WO2009053549A1 - Rimonabant dmso solvate, method for preparing same and pharmaceutical compositions containing same - Google Patents

Rimonabant dmso solvate, method for preparing same and pharmaceutical compositions containing same Download PDF

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WO2009053549A1
WO2009053549A1 PCT/FR2008/001158 FR2008001158W WO2009053549A1 WO 2009053549 A1 WO2009053549 A1 WO 2009053549A1 FR 2008001158 W FR2008001158 W FR 2008001158W WO 2009053549 A1 WO2009053549 A1 WO 2009053549A1
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rimonabant
dmso
solvate
disorders
dmso solvate
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WO2009053549A8 (en
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Gérard Coquerel
Baptiste Fours
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Sanofi-Aventis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the solvate of DMSO (dimethylsulfoxide) rimonabant, its preparation process and pharmaceutical compositions containing it.
  • DMSO dimethylsulfoxide
  • Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide. This compound, its salts and its solvates are described in the European patent
  • Ramonabant DMSO solvate refers to any rimonabant-based molecular complex incorporating DMSO in its crystal lattice.
  • said solvate consists of a molecule of rimonabant and two molecules of DMSO (disolvate).
  • the DMSO solvate of rimonabant preferentially exists in crystallized form.
  • the present invention relates to the Rimonabant DMSO solvate, and more particularly to a crystalline form of the Rimonabant DMSO solvate.
  • Obtaining a solvate of rimonabant with DMSO is particularly advantageous because the solvate of DMSO rimonabant is an active principle administrable to humans.
  • the dMSO solvate of rimonabant is particularly advantageous as an intermediate in the final stage (s) of synthesis of rimonabant.
  • Rimonabant can thus be prepared by desolvation of the solvate of
  • DMSO of rimonabant according to methods known to those skilled in the art.
  • the desolvation can for example be carried out by drying optionally at reduced pressure. Alternatively, it can also be carried out by drying at elevated temperatures.
  • the process for the preparation of rimonabant characterized in that the rimonabant is obtained by desolvation of the DMSO solvate of rimonabant constitutes an object of the present invention.
  • the crystalline form of the Rimonabant DMSO solvate constitutes a powder whose characteristics are improved with respect to the powders constituted either by the crystalline form I of rimonabant or by the crystalline form II of rimonabant.
  • the flow of the powder can be improved and the active ingredient content better controlled. Thanks to the better flowability, the tableting process can be simplified by eliminating certain steps such as wet granulation, drying and calibration, which increases the rates and reduces the cost of production.
  • the present invention also relates to the process for obtaining the Rimonabant DMSO solvate.
  • This process is characterized in that the rimonabant is dissolved in DMSO. More particularly, this process is characterized in that: a) a suspension of rimonabant is prepared in DMSO; and b) the Rimonabant DMSO solvate thus formed is isolated.
  • step a) is carried out at room temperature, with stirring.
  • the process for preparing the rimonabant DMSO solvate according to the invention is characterized in that: a) a suspension of rimonabant in DMSO is prepared; b) cooling; c) isolating the solvate of DMSO rimonabant thus formed.
  • the dMSO solvate of rimonabant formed by the process according to the invention is isolated by filtration.
  • a suspension of rimonabant in DMSO is prepared. More particularly, a suspension of rimonabant with a mass concentration of between 25% and 75% and preferably about 50% by weight in DMSO is prepared.
  • the cooling step is carried out by placing the suspension at a temperature between 0 ° C. and 10 ° C., preferably between about 3 ° C. and 5 ° C., more preferably 4 ° C., for example in a chamber. refrigerated, and for a sufficient time to the formation of said solvate.
  • the formation of said solvate is accompanied by an increase in the viscosity of said suspension.
  • a homogenization step is carried out, by heating said suspension at a temperature of between 50 ° C. and 150 ° C., preferably about 100 ° C.
  • the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
  • the solvate of DMSO of rimonabant is characterized by various elements of its physicochemical analysis.
  • the crystalline form of the Rimonabant DMSO solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
  • TG-DSC analysis can be performed for the Rimonabant DMSO solvate by a NETZSCH STA 449C differential enthalpy analyzer.
