WO2009053552A1 - Rimonabant methanol solvate, method for preparing same and pharmaceutical compositions containing same - Google Patents

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

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Publication number
WO2009053552A1
WO2009053552A1 PCT/FR2008/001161 FR2008001161W WO2009053552A1 WO 2009053552 A1 WO2009053552 A1 WO 2009053552A1 FR 2008001161 W FR2008001161 W FR 2008001161W WO 2009053552 A1 WO2009053552 A1 WO 2009053552A1
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rimonabant
methanol solvate
methanol
disorders
solvate
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PCT/FR2008/001161
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French (fr)
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Olivier Monnier
Philippe Ochsenbein
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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 subject of the present invention is the methanol solvate of rimonabant, 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.
  • rimonabant methanol solvate is understood to mean any rimonabant-based molecular complex incorporating methanol into its crystal lattice.
  • said solvate consists of a rimonabant molecule and a half (1/2) molecule of methanol (hemisolvate).
  • the methanol solvate of rimonabant preferentially exists in crystallized form.
  • the present invention relates to the methanol solvate of rimonabant, and more particularly to a crystalline form of the methanol solvate of rimonabant.
  • a solvate of rimonabant with methanol is particularly advantageous because the methanol solvate of rimonabant is an active principle that can be administered to man.
  • the methanol 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 methanol solvate 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 methanol solvate of rimonabant constitutes an object of the present invention.
  • 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 methanol solvate of rimonabant.
  • This process is characterized in that the rimonabant is dissolved in methanol. More particularly, this process is characterized in that: a) a suspension of rimonabant in methanol is prepared; b) the methanol solvate of rimonabant thus formed is isolated.
  • step a) is carried out at room temperature.
  • the rimonabant methanol solvate formed by the process according to the invention is isolated by filtration.
  • the form II rimonabant (as described in WO 2003/040105), optionally micronized, is suspended.
  • said suspension is stirred for a time sufficient to form said solvate.
  • the stirring is maintained until the reaction medium is solid.
  • the stirring time is between 10 seconds and 1 hour, preferably between 1 and 10 minutes.
  • a suspension of rimonabant in methanol is prepared. More particularly, a concentration suspension of between 5 and 50% by weight, preferably between 10 and 20% by weight of rimonabant in methanol is prepared.
  • the product obtained is advantageously dried at a temperature between room temperature and 40 0 C, preferably at room temperature.
  • the methanol solvate of rimonabant is characterized by various elements of its physico-chemical analysis.
  • the crystalline form of the rimonabant methanol solvate is characterized by the characteristic lines of the X-ray powder diffractogram.
  • the methanol solvate of rimonabant can be analyzed by TG-DSC by a NETZSCH STA 449C TG-DSC analyzer.
  • FIG. 2 The diagram of the DSC analysis is shown in FIG. 2.
  • This phase is efflorescent because the loss of mass begins at 20 0 C.
  • a second endothermic phenomenon at 98.1 0 C (without associated mass loss) is followed by a low melting peak around 156 ° C: it s' probably acts as partial amorphization.
  • the crystalline form of the methanol solvate of rimonabant can also be characterized by its infra-red spectrum (I.R.).
  • the crystalline form of the methanol solvate of rimonabant 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, including as anorexigenic, schizophrenia, delusional disorders, psychotic disorders, disorders related to the use of psychotic substances and anticancer chemotherapy.
  • rimonabant micronized form II
  • ACROS methanol
  • the suspension is homogenized at 60 ° C. with magnetic stirring and then immediately cooled to room temperature. After a few minutes, the solvate crystallizes.
  • the solid phase is isolated by filtration under vacuum on filter funnel of porosity 3 and analyzed by XRPD.
  • the RX diagram on powder, represented in FIG. 1, reveals a new diffraction profile, whose characteristic lines are reported in the following table 1:

