WO2001085092A2 - Antidiarrheal cannabinoid cb-1 receptor antagonist - Google Patents

Antidiarrheal cannabinoid cb-1 receptor antagonist Download PDF

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Publication number
WO2001085092A2
WO2001085092A2 PCT/FR2001/001432 FR0101432W WO0185092A2 WO 2001085092 A2 WO2001085092 A2 WO 2001085092A2 FR 0101432 W FR0101432 W FR 0101432W WO 0185092 A2 WO0185092 A2 WO 0185092A2
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Prior art keywords
compound
cannabinoid
diarrhea
antidiarrheal
receptor antagonist
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PCT/FR2001/001432
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French (fr)
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WO2001085092A3 (en
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Tiziano Croci
Luciano Manara
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Sanofi-Synthelabo
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Publication of WO2001085092A3 publication Critical patent/WO2001085092A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • the present invention relates to a new use of a cannabinoid receptor antagonist called CB ⁇ receptors. More particularly, the invention relates to the use of a CBj receptor antagonist for the preparation of medicaments useful as antidiarrheals.
  • N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) - 4-methylpyrazole-3-carboxamide hereinafter called compound A, of formula (I): its pharmaceutically acceptable salts and their solvates, are described in European patent EP-656 354 and by M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240-2424), as central cannabinoid CB ⁇ receptor antagonists.
  • the compound A and its salts which are CBj cannabinoid receptor antagonists can be used for the treatment of appetite disorders, in particular as an appetite suppressant, and in the treatment of disorders linked to the use of psychotropic substances.
  • Delta (9) -tetrahydrocannabinol (Delta (9) -THC) is the main active ingredient extracted from Cannabis Sativa (Tuner, 1985, in Marijuana 84, Ed. Harvey, DY, IRL Press, Oxford). ⁇ is described in Eur. J. Pharmacol., 1999, 371 (2-3). 187-196 that Delta (9) -THC inhibits gastric motility by action on CB ⁇ receptors.
  • the present invention therefore relates to the use of N-piperidino-5- (4-chlorophenyl) -l- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide, of one of its pharmaceutically acceptable salts or one of their solvates for the preparation of medicaments useful as antidiarrheals.
  • the administration of compound A, of a pharmaceutically acceptable salt or solvates thereof makes it possible to treat acute or chronic diarrheal disorders of different types and from different origins, for example, and in a nonlimiting manner aqueous diarrheas; diarrhea induced by drug treatment (chemotherapy, antibiotic treatment, etc.); functional diarrhea such as irritable bowel syndrome or irritable bowel disease; radiotherapy-induced diarrhea; diarrhea induced by endocrine tumors, such as carcinoid syndrome, gastrinoma, vipoma, inflammatory diarrhea such as infectious diarrhea, diarrhea due to a food allergy or poor absorption of a food or a foreign body, diarrhea due to ulcerative colitis or Crohn's disease.
  • aqueous diarrheas diarrhea induced by drug treatment (chemotherapy, antibiotic treatment, etc.)
  • functional diarrhea such as irritable bowel syndrome or irritable bowel disease
  • radiotherapy-induced diarrhea diarrhea induced by endocrine tumors, such as carcinoid syndrome, gastrinoma, vipoma
  • inflammatory diarrhea such as infectious diarrhea
  • compound A one of its pharmaceutically acceptable salts or one of their solvates, in combination with another active ingredient, for the preparation of medicaments useful for treating diarrhea.
  • compound A can be combined with a thickening agent for the gastric contents, with an intestinal absorbent or with a gastrointestinal dressing such as clays, pectin, cellulose, methylcellulose, for example.
  • a thickening agent for the gastric contents with an intestinal absorbent or with a gastrointestinal dressing such as clays, pectin, cellulose, methylcellulose, for example.
  • a gastrointestinal dressing such as clays, pectin, cellulose, methylcellulose, for example.
  • compound A, one of its pharmaceutically acceptable salts or one of their solvates, alone or in combination with another active principle must be formulated in pharmaceutical composition.
  • the active principle in the pharmaceutical compositions suitable for use according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local administration, can be administered in unitary form of administration, in mixture with conventional pharmaceutical carriers, animals and humans.
  • suitable unit administration forms include oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants , forms of local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration.
  • the active principle or the active principles are generally formulated in dosage units.
