HK1218745B - Novel complexes of agomelatine and sulphonic acids, method for preparing same and the pharmaceutical compositions that contain them - Google Patents

Description

Novel complex of agomelatine and sulfonic acid, method for preparing same, and pharmaceutical composition containing same

The present invention relates to a novel complex of agomelatine and sulfonic acid, a method for preparing the complex, and a pharmaceutical composition comprising the complex.

Agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide has the structure of formula (II):

Agomelatine is marketed by the French company Servier under the trade name or as a melatonergic system receptor agonist and 5- _HT2C receptor antagonist. It is the first melatonergic antidepressant used to treat major depressive disorder, improve sleep, and enhance sexual function.

European patent specifications EP 0 447 285 and EP 1 564 202 describe agomelatine, its preparation and its therapeutic use.

The present invention relates to the preparation of complexes of agomelatine and sulfonic acid having a specific stoichiometry of 2 molar equivalents of agomelatine per 1 molar equivalent of sulfonic acid. These complexes possess superior properties in terms of solubility, stability, and purity, making it possible to design them for the preparation of pharmaceutical compositions containing agomelatine. Furthermore, the stoichiometry of the complexes of the present invention offers advantages in terms of the weight of the active ingredient of the complex (i.e., agomelatine), making it possible to prepare pharmaceutical formulations containing lower amounts of the complexes.

The present invention relates to a complex of agomelatine and sulfonic acid, which has the structure of formula (I):

wherein x represents 0 or 1, and RSO ₃ H represents 1,5-naphthalene disulfonic acid or benzenesulfonic acid.

A preferred compound of the present invention is the following complex of agomelatine and sulfonic acid:

-Agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex,

-Agomelatine/1,5-naphthalene disulfonic acid (2/1) monohydrate complex,

-Agomelatine/benzenesulfonic acid (2/1) complex.

The agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex is characterized by the X-ray powder diffraction pattern shown in Figure 1, which was measured using a Panalytical Xpert Pro MPD diffractometer (copper cathode). The main spectral lines are represented by the interplanar spacing d, the Bragg angle 2θ (expressed in degrees ± 0.2) and the relative intensity (expressed as a percentage of the most intense line), and are listed in Table 1:

Table 1: Table of diffraction peaks of agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex

When characterizing the complexes of the present invention by X-ray diffraction measurements, there may be measurement errors in the identified peaks, sometimes due to the equipment or environment used. More specifically, even with sophisticated equipment, 2θ values can have errors of approximately ±0.2, and sometimes approximately ±0.1. Therefore, when identifying the structure of the complex, measurement errors must be considered accordingly.

The crystal structure of agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex was determined, and the following parameters were identified:

-Space group:P 1 21/c 1(14)

-Unit cell parameters: α＝90°, β＝93.059(2)°, γ＝90°

-Unit cell volume:

The agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex was also characterized by DSC (Differential Scanning Calorimetry) in the spectrum shown in Figure 2 which shows an endothermic peak at a temperature of about 237°C corresponding to the melting of the complex.

The present invention also relates to an agomelatine/1,5-naphthalenedisulfonic acid (2/1) monohydrate complex, characterized by its X-ray powder diffraction pattern shown in FIG3 , measured using a Panalytical Xpert Pro MPD diffractometer (copper cathode). The main spectral lines are represented by interplanar spacing d, Bragg angle 2θ (expressed in degrees ± 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 agomelatine/1,5-naphthalene disulfonic acid (2/1) monohydrate complex

When characterizing the complexes of the present invention by X-ray diffraction measurements, there may be measurement errors in the identified peaks, sometimes due to the equipment or environment used. More specifically, even with sophisticated equipment, 2θ values can have errors of approximately ±0.2, and sometimes approximately ±0.1. Therefore, when identifying the structure of the complex, measurement errors must be considered accordingly.

The crystal structure of agomelatine/1,5-naphthalenedisulfonic acid (2/1) monohydrate complex was determined, and the following parameters were identified:

-Space group: P-1(2)

-Unit cell parameters: α＝76.967(2)°, β＝75.339(1)°, γ＝78.675(2)°

-Unit cell volume:

The agomelatine/1,5-naphthalenedisulfonic acid (2/1) monohydrate complex was also characterized by DSC (Differential Scanning Calorimetry) in the spectrum shown in FIG4 , which shows two endothermic peaks: one at about 116° C., corresponding to the dehydration of the complex, and the other at about 238° C., corresponding to the melting of the complex.