  • the melting peak and the enthalpy difference of the substance ( ⁇ H) are measured before and after melting, in Joule per gram of material.
  • the crystalline form of the Rimonabant DMSO solvate can also be characterized by its infra-red spectrum (IR).
  • the crystalline form of the Rimonabant DMSO solvate can also be characterized by its crystalline structure for which the mesh parameters are determined by single crystal X-ray diffraction. From the mesh parameters and the atomic coordinates x, y, z of the atoms of the molecule, computation software makes it possible to draw projected views of the crystal lattice of the molecule concerned.
  • the present invention also relates to said rimonabant solvate obtainable by the process according to the invention.
  • the present invention relates to pharmaceutical compositions containing as active principle said rimonabant solvate according to the invention.
  • said pharmaceutical composition is in the form of a dosage unit in which the active ingredient is mixed with at least one pharmaceutical excipient.
  • the present invention also relates to the use of said rimonabant solvate for the preparation of a psychotropic drug, for the treatment of thymic disorders, anxiety disorders, mood disorders, vomiting, memory disorders , cognitive disorders, neuropathies, migraine, stress, psychosomatic diseases, epilepsy, dyskinesias, Parkinson's disease, appetite disorders, especially as anorectic, schizophrenia, delusional disorders, psychotic disorders, disorders related to the use of psychotic substances and anticancer chemotherapy.
  • the TG-DSC analysis is carried out at 20 ° to 160 ° C. on a NETZSCH STA 449C apparatus.

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Abstract

The invention relates to a rimonabant DMSO solvate, to a method for preparing the same and to the therapeutic uses thereof.

Description

LE SOLVATE DE DMSO DE Rl MONABANT, SON PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES EN CONTENANT. RAS MONABANT DMSO SOLVATE, PREPARATION METHOD THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME.
La présente invention a pour objet le solvate de DMSO (diméthylsulfoxyde) de rimonabant, son procédé de préparation et les compositions pharmaceutiques en contenant.The present invention relates to the solvate of DMSO (dimethylsulfoxide) rimonabant, its preparation process and pharmaceutical compositions containing it.
Le rimonabant est la dénomination commune internationale du N- pipéridino-5-(4-chIorophényl)-1-(2,4-dichlorophényl)-4-méthylpyrazole-3- carboxamide. Ce composé, ses sels et ses solvats sont décrits dans le brevet européenRimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide. This compound, its salts and its solvates are described in the European patent
656354.656354.
On a maintenant trouvé un solvat particulier : le solvate de DMSO de rimonabant qui présente des propriétés avantageuses.A particular solvate has now been found: the Rimonabant DMSO solvate which has advantageous properties.
Selon la définition de solvate donnée par Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, on entend par solvate de DMSO de rimonabant tout complexe moléculaire à base de rimonabant incorporant le DMSO dans son réseau cristallin.According to the solvate definition given by Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, the term "Rimonabant DMSO solvate" refers to any rimonabant-based molecular complex incorporating DMSO in its crystal lattice.
Selon un autre objet de la présente invention, ledit solvate est constitué d'une molécule de rimonabant et de deux molécules de DMSO (disolvate). Le solvate de DMSO de rimonabant existe préférentiellement sous forme cristallisée. La présente invention est relative au solvate de DMSO de rimonabant, et plus particulièrement à une forme cristalline du solvate de DMSO de rimonabant.According to another object of the present invention, said solvate consists of a molecule of rimonabant and two molecules of DMSO (disolvate). The DMSO solvate of rimonabant preferentially exists in crystallized form. The present invention relates to the Rimonabant DMSO solvate, and more particularly to a crystalline form of the Rimonabant DMSO solvate.
Le fait d'obtenir un solvate du rimonabant avec le DMSO est particulièrement avantageux car le solvate de DMSO de rimonabant constitue un principe actif administrable à l'homme.Obtaining a solvate of rimonabant with DMSO is particularly advantageous because the solvate of DMSO rimonabant is an active principle administrable to humans.
