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WO2000045846A1 - Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms - Google Patents

Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms Download PDF

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Publication number
WO2000045846A1
WO2000045846A1 PCT/FR2000/000193 FR0000193W WO0045846A1 WO 2000045846 A1 WO2000045846 A1 WO 2000045846A1 FR 0000193 W FR0000193 W FR 0000193W WO 0045846 A1 WO0045846 A1 WO 0045846A1
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WO
WIPO (PCT)
Prior art keywords
group
azabicyclo
nicotine
monoamine oxidase
pharmaceutical composition
Prior art date
Application number
PCT/FR2000/000193
Other languages
French (fr)
Inventor
Dominique Caille
Pascal George
Samir Jegham
Pascale Robineau
Bernard Scatton
Branimir Zivkovic
Original Assignee
Sanofi-Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to CA002361437A priority Critical patent/CA2361437A1/en
Priority to AU22988/00A priority patent/AU2298800A/en
Priority to JP2000596965A priority patent/JP2002536342A/en
Priority to EP00901660A priority patent/EP1150715A1/en
Publication of WO2000045846A1 publication Critical patent/WO2000045846A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/465—Nicotine; Derivatives thereof
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • the subject of the present invention is a new pharmaceutical composition comprising nicotine or a nicotinic receptor ligand intended for smoking cessation.
  • Tobacco consumption is considered a real public health problem, since tobacco is the cause of several serious diseases such as cardiovascular, respiratory and certain types of cancer.
  • taking this type of medication is not without side effects, in particular an increase in blood pressure, heart rate and gastrointestinal effects.
  • the compounds available on the market such as (Nikoban 5 , Bantron ® , CigArrest ⁇ and Nic-Fit ⁇ ) for example are often administered with antacids to avoid undesirable gastrointestinal effects.
  • Nicotine like other substances of various origins (alcohol, cocaine 7), causes addiction. These molecules act via separate primary mechanisms leading to the activation of a common mechanism responsible for the pleasure induced by their consumption.
  • dopamine plays a major role linked to its involvement in hedonic behavior.
  • MAOIs Monoamine oxidase inhibitors
  • MAOIs of type B are potentially useful in this type of treatment (see Fowler et al., Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAOB) inhibition J. Add. Di sease (1998 ), 17, 23-34 and Fowler et al. Nature (1996), 379, 733-736)
  • MAOB brain monoamine oxidase B
  • patent application 095/28934 the use of monoamine oxidase A inhibitors for the control of Smoking consumption, and especially during cravings, is described. By increasing the amount of dopamine at the pleasure centers located in the limbic system, these compounds could reproduce the hedonic sensation associated with smoking and promote smoking cessation.
  • US Patent 5,803,081 mentions the possibility of producing a chewing gum containing cut tobacco treated with propolis, as a reservoir for a prolonged release of nicotine, and possibly of a monoamine oxidase B inhibitor as found in tobacco smoke.
  • the advantages cited for this chewing gum lie in the pretreatment of tobacco with propolis, making it possible to avoid peaks of nicotine release while prolonging the flavor of the chewing gum.
  • a monoamine oxidase B inhibitor not described there as essential for achieving the above-mentioned advantages, but also no monoamine oxidase B inhibitor is specifically mentioned in its structure or even in its possible role in this chewing gum.
  • the chewing gum itself is not illustrated by an example of a technical embodiment.
  • the aim of the present invention is to provide a pharmaceutical composition comprising nicotine or a ligand for nicotmic receptors, useful in smoking cessation and whose cardiovascular side effects are reduced.
  • the Applicant has indeed been able to demonstrate, surprisingly, that the side effects subsequent to the administration of nicotine or a ligand for nicotinic receptors can be considerably reduced by virtue of the co-administration of a monoamine oxidase inhibitor.
  • the subject of the invention is therefore a pharmaceutical composition
  • a pharmaceutical composition comprising nicotine or a ligand for nicotinic receptors and a monoamine oxidase inhibitor, useful for smoking cessation and whose cardiovascular side effects are reduced.
  • nicotinic receptor ligand is understood to mean, in the context of the present invention, in particular agonists of nicotinic receptors such as cytisine, lobelin, ABT-418 (Abbott), epibatidine, GTS-21, AR -R17779 (AstraZeneca), ABT-594 (Abbott), ABT-089 (Abbott), but also other nicotinic receptor ligands such as: AN-072 (Elan), eperisone (Eisai), rapacuronium bromide (Akzo Nobel), altinicline (Sibia), conantokin-G (Cognetix), GW-280430 (Glaxo Wellcome), RJR-2403 (Targacept), galantamine, SIB 1553 A (Sibia) , A-85380 (Abbott), metanicotine, RJR-2531 (RJ Reynolds Tobacco), RJR-2557 (RJ Reynolds Tob
  • one of the symbols X, Y and Z represents a nitrogen atom
  • another represents a group of formula CR 3 and the third represents a nitrogen atom or a group of formula CR 4 , R 3 and R.
