WO2009053550A1 - Rimonabant n-methylpyrrolidone solvate, method for preparing same and pharmaceutical compositions containing same - Google Patents
Rimonabant n-methylpyrrolidone solvate, method for preparing same and pharmaceutical compositions containing same Download PDFInfo
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- WO2009053550A1 WO2009053550A1 PCT/FR2008/001159 FR2008001159W WO2009053550A1 WO 2009053550 A1 WO2009053550 A1 WO 2009053550A1 FR 2008001159 W FR2008001159 W FR 2008001159W WO 2009053550 A1 WO2009053550 A1 WO 2009053550A1
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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- 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
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- the subject of the present invention is the rimonabant N-methylpyrrolidone solvate, its process of preparation and the pharmaceutical compositions containing it.
- Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
- Ramonabant N-methylpyrrolidone solvate is understood to mean any rimonabant-based molecular complex incorporating N-methylpyrrolidone. its crystal lattice.
- said solvate consists of a rimonabant molecule and a molecule of N-methylpyrrolidone (monosolvate).
- the N-methylpyrrolidone solvate of rimonabant preferentially exists in crystallized form.
- the present invention relates to the rimonabant N-methylpyrrolidone solvate, and more particularly to a crystalline form of the rimonabant N-methylpyrrolidone solvate.
- Achieving a solvate of rimonabant with N-methylpyrrolidone is particularly advantageous because the solvate of N-methylpyrrolidone rimonabant is an active ingredient that can be administered to humans.
- the rimonabant N-methylpyrrolidone solvate is particularly advantageous as an intermediate in the final stage (s) of rimonabant synthesis.
- Rimonabant can thus be prepared by desolvation of the Rimonabant N-methylpyrrolidone solvate according to the 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.
- rimonabant characterized in that the rimonabant is obtained by desolvation of the rimonabant N-methylpyrrolidone solvate constitutes an object of the present invention.
- the crystalline form of the rimonabant N-methylpyrrolidone 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 N-methylpyrrolidone solvate.
- This process is characterized in that the rimonabant is dissolved in N-methylpyrrolidone. More particularly, this process is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) the rimonabant N-methylpyrrolidone solvate thus formed is isolated.
- rimonabant in Form II (as described in WO 2003/040105) is suspended.
- step a) is carried out at room temperature.
- the process for preparing the rimonabant N-methylpyrrolidone solvate according to the invention is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) heating until solubilization; c) isolating the solvate of N-methylpyrrolidone rimonabant thus formed.
- the process for preparing the rimonabant N-methylpyrrolidone solvate according to the invention is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) heating until solubilization; c) cooling; d) the rimonabant N-methylpyrrolidone solvate thus formed is isolated.
- the heating step is carried out at a temperature of between 30 ° C. and the boiling point of the solvent, preferably about 60 ° C.
- the cooling step is performed at a temperature such that crystallization occurs; preferably, the temperature is between 0 ° C. and 40 ° C., preferably at room temperature.
- the rimonabant N-methylpyrrolidone solvate formed by the process according to the invention is isolated by filtration.
- a suspension of rimonabant in N-methylpyrrolidone is prepared. More particularly, a comrise concentration suspension is prepared between 20 and 70% by weight, preferably between 50 and 60% by weight of rimonabant in N-methylpyrrolidone.
- the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
- Rimonabant N-methylpyrrolidone The solvate of Rimonabant N-methylpyrrolidone is characterized by various elements of its physicochemical analysis.
- the crystalline form of the rimonabant N-methylpyrrolidone solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
- Thermogravimetric analysis can be carried out for the solvate of Rimonabant N-methylpyrrolidone by a thermogravimetric analysis apparatus
- thermogram recorded from 20 to 500 ° C. (FIG. 2) has a loss of mass of 17.6%, before the degradation of the product, corresponding to the stoichiometry of an NMP monosolvate.
- the crystalline form of the rimonabant N-methylpyrrolidone solvate can also be analyzed by Differential Scanning Calorimetry (Differential Scanning Calibration), for example on a SETARAM DSC141 differential enthalpy analysis apparatus; it operates under a nitrogen atmosphere, at a rate of 2 ° C / minute.
- Differential Scanning Calorimetry Differential Scanning Calibration
- the crystalline form of the rimonabant N-methylpyrrolidone solvate can also be characterized by its infra-red spectrum (IR).