The present invention also relates to an agomelatine/benzenesulfonic acid (2/1) complex, characterized by its X-ray powder diffraction pattern shown in FIG5 , measured using a Panalytical Xpert Pro MPD diffractometer (copper cathode). The main spectral lines are represented by interplanar spacing d, Bragg angle 2θ (expressed in degrees ± 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/benzenesulfonic acid (2/1) complex

When characterizing the complexes of the present invention by X-ray diffraction measurements, there may be measurement errors in the identified peaks, sometimes due to the equipment or environment used. More specifically, even with sophisticated equipment, 2θ values can have errors of approximately ±0.2, and sometimes approximately ±0.1. Therefore, when identifying the structure of the complex, measurement errors must be considered accordingly.

The crystal structure of agomelatine/benzenesulfonic acid (2/1) complex was determined and the following parameters were identified:

-Space group: P-1(2)

-Unit cell parameters: α＝100.445(2)°, β＝99.470(2)°, γ＝89.054(3)°

-Unit cell volume:

The agomelatine/benzenesulfonic acid (2/1) complex was also characterized by DSC (Differential Scanning Calorimetry) in the spectrum shown in Figure 6, which shows an endothermic peak at about 116°C corresponding to the melting of the complex.

The present invention also relates to a method for obtaining a complex of agomelatine and sulfonic acid, wherein:

- mixing the two components in the desired ratio in an organic solvent or an aqueous-organic solvent;

- stirring the resulting solution and optionally heating it at a temperature not exceeding the boiling point of the chosen solvent;

- cooling the mixture while stirring, and the complex precipitates naturally or after adding a second solvent;

- The resulting precipitate was filtered and dried.

In the method of the present invention, the solvent used is preferably a ketone, such as acetone; an ether, such as diisopropyl ether, tetrahydrofuran, or methyl tert-butyl ether; or an aromatic hydrocarbon, such as toluene. When a second solvent is used to facilitate precipitation of the complex, the solvent of choice is an alcohol, such as methanol, ethanol, or tert-butanol; an alkane, such as n-hexane or n-heptane; or benzonitrile.

An alternative method involves co-grinding the two components of the co-crystal. This co-grinding is preferably carried out in a steel tank. A variant of this method involves adding an organic solvent during the grinding process; in this case, the resulting co-crystal is then dried. Among the solvents used, ketones, such as acetone, or ethers, such as diisopropyl ether or methyl tert-butyl ether, may be mentioned in particular. Alcohols, such as methanol, ethanol, or tert-butanol may also be used.

Advantageously, the grinding is performed using non-oxidizable balls. The grinding is performed using vibration, preferably with a vibration frequency in the range of 20 to 30 Hz. The vibration may be applied for a time in the range of 5 minutes to 3 hours.

Another alternative method involves mixing two solutions of each component and rapidly freezing the resulting mixture at very low temperatures, followed by drying the resulting co-crystals at the same low temperature. The two components are advantageously mixed in an organic solvent or an aqueous-organic solvent. Freezing and drying are preferably carried out at temperatures between -40°C and -60°C, most preferably at -40°C.

Another advantageous process according to the invention comprises mixing agomelatine powder and the acid powder in a mixer and then extruding the mixture by die-free twin-screw extrusion to obtain solid granules directly at the extruder outlet. The screw profile used is preferably a high-shear profile, optionally with a kneader element to improve the contact surface between the components. The L/D parameter of the screw can vary from 10 to 40, and the rotation speed is from 10 to 200 rpm. The temperature used varies from 40 to 100°C.

The resulting complexes of agomelatine and sulfonic acid exhibit significantly improved solubility compared to agomelatine itself, making them more suitable for use in the preparation of pharmaceutical formulations. The complexes of agomelatine and sulfonic acid of the present invention also exhibit excellent stability and very high purity. Furthermore, they are obtained by a simple method that does not involve any difficult steps.

Pharmaceutical forms containing the complexes of the present invention are useful for treating disorders of the melatoninergic system, more particularly for treating stress, sleep disorders, anxiety disorders, especially generalized anxiety disorder, obsessive-compulsive disorder, mood disorders, especially bipolar disorder, major depression, seasonal affective disorder, cardiovascular disorders, digestive disorders, insomnia and fatigue caused by jet lag, schizophrenia, panic attacks, depression, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, Alzheimer's disease, various disorders associated with normal or pathological aging, migraines, memory loss, Alzheimer's disease, and also for cerebral circulatory disorders. In another area of activity, the cocrystals of the present invention can be used for sexual dysfunction, as ovulation inhibitors and immunomodulators, and for the treatment of cancer.