  • each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C, -C 6 ) alkyl or (Ci-Cg) group alkoxy
  • R x and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy group, alkyl, (Ci-Cg) - alkoxy, or phenyl optionally substituted by one or two halogen atoms, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a group (C x -C 6 ) alkyl, by one or two groups alkoxy, by
  • R 3 and R 4 each represent , independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Ci-Cg) alkyl or (Ci-Cg) alkoxy group
  • R and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Cj-Cg) alkyl group, alkoxy, or phenyl optionally substituted by a halogen atom, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a group alkoxy, by an acetyl group, by a methylenedioxy group, by a trifluoromethoxy group, by
  • agonists are preferred.
  • composition according to the present invention the increase in blood pressure and heart rate is minimized.
  • the composition provides greater safety and better tolerance and therefore better compliance of the treatment for the patient.
  • a reversible monoamine oxidase A inhibitor or A reversible mixed A or B, reversible or irreversible B with nicotine or a nicotinic receptor ligand can have an amplifying effect on the beneficial effects of nicotine by example the feeling of pleasure, the improvement of the mood, the improvement of the psychomotor and cognitive performances while reducing the side effects, in particular cardiovascular.
  • compositions comprising nicotine or a nicotinic receptor ligand and a reversible monoamine oxidase inhibitor.
  • the monoamine oxidase inhibitor can be a reversible monoamine oxidase A inhibitor, a reversible or irreversible monoamine oxidase B inhibitor or an inhibitor of the reversible mixed monoamine oxidase A, B.
  • Befloxatone and moclobemide are most particularly preferred as a reversible monoamine oxidase A inhibitor, as is (-) 3 - [2- (3, 3, 3 -trifluoropropyl) -
  • the MAOIs will be preferred for the compositions according to the present invention.
  • Another object of the present invention consists of a pharmaceutical composition comprising nicotine or nicotinic receptor ligand and a monoamine oxidase inhibitor as a combination product for simultaneous, separate or spread over time intended for smoking cessation.
  • spontaneous use is understood to mean the administration of the compounds of the composition according to the invention included in one and the same pharmaceutical form.
  • separate use is meant the administration, at the same time, of the two compounds of the composition according to the invention each included in a separate pharmaceutical form.
  • use spread over time is understood to mean the successive administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then of the second compound of the composition according to the invention, included in a pharmaceutical form separate.
  • the period of time between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours.
  • the pharmaceutical forms comprising either only one of the constituent compounds of the composition according to the invention or the combination of the two compounds, which can be used in the different types of uses described above, can for example be suitable for oral, nasal, parenteral or transdermal administration.
  • the two separate pharmaceutical forms can be intended for the same route of administration or for a different route of administration (oral and transdermal or oral and nasal or parenteral and transdermal etc).
  • compositions suitable for oral administration mention may be made of tablets, capsules, pills and chewing gums with immediate or prolonged release.
  • dosage forms such as suspensions or injectable solutions are suitable.
  • composition according to the invention can then be administered in a single daily dose or in divided daily doses. In the latter case, the composition can be administered in 2 to 3 doses per day.
  • transdermal patches or patches are for example suitable for transdermal administration.
  • gels or emulsions are also suitable.
  • transdermal patch or patch which allows slow and regular administration for at least one of the two compounds of the combination.
  • the patient's autonomy vis-à-vis his treatment is thus favored.
  • the patch makes it possible to obtain a release of the composition which can last between 8 and 72 hours.
  • compositions suitable for use in a patch or patch can be in the form of a gel, ointment, solution, cream or emulsion. They can be prepared according to conventional methods for those skilled in the art.
  • compositions can also be formulated as a nasal spray, pulmonary spray or suppository.
  • At least one of the two components of the combination is administered transdermally, for example by patch or transdermal patch.
  • compositions according to the The present invention is dosed to allow daily administration of 2 to 20 mg of nicotine or of nicotinic receptor ligand and from 1 to 20 mg of monoamine oxidase inhibitor.
  • the present invention also relates to the use of nicotine or a ligand for nicotinic receptors and a monoamine oxidase inhibitor for the manufacture of a medicament intended for smoking cessation.
  • Befloxatone or moclobemide is suspended in a vehicle (Tween 80 0.5% w / v, methylcellulose 0.5% w / v in water for injection). Nicotine is dissolved in water for an injectable preparation.
  • the animals underwent, under general anesthesia by mtrapé ⁇ tonéale injection of ketamme (116 mg / kg ⁇ .p.), a cathtate ⁇ sme of the carotid and the jugular vein with exteriorization of the catheters in dorsoscapular region.
  • ketamme 116 mg / kg ⁇ .p.
  • a cathlus ⁇ sme of the carotid and the jugular vein with exteriorization of the catheters in dorsoscapular region.
  • the day after implantation the animals were connected to measuring devices allowing the continuous recording of blood pressure and heart rate. After a stabilization period of approximately 30 minutes, the animals received the oral treatment, then 45 minutes later, three increasing doses of nicotine, administered intravenously at an interval of 5 minutes.
  • Average blood pressure and heart rate were measured before treatment, before each administration of nicotine, and at the peak of the effect of these administrations.