- the crystalline form of the rimonabant N-methylpyrrolidone 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.
- Example preparation of the crystalline form of the N-methylpyrrolidone solvate of rimonabant.
- rimonabant in micronized form II are suspended in 2.4 g of N-methylpyrrolidone (ACROS: 99%) at room temperature with stirring.
- the suspension is homogenized at 60 ° C. with magnetic stirring.
- XRPD, thermogravimetric and DSC analyzes are performed on the solid phase recovered by filtration. A defined compound of stoichiometry 1-1 has been demonstrated.
- Thermogravimetric analysis can be carried out for the rimonabant N-methylpyrrolidone solvate by a thermogravimetric analysis device NETZSCH TG 209; it is operated under a nitrogen atmosphere, at a rate of 2 ° C / minute.
- An analysis is carried out at 20 to 250 ° C at the same speed. Desolvation is composed of two main accelerations of mass loss: a first at 94.7 0 C followed by a progressive mass loss and a second at 139 0 C.
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Abstract
Description
LE SOLVATE DE N-METHYLPYRROLIDONE DE RIMONABANT, SON PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES EN CONTENANT. RIMONABANT N-METHYLPYRROLIDONE SOLVATE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
La présente invention a pour objet le solvate de N-méthylpyrrolidone de rimonabant, son procédé de préparation et les compositions pharmaceutiques en contenant.The subject of the present invention is the rimonabant N-methylpyrrolidone solvate, its process of preparation and the pharmaceutical compositions containing it.
Le rimonabant est la dénomination commune internationale du N-pipéridino-5- (4-chlorophényl)-1-(2,4-dichlorophényl)-4-méthylpyrazole-3-carboxamide.Rimonabant is the international non-proprietary name for N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide.
Ce composé, ses sels et ses solvats sont décrits dans le brevet européen 656354.This compound, its salts and its solvates are described in European Patent 656354.
On a maintenant trouvé un solvat particulier : le solvate de N-méthylpyrrolidone de rimonabant qui présente des propriétés avantageuses.A particular solvate has now been found: the rimonabant N-methylpyrrolidone 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 N- méthylpyrrolidone de rimonabant tout complexe moléculaire à base de rimonabant incorporant le N-méthylpyrrolidone dans son réseau cristallin.According to the definition of solvate given by Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, the term "Rimonabant N-methylpyrrolidone solvate" is understood to mean any rimonabant-based molecular complex incorporating N-methylpyrrolidone. its crystal lattice.
Selon un autre objet de la présente invention, ledit solvate est constitué d'une molécule de rimonabant et d'une molécule de N-méthylpyrrolidone (monosolvate).According to another object of the present invention, said solvate consists of a rimonabant molecule and a molecule of N-methylpyrrolidone (monosolvate).
Le solvate de N-méthylpyrrolidone de rimonabant existe préférentiellement sous forme cristallisée. La présente invention est relative au solvate de N- méthylpyrrolidone de rimonabant, et plus particulièrement à une forme cristalline du solvate de N-méthylpyrrolidone de rimonabant.The N-methylpyrrolidone solvate of rimonabant preferentially exists in crystallized form. The present invention relates to the rimonabant N-methylpyrrolidone solvate, and more particularly to a crystalline form of the rimonabant N-methylpyrrolidone solvate.
Le fait d'obtenir un solvate du rimonabant avec le N-méthylpyrrolidone est particulièrement avantageux car le solvate de N-méthylpyrrolidone de rimonabant constitue un principe actif administrable à l'homme.Achieving a solvate of rimonabant with N-methylpyrrolidone is particularly advantageous because the solvate of N-methylpyrrolidone rimonabant is an active ingredient that can be administered to humans.
Par ailleurs, le solvate de N-méthylpyrrolidone de rimonabant est particulièrement avantageux à titre d'intermédiaire dans l'(es) étape(s) finale(s) de synthèse du rimonabant.Moreover, the rimonabant N-methylpyrrolidone solvate is particularly advantageous as an intermediate in the final stage (s) of rimonabant synthesis.
Le rimonabant peut ainsi être préparé par désolvatation du solvate de N- méthylpyrrolidone 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.Rimonabant can thus be prepared by desolvation of the Rimonabant N-methylpyrrolidone solvate according to the 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 N-méthylpyrrolidone 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 rimonabant N-methylpyrrolidone solvate constitutes an object of the present invention.