The present invention also relates to a pharmaceutical composition comprising, as active ingredient, the complex of agomelatine and sulfonic acid of the present invention, and one or more auxiliary agents or excipients.

Among the pharmaceutical compositions of the invention, mention may more particularly be made of those suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, granules, sublingual tablets, capsules, lozenges, suppositories, creams, ointments, skin gels, injections, drinkable suspensions and chewing gums.

The dosage available may vary depending on the nature and severity of the disorder, the route of administration and the age and weight of the patient.The dosage is 0.1 mg to 1 g agomelatine per day, administered in one or more divided doses.

Representative embodiments of the present invention are illustrated using the accompanying drawings to better appreciate the subject matter, features, and advantages of the present invention.

FIG1 : X-ray powder diffraction pattern of the agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex of Example 1.

FIG2 : DSC thermogram of the agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex of Example 1.

FIG3 : X-ray powder diffraction pattern of the agomelatine/1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.

FIG4 : DSC thermogram of the agomelatine/1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.

FIG5 : X-ray powder diffraction pattern of the agomelatine/benzenesulfonic acid (2/1) complex of Example 3.

FIG6 : DSC thermogram of the agomelatine/benzenesulfonic acid (2/1) complex of Example 3.

Example 1 : Agomelatine/1,5-naphthalene disulfonic acid (2/1) complex

Operation 1

Agomelatine (5.00 g, 2 equivalents) and anhydrous 1,5-naphthalenedisulfonic acid (2.96 g, 1 equivalent) were placed in a reactor. 20 ml of acetone was added. The suspension was stirred at reflux for 1 hour and then immediately filtered. The filter cake was washed twice with acetone and then dried for 1 hour. 25 g of a white solid corresponding to the title product was obtained.

Yield: 78.5%

Melting point: 237°C

Operation 2

Agomelatine (2.98 g, 2 equivalents) and 1,5-naphthalenedisulfonic acid tetrahydrate (2.18 g, 1 equivalent) were transferred to a 250 ml flask. 100 ml of acetone was added, and the reaction mixture was refluxed for 3 hours (crystallization occurred after approximately 1 hour). The suspension was cooled to ambient temperature and stirred for 1 hour. 4.03 g of a white solid corresponding to the title product was isolated by filtration and dried at 40°C under vacuum (10 mbar) for 15 hours.

Yield: 85.0%

Melting point: 237°C

Operation 3

Agomelatine (5.00 g, 2 equivalents) and anhydrous 1,5-naphthalenedisulfonic acid (2.96 g, 1 equivalent) were placed in a reactor. 40 ml of methyl tert-butyl ether was added. The suspension was stirred at reflux for 3 hours and then immediately filtered. The filter cake was washed twice with methyl tert-butyl ether and then dried for 1 hour. 5.28 g of the title product was obtained as a white solid.

Yield: 66.3%

Melting point: 237°C

Example 2 : Agomelatine/1,5-naphthalene disulfonic acid (2/1) monohydrate complex

Operation 1

Agomelatine (5.00 g, 1 equivalent) and anhydrous 1,5-naphthalenedisulfonic acid (5.92 g, 1 equivalent) were placed in a reactor. 10 ml of ethanol and 20 ml of water were added. The suspension was stirred at reflux for 0.5 hours to clarify. The mixture was then cooled naturally with stirring for 0.5 hours and filtered. The filter cake was washed with ethanol and water, then dried for 1 hour. 5.15 g of a white solid was obtained.

Yield: 63.2%

Melting point: 116℃ (dehydration endothermic), 238℃

Operation 2

Agomelatine (5.00 g, 1 equivalent) and 1,5-naphthalene disulfonic acid tetrahydrate (7.40 g, 1 equivalent) were transferred to a reactor. 10 ml of ethanol and 20 ml of water were added. The suspension was stirred at reflux for 0.5 hours to clarify. The mixture was then cooled naturally under stirring for 0.5 hours and filtered. The filter cake was washed with ethanol and water, then dried for 1 hour. 4.90 g of a white solid was obtained.