  • nicotine causes an increase in average blood pressure in the control animals and a slight increase in heart rate.
  • Befloxatone 1 mg / kg po and moclobemide 10 mg / kg po reduce the increases in blood pressure and heart rate induced, between 45 min and 60 min after treatment, by intravenous administration of nicotine. (TAB.l to 4).
  • TAB.l Average blood pressure (mm Hg), awake rat
  • TAB .3 Average blood pressure (mm Hg), awake rat
  • NS not significantly different from the vehicle group (P> 0.05, Dunnett test after two-factor analysis of variance with repeated measurements)
  • Tablets containing 10 mg of befloxatone are manufactured according to the following composition
  • the first five components are mel aged, granulated with water, dried and graded.
  • the granules are then mixed with the magnesium stearate and compressed to form tablets of 200 mg by mass, using a rotary press.
  • a transdermal patch with an area of 20 cm 2 capable of delivering 14 mg in 24 hours is prepared according to the following composition:
  • the granules are prepared by wet granulation according to the following compositions:
  • microcrystalline cellulose 15 microcrystalline cellulose 20% povidone 4% hydroxypropyl methylcellulose 25% magnesium stearate 1%
  • bilayer tablets are prepared by compression using a press
  • Manesty BL Each layer contains 100 mg of granules so that each tablet contains 5 mg of befloxatone and 5 mg of nicotine.
  • the tablets containing 10 mg of befloxatone are prepared according to the following composition:
  • magnesium stearate 0.50 colloidal silica 0.10 The first five components of each pellet are mixed, pelletized with water, dried and graded. The granules are then mixed with magnesium stearate and colloidal silica and then gelatin capsules of size 2 of 160 mg of the granules thus prepared are filled.
  • a solution for nasal administration containing 50 mg of nicotine, 900 mg of sodium chloride, 10 mg of benzalkonium chloride, 100 mg of EDTA sodium and 100 mg of sterilized water is prepared. This solution is filtered and distributed in ampoules.

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Abstract

The invention concerns novel pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor designed for treating tobacco withdrawal symptoms.

Description

COMPOSITIONS PHARMACEUTIQUES CONTENANT DE LA NICOTINE OU UN LIGAND DES RECEPTEURS NICOTINIOUES ET UN INHIBITEUR DE LA MONAMINE OXYDASE ET LEUR APPLICATION DANS LE SEVRAGE TABAGIOUEPHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE OR A NICOTINIOU RECEPTOR LIGAND AND A MONAMINE OXIDASE INHIBITOR AND THEIR APPLICATION IN TABAGIOUE WEANING
La présente invention a pour objet une nouvelle composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotinique destinée au sevrage tabagique .The subject of the present invention is a new pharmaceutical composition comprising nicotine or a nicotinic receptor ligand intended for smoking cessation.
La consommation de tabac est considérée comme un vrai problème de santé publique, dans la mesure où le tabac est à l'origine de plusieurs maladies graves telles que les maladies cardio-vasculaires , respiratoires et certains types de cancer. L'administration de la nicotine ou d'un analogue tel que la lobéline par voie transdermique ou au moyen de gomme à mâcher ou spray nasal par exemple, constitue un traitement de substitution à la consommation de tabac et par conséquent un outil de sevrage tabagique. Cependant, la prise de ce type de médication n'est pas dénuée d'effets indésirables, en particulier, une élévation de la pression artérielle, de la fréquence cardiaque et des effets gastro- intestinaux. D'ailleurs, les composés disponibles sur le marché comme (Nikoban5, Bantron®, CigArrestΦ et Nic-FitΦ) par exemple sont souvent administrés avec des antiacides pour éviter les effets gastrointestinaux indésirables.Tobacco consumption is considered a real public health problem, since tobacco is the cause of several serious diseases such as cardiovascular, respiratory and certain types of cancer. The administration of nicotine or an analog such as lobelin by the transdermal route or by means of chewing gum or nasal spray, for example, constitutes a substitution treatment for the consumption of tobacco and therefore a smoking cessation tool. However, taking this type of medication is not without side effects, in particular an increase in blood pressure, heart rate and gastrointestinal effects. Moreover, the compounds available on the market such as (Nikoban 5 , Bantron ® , CigArrest Φ and Nic-Fit Φ ) for example are often administered with antacids to avoid undesirable gastrointestinal effects.
La nicotine, comme d'autres substances d'origines diverses (alcool, cocaine ... ) , provoque une dépendance. Ces molécules agissent via des mécanismes primaires distincts conduisant à l'activation d'un mécanisme commun responsable du plaisir induit par leur consommation. Parmi les neurotransmetteurs du système nerveux central impliqués dans les phénomènes de dépendances, la dopamine joue un rôle majeur lié à son implication dans les comportements hédoniques .Nicotine, like other substances of various origins (alcohol, cocaine ...), causes addiction. These molecules act via separate primary mechanisms leading to the activation of a common mechanism responsible for the pleasure induced by their consumption. Among the neurotransmitters of the central nervous system involved in dependence phenomena, dopamine plays a major role linked to its involvement in hedonic behavior.