Ainsi, la forme cristalline du solvate de N-méthylpyrrolidone 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 N-methylpyrrolidone 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 N-méthylpyrrolidone de rimonabant. Ce procédé est caractérisé en ce que l'on dissout le rimonabant dans le N-méthylpyrrolidone. Plus particulièrement, ce procédé est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N-méthylpyrrolidone, b) on isole le solvate de N-méthylpyrrolidone de rimonabant ainsi formé.The present invention also relates to the process for obtaining the Rimonabant N-methylpyrrolidone solvate. This process is characterized in that the rimonabant is dissolved in N-methylpyrrolidone. More particularly, this process is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) the rimonabant N-methylpyrrolidone solvate thus formed is isolated.
Selon un aspect avantageux, le rimonabant sous forme II (telle que décrite dans WO 2003/040105) est mis en suspension.In an advantageous aspect, rimonabant in Form II (as described in WO 2003/040105) is suspended.
Préférentiellement, selon le procédé de l'invention, l'étape a) est réalisée à température ambiante.Preferably, according to the method of the invention, step a) is carried out at room temperature.
De manière particulière, le procédé de préparation du solvate de N- méthylpyrrolidone de rimonabant selon l'invention est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N-méthylpyrrolidone ; b) on chauffe jusqu'à solubilisation; c) on isole le solvate de N-méthylpyrrolidone de rimonabant ainsi formé.In particular, the process for preparing the rimonabant N-methylpyrrolidone solvate according to the invention is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) heating until solubilization; c) isolating the solvate of N-methylpyrrolidone rimonabant thus formed.
De manière plus particulière, le procédé de préparation du solvate de N- méthylpyrrolidone de rimonabant selon l'invention est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le N-méthylpyrrolidone ; b) on chauffe jusqu'à solubilisation ; c) on refroidit ; d) on isole le solvate de N-méthylpyrrolidone de rimonabant ainsi formé. De préférence, l'étape de chauffage est réalisée à une température comprise entre 300C et la température d'ébullition du solvant, de préférence environ 6O0C.More particularly, the process for preparing the rimonabant N-methylpyrrolidone solvate according to the invention is characterized in that: a) a suspension of rimonabant in N-methylpyrrolidone is prepared; b) heating until solubilization; c) cooling; d) the rimonabant N-methylpyrrolidone solvate thus formed is isolated. Preferably, the heating step is carried out at a temperature of between 30 ° C. and the boiling point of the solvent, preferably about 60 ° C.
De préférence, l'étape de refroidissement est réalisée à une température telle qu'une cristallisation se produise ; de préférence, la température est comprise entre 00C et 4O0C, de préférence à température ambiante. Le solvate de N-méthylpyrrolidone de rimonabant formé par le procédé selon l'invention est isolé par filtration.Preferably, the cooling step is performed at a temperature such that crystallization occurs; preferably, the temperature is between 0 ° C. and 40 ° C., preferably at room temperature. The rimonabant N-methylpyrrolidone solvate formed by the process according to the invention is isolated by filtration.
De façon particulière, à l'étape a), on prépare une suspension de rimonabant dans le N-méthylpyrrolidone. Plus particulièrement, on prépare une suspension de concentration comrise entre 20 et 70% massique, préférentiellement entre 50 et 60% massique de rimonabant dans le N-méthylpyrrolidone.In particular, in step a), a suspension of rimonabant in N-methylpyrrolidone is prepared. More particularly, a comrise concentration suspension is prepared between 20 and 70% by weight, preferably between 50 and 60% by weight of rimonabant in N-methylpyrrolidone.
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 N-méthylpyrrolidone de rimonabant est caractérisé par différents éléments de son analyse physico-chimique.The solvate of Rimonabant N-methylpyrrolidone is characterized by various elements of its physicochemical analysis.
La forme cristalline du solvate de N-méthylpyrrolidone de rimonabant est caractérisée par les raies caractéristiques du diffractogramme de rayons X sur poudre.The crystalline form of the rimonabant N-methylpyrrolidone 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 = 1 ,54178Â .The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; CuKa source, λ = 1, 54178.
Les raies caractéristiques du diffractogramme sont reportées dans le tableau 1 suivant : TABLEAU 1 :The characteristic lines of the diffractogram are reported in the following Table 1: TABLE 1:
Rayons X sur poudre, forme cristalline du solvate de N-méthylpyrrolidone de rimonabantX-rays on powder, crystalline form of rimonabant N-methylpyrrolidone solvate
Le diffractogramme correspondant au solvate de N-méthylpyrrolidone de rimonabant est reproduit dans la figure 1.The diffractogram corresponding to the solvate of Rimonabant N-methylpyrrolidone is reproduced in FIG.