  • the dosage unit contains from 0.5 to 300 mg, advantageously from 5 to 60 g, preferably from 5 to 40 mg of active principle per dosage unit, for daily administrations, one or more times a day.
  • the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
  • a solid composition is prepared in the form of tablets, it is possible to add to the active ingredient (s) micronized (s) or not a wetting agent such as sodium lauryl sulfate and the whole is mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like.
  • a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like.
  • the tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
  • a preparation in capsules is obtained by mixing the active principle or the active principles with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
  • a diluent such as a glycol or a glycerol ester
  • a preparation in the form of a syrup or elixir may contain the active principle or active principles together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
  • a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
  • the powders or granules dispersible in water can contain the active principle or the active principles in mixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone or polyvidone, as well as with sweeteners or flavor correctors.
  • dispersing agents or wetting agents such as polyvinylpyrrolidone or polyvidone
  • suspending agents such as polyvinylpyrrolidone or polyvidone
  • sweeteners or flavor correctors for parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol.
  • a cosolvent for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80.
  • the active principle can be dissolved by a triglyceride or a glycerol ester.
  • the active principle or the active principles can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
  • the active principle or the active principles can also be presented in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
  • compound A is administered by the oral route, in a single dose per day.
  • the invention also relates to a method which consists in administering a therapeutically effective amount of compound A, of a pharmaceutically acceptable salt thereof or one of their solvates.
  • EXAMPLE 4 tablet containing 10 mg of compound A.
  • EXAMPLE 5 tablet dosed with 30 mg of compound A.

Abstract

The invention concerns the use of an antagonist of cannabinoid receptors called CB1 receptors for preparing medicines for use as antidiarrheal agents, more particularly N-piperidino-5-(4-chlorophenyl)-1-(2-dichlorophenyl)-4-methylpyrazole-3-carboxamide, also known under the designation SR 141716 (A) or rimonalant.

Description

UTILISATION D'UN ANTAGONISTE DES RECEPTEURS AUX CANNABINOÏDES CBi POUR LA PREPARATION DE MEDICAMENTS UTILES USE OF A CBi CANNABINOID RECEPTOR ANTAGONIST FOR THE PREPARATION OF USEFUL DRUGS
COMME ANTIDIARRHEIQUESAS ANTIDIARRHEICS
La présente invention concerne une nouvelle utilisation d'un antagoniste des récepteurs aux cannabinoïdes dits récepteurs CB^. Plus particulièrement, l'invention se rapporte à l'utilisation d'un antagoniste des récepteurs CBj pour la préparation de médicaments utiles comme antidiarrhéiques.The present invention relates to a new use of a cannabinoid receptor antagonist called CB ^ receptors. More particularly, the invention relates to the use of a CBj receptor antagonist for the preparation of medicaments useful as antidiarrheals.
Des familles de composés ayant une affinité pour les récepteurs aux cannabinoïdes ont été décrites dans plusieurs brevets et demandes de brevets, en particulier la demande européenne EP-576 357, qui décrit des dérivés du pyrazole, et la demande WO 96/02248 qui décrit notamment des dérivés du benzofurane.Families of compounds having an affinity for cannabinoid receptors have been described in several patents and patent applications, in particular European application EP-576,357, which describes derivatives of pyrazole, and WO 96/02248 which describes in particular benzofuran derivatives.
Plus particulièrement, le N-pipéridino-5-(4-chlorophényl)-l-(2,4-dichlorophényl)- 4-méthylpyrazole-3-carboxamide, ci-après dénommé composé A, de formule (I) :
Figure imgf000002_0001
ses sels pharmaceutiquement acceptables et leurs solvats, sont décrits dans le brevet européen EP-656 354 et par M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240- 244), comme antagonistes des récepteurs aux cannabinoïdes centraux CB^.More particularly, N-piperidino-5- (4-chlorophenyl) -1- (2,4-dichlorophenyl) - 4-methylpyrazole-3-carboxamide, hereinafter called compound A, of formula (I):
Figure imgf000002_0001
its pharmaceutically acceptable salts and their solvates, are described in European patent EP-656 354 and by M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240-2424), as central cannabinoid CB ^ receptor antagonists.