Par ailleurs, le solvate de DMSO de rimonabant est particulièrement avantageux à titre d'intermédiaire dans l'(es) étape(s) finale(s) de synthèse du rimonabant. Le rimonabant peut ainsi être préparé par désolvatation du solvate deMoreover, the dMSO solvate of rimonabant is particularly advantageous as an intermediate in the final stage (s) of synthesis of rimonabant. Rimonabant can thus be prepared by desolvation of the solvate of
DMSO de rimonabant selon les méthodes connues de l'homme du métier. La désolvatation peut par exemple être réalisée par séchage éventuellement à pression réduite. Alternativement, elle peut également être réalisée par séchage à des températures élevées.DMSO of rimonabant according to methods known to those skilled in the art. The desolvation can for example be carried out by drying optionally at reduced pressure. Alternatively, it can also be carried out by drying at elevated temperatures.
Le procédé de préparation du rimonabant caractérisé en ce que le rimonabant est obtenu par désolvatation du solvate de DMSO de rimonabant constitue un objet de la présente invention.The process for the preparation of rimonabant, characterized in that the rimonabant is obtained by desolvation of the DMSO solvate of rimonabant constitutes an object of the present invention.
Ainsi, la forme cristalline du solvate de DMSO de rimonabant constitue une poudre dont les caractéristiques sont améliorées par rapport aux poudres constituées soit par la forme cristalline I du rimonabant, soit par la forme cristalline II du rimonabant. En particulier, lors de la préparation de comprimés, l'écoulement de la poudre peut être amélioré et la teneur en principe actif mieux contrôlée. Grâce à la meilleure coulabilité, le procédé de fabrication de comprimés peut être simplifié en supprimant certaines étapes telles que la granulation humide, le séchage et le calibrage, ce qui permet d'augmenter les cadences et de diminuer le coût de production.Thus, the crystalline form of the Rimonabant DMSO solvate constitutes a powder whose characteristics are improved with respect to the powders constituted either by the crystalline form I of rimonabant or by the crystalline form II of rimonabant. In particular, during the preparation of tablets, the flow of the powder can be improved and the active ingredient content better controlled. Thanks to the better flowability, the tableting process can be simplified by eliminating certain steps such as wet granulation, drying and calibration, which increases the rates and reduces the cost of production.
La présente invention est également relative au procédé d'obtention du solvate de DMSO de rimonabant. Ce procédé est caractérisé en ce que l'on dissout le rimonabant dans le DMSO. Plus particulièrement, ce procédé est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le DMSO, b) on isole le solvate de DMSO de rimonabant ainsi formé.The present invention also relates to the process for obtaining the Rimonabant DMSO solvate. This process is characterized in that the rimonabant is dissolved in DMSO. More particularly, this process is characterized in that: a) a suspension of rimonabant is prepared in DMSO; and b) the Rimonabant DMSO solvate thus formed is isolated.
Préférentiellement, selon le procédé de l'invention, l'étape a) est réalisée à température ambiante, sous agitation.Preferably, according to the method of the invention, step a) is carried out at room temperature, with stirring.
De manière particulière, le procédé de préparation du solvate de DMSO de rimonabant selon l'invention est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le DMSO ; b) on refroidit ; c) on isole le solvate de DMSO de rimonabant ainsi formé.In particular, the process for preparing the rimonabant DMSO solvate according to the invention is characterized in that: a) a suspension of rimonabant in DMSO is prepared; b) cooling; c) isolating the solvate of DMSO rimonabant thus formed.