Teneur en N-méthylpyrrolidone Thermogravimétrie :N-methylpyrrolidone content Thermogravimetry:
L'analyse thermogravimétrique peut être réalisée pour le solvate de N-méthylpyrrolidone de rimonabant par un appareil d'analyse thermogravimétriqueThermogravimetric analysis can be carried out for the solvate of Rimonabant N-methylpyrrolidone by a thermogravimetric analysis apparatus
NETZSCH TG 209; on opère à vitesse de 2°C/minute. Le thermogramme enregistré de 20 à 5000C (figure 2) présente une perte de masse de 17,6%, avant la dégradation du produit, correspondant à la stœchiométrie d'un monosolvate de NMPNETZSCH TG 209; it operates at a speed of 2 ° C / minute. The thermogram recorded from 20 to 500 ° C. (FIG. 2) has a loss of mass of 17.6%, before the degradation of the product, corresponding to the stoichiometry of an NMP monosolvate.
(Δm/m théorique=17,6%). Une analyse est effectuée de 20 à 25O0C à la même vitesse. La désolvatation est composée de deux accélérations principales de perte de masse : une première à 94,70C suivie d'une perte de masse progressive et d'une secondé e 1390C.(Dm / mt Héo riqu e = 17.6%). An analysis is carried out at 20 to 25 ° C. at the same speed. Desolvation is composed of two main accelerations of mass loss: a first at 94.7 0 C followed by a gradual loss of mass and a secondary e 139 0 C.
La forme cristalline du solvate de N-méthylpyrrolidone de rimonabant peut également être analysée par analyse enthalpique différentielle (en anglais : Differential Scanning Calorimetry), par exemple sur un appareil d'analyse enthalpique différentielle SETARAM DSC141 ; on opère sous atmosphère d'azote, à la vitesse de 2°C/minute.The crystalline form of the rimonabant N-methylpyrrolidone solvate can also be analyzed by Differential Scanning Calorimetry (Differential Scanning Calibration), for example on a SETARAM DSC141 differential enthalpy analysis apparatus; it operates under a nitrogen atmosphere, at a rate of 2 ° C / minute.
La forme cristalline du solvate de N-méthylpyrrolidone de rimonabant peut également être caractérisée par son spectre infra-rouge (I. R.). La forme cristalline du solvate de N-méthylpyrrolidone 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.The crystalline form of the rimonabant N-methylpyrrolidone solvate can also be characterized by its infra-red spectrum (IR). The crystalline form of the rimonabant N-methylpyrrolidone 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.
La présente invention concerne également ledit solvate de rimonabant susceptible d'être obtenu par le procédé selon l'invention.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 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.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 N-méthylpyrrolidone de rimonabant.Example: preparation of the crystalline form of the N-methylpyrrolidone solvate of rimonabant.
2,6 g de rimonabant sous forme II micronisée sont mis en suspension dans 2,4 g de N-méthylpyrrolidone (ACROS : 99%) à température ambiante sous agitation. La suspension est homogénéisée à 600C sous agitation magnétique. En refroidissant lentement la solution à température ambiante une recristallisation se produit. Des analyses XRPD, thermogravimétrique et DSC sont effectuées sur la phase solide récupérée par filtration. Un composé défini de stœchiométrie 1-1 a été mis en évidence.2.6 g of rimonabant in micronized form II are suspended in 2.4 g of N-methylpyrrolidone (ACROS: 99%) at room temperature with stirring. The suspension is homogenized at 60 ° C. with magnetic stirring. By slowly cooling the solution to room temperature, a recrystallization product. XRPD, thermogravimetric and DSC analyzes are performed on the solid phase recovered by filtration. A defined compound of stoichiometry 1-1 has been demonstrated.
Le profil de diffraction des rayons X (RX) de la poudre (angle de diffraction) est établi avec un diffractomètre Siemens D5005; source CuKa, λ = 1 ,54178Â .The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; CuKa source, λ = 1, 54178.
(3.000°-30.000° ; pas : 0,040° - durée 4 s ; température 25° C).(3,000 ° -30,000 °, not: 0,040 ° - duration 4 s, temperature 25 ° C).