Il est décrit que le composé A et ses sels qui sont des antagonistes des récepteurs aux cannabinoïdes CBj peuvent être utilisés pour le traitement des troubles de l'appétit, notamment en tant qu'anorexigène, et dans le traitement des troubles liés à l'utilisation de substances psychotropes.It is described that the compound A and its salts which are CBj cannabinoid receptor antagonists can be used for the treatment of appetite disorders, in particular as an appetite suppressant, and in the treatment of disorders linked to the use of psychotropic substances.
Le delta(9)-tétrahydrocannabinol (Delta(9)-THC) est le principal constituant actif extrait de Cannabis Sativa (Tuner, 1985, in Marijuana 84, Ed. Harvey, DY, IRL Press, Oxford). ïï est décrit dans Eur. J. Pharmacol., 1999, 371(2-3). 187-196 que le Delta(9)-THC inhibe la motilité gastrique par action sur les récepteurs CB^.Delta (9) -tetrahydrocannabinol (Delta (9) -THC) is the main active ingredient extracted from Cannabis Sativa (Tuner, 1985, in Marijuana 84, Ed. Harvey, DY, IRL Press, Oxford). ïï is described in Eur. J. Pharmacol., 1999, 371 (2-3). 187-196 that Delta (9) -THC inhibits gastric motility by action on CB ^ receptors.
Par ailleurs, A.A. Izzo et al (Eur. J. Pharmacol, 1999, 384(1), 37-42) et Naunyn- Schiniedebergs (Arch. Pharmacol., 1999, 359(1), 65-70) ont étudié, chez le rongeur, le rôle des récepteurs aux cannabinoïdes sur la motilité intestinale, la défécation et la diarrhée : ils ont trouvé que l'activation exogène des récepteurs aux cannabinoïdes CB^ produit une réduction de la motilité intestinale dans la partie supérieure du tractus gastro-intestinal ; ils ont aussi observé que le composé A augmente la défécation, le transit gastro-intestinal et l'accumulation de fluide intestinal. De façon surprenante, on a maintenant trouvé que le composé A, ses sels pharmaceutiquement acceptables et leurs solvats inhibent la diarrhée, montrant ainsi un effet antidiarrhéique.Furthermore, AA Izzo et al (Eur. J. Pharmacol, 1999, 384 (1), 37-42) and Naunyn-Schiniedebergs (Arch. Pharmacol., 1999, 359 (1), 65-70) studied, in the rodent, the role of cannabinoid receptors on bowel motility, defecation and diarrhea: they found that exogenous activation of the CB ^ cannabinoid receptors produced a reduction in intestinal motility in the upper part of the gastrointestinal tract; they also observed that compound A increases defecation, gastrointestinal transit and the accumulation of intestinal fluid. Surprisingly, it has now been found that compound A, its pharmaceutically acceptable salts and their solvates inhibit diarrhea, thus showing an antidiarrheal effect.
Selon un de ses aspects, la présente invention concerne donc l'utilisation du N- pipéridino-5-(4-chlorophényl)-l-(2,4-dichlorophényl)-4-méthylpyrazole-3- carboxamide, d'un de ses sels pharmaceutiquement acceptable ou d'un de leurs solvats pour la préparation de médicaments utiles comme antidiarrhéiques.According to one of its aspects, the present invention therefore relates to the use of N-piperidino-5- (4-chlorophenyl) -l- (2,4-dichlorophenyl) -4-methylpyrazole-3-carboxamide, of one of its pharmaceutically acceptable salts or one of their solvates for the preparation of medicaments useful as antidiarrheals.
Ainsi, l'administration du composé A, d'un de ses sels pharmaceutiquement acceptable ou solvats, permet de traiter les troubles diarrhéiques aigus ou chroniques de différents types et de différentes origines, par exemple, et de manière non limitatives les diarrhées aqueuses ; les diarrhées induites par un traitement médicamenteux (chimiothérapie, traitement antibiotique....) ; les diarrhées fonctionnelles telles que le syndrome du colon irritable ou la maladie du colon irritable ; les diarrhées induites par la radiothérapie ; les diarrhées induites par les tumeurs endocrines, telles que le syndrome carcinoïde, le gastrinome, le vipome, les diarrhées d'origine inflammatoire comme les diarrhées infectieuses, les diarrhées dues à une allergie alimentaire ou à une mauvaise absorption d'un aliment ou d'un corps étranger, les diarrhées dues à une colite ulcérative ou à une maladie de Crohn.Thus, the administration of compound A, of a pharmaceutically acceptable salt or solvates thereof, makes it possible to treat acute or chronic diarrheal disorders of different types and from different origins, for example, and in a nonlimiting manner aqueous diarrheas; diarrhea induced by drug treatment (chemotherapy, antibiotic treatment, etc.); functional diarrhea such as irritable bowel syndrome or irritable bowel disease; radiotherapy-induced diarrhea; diarrhea induced by endocrine tumors, such as carcinoid syndrome, gastrinoma, vipoma, inflammatory diarrhea such as infectious diarrhea, diarrhea due to a food allergy or poor absorption of a food or a foreign body, diarrhea due to ulcerative colitis or Crohn's disease.