Les inhibiteurs de la monoamine oxydase (IMAO) - la monoamine oxydase étant un flavoenzyme impliqué dans le catabolisme des aminés biogènes dont la dopamine - ont été décrits comme potentiellement bénéfiques dans le traitement du sevrage tabagique (I Berlin et coll . , Clin . Pharmacol . Ther (1995), 58(4), 444-452)Monoamine oxidase inhibitors (MAOIs) - monoamine oxidase being a flavoenzyme involved in the catabolism of biogenic amines including dopamine - have been described as potentially beneficial in the treatment of smoking cessation (I Berlin et al., Clin. Pharmacol. Ther (1995), 58 (4), 444-452)
Il est également connu par exemple, que les IMAO de type B sont potentiellement utiles dans ce type de traitement (voir Fowler et coll., Neuropharmacological actions of cigarette smoke : brain monoamine oxydase B (MAOB) inhibition J . add . di sease (1998), 17, 23-34 et Fowler et coll. Nature (1996), 379, 733-736) De même, dans la demande de brevet 095/28934, l'utilisation des inhibiteurs de la monoamine oxydase A pour le contrôle de la consommation tabagique, et en particulier lors des états de manque, est décrite. En augmentant la quantité de dopamine au niveau des centres du plaisir localisés dans le système limbique, ces composés pourraient en reproduire la sensation hedonique associée au tabagisme et favoriser le sevrage tabagique. Le brevet US 5,803,081 évoque la possibilité de réaliser une gomme à mâcher (chewmg gum) contenant du tabac coupé traité au propolis, à titre de réservoir pour une libération prolongée de nicotine, et éventuellement d'un inhibiteur de monoamine oxydase B tel que trouvé dans la fumée du tabac . Les avantages cités pour cette gommme à mâcher réside dans le prétraitement du tabac par le propolis, permettant d'éviter des pics de libération de la nicotine tout en prolongeant la saveur de la gomme à mâcher. Toutefois, non seulement, la présence d'inhibiteur de la monoamine oxydase B n'y est pas décrite comme indispensable pour atteindre les avantages précités, mais encore aucun inhibiteur de la monoamine oxydase B n'est spécifiquement cité dans sa structure ni même dans son éventuel rôle dans cette gomme à mâcher. Par ailleurs, la gomme à mâcher elle-même n'est pas illustrée par un exemple de réalisation technique.It is also known, for example, that MAOIs of type B are potentially useful in this type of treatment (see Fowler et al., Neuropharmacological actions of cigarette smoke: brain monoamine oxidase B (MAOB) inhibition J. Add. Di sease (1998 ), 17, 23-34 and Fowler et al. Nature (1996), 379, 733-736) Similarly, in patent application 095/28934, the use of monoamine oxidase A inhibitors for the control of Smoking consumption, and especially during cravings, is described. By increasing the amount of dopamine at the pleasure centers located in the limbic system, these compounds could reproduce the hedonic sensation associated with smoking and promote smoking cessation. US Patent 5,803,081 mentions the possibility of producing a chewing gum containing cut tobacco treated with propolis, as a reservoir for a prolonged release of nicotine, and possibly of a monoamine oxidase B inhibitor as found in tobacco smoke. The advantages cited for this chewing gum lie in the pretreatment of tobacco with propolis, making it possible to avoid peaks of nicotine release while prolonging the flavor of the chewing gum. However, not only is the presence of a monoamine oxidase B inhibitor not described there as essential for achieving the above-mentioned advantages, but also no monoamine oxidase B inhibitor is specifically mentioned in its structure or even in its possible role in this chewing gum. Furthermore, the chewing gum itself is not illustrated by an example of a technical embodiment.
Le but de la présente invention est de fournir une composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotmiques, utile dans le sevrage tabagique et dont les effets secondaires cardio-vasculaires sont réduits .The aim of the present invention is to provide a pharmaceutical composition comprising nicotine or a ligand for nicotmic receptors, useful in smoking cessation and whose cardiovascular side effects are reduced.
La demanderesse a en effet pu mettre en évidence, de façon surprenante, que les effets secondaires subséquents à l'administration de nicotine ou un ligand des récepteurs nicotiniques peuvent être considérablement réduits grâce à la co-administration d'un inhibiteur de la monoamine oxydase .The Applicant has indeed been able to demonstrate, surprisingly, that the side effects subsequent to the administration of nicotine or a ligand for nicotinic receptors can be considerably reduced by virtue of the co-administration of a monoamine oxidase inhibitor.
L'invention a donc pour objet une composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotiniques et un inhibiteur de la monoamine oxydase, utile pour le sevrage tabagique et dont les effets secondaires cardio-vasculaires sont réduits.The subject of the invention is therefore a pharmaceutical composition comprising nicotine or a ligand for nicotinic receptors and a monoamine oxidase inhibitor, useful for smoking cessation and whose cardiovascular side effects are reduced.