Abstract

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

Description

LE SOLVATE DE METHANOL DE RIMONABANT, SON PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES EN CONTENANT. RIMONABANT METHANOL SOLVATE, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
La présente invention a pour objet le solvate de méthanol de rimonabant, son procédé de préparation et les compositions pharmaceutiques en contenant.The subject of the present invention is the methanol solvate of rimonabant, 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 méthanol de rimonabant qui présente des propriétés avantageuses.We have now found a particular solvate: the methanol solvate of rimonabant 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 méthanol de rimonabant tout complexe moléculaire à base de rimonabant incorporant le méthanol dans son réseau cristallin.According to the solvate definition given by Haleblian et al., Journal of Pharmaceutical Sciences, 64, 8, 1269-1288, 1975, rimonabant methanol solvate is understood to mean any rimonabant-based molecular complex incorporating methanol into its crystal lattice.
Selon un autre objet de la présente invention, ledit solvate est constitué d'une molécule de rimonabant et d'une demie (1/2) molécule de méthanol (hémisolvate).According to another object of the present invention, said solvate consists of a rimonabant molecule and a half (1/2) molecule of methanol (hemisolvate).
Le solvate de méthanol de rimonabant existe préférentiellement sous forme cristallisée. La présente invention est relative au solvate de méthanol de rimonabant, et plus particulièrement à une forme cristalline du solvate de méthanol de rimonabant.The methanol solvate of rimonabant preferentially exists in crystallized form. The present invention relates to the methanol solvate of rimonabant, and more particularly to a crystalline form of the methanol solvate of rimonabant.
Le fait d'obtenir un solvate du rimonabant avec le méthanol est particulièrement avantageux car le solvate de méthanol de rimonabant constitue un principe actif administrable à l'homme .The fact of obtaining a solvate of rimonabant with methanol is particularly advantageous because the methanol solvate of rimonabant is an active principle that can be administered to man.
Par ailleurs, le solvate de méthanol de rimonabant est particulièrement avantageux à titre d'intermédiaire dans l'(es) étape(s) finale(s) de synthèse du rimonabant.Moreover, the methanol solvate of rimonabant is particularly advantageous as an intermediate in the final stage (s) of synthesis of rimonabant.
Le rimonabant peut ainsi être préparé par désolvatation du solvate de méthanol de rimonabant selon les méthodes connues de l'homme du métier.Rimonabant can thus be prepared by desolvation of the methanol solvate of rimonabant according to methods known to those skilled in the art.
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. Le procédé de préparation du rimonabant caractérisé en ce que le rimonabant est obtenu par désolvatation du solvate de méthanol de rimonabant constitue un objet de la présente invention.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 methanol solvate of rimonabant constitutes an object of the present invention.
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.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 méthanol de rimonabant. Ce procédé est caractérisé en ce que l'on dissout le rimonabant dans le méthanol. Plus particulièrement, ce procédé est caractérisé en ce que : a) on prépare une suspension de rimonabant dans le méthanol, b) on isole le solvate de méthanol de rimonabant ainsi formé. Préférentiellement, selon le procédé de l'invention, l'étape a) est réalisée à température ambiante.The present invention also relates to the process for obtaining the methanol solvate of rimonabant. This process is characterized in that the rimonabant is dissolved in methanol. More particularly, this process is characterized in that: a) a suspension of rimonabant in methanol is prepared; b) the methanol solvate of rimonabant thus formed is isolated. Preferably, according to the method of the invention, step a) is carried out at room temperature.