Selon la présente invention, on peut également utiliser le composé A, un de ses sels pharmaceutiquement acceptable ou un de leurs solvats, en association avec un autre principe actif, pour la préparation de médicaments utiles pour traiter les diarrhées.According to the present invention, it is also possible to use compound A, one of its pharmaceutically acceptable salts or one of their solvates, in combination with another active ingredient, for the preparation of medicaments useful for treating diarrhea.
Par exemple le composé A peut être associé à un agent épaississant du contenu gastrique, à un absorbant intestinal ou à un pansement gastro-intestinal tels que les argiles, la pectine, la cellulose, la méthylcellulose, par exemple. Pour son utilisation en tant que médicament, le composé A, un de ses sels pharmaceutiquement acceptable ou un de leurs solvats, seul ou en association avec un autre principe actif, doit être formulé en composition pharmaceutique.For example, compound A can be combined with a thickening agent for the gastric contents, with an intestinal absorbent or with a gastrointestinal dressing such as clays, pectin, cellulose, methylcellulose, for example. For its use as a medicament, compound A, one of its pharmaceutically acceptable salts or one of their solvates, alone or in combination with another active principle, must be formulated in pharmaceutical composition.
Dans les compositions pharmaceutiques adaptées à l'utilisation selon la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique ou locale, le principe actif, seul ou en association avec un autre principe actif, peut être administré sous forme unitaire d'administration, en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules, les pilules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les aérosols, les implants, les formes d'administration locale, transdermique, sous-cutanée, intramusculaire, intraveineuse, intranasale ou intraoculaire.In the pharmaceutical compositions suitable for use according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or local administration, the active principle, alone or in combination with another active principle, can be administered in unitary form of administration, in mixture with conventional pharmaceutical carriers, animals and humans. Suitable unit administration forms include oral forms such as tablets, capsules, pills, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, aerosols, implants , forms of local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration.
Dans les compositions pharmaceutiques adaptées à l'utilisation selon la présente invention, le principe actif ou les principes actifs sont généralement formulés en unités de dosage. L'unité de dosage contient de 0,5 à 300 mg, avantageusement de 5 à 60 g, de préférence de 5 à 40 mg de principe actif par unité de dosage, pour les administrations quotidiennes, une ou plusieurs fois par jour.In the pharmaceutical compositions suitable for use according to the present invention, the active principle or the active principles are generally formulated in dosage units. The dosage unit contains from 0.5 to 300 mg, advantageously from 5 to 60 g, preferably from 5 to 40 mg of active principle per dosage unit, for daily administrations, one or more times a day.
Bien que ces dosages soient des exemples de situations moyennes, il peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés, de tels dosages appartiennent également à l'invention. Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, l'âge, le poids et la réponse dudit patient.Although these dosages are examples of average situations, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of said patient.
Lorsque l'on prépare une composition solide sous forme de comprimés, on peut ajouter au(x) principe(s) actif (s) micronisé(s) ou non un agent mouillant tel que le laurylsulfate de sodium et on mélange le tout avec un véhicule pharmaceutique tel que la silice, l'amidon, le lactose, le stéarate de magnésium, le talc ou analogues. On peut enrober les comprimés de saccharose, de divers polymères ou d'autres matières appropriées ou encore les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.When a solid composition is prepared in the form of tablets, it is possible to add to the active ingredient (s) micronized (s) or not a wetting agent such as sodium lauryl sulfate and the whole is mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like. The tablets can be coated with sucrose, various polymers or other suitable materials or else they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
On obtient une préparation en gélules en mélangeant le principe actif ou les principes actifs avec un diluant tel qu'un glycol ou un ester de glycérol et en incorporant le mélange obtenu dans des gélules molles ou dures.A preparation in capsules is obtained by mixing the active principle or the active principles with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained in soft or hard capsules.