Le Diagramme RX sur poudre, représenté à la figure 1, fait apparaître un nouveau profil de diffraction, dont les raies caractéristiques sont reportées dans le tableau 1 suivant :The RX diagram on powder, represented in FIG. 1, reveals a new diffraction profile, whose characteristic lines are reported in the following table 1:
L'analyse thermogravimétrique peut être réalisée pour le solvate de N- méthylpyrrolidone de rimonabant par un appareil d'analyse thermogravimétrique NETZSCH TG 209; on opère sous atmosphère d'azote, à vitesse de 2°C/minute. Le thermogramme enregistré de 20 à 500°C (figure 2) présente une perte de masse de 17,6%, avant la dégradation du produit, correspondant à la stœchiométrie d'un monosolvate de NMP (Δm/m théorique =17,6%). Une analyse est effectuée de 20 à 250°C à la même vitesse. La désolvatation est composée de deux accélérations principales de perte de masse : une première à 94,70C suivie d'une perte de masse progressive et d'une seconde à 1390C. Thermogravimetric analysis can be carried out for the rimonabant N-methylpyrrolidone solvate by a thermogravimetric analysis device NETZSCH TG 209; it is operated under a nitrogen atmosphere, at a rate of 2 ° C / minute. The thermogram recorded from 20 to 500 ° C (Figure 2) has a mass loss of 17.6% before degradation of the product, corresponding to the stoichiometry of a monosolvate of NMP (Dm / m tea ori r y = 17.6%). An analysis is carried out at 20 to 250 ° C at the same speed. Desolvation is composed of two main accelerations of mass loss: a first at 94.7 0 C followed by a progressive mass loss and a second at 139 0 C.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0756958A FR2919863A1 (en) | 2007-08-06 | 2007-08-06 | RIMONABANT N-METHYLPYRROLIDONE SOLVATE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| FR0756958 | 2007-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2009053550A1 true WO2009053550A1 (en) | 2009-04-30 |
Family
ID=39110738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR2008/001159 Ceased WO2009053550A1 (en) | 2007-08-06 | 2008-08-04 | Rimonabant n-methylpyrrolidone solvate, method for preparing same and pharmaceutical compositions containing same |
Country Status (2)
| Country | Link |
|---|---|
| FR (1) | FR2919863A1 (en) |
| WO (1) | WO2009053550A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0656354A1 (en) * | 1993-12-02 | 1995-06-07 | Sanofi | Substituted N-piperidino 3-pyrazolecarboxamide |
| WO2003040105A1 (en) * | 2001-11-08 | 2003-05-15 | Sanofi-Synthelabo | Polymorphous form of rimonabant, preparation method and pharmaceutical compositions containing same |
| CN1699348A (en) * | 2005-05-19 | 2005-11-23 | 金鑫 | N-piperidino-1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazole-3-formamide organic salts and their pharmaceutical compositions |
| WO2006039334A1 (en) * | 2004-09-29 | 2006-04-13 | Schering Corporation | Combinations of substituted azetidonones and cb1 antagonists |
-
2007
- 2007-08-06 FR FR0756958A patent/FR2919863A1/en active Pending
-
2008
- 2008-08-04 WO PCT/FR2008/001159 patent/WO2009053550A1/en not_active Ceased
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0656354A1 (en) * | 1993-12-02 | 1995-06-07 | Sanofi | Substituted N-piperidino 3-pyrazolecarboxamide |
| WO2003040105A1 (en) * | 2001-11-08 | 2003-05-15 | Sanofi-Synthelabo | Polymorphous form of rimonabant, preparation method and pharmaceutical compositions containing same |
| WO2006039334A1 (en) * | 2004-09-29 | 2006-04-13 | Schering Corporation | Combinations of substituted azetidonones and cb1 antagonists |
| CN1699348A (en) * | 2005-05-19 | 2005-11-23 | 金鑫 | N-piperidino-1-(2,4-dichlorophenyl)-4-methyl-5-(4-chlorophenyl)pyrazole-3-formamide organic salts and their pharmaceutical compositions |
Non-Patent Citations (1)
| Title |
|---|
| DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; JIN, XIN: "Preparation of salts of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide", XP002471296, retrieved from STN Database accession no. 2006:889891 * |
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| Publication number | Publication date |
|---|---|
| FR2919863A1 (en) | 2009-02-13 |
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