On entend par ligand des récepteurs nicotinique, dans le cadre de la présente invention, notamment les agonistes des récepteurs nicotiniques tels que la cytisine, la lobéline, l'ABT-418 (Abbott), 1 ' épibatidine , le GTS-21, le AR-R17779 (AstraZeneca) , le ABT-594 (Abbott) , le ABT-089 (Abbott) , mais aussi d'autres ligands des récepteurs nicotiniques tels que : le AN-072 (Elan), l'eperisone (Eisai) , le bromure de rapacuronium (Akzo Nobel), 1 ' altinicline (Sibia) , le conantokin-G (Cognetix) , le GW-280430 (Glaxo Wellcome) , le RJR-2403 (Targacept) , la galantamine, le SIB 1553 A (Sibia) , le A-85380 (Abbott) , la métanicotine, le RJR-2531 (R. J. Reynolds Tobacco) , le RJR-2557 (R. J. Reynolds Tobacco) , le DBO-83 (universités de Florence et Milan) , la 9-bromo-l ,2,3,4,5, 6-hexahydro-8H-l , 5-méthanopyrido [1 , 2-a] [1 , 5] diazocin-8-one (Pfizer), la 11-fluoro-1 , 2 , 3 , 4 , 5 , 6- hexahydro-8H-l , 5-méthanopyrido [1, 2-a] [1,5] diazocin-8-one (Pfizer), la 9-phényl-l , 2 , 3 , 4 , 5 , 6-hexahydro-8H-l , 5- méthanopyrido [1, 2-a] [1 , 5] diazocin-8-one (Pfizer), la 9-benzyl-l, 2,3,4,5, 6-hexahydro-8H-l , 5-méthanopyrido [1, 2-a] [1, 5] diazocin-8-one (Pfizer), la 9-acétyl-l , 2 , 3 , 4 , 5 , 6- hexahydro-8H-l , 5-méthanopyrido [1,2-a] [1,5] diazocin-8-one (Pfizer), la 9- (2-pyridyl) -1 , 2 , 3 , 4 , 5 , 6-hexahydro-8H-l , 5- méthanopyrido [1, 2-a] [1 , 5] diazocin-8-one (Pfizer), 9- (2 , 4-dιf luorophényl) -1,2,3,4,5, 6-hexahydro-8H-l , 5- méthanopyrido [1 , 2 -a] [1 , 5] dιazocm-8-one (Pfizer) , la 9- (2-thιazolyl) -1,2,3,4,5, 6-hexahydro-8H-l , 5- méthanopyrido [1 , 2 -a] [1 , 5] dιazocm-8-one (Pfizer) , 1 ' endo-6- (3 -pyπdyl ) -2 -azabicyclo [2.2.2] octane (Sumitomo Pharmaceu icals) , 1 ' endo-6- (5-pyrιmιdmyl) -2 - azabicyclo [2.2.2] octane (Sumitomo Pharmaceuticals) , le 6- (5-bromo-3 -pyπdyl) -2 -azabicyclo [2.2.2] oct-5-ène (Sumitomo Pharmaceuticals) , le 6- (5-éthynyl-3-pyπdyl) - 2-azabιcyclo [2.2.2] octane (Sumitomo Pharmaceuticals) , le (±) -8-méthyl-3- (3-pyπdyl) -8 -azabicyclo [3.2.1] oct-2-ene (Neurosearch) , le ( + ) -8- (benzyl) -3 - (3 -pyridyl) -8- azabicyclo [3.2.1] oct-2-ène (Neurosearch) , le (±)-3- (6-chloro-3-pyrιdmyl) -8 -méthyl -8 -azabicyclo [3.2.1] oct- 2-ene (Neurosearch) , le (±) -3- (8-méthyl-8- azabicyclo [3.2.1] oct-2-en-3-yl) aniline (Neurosearch) , la spiro [1 , 3-benzodιoxole-2 , 3 ' -qumuclidine] (Neurosearch) , la 5-méthylspιro [1,3 -benzodιoxole-2 , 3 ' -qumuclidme] (Neurosearch) , la 5-tert-butylspιro [1 , 3 -benzodioxole- 2 , 3 ' -qumuclidme] (Neurosearch) , la (±) -3 - (5-méthoxy-The term nicotinic receptor ligand is understood to mean, in the context of the present invention, in particular agonists of nicotinic receptors such as cytisine, lobelin, ABT-418 (Abbott), epibatidine, GTS-21, AR -R17779 (AstraZeneca), ABT-594 (Abbott), ABT-089 (Abbott), but also other nicotinic receptor ligands such as: AN-072 (Elan), eperisone (Eisai), rapacuronium bromide (Akzo Nobel), altinicline (Sibia), conantokin-G (Cognetix), GW-280430 (Glaxo Wellcome), RJR-2403 (Targacept), galantamine, SIB 1553 A (Sibia) , A-85380 (Abbott), metanicotine, RJR-2531 (RJ Reynolds Tobacco), RJR-2557 (RJ Reynolds Tobacco), DBO-83 (universities of Florence and Milan), 9-bromo-l , 2,3,4,5,6-hexahydro-8H-1,5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one (Pfizer), la 11-fluoro-1, 2, 3, 4, 5, 6- hexahydro-8H-1,5, methanopyrido [1, 2-a] [1,5] diazocin-8-one (Pfizer), 9-phenyl-1,2,3 , 4, 5, 6-hexahydro-8H-1, 5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one (Pfizer), 9-benzyl-1, 2,3,4, 5, 6-hexahydro-8H-1, 5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one (Pfizer), 9-acetyl-1, 2, 3, 4, 5, 6 - hexahydro-8H-1,5-methanopyrido [1,2-a] [1,5] diazocin-8-one (Pfizer), la 9- (2-pyridyl) -1, 2, 3, 4, 5, 6-hexahydro-8H-l, 5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one (Pfizer), 9- (2,4-dιf