical compositions according to claim 12 useful for the manufacture of medicaments for treating disorders of the melatoninergic system. 14. Pharmaceutical compositions according to claim 12 which are useful for the manufacture of medicaments for the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorder, obsessive-compulsive disorders, mood disorders and other disorders. bipolar disorder, major depression, seasonal depression, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as in cerebral circulation disorders and dysfunction as ovulation inhibitors, immunomodulators and in the treatment of cancers. 15. Complexes of agomelatine and sulfonic acids of formula (I) according to one of claims 1 to 7 for the treatment of disorders of the melatoninergic system. 16. Complexes of agomelatine and sulfonic acids of formula (I) according to one of claims 1 to 7 for the treatment of stress, sleep disorders, anxiety disorders including generalized anxiety disorder, obsessive-compulsive disorders, mood disorders and in particular bipolar disorders, major depression, seasonal depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as in disorders of the cerebral circulation as well as in dystrophy. sexual function, as ovulation inhibitors, immunomodulators and in the treatment of cancers.