Yield: 60.2%

Melting point: 116℃ (dehydration endothermic), 238℃

Operation 3

Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) were placed in a 50 ml non-oxidizable jar. Two 12 mm diameter stainless steel balls were added, and the jar was sealed. Vibration at 30 Hz was applied for 15 minutes. After drying overnight at ambient temperature, 0.805 g of solid was obtained.

Melting point: 116℃ (dehydration endothermic), 238℃

Operation 4

Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) were placed in a 50 ml non-oxidizable jar. Two 12 mm diameter stainless steel balls were added, and the jar was sealed. 100 μl of methyl tert-butyl ether was added. The jar was shaken at a frequency of 30 Hz for 30 minutes. After drying overnight at ambient temperature, 0.803 g of solid was obtained.

Melting point: 116℃ (dehydration endothermic), 238℃

Example 3 : Agomelatine/Benzenesulfonic Acid (2/1) Complex

Agomelatine (5.00 g, 2 equivalents) and benzenesulfonic acid (1.62 g, 1 equivalent) were transferred to a reactor. 10 ml of ethanol and 15 ml (10 ml + 5 ml) of toluene were added. The suspension was stirred at reflux for 0.5 hours to clarify (if the solution was not clear, more ethanol was added until it became clear). The mixture was then cooled naturally to 5°C for 0.5 hours while stirring, and the suspension was filtered. The filter cake was dried for 1 hour. 4.31 g of a white solid corresponding to the title product was obtained.

Yield: 65.2%

Melting point: 116°C

In the above examples, it is possible to use commercially available agomelatine or agomelatine prepared by one of the methods described in the prior art.

Example 4 : Pharmaceutical composition: capsule containing 25 mg agomelatine

Pharmaceutical composition containing the compound of Example 1

Pharmaceutical composition containing the compound of Example 2

Pharmaceutical composition containing the compound of Example 3

Example 5 : Pharmaceutical composition: Tablets each containing 25 mg of agomelatine A formulation of 1000 tablets, each containing 25 mg of agomelatine

A formulation of 1000 tablets containing 25 mg agomelatine per tablet was prepared

A formulation of 1000 tablets containing 25 mg agomelatine per tablet was prepared

Measurement methods and results

1. Sample purity

Chromatographic conditions: C18 column; mobile phase: phosphate buffer 10 mmol/L (adjusted to pH 7.0 with NaOH): acetonitrile 2:7 (v/v); column temperature: 40°C; measurement wavelength: 220 nm; internal standard method, using the compound of Example 1.

A 1 mg/ml solution of each compound of the present invention was prepared using the mobile phase. 10 μl of each solution was injected into the liquid chromatography system and the chromatogram was recorded.

Each compound of the present invention has a purity greater than or equal to 99%.

2. Stability

Samples of the compounds of Examples 1, 2, and 3 were placed in an incubator under denaturing conditions and the stability was determined by DSC measurements over a period of 2 months. The results are presented in Table 4:

Table 4

25℃,60%RH OB 50℃ CB 70℃ CB Compound of Example 1 Stablize Stablize Stablize Compound of Example 2 Stablize Stablize Stablize Compound of Example 3 Stablize Stablize Stablize

RH = relative humidity; OB = open bottle; CB = closed bottle

The compounds of the present invention are stable under highly denaturing conditions, which facilitates their use in pharmaceutical compositions.

3. Solubility

The compounds of Examples 1, 2 and 3 were tested by HPLC using an external standard method and compared to agomelatine in Form II. The results are presented in Table 5 as % increase in solubility relative to that of agomelatine in Form II:

Table 5

The results showed that the complex of agomelatine and sulfonic acid of the present invention had higher solubility than Form II agomelatine itself in water, in 0.1N HCl similar to human gastric fluid, or in a buffer solution at pH 6.8. These results indicate that the complex has the potential to be far superior to Form II agomelatine in terms of bioavailability.

4. DSC Analysis

Unless otherwise stated, approximately 5-10 mg of the compounds of Examples 1, 2, and 3 were weighed into aluminum crucibles sealed with perforated (non-sealed) aluminum lids. The samples were introduced into a TA Q1000 apparatus (equipped with a cooler), cooled, and maintained at 25° C. After thermal stabilization, the samples and reference were heated from 200° C. to 250° C. at a rate of 10° C./min, and the response to the heat flow was recorded. Nitrogen was used as a purge gas at a flow rate of 100 cm ³ /min.

The DSC thermograms obtained using the compounds of Examples 1, 2 and 3 are shown in Figures 2, 4 and 6.