luorophenyl) -1,2,3,4,5,6-hexahydro-8H-1,5,5-methanopyrido [1, 2 -a] [1, 5] dιazocm-8-one ( Pfizer), 9- (2-thιazolyl) -1,2,3,4,5, 6-hexahydro-8H-1,5,5-methanopyrido [1, 2 -a] [1, 5] dιazocm-8-one (Pfizer), 1 'endo-6- (3 -pyπdyl) -2 -azabicyclo [2.2.2] octane (Sumitomo Pharmaceu icals), 1' endo-6- (5-pyrιmιdmyl) -2 - azabicyclo [2.2.2 ] octane (Sumitomo Pharmaceuticals), 6- (5-bromo-3 -pyπdyl) -2 -azabicyclo [2.2.2] oct-5-ene (Sumitomo Pharmaceuticals), 6- (5-ethynyl-3-pyπdyl) - 2-azabιcyclo [2.2.2] octane (Sumitomo Pharmaceuticals), le (±) -8-methyl-3- (3-pyπdyl) -8 -azabicyclo [3.2.1] oct-2-ene (Neurosearch) (+) -8- (benzyl) -3 - (3 -pyridyl) -8- azabicyclo [3.2.1] oct-2-ene (Neurosearch), le (±) -3- (6-chloro-3-pyrιdmyl ) -8 -methyl -8 -azabicyclo [3.2.1] oct- 2-ene (Neurosearch), le (±) -3- (8-methyl-8- azabicyclo [3.2.1] oct-2-en-3 -yl) aniline (Neurosearch), spiro [1, 3-benzodιoxole-2, 3 '-qumuclidine] (Neu rosearch), 5-methylspιro [1,3 -benzodιoxole-2, 3 '-qumuclidme] (Neurosearch), 5-tert-butylspιro [1, 3 -benzodioxole- 2, 3' -qumuclidme] (Neurosearch) (±) -3 - (5-methoxy-
3-pyπdmyl) -9-azabιcyclo [3.3.1] non-2-ène (Neurosearch) , la (±) -3- (5-méthoxy-3-pyπdιnyl) -9-méthyl-9- azabicyclo [3.3.1] non-2-ène (Neurosearch) , la (±)-3- (9- méthyl-9-azabιcyclo [3.3.1] non-2-èn-3-yl) phénylamme (Neurosearch) , le (±) -3 - (3 -pyridmyl) -9- azabicyclo [3.3.1] non-2-ène (Neurosearch) , la (±) -9 -méthyl -3- (3 -pyridmyl) -9 -azabicyclo [3.3. l]non-2-ène (Neurosearch) , le spiro [1-azabιcyclo [2.2.2] octane- 3-2 ' (3 Η) -furo [2 , 3-b] pyπdme] 7 ' -oxide (AstraZeneca) , la 1- (6-chloro-5-méthoxypyndm-3-yl) perhydro-1 , 4-dιazépme (Neurosearch) , la 1- (5-méthoxypyrιdme-3 -yl) perhydro- 1 , 4-dιazépme (Neurosearch) , la 1- (5-méthoxypyrιdm-3- yl) perhydro-1 , 5-dιazocme (Neurosearch) , la 3- (perhydro-1 , 4-dιazépm-l-yl) qumolme (Neurosearch) , la 1- (6-bromopyπdm-3 -yl) perhydro-1 , 4-dιazépme3-pyπdmyl) -9-azabιcyclo [3.3.1] non-2-ene (Neurosearch), la (±) -3- (5-methoxy-3-pyπdιnyl) -9-methyl-9- azabicyclo [3.3.1 ] non-2-ene (Neurosearch), la (±) -3- (9- methyl-9-azabιcyclo [3.3.1] non-2-en-3-yl) phenylamme (Neurosearch), le (±) - 3 - (3 -pyridmyl) -9- azabicyclo [3.3.1] non-2-ene (Neurosearch), la (±) -9 -methyl -3- (3 -pyridmyl) -9 -azabicyclo [3.3. l] non-2-ene (Neurosearch), the spiro [1-azabιcyclo [2.2.2] octane- 3-2 '(3 Η) -furo [2, 3-b] pyπdme] 7' -oxide (AstraZeneca) , 1- (6-chloro-5-methoxypyndm-3-yl) perhydro-1, 4-dιazépme (Neurosearch), 1- (5-méthoxypyrιdme-3 -yl) perhydro- 1, 4-dιazépme (Neurosearch) , 1- (5-methoxypyrιdm-3- yl) perhydro-1, 5-dιazocme (Neurosearch), 3- (perhydro-1, 4-dιazépm-l-yl) qumolme (Neurosearch), 1- (6 -bromopyπdm-3 -yl) perhydro-1, 4-dιazépme
(Neurosearch) , la 1- (5-propoxypyrιdm-3-yl) perhydro-1 , 4- diazépme (Neurosearch) , la(Neurosearch), 1- (5-propoxypyrιdm-3-yl) perhydro-1, 4- diazepme (Neurosearch), la
4- (3 -pyridmyloxy) perhydroazépme (Neurosearch) , la4- (3 -pyridmyloxy) perhydroazepme (Neurosearch), the
2 -méthyl -1 ,2,3,5,6,7,8, 9-octahydro-5 , 9-méthanopyrrolo [3,4-h] [3] benzazépιne-1 , 3-dιone (Pfizer), la 1 , 3 -diméthyl -1,2,3,5,6,7,8, 9-octahydro-5 , 9-méthanoιmιdazo [4,5-h] [3 ] benzazépm-2 -one (Pfizer), la2 -methyl -1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo [3,4-h] [3] benzazépιne-1, 3-dιone (Pfizer), la 1, 3 -diméthyl -1,2,3,5,6,7,8, 9-octahydro-5, 9- methanoιmιdazo [4,5-h] [3] benzazépm-2 -one (Pfizer), the