Une préparation sous forme de sirop ou d'élixir peut contenir le principe actif ou les principes actifs conjointement avec un édulcorant, acalorique de préférence, du méthylparaben et du propylparaben comme antiseptiques, ainsi qu'un agent donnant du goût et un colorant approprié.A preparation in the form of a syrup or elixir may contain the active principle or active principles together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
Les poudres ou les granules dispersibles dans l'eau peuvent contenir le principe actif ou les principes actifs en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinylpyrrolidone ou polyvidone, de même qu'avec des édulcorants ou des correcteurs du goût. Pour une administration parentérale, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des agents solubilisants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylèneglycol. Ainsi, pour préparer une solution aqueuse injectable par voie intraveineuse on peut utiliser un cosolvant, par exemple un alcool tel que l'éthanol ou un glycol tel que le polyéthylèneglycol ou le propylèneglycol, et un tensioactif hydrophile tel que le polysorbate 80. Pour préparer une solution huileuse injectable par voie intramusculaire, on peut solubiliser le principe actif par un triglycéride ou un ester de glycérol.The powders or granules dispersible in water can contain the active principle or the active principles in mixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone or polyvidone, as well as with sweeteners or flavor correctors. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or solubilizing agents, for example propylene glycol or butylene glycol. Thus, to prepare an aqueous solution for intravenous injection one can use a cosolvent, for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80. oily solution injectable intramuscularly, the active principle can be dissolved by a triglyceride or a glycerol ester.
Pour l'administration transdermique, on peut utiliser des patches sous forme multilaminée ou à réservoir dans lequel le principe actif est en solution alcoolique.For transdermal administration, it is possible to use patches in multilaminate or reservoir form in which the active principle is in alcoholic solution.
Le principe actif ou les principes actifs peuvent être formulés également sous forme de microcapsules ou microsphères, éventuellement avec un ou plusieurs supports ou additifs.The active principle or the active principles can also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.
Le principe actif ou les principes actifs peuvent être également présentés sous forme de complexe avec une cyclodextrine, par exemple α-, β- ou γ- cyclodextrine, 2- hydroxypropyl-β-cyclodextrine ou méthyl-β-cyclodextrine.The active principle or the active principles can also be presented in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.
Parmi les formes à libération prolongée utiles dans le cas de traitements chroniques, on peut utiliser des implants. Ceux-ci peuvent être préparés sous forme de suspension huileuse ou sous forme de suspension de microsphères dans un milieu isotonique.Among the sustained-release forms useful in the case of chronic treatments, implants can be used. These can be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
De façon préférentielle, le composé A est administré par la voie orale, en une prise unique par jour. Selon un autre de ses aspects, l'invention concerne aussi une méthode qui consiste à administrer une quantité thérapeutiquement efficace du composé A, d'un de ses sels pharmaceutiquement acceptable ou un de leurs solvats.Preferably, compound A is administered by the oral route, in a single dose per day. According to another of its aspects, the invention also relates to a method which consists in administering a therapeutically effective amount of compound A, of a pharmaceutically acceptable salt thereof or one of their solvates.
Les effets du composé A ont été étudiés chez le chien sur un modèle de diarrhée induite par de l'huile de ricin. On administre par voie intra-gastrique à des chiens beagles, de 10 + 2 kg, l'huile de ricin (1 ml/kg) 2 heures après un repas léger. Les animaux traités reçoivent en outre, le composé A, à différentes doses, avec le repas.The effects of compound A have been studied in dogs on a castor oil-induced diarrhea model. Beagle dogs, 10 + 2 kg, castor oil (1 ml / kg) are administered intragastrically 2 hours after a light meal. The treated animals also receive compound A, in different doses, with the meal.
Le comportement des animaux et les épisodes diarrhéiques sont ensuite suivis pendant 24 heures.The behavior of the animals and the diarrheal episodes are then followed for 24 hours.