Le solvate de DMSO de rimonabant formé par le procédé selon l'invention est isolé par filtration. De façon particulière, à l'étape a), on prépare une suspension de rimonabant dans le DMSO. Plus particulièrement, on prépare une suspension de rimonabant à concentration massique comprise entre 25 à 75%, de préférence environ 50% massique dans le DMSO. De façon particulière, l'étape de refroidissement est réalisée en plaçant la suspension à température comprise entre 00C et 100C, de préférence entre environ 3°C et 5°C, plus préférentiellement 4°C, par exemple dans une chambre réfrigérée, et ce pendant une durée suffisante à la formation dudit solvate. De préférence, la formation dudit solvate s'acompagne d'une augmentation de la viscosité de ladite suspension.The dMSO solvate of rimonabant formed by the process according to the invention is isolated by filtration. In particular, in step a), a suspension of rimonabant in DMSO is prepared. More particularly, a suspension of rimonabant with a mass concentration of between 25% and 75% and preferably about 50% by weight in DMSO is prepared. In a particular way, the cooling step is carried out by placing the suspension at a temperature between 0 ° C. and 10 ° C., preferably between about 3 ° C. and 5 ° C., more preferably 4 ° C., for example in a chamber. refrigerated, and for a sufficient time to the formation of said solvate. Preferably, the formation of said solvate is accompanied by an increase in the viscosity of said suspension.
Selon un aspect particulier, on réalise, avant l'étape de refroidissement, une étape d'homogénéisation, en chauffant ladite suspension à température comprise entre 5O0C et 150°C, de préférence environ 1000C.According to one particular aspect, before the cooling step, a homogenization step is carried out, by heating said suspension at a temperature of between 50 ° C. and 150 ° C., preferably about 100 ° C.
Après la filtration de la dernière étape, le produit obtenu est avantageusement séché à une température comprise entre la température ambiante et 400C, préférentiellement à température ambiante.After filtration of the last step, the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
Le solvate de DMSO de rimonabant est caractérisé par différents éléments de son analyse physico-chimique.The solvate of DMSO of rimonabant is characterized by various elements of its physicochemical analysis.
La forme cristalline du solvate de DMSO de rimonabant est caractérisée par les raies caractéristiques du diffractogramme de rayons X sur poudre.The crystalline form of the Rimonabant DMSO solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
Le profil de diffraction des rayons X (RX) de la poudre (angle de diffraction) est établi avec un diffractomètre Siemens D5005; source CuKa, λ =The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; source CuKa, λ =
1.54178Â . Les raies caractéristiques du diffractogramme sont reportées dans le tableau 1 suivant : TABLEAU 1 : Rayons X sur poudre, forme cristalline du solvate de DMSO de rimonabant1.54178. The characteristic lines of the diffractogram are reported in the following Table 1: TABLE 1: X-Rays on Powder, Crystalline Form of Rimonabant DMSO Solvate
Figure imgf000005_0001
Figure imgf000005_0001
Le diffractogramme correspondant au solvate de DMSO de rimonabant est reproduit dans la figure 1.The diffractogram corresponding to the DMSO solvate of rimonabant is reproduced in FIG.
Teneur en DMSODMSO content
Thermogravimétrie - Analyse enthalpique différentielle (en anglais : Differential Scanning Calorimetry) :Thermogravimetry - Differential Scanning Calorimetry:
L'analyse TG-DSC peut être réalisée pour le solvate de DMSO de rimonabant par un appareil d'analyse enthalpique différentielle NETZSCH STA 449C. On mesure le pic de fusion et la différence d'enthalpie de la substance (ΔH) avant et après la fusion, en Joule par gramme de matière.TG-DSC analysis can be performed for the Rimonabant DMSO solvate by a NETZSCH STA 449C differential enthalpy analyzer. The melting peak and the enthalpy difference of the substance (ΔH) are measured before and after melting, in Joule per gram of material.
Le diagramme de l'analyse TG-DSC est représenté à la figure 2 :The diagram of the TG-DSC analysis is shown in Figure 2:
L'analyse est réalisée de 20 à 1600C. Un pic endothermique est enregistré à environ 62°C associé à une perte de masse de 23,90%. Cette perte massique correspond à un solvat du rimonabant avec deux molécules de DMSO (perte de masse théorique = 25,17%).The analysis is carried out at 20 ° to 160 ° C. An endothermic peak is recorded at about 62 ° C. combined with a loss of mass of 23.90%. This mass loss corresponds to a solvate of rimonabant with two molecules of DMSO (theoretical loss of mass = 25.17%).