5. Crystal Structure Analysis

The measuring conditions of the X-ray powder diffraction patterns of the products of Examples 1, 2 and 3 are as follows:

Approximately 50 mg of the compounds of Examples 1, 2, and 3 were placed between the two membranes and fixed to a sample carrier. The samples were then placed in a PANALYTICAL XPERT-PRO MPD diffractometer in transmission mode under the following conditions:

Generator parameters: 45kV/40mA

Configuration θ/θ

Anode:Cu

1.54060

1.54443

1.39225

K-A2/K-A1 ratio 0.50000

Scan mode: continuous, from 3° to 55° (Bragg angle 2θ)

Step size [°2θ] 0.0170

Step duration [s] 35.5301

Starting angle [°2θ] 3.0034

Completed angle [°2θ] 54.9894

Rotation: Yes

The X-ray powder diffraction patterns obtained in Examples 1, 2 and 3 are shown in Figures 1, 3 and 5.

Claims (10)

1. A complex of agomelatine and sulfonic acid of formula (I): Where x represents 0, and RSO _3H represents 1,5-naphthalenedisulfonic acid, which is an agomelatine/1,5-naphthalenedisulfonic acid (2/1) complex, characterized by its X-ray powder diffraction pattern, which is expressed by the following interplanar spacing d, Bragg angle 2θ (expressed in ° ± 0.2), and relative intensity: It includes forms where the diffraction angle corresponds to within ±0.2°. 2. The complex of agomelatine and sulfonic acid of formula (I): Where x represents 1, and RSO _3H represents 1,5-naphthalenedisulfonic acid, which is an agomelatine/1,5-naphthalenedisulfonic acid (2/1) monohydrate complex, characterized by its X-ray powder diffraction pattern, which is expressed by the following interplanar spacing d, Bragg angle 2θ (expressed in ° ± 0.2), and relative intensity: It includes forms where the diffraction angle corresponds to within ±0.2°. 3. The complex of agomelatine and sulfonic acid of formula (I): Where x represents 0, and RSO ₃ H represents benzenesulfonic acid, which is an agomelatine/benzenesulfonic acid (2/1) complex, characterized by its X-ray powder diffraction pattern, which is expressed by the following interplanar spacing d, Bragg angle 2θ (expressed in ° ± 0.2), and relative intensity: It includes forms where the diffraction angle corresponds to within ±0.2°. 4. A method for obtaining a complex of agomelatine and sulfonic acid according to any one of claims 1 to 3, characterized in that: - Mix agomelatine and sulfonic acid in an organic solvent or an aqueous-organic solvent in the desired proportion; - Stir the resulting solution and optionally heat it at a temperature not exceeding the boiling point of the selected solvent; - Cool the mixture while stirring, and the eutectic will precipitate naturally, or it can precipitate after adding a second solvent; - Filter the resulting precipitate and dry it. 5. A method for preparing a complex of agomelatine and sulfonic acid according to any one of claims 1 to 3, characterized in that the two components are ground together. 6. A pharmaceutical composition comprising, as an active ingredient, one of a complex of agomelatine and sulfonic acid according to any one of claims 1 to 3, and one or more inert, non-toxic, pharmaceutically acceptable carriers. 7. Use of the complex of gomelatine and sulfonic acid of formula (I) according to any one of claims 1 to 3 in the preparation of a medicament for treating melatonin-releasing disorders. 8. Use of the complex of agomelatine and sulfonic acid of formula (I) according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of stress, sleep disorders, anxiety, obsessive-compulsive disorder, mood disorders, seasonal affective disorder, cardiovascular disease, digestive disorders, schizophrenia, panic attacks, depression, appetite disorders, obesity, pain, epilepsy, diabetes, Parkinson's disease, Alzheimer's disease, memory loss, cerebral circulatory disorders, sexual dysfunction, as an ovulation inhibitor and immunomodulator, and for the treatment of cancer. 9. Use of the complex of agomelatine and sulfonic acid of formula (I) according to any one of claims 1 to 3 in the preparation of a medicament for the treatment of generalized anxiety disorder, bipolar disorder, major depressive disorder, insomnia and fatigue caused by jet lag, psychotic mental disorders, various disorders associated with normal or pathological aging, migraine and Alzheimer's disease. 10. Use in the preparation of a medicament of a complex of formula (I) of any one of claims 1 to 3 and sulfonic acid for the treatment of insomnia.