Les résultats sont indiqués dans le tableau ci-après. Tableau 1
Figure imgf000006_0001
The results are shown in the table below. Table 1
Figure imgf000006_0001
L'administration d'huile de ricin induit des diarrhées chez tous les chiens non traités et on constate que le composé A inhibe de façon dose dépendante les diarrhées induites.The administration of castor oil induces diarrhea in all untreated dogs and it is found that compound A inhibits in a dose dependent manner the induced diarrhea.
Sur le plan expérimental, on observe également que l'effet antidiarrhéique du composé A ne s'accompagne pas d'un effet constipant.On the experimental level, it is also observed that the antidiarrheal effect of compound A is not accompanied by a constipating effect.
EXEMPLE 1 : gélule dosée à 5 mg de composé A.EXAMPLE 1 capsule 5 mg of compound A.
Composé A micronisé 5,00 mgCompound A micronized 5.00 mg
Amidon de maïs 51 ,00 mgCorn starch 51, 00 mg
Lactose monohydrate 99,33 mgLactose monohydrate 99.33 mg
Polyvidone 4,30 mgPolyvidone 4.30 mg
Laurylsulfate de sodium 0,17 mgSodium lauryl sulfate 0.17 mg
Carboxyméthyl cellulose de sodium réticulée 8,50 mg Eau purifiée : Q.S. pour granulation humideCrosslinked sodium carboxymethyl cellulose 8.50 mg Purified water: Q.S. for wet granulation
Stéarate de magnésium 1,70 mgMagnesium stearate 1.70 mg
Pour une gélule blanc opaque n° 3 remplie à 170 mg EXEMPLE 2 : gélule dosée à 10 mg de composé A.For an opaque white capsule No. 3 filled with 170 mg EXAMPLE 2: capsule dosed with 10 mg of compound A.
Composé A micronisé 10,00 mgCompound A micronized 10.00 mg
Amidon de maïs 51 ,00 mgCorn starch 51, 00 mg
Lactose monohydrate 94,33 mgLactose monohydrate 94.33 mg
Polyvidone 4,30 mgPolyvidone 4.30 mg
Laurylsulfate de sodium 0,17 mgSodium lauryl sulfate 0.17 mg
Carboxyméthyl cellulose de sodium réticulée 8,50 mg Eau purifiée : Q.S. pour granulation humideCrosslinked sodium carboxymethyl cellulose 8.50 mg Purified water: Q.S. for wet granulation
Stéarate de magnésium 1,70 mgMagnesium stearate 1.70 mg
Pour une gélule blanc opaque n° 3 remplie à 170 mg EXEMPLE 3 : gélule dosée à 20 mg de composé A.For an opaque white capsule No. 3 filled to 170 mg EXAMPLE 3 capsule containing 20 mg of compound A.
Composé A micronisé 20,00 mgCompound A micronized 20.00 mg
Amidon de maïs 51 ,00 mgCorn starch 51, 00 mg
Lactose monohydrate 84,33 mgLactose monohydrate 84.33 mg
Polyvidone 4,30 mgPolyvidone 4.30 mg
Laurylsulfate de sodium 0,17 mgSodium lauryl sulfate 0.17 mg
Carboxyméthyl cellulose de sodium réticulée 8,50 mg Eau purifiée : Q.S. pour granulation humideCrosslinked sodium carboxymethyl cellulose 8.50 mg Purified water: Q.S. for wet granulation
Stéarate de magnésium 1,70 mgMagnesium stearate 1.70 mg
Pour une gélule blanc opaque remplie à 170 mg EXEMPLE 4 : comprimé dosé à 10 mg de composé A.For an opaque white capsule filled to 170 mg EXAMPLE 4: tablet containing 10 mg of compound A.
Composé A micronisé 10,00 mgCompound A micronized 10.00 mg
Amidon de maïs 50,00 mg Lactose monohydrate 200 mesh 211 ,50 mgCorn starch 50.00 mg Lactose monohydrate 200 mesh 211, 50 mg
Hydroxypropylméthylcellulose 6 cP 9,00 mgHydroxypropylmethylcellulose 6 cP 9.00 mg
Carboxyméthylamidon sodique 15,00 mgCarboxymethyl sodium starch 15.00 mg
Laurylsulfate de sodium 1,50 mgSodium lauryl sulfate 1.50 mg
Stéarate de magnésium 3,00 mg Eau purifiée : Q.S.Magnesium stearate 3.00 mg Purified water: Q.S.