La forme cristalline du solvate de DMSO de rimonabant peut également être caractérisée par son spectre infra-rouge (I. R.). La forme cristalline du solvate de DMSO de rimonabant peut également être caractérisée par sa structure cristalline pour laquelle les paramètres de maille sont déterminés par diffraction des rayons X sur monocristal. A partir des paramètres de maille et des coordonnées atomiques x, y, z des atomes de la molécule, des logiciels de calcul permettent de tracer des vues projetées de la maille cristalline de la molécule concernée. La présente invention concerne également ledit solvate de rimonabant susceptible d'être obtenu par le procédé selon l'invention.The crystalline form of the Rimonabant DMSO solvate can also be characterized by its infra-red spectrum (IR). The crystalline form of the Rimonabant DMSO solvate can also be characterized by its crystalline structure for which the mesh parameters are determined by single crystal X-ray diffraction. From the mesh parameters and the atomic coordinates x, y, z of the atoms of the molecule, computation software makes it possible to draw projected views of the crystal lattice of the molecule concerned. The present invention also relates to said rimonabant solvate obtainable by the process according to the invention.
Selon un autre objet, la présente invention concerne les compositions pharmaceutiques contenant en tant que principe actif ledit solvate de rimonabant selon l'invention. Préférentiellement, ladite composition pharmaceutique se présente sous forme d'unité de dosage dans laquelle le principe actif est mélangé à au moins un excipient pharmaceutique.According to another object, the present invention relates to pharmaceutical compositions containing as active principle said rimonabant solvate according to the invention. Preferably, said pharmaceutical composition is in the form of a dosage unit in which the active ingredient is mixed with at least one pharmaceutical excipient.
Selon un autre objet, la présente invention concerne également l'utilisation dudit solvate de rimonabant pour la préparation d'un médicament psychotrope, pour le traitement des troubles thymiques, des troubles anxieux, des troubles de l'humeur, du vomissement, des troubles mnésiques, des troubles cognitifs, des neuropathies, de la migraine, du stress, des maladies d'origine psychosomatique, de Pépilepsie, des diskynésies, de la maladie de Parkinson, des troubles de l'appétit, notamment en tant qu'anorexigène, de la schizophrénie, des troubles délirants, des troubles psychotiques, des troubles liés à l'utilisation de substances psychotiques et de la chimiothérapie anticancéreuse.According to another subject, the present invention also relates to the use of said rimonabant solvate for the preparation of a psychotropic drug, for the treatment of thymic disorders, anxiety disorders, mood disorders, vomiting, memory disorders , cognitive disorders, neuropathies, migraine, stress, psychosomatic diseases, epilepsy, dyskinesias, Parkinson's disease, appetite disorders, especially as anorectic, schizophrenia, delusional disorders, psychotic disorders, disorders related to the use of psychotic substances and anticancer chemotherapy.
Les exemples suivants sont donnés à titre illustratif et non limitatif de la présente invention.The following examples are given by way of non-limiting illustration of the present invention.
Exemple : préparation de la forme cristalline du solvate de DMSO de rimonabant.Example: preparation of the crystalline form of the Rimonabant DMSO solvate.
Dans un tube vial scellé de 8 ml, une suspension de rimonabant est réalisée à 50% massique dans le DMSO, à température ambiante. Celle-ci est mise sous agitation puis homogénéisée à 1000C. Une trempe est effectuée en plaçant la solution dans une chambre réfrigérée à 4°C. Rapidement, la solution voie sa viscosité augmenter brutalement. Son aspect évolue lentement vers un solide de couleur blanche. Au bout de 4 semaines, la phase solide est récupérée puis séchée sur papier Joseph. L'analyse XRPD, représentée à la figure 1, (3.000°-30.000° ; pas : 0.040° ; durée 4 s ; température 25°C) fait apparaître un nouveau profil de diffraction, dont les raies caractéristiques sont reportées dans le tableau 1 suivant :In a sealed vial tube of 8 ml, a suspension of rimonabant is carried out at 50% by mass in DMSO at room temperature. This is stirred and then homogenized at 100 ° C. Quenching is performed by placing the solution in a refrigerated chamber at 4 ° C. Rapidly, the solution sees its viscosity increase abruptly. Its appearance slowly evolves towards a solid of white color. After 4 weeks, the solid phase is recovered and then dried on Joseph paper. The XRPD analysis, represented in FIG. 1, (3,000 ° -30,000 °, step: 0.040 °, duration 4 s, temperature 25 ° C.) appear a new diffraction profile, whose characteristic lines are reported in the following table 1:
Figure imgf000007_0001
Figure imgf000007_0001
L'analyse TG-DSC est réalisée de 20 à 16O0C sur un appareil NETZSCH STA 449C. Un pic endothermique est enregistré à environ 620C associé à une perte de masse de 23,90%. Cette perte massique correspond à un solvat du rimonabant avec deux molécules de DMSO (perte de masse théorique = 25,17%).The TG-DSC analysis is carried out at 20 ° to 160 ° C. on a NETZSCH STA 449C apparatus. An endothermic peak is recorded at about 62 0 C associated with a loss of mass of 23.90%. This mass loss corresponds to a solvate of rimonabant with two molecules of DMSO (theoretical loss of mass = 25.17%).