1,2,3,5,6,7,8, 9-octahydro-5 , 9-méthanopyrrolo [3 , 4-h] [3] benzazépme-1 , 3 -dione (Pfizer), la 7 , 8-dιfluoro-2 , 3 , 4 , 5- tétrahydro-lH-1 , 5-méthano-3 -benzazépme (Pfizer), le 8-éthynyl -2,3,4, 5-tétrahydro-lH-l , 5-méthano-3 -benzazépme-7 -carbonitrile (Pfizer), la 7-chloro-8- (trifluorométhyl) - 2,3,4, 5- tétrahydro-lH-1 , 5-méthano-3 -benzazépme (Pfizer) , le 8- (trifluorométhyl) -2, 3,4, 5-tétrahydro-lH-l, 5- méthano-3-benzazépme-7-carbonιtrιle (Pfizer) , ainsi que ceux décrits :1,2,3,5,6,7,8, 9-octahydro-5, 9-methanopyrrolo [3, 4-h] [3] benzazépme-1, 3 -dione (Pfizer), la 7, 8-dιfluoro -2, 3, 4, 5-tetrahydro-1H-1, 5-methano-3 -benzazepme (Pfizer), 8-ethynyl -2,3,4,5-tetrahydro-1H-1,5-methano-3 -benzazepme-7 -carbonitrile (Pfizer), 7-chloro-8- (trifluoromethyl) - 2,3,4,5-tetrahydro-1H-1, 5-methano-3 -benzazépme (Pfizer), 8- ( trifluoromethyl) -2, 3,4, 5-tetrahydro-1H-1, 5-methano-3-benzazépme-7-carbonιtrιle (Pfizer), as well as those described:
- dans la demande de brevet W098/42713, c'est à dire les dérivés de 2 , 3 -dihydrofuro [3 , 2-b] pyπdme et plus particulièrement les composés (R, R) , ( S, S) , {R, S) et ( S, R) de la 2-pyrrolιdm-2-yl-2, 3 -dihydrofuro [3 , 2-jb] pyndme et,- In patent application WO98 / 42713, that is to say the derivatives of 2, 3 -dihydrofuro [3, 2-b] pyπdme and more particularly the compounds (R, R), (S, S), {R , S) and (S, R) of 2-pyrrolιdm-2-yl-2, 3 -dihydrofuro [3, 2-jb] pyndme and,
- dans la demande de brevet WO99/02517, c'est à dire les dérivés de 6, 7-dihydro-5H-2-pyrmdme et plus particulièrement les composés (R, R) , ( S, S) , (R, S) et ( S, R) de la 6-pyrrolιdm-2-yl-6 , 7-dιhydro-5H-2-pyπdme- In patent application WO99 / 02517, that is to say the derivatives of 6, 7-dihydro-5H-2-pyrmdme and more particularly the compounds (R, R), (S, S), (R, S ) and (S, R) of 6-pyrrolιdm-2-yl-6, 7-deιhydro-5H-2-pyπdme
- les composés décrits dans la demande de brevet PCT/FR99/02974 utiles dans le traitement ou la prévention des désordres liés à un dysfonctionnement des récepteurs nicotiniques, notamment au niveau du système nerveux central ou du système gastromtestmal (par exemple les altérations cognitives, schizophrénie, dépression, douleur...), répondant à la formule générale (I)- the compounds described in patent application PCT / FR99 / 02974 useful in the treatment or prevention of disorders linked to a dysfunction of the nicotinic receptors, in particular at the level of the central nervous system or the gastromtestmal system (for example cognitive alterations, schizophrenia , depression, pain ...), corresponding to the general formula (I)
dans laquelle
Figure imgf000007_0001
l'un des symboles X, Y et Z représente un atome d'azote, un autre représente un groupe de formule C-R3 et le troisième représente un atome d'azote ou un groupe de formule C-R4, R3 et R., représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (C,-C6) alkyle ou (Ci-Cg) alcoxy, Rx et R2 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle , cyano, hydroxy,
Figure imgf000008_0001
alkyle, (Ci-Cg) - alcoxy, ou phényle éventuellement substitué par un ou deux atomes d'halogènes, par un ou deux groupes trifluoro- méthyle, par un groupe cyano, par un groupe nitro, par un groupe hydroxy, par un groupe (Cx-C6) alkyle, par un ou deux groupes
Figure imgf000008_0002
alcoxy, par un groupe méthylènedioxy, par un groupe acétyle, par un groupe trifluorométhoxy ou par un groupe méthylthio, R représente un atome d'hydrogène ou un groupe (Ci-Ce) alkyle, étant toutefois exclus les composés de formule générale (I) dans laquelle X représente un groupe de formule CH, Y et Z représentent chacun un atome d'azote, et Rλ ou R2 ne représente pas un groupe phényle éventuellement substitué, - les composés décrits dans la demande de brevet PCT/FR99/02975, également utiles dans le traitement ou la prévention des désordres liés à un dysfonctionnement des récepteurs nicotiniques, notamment au niveau du système nerveux central ou du système gastrointestinal, répondant à la formule générale (I)in which
Figure imgf000007_0001
one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula CR 3 and the third represents a nitrogen atom or a group of formula CR 4 , R 3 and R., each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C, -C 6 ) alkyl or (Ci-Cg) group alkoxy, R x and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy group,
Figure imgf000008_0001
alkyl, (Ci-Cg) - alkoxy, or phenyl optionally substituted by one or two halogen atoms, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a group (C x -C 6 ) alkyl, by one or two groups
Figure imgf000008_0002
alkoxy, by a methylenedioxy group, by an acetyl group, by a trifluoromethoxy group or by a methylthio group, R represents a hydrogen atom or a (Ci-C e ) alkyl group, being however excluded the compounds of general formula (I ) in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R λ or R 2 does not represent an optionally substituted phenyl group, - the compounds described in patent application PCT / FR99 / 02975, also useful in the treatment or prevention of disorders linked to dysfunction of the nicotinic receptors, in particular in the central nervous system or the gastrointestinal system, corresponding to the general formula (I)
dans laquelle
Figure imgf000008_0003
l'un des symboles X, Y et Z représente un atome d'azote, un autre représente un groupe de formule C-R3 et le troisième représente un atome d'azote ou un groupe de formule C-R4, R3 et R4 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (Ci-Cg) alkyle ou (Ci-Cg) alcoxy, R et R2 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (Cj-Cg) alkyle,
Figure imgf000009_0001
alcoxy, ou phényle éventuellement substitué par un atome d'halogène, par un ou deux groupes trifluorométhyle, par un groupe cyano, par un groupe nitro, par un groupe hydroxy, par un groupe
Figure imgf000009_0002
alcoxy, par un groupe acétyle, par un groupe méthylènedioxy, par un groupe trifluorométhoxy, par un groupe methylthio ou par un groupe phényle.in which
Figure imgf000008_0003
one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula CR 3 and the third represents a nitrogen atom or a group of formula CR 4 , R 3 and R 4 each represent , independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Ci-Cg) alkyl or (Ci-Cg) alkoxy group, R and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Cj-Cg) alkyl group,
Figure imgf000009_0001
alkoxy, or phenyl optionally substituted by a halogen atom, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a group
Figure imgf000009_0002
alkoxy, by an acetyl group, by a methylenedioxy group, by a trifluoromethoxy group, by a methylthio group or by a phenyl group.
Parmi les ligands des récepteurs nicotiniques, on préfère les agonistes.Among the nicotinic receptor ligands, agonists are preferred.
Grâce à la composition selon la présente invention, l'augmentation de la pression artérielle et de la fréquence cardiaque est minimisée. La composition assure une plus grande sécurité et une meilleure tolérance et donc une meilleure compliance du traitement pour le patient.Thanks to the composition according to the present invention, the increase in blood pressure and heart rate is minimized. The composition provides greater safety and better tolerance and therefore better compliance of the treatment for the patient.
Par ailleurs, l'association d'un inhibiteur de la monoamine oxydase A réversible ou A,B mixte réversible ou bien B réversible ou irréversible, avec la nicotine ou un ligand des récepteurs nicotiniques peut avoir un effet amplificateur des effets bénéfiques de la nicotine par exemple la sensation de plaisir, l'amélioration de l'humeur, l'amélioration des performances psychomotrices et cognitives tout en réduisant les effets secondaires, notamment cardio-vasculaires .In addition, the combination of a reversible monoamine oxidase A inhibitor or A reversible mixed A or B, reversible or irreversible B with nicotine or a nicotinic receptor ligand can have an amplifying effect on the beneficial effects of nicotine by example the feeling of pleasure, the improvement of the mood, the improvement of the psychomotor and cognitive performances while reducing the side effects, in