Pour un comprimé terminé à 300 mg EXEMPLE 5 : comprimé dosé a 30 mg de composé A.For a tablet finished at 300 mg EXAMPLE 5: tablet dosed with 30 mg of compound A.
Composé A micronisé 30,00 mg Amidon de maïs 80,00 mgCompound A micronized 30.00 mg Corn starch 80.00 mg
Lactose monohydrate 200 mesh 252,00 mgLactose monohydrate 200 mesh 252.00 mg
Povidone K 30 12,00 mgPovidone K 30 12.00 mg
Carboxyméthylcellulose sodique réticulée 20,00 mgCrosslinked sodium carboxymethylcellulose 20.00 mg
Laurylsulfate de sodium 2,00 mg Stéarate de magnésium 4,00 mg Eau purifiée : Q.S.Sodium lauryl sulfate 2.00 mg Magnesium stearate 4.00 mg Purified water: Q.S.
Pour un comprimé terminé à 400 mg For a tablet finished at 400 mg

Claims

REVENDICATIONS
1. Utilisation du N-pipéridino-5-(4-chlorophényl)- 1 -(2,4-dichlorophényl)-4- méthylpyrazole-3-carboxamide, d'un de ses sels pharmaceutiquement acceptable ou d'un de leurs solvats, pour la préparation de médicaments utiles comme antidiarrhéiques. 1. Use of N-piperidino-5- (4-chlorophenyl) - 1 - (2,4-dichlorophenyl) -4- methylpyrazole-3-carboxamide, one of its pharmaceutically acceptable salts or one of their solvates, for the preparation of useful drugs such as antidiarrheals.
PCT/FR2001/001432 2000-05-12 2001-05-11 Antidiarrheal cannabinoid cb-1 receptor antagonist WO2001085092A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001260406A AU2001260406A1 (en) 2000-05-12 2001-05-11 Antidiarrheal cannabinoid cb-1 receptor antagonist

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0006178A FR2809621B1 (en) 2000-05-12 2000-05-12 USE OF A CENTRAL CANNABINOID RECEPTOR ANTAGONIST FOR THE PREPARATION OF MEDICINES SUITABLE AS ANTIDIARRHOISTS
FR00/06178 2000-05-12

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EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
WO2007039797A1 (en) * 2005-10-03 2007-04-12 Pfizer Products Inc. Use of cannabinoid receptor-1 antagonist for treating inflammation and arthritis
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
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EP2305220A2 (en) 2004-03-09 2011-04-06 Institut National de la Santé et de la Recherche Médicale - Inserm Use of antagonists of the CB1 receptor for the manufacture of a composition useful for the treatment of hepatic diseases
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US6972295B2 (en) 2002-03-12 2005-12-06 Merck & Co., Inc. Substituted amides
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US7423067B2 (en) 2002-03-26 2008-09-09 Merck & Co., Inc. Diphenyl cyclopentyl amides as cannabinoid-1 receptor inverse agonists
US7271266B2 (en) 2002-03-28 2007-09-18 Merck & Co., Inc. Substituted 2,3-diphenyl pyridines
US7667053B2 (en) 2002-04-12 2010-02-23 Merck & Co., Inc. Bicyclic amides
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7354929B2 (en) 2003-04-23 2008-04-08 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7141669B2 (en) 2003-04-23 2006-11-28 Pfizer Inc. Cannabiniod receptor ligands and uses thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
EP2305220A2 (en) 2004-03-09 2011-04-06 Institut National de la Santé et de la Recherche Médicale - Inserm Use of antagonists of the CB1 receptor for the manufacture of a composition useful for the treatment of hepatic diseases
EP2343302A1 (en) 2004-07-12 2011-07-13 Cadila Healthcare Limited Tricyclic pyrazole derivatives as cannabinoid receptor modulators
EP1623741A2 (en) 2004-07-22 2006-02-08 Cadila Healthcare Ltd. Cannabinoid receptor ligands for hair growth modulation
WO2007039797A1 (en) * 2005-10-03 2007-04-12 Pfizer Products Inc. Use of cannabinoid receptor-1 antagonist for treating inflammation and arthritis

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FR2809621B1 (en) 2002-09-06
FR2809621A1 (en) 2001-12-07
AU2001260406A1 (en) 2001-11-20

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