Le diagramme est représenté à la figure 2. The diagram is shown in Figure 2.

Claims

REVENDICATIONS
1. Le solvate de DMSO de rimonabant.1. DMSO solvate of rimonabant.
2. Le solvate de DMSO de rimonabant selon la revendication 1 caractérisé en ce qu'il s'agit de disolvate de DMSO de rimonabant.2. The solvate of DMSO rimonabant according to claim 1 characterized in that it is disolvate DMSO rimonabant.
3. Le solvate de DMSO de rimonabant selon la revendication 1 ou 2 , sous forme cristalline.3. The dMSO solvate of rimonabant according to claim 1 or 2, in crystalline form.
4. Le solvate de DMSO de rimonabant selon la revendication 1 , 2 ou 3, caractérisé par les raies du diffractogramme de rayons X sur poudre décrites ci- après :4. The dMSO solvate of rimonabant according to claim 1, 2 or 3, characterized by the lines of the X-ray powder diffractogram described below:
Figure imgf000008_0001
Figure imgf000008_0001
5. Procédé de préparation du solvate de DMSO de rimonabant selon l'une quelconque des revendications 1 à 4, caractérisé en ce que : a) on prépare une suspension de rimonabant dans le DMSO, b) on isole Ie solvate de DMSO de rimonabant ainsi formé.5. Process for the preparation of the Rimonabant DMSO solvate according to any one of claims 1 to 4, characterized in that: a) a suspension of rimonabant is prepared in DMSO, b) the Rimonabant DMSO solvate is isolated, and form.
6. Procédé selon la revendication 5 tel que l'étape a) est réalisée à température ambiante.6. The method of claim 5 such that step a) is carried out at room temperature.
7. Procédé selon la revendication 5 ou 6 tel que ladite suspension de rimonabant a une concentration massique comprise entre 25 à 75%.7. The method of claim 5 or 6 such that said suspension of rimonabant has a mass concentration of between 25 to 75%.
8. Procédé selon la revendication 5, 6 ou 7 tel qu'une étape de refroidissement est réalisée avant l'isolation dudit solvate. 8. The method of claim 5, 6 or 7 such that a cooling step is performed before the isolation of said solvate.
9. Procédé selon la revendication 8 tel que l'étape de refroidissement est réalisée en plaçant la suspension à température comprise entre 00C et 100C.9. The method of claim 8 such that the cooling step is carried out by placing the suspension at a temperature between 0 0 C and 10 0 C.
10. Procédé selon l'une quelconque des revendications 5 à 9, tel que avant l'étape de refroidissement, on réalise une étape d'homogénéisation à température comprise entre 5O0C et 15O0C.10. Process according to any one of claims 5 to 9, such that before the cooling step, a homogenization step is carried out at a temperature of between 50 ° C. and 150 ° C.
11. Procédé selon l'une quelconque des revendications 5 à 10 tel que le solvate de DMSO de rimonabant formé est isolé par filtration.11. A process according to any one of claims 5 to 10 such that the formed Rimonabant DMSO solvate is isolated by filtration.
12. Procédé selon l'une quelconque des revendications 5 à 11 tel que le produit obtenu est séché à une température comprise entre la température ambiante et 4O0C.12. Method according to any one of claims 5 to 11 such that the product obtained is dried at a temperature between room temperature and 40 ° C.
13. Le solvate de DMSO de rimonabant susceptible d'être obtenu par le procédé selon l'une quelconque des revendications 5 à 12.13. The DMSO solvate of rimonabant obtainable by the method according to any one of claims 5 to 12.
14. Composition pharmaceutique contenant en tant que principe actif le solvate de DMSO de rimonabant selon l'une quelconque des revendications 1 à 4 ou 13.A pharmaceutical composition containing as an active ingredient the rimonabant DMSO solvate according to any one of claims 1 to 4 or 13.
15. Composition pharmaceutique selon la revendication 14 sous forme d'unité de dosage dans laquelle le principe actif est mélangé à au moins un excipient pharmaceutique.15. Pharmaceutical composition according to claim 14 in the form of a dosage unit in which the active ingredient is mixed with at least one pharmaceutical excipient.
16. Utilisation du solvate de DMSO de rimonabant selon l'une quelconque des revendications 1 à 4 ou 13 pour la préparation d'un médicament psychotrope, pour le traitement des troubles thymiques, des troubles anxieux, des troubles de l'humeur, du vomissement, des troubles mnésiques, des troubles cognitifs, des neuropathies, de la migraine, du stress, des maladies d'origine psychosomatique, de l'épilepsie, des diskynésies, de la maladie de Parkinson, des troubles de l'appétit, notamment en tant qu'anorexigène, de la schizophrénie, des troubles délirants, des troubles psychotiques, des troubles liés à l'utilisation de substances psychotiques et de la chimiothérapie anticancéreuse. 16. Use of the dMSO solvate of rimonabant according to any one of claims 1 to 4 or 13 for the preparation of a psychotropic drug, for the treatment of mood disorders, anxiety disorders, mood disorders, vomiting , memory disorders, cognitive disorders, neuropathies, migraine, stress, psychosomatic diseases, epilepsy, dyskinesias, Parkinson's disease, appetite disorders, especially as anorexigenic, schizophrenia, delusional disorders, psychotic disorders, psychotic substance use disorders and cancer chemotherapy.
17. Procédé de préparation du rimonabant caractérisé en ce que le rimonabant est obtenu par désolvatation du solvate de DMSO de rimonabant selon l'une quelconque des revendications 1 à 4 ou 13. 17. Process for the preparation of rimonabant, characterized in that the rimonabant is obtained by desolvation of the rimonabant DMSO solvate according to any one of Claims 1 to 4 or 13.
PCT/FR2008/001158 2007-08-06 2008-08-04 Rimonabant dmso solvate, method for preparing same and pharmaceutical compositions containing same WO2009053549A1 (en)

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FR0756960A FR2919865A1 (en) 2007-08-06 2007-08-06 RIMONABANT DMSO SOLVATE, PROCESS FOR PREPARING THE SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR0756960 2007-08-06

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (en) * 1993-12-02 1995-06-07 Sanofi Substituted N-piperidino 3-pyrazolecarboxamide
FR2761265A1 (en) * 1997-03-28 1998-10-02 Sanofi Sa PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION OF A DERIVATIVE OF N-PIPERIDINO-3-PYRAZOLECARBOXAMIDE, ITS SALTS AND THEIR SOLVATES
WO2003040105A1 (en) * 2001-11-08 2003-05-15 Sanofi-Synthelabo Polymorphous form of rimonabant, preparation method and pharmaceutical compositions containing same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0656354A1 (en) * 1993-12-02 1995-06-07 Sanofi Substituted N-piperidino 3-pyrazolecarboxamide
FR2761265A1 (en) * 1997-03-28 1998-10-02 Sanofi Sa PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION OF A DERIVATIVE OF N-PIPERIDINO-3-PYRAZOLECARBOXAMIDE, ITS SALTS AND THEIR SOLVATES
WO2003040105A1 (en) * 2001-11-08 2003-05-15 Sanofi-Synthelabo Polymorphous form of rimonabant, preparation method and pharmaceutical compositions containing same

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