Le solvate de méthanol de rimonabant formé par le procédé selon l'invention est isolé par filtration.The rimonabant methanol solvate formed by the process according to the invention is isolated by filtration.
De préférence, le rimonabant sous forme II (telle que décrite dans WO 2003/040105), éventuellement micronisée, est mis en suspension.Preferably, the form II rimonabant (as described in WO 2003/040105), optionally micronized, is suspended.
De façon particulière, on agite ladite suspension pendant une durée suffisante à la formation dudit solvate. De préférence, l'agitation est maintenue jusqu'à temps que le milieu réactionnel prenne en masse. La durée d'agitation est comprise entre 10 secondes et 1 heure, de préférence entre 1 et 10 minutes.In particular, said suspension is stirred for a time sufficient to form said solvate. Preferably, the stirring is maintained until the reaction medium is solid. The stirring time is between 10 seconds and 1 hour, preferably between 1 and 10 minutes.
Selon un autre mode de réalisation, il peut être avantageux d'homogénéiser la suspension à température comprise entre 300C et la température d'ébullition du solvant, de préférence entre 50 et 7O0C, plus préférentiellement environ 600C, puis de refroidir ladite suspension à une température suffisante pour initier et/ou accélérer la cristallisation. Préférentiellement, le refroidissement est effectué par refroidissement à température ambiante. De façon particulière, à l'étape a), on prépare une suspension de rimonabant dans le méthanol. Plus particulièrement, on prépare une suspension de concentration comprise entre 5 et 50% massique, préférentiellement entre 10 et 20% massique de rimonabant dans le méthanol.According to another embodiment, it may be advantageous to homogenize the suspension at a temperature of between 30 ° C. and the boiling point of the solvent, preferably between 50 and 70 ° C., more preferably approximately 60 ° C., and then cooling said suspension to a temperature sufficient to initiate and / or accelerate crystallization. Preferably, the cooling is carried out by cooling to ambient temperature. In particular, in step a), a suspension of rimonabant in methanol is prepared. More particularly, a concentration suspension of between 5 and 50% by weight, preferably between 10 and 20% by weight of rimonabant in methanol is prepared.
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 méthanol de rimonabant est caractérisé par différents éléments de son analyse physico-chimique.The methanol solvate of rimonabant is characterized by various elements of its physico-chemical analysis.
La forme cristalline du solvate de méthanol de rimonabant est caractérisée par les raies caractéristiques du diffractogramme de rayons X sur poudre.The crystalline form of the rimonabant methanol 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 = 1.54178A ; domaine de balayage 3° à 30°(2 thêta) ; palier : 0,04°; durée de palier : 4s.The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; CuKa source, λ = 1.54178A; scanning range 3 ° to 30 ° (2 theta); bearing: 0.04 °; duration of landing: 4s.
Les raies caractéristiques du diffractogramme sont reportées dans le tableau 1 suivant :The characteristic lines of the diffractogram are reported in the following Table 1:
TABLEAU 1 : Rayons X sur poudre, forme cristalline du solvate de méthanol de rimonabantTABLE 1: X-rays on powder, crystalline form of rimonabant methanol solvate
Figure imgf000004_0001
Figure imgf000004_0001
Le diffractogramme correspondant au solvate de méthanol de rimonabant est reproduit dans la figure 1. Teneur en méthanolThe diffractogram corresponding to the methanol solvate of rimonabant is reproduced in FIG. Methanol content
Thermogravimétrie-Analyse enthalpique différentielle (en anglais : Differential Scanning Calorimetry) :Thermogravimetry-Differential Scanning Calorimetry (Differential Scanning Calorimetry):
Le solvate de méthanol de rimonabant peut être analysé par TG-DSC par un appareil d'analyse TG-DSC NETZSCH STA 449C.The methanol solvate of rimonabant can be analyzed by TG-DSC by a NETZSCH STA 449C TG-DSC analyzer.
Le diagramme de l'analyse DSC est représenté à la figure 2. Un pic endothermique de désolvatation à 45,5°C (onset) est lié à une perte de masse de 3,44% correspondant à une stœchiométrique 1-1/2 : hemisolvate de méthanol (Δm/m théorique = 3,33%). Cette phase est efflorescente car la perte de masse débute dès 200C. Un second phénomène endothermique à 98,10C (sans perte de masse associée) est suivi d'un faible pic de fusion autour de 156°C : il s'agit probablement d'une amorphisation partielle.The diagram of the DSC analysis is shown in FIG. 2. An endothermic peak of desolvation at 45.5 ° C (onset) is related to a mass loss of 3.44% corresponding to a stoichiometric 1-1 / 2: methanol hemisolvate (Dm / m t héorique = 3.33%). This phase is efflorescent because the loss of mass begins at 20 0 C. A second endothermic phenomenon at 98.1 0 C (without associated mass loss) is followed by a low melting peak around 156 ° C: it s' probably acts as partial amorphization.
La forme cristalline du solvate de méthanol de rimonabant peut également être caractérisée par son spectre infra-rouge (I. R.).The crystalline form of the methanol solvate of rimonabant can also be characterized by its infra-red spectrum (I.R.).
La forme cristalline du solvate de méthanol 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 methanol solvate of rimonabant 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, including as anorexigenic, 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 méthanol de rimonabant.Example: preparation of the crystalline form of the methanol solvate of rimonabant.
275 mg de rimonabant (forme II micronisée) sont mis en suspension dans 2,1 g de méthanol (ACROS : 99%) à température ambiante sous agitation. La suspension est homogénéisée à 6O0C sous agitation magnétique puis aussitôt refroidie à température ambiante. Après quelques minutes, le solvate cristallise. La phase solide est isolée par filtration sous vide sur entonnoir filtrant de porosité 3 et analysée par XRPD. 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 :275 mg of rimonabant (micronized form II) are suspended in 2.1 g of methanol (ACROS: 99%) at room temperature with stirring. The suspension is homogenized at 60 ° C. with magnetic stirring and then immediately cooled to room temperature. After a few minutes, the solvate crystallizes. The solid phase is isolated by filtration under vacuum on filter funnel of porosity 3 and analyzed by XRPD. The RX diagram on powder, represented in FIG. 1, reveals a new diffraction profile, whose characteristic lines are reported in the following table 1:
Figure imgf000006_0001
Figure imgf000006_0001
Le profil de diffraction des rayons X (RX) de la poudre (angle de diffraction) est établi avec un diffractomètre Siemens D5005; source CuKa, λ = 1.54178A ; domaine de balayage 3.000° à 30.000°(2 thêta) ; palier : 0,04°; durée de palier : 4s, température 25°C.The X-ray diffraction pattern (X-ray) of the powder (diffraction angle) is established with a Siemens D5005 diffractometer; CuKa source, λ = 1.54178A; scanning range 3,000 ° to 30,000 ° (2 theta); bearing: 0.04 °; bearing time: 4s, temperature 25 ° C.
L'analyse DSC est représentée à la figure 2. Un pic endothermique de désolvatation à 45,5°C (onset) est lié à une perte de masse de 3,44% correspondant à une stœchiométrique 1-1/2 : hemisolvate de méthanol (Δm/m théorique = 3,33%). Cette phase est efflorescente car la perte de masse débute dès 200C. Un second phénomène endothermique à 98,10C (sans perte de masse associée) est suivi d'un faible pic de fusion autour de 1560C : il s'agit probablement d'une amorphisation partielle. The DSC analysis is shown in FIG. 2. An endothermic peak of desolvation at 45.5 ° C. (onset) is linked to a corresponding mass loss of 3.44%. in a stoichiometric 1-1 / 2: methanol hemisolvate (Dm / m t héorique = 3.33%). This phase is efflorescent because the loss of mass begins at 20 0 C. A second endothermic phenomenon at 98.1 0 C (without associated mass loss) is followed by a low melting peak around 156 0 C: it s' probably acts as partial amorphization.

Claims

REVENDICATIONS
1. Le solvate de méthanol de rimonabant.1. The methanol solvate of rimonabant.
2. Le solvate de méthanol de rimonabant selon la revendication 1 , caractérisé en ce qu'il s'agit de l'hémisolvate de méthanol de rimonabant.2. The methanol solvate of rimonabant according to claim 1, characterized in that it is the methanol hemisolvate rimonabant.
3. Le solvate de méthanol de rimonabant selon la revendication 1 ou 2 sous forme cristalline.3. The methanol solvate of rimonabant according to claim 1 or 2 in crystalline form.
4. Le solvate de méthanol 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 rimonabant methanol solvate 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 méthanol de rimonabant selon l'une quelconque des revendications 1 à 4, caractérisé en ce que : a) on prépare une suspension de rimonabant dans le méthanol, b) on isole le solvate de méthanol de rimonabant ainsi formé.5. Process for the preparation of the methanol solvate of rimonabant according to any one of claims 1 to 4, characterized in that: a) a suspension of rimonabant in methanol is prepared, b) the methanol solvate is isolated from rimonabant 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 la suspension préparée a une concentration comprise entre 5 et 50% massique de rimonabant dans le méthanol.7. The method of claim 5 or 6 such that the suspension prepared has a concentration of between 5 and 50% by weight of rimonabant in methanol.
8. Procédé selon la revendication 5, 6 ou 7 tel que le rimonabant mis en suspension est sous forme II. 8. The method of claim 5, 6 or 7 such that the suspended rimonabant is in form II.
9. Procédé selon l'une quelconque des revendications 5 à 8 tel que la suspension est maintenue sous agitation.9. Process according to any one of claims 5 to 8 such that the suspension is kept stirring.
10. Procédé selon l'une quelconque des revendications 5 à 8, tel que la suspension préparée est homogénéisée à température comprise entre 300C et la température d'ébullition du solvant, puis refroidie.10. Process according to any one of claims 5 to 8, such that the suspension prepared is homogenized at a temperature between 30 0 C and the boiling point of the solvent, and then cooled.
11. Procédé selon la revendication 10 tel que le refroidissement est effectué à température ambiante.11. The method of claim 10 such that the cooling is performed at room temperature.
12. Procédé selon l'une quelconque des revendications 5 à 11 tel que le solvate de méthanol de rimonabant formé est isolé par filtration.12. Process according to any one of Claims 5 to 11, such that the formed rimonabant methanol solvate is isolated by filtration.
13. Procédé selon l'une quelconque des revendications 5 à 12 tel que le produit obtenu est séché à une température comprise entre la température ambiante et 400C.13. Method according to any one of claims 5 to 12 such that the product obtained is dried at a temperature between room temperature and 40 0 C.
14. Le solvate de méthanol de rimonabant susceptible d'être obtenu par le procédé selon l'une quelconque des revendications 5 à 13.14. The methanol solvate of rimonabant obtainable by the method according to any one of claims 5 to 13.
15. Composition pharmaceutique contenant en tant que principe actif le solvate de méthanol de rimonabant selon l'une quelconque des revendications 1 à 4 ou 14.15. Pharmaceutical composition containing as active ingredient the methanol solvate of rimonabant according to any one of claims 1 to 4 or 14.
16. Composition pharmaceutique selon la revendication 15 sous forme d'unité de dosage dans laquelle le principe actif est mélangé à au moins un excipient pharmaceutique.16. Pharmaceutical composition according to claim 15 in the form of a dosage unit in which the active ingredient is mixed with at least one pharmaceutical excipient.
17. Utilisation du solvate de méthanol de rimonabant selon l'une quelconque des revendications 1 à 4 ou 14 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.17. Use of the methanol solvate of rimonabant according to any one of claims 1 to 4 or 14 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 anorectic, schizophrenia, delusional disorders, psychotic disorders, disorders related to the use of psychotic substances and anticancer chemotherapy.
18. Procédé de préparation du rimonabant caractérisé en ce que le rimonabant est obtenu par désolvatation du solvate de méthanol de rimonabant selon l'une quelconque des revendications 1 à 4 ou 14. 18. Process for the preparation of rimonabant, characterized in that the rimonabant is obtained by desolvation of the rimonabant methanol solvate according to any one of Claims 1 to 4 or 14.
PCT/FR2008/001161 2007-08-06 2008-08-04 Rimonabant methanol solvate, method for preparing same and pharmaceutical compositions containing same WO2009053552A1 (en)

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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
WO2006087732A1 (en) * 2005-01-06 2006-08-24 Cadila Healthcare Limited An amorphous and three crystalline forms of rimonabant hydrochloride
EP1816125A1 (en) * 2006-02-02 2007-08-08 Ranbaxy Laboratories, Ltd. Novel crystalline forms of an antagonist of CB1 cannabinoid receptor and preparation method thereof

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
WO2006087732A1 (en) * 2005-01-06 2006-08-24 Cadila Healthcare Limited An amorphous and three crystalline forms of rimonabant hydrochloride
EP1816125A1 (en) * 2006-02-02 2007-08-08 Ranbaxy Laboratories, Ltd. Novel crystalline forms of an antagonist of CB1 cannabinoid receptor and preparation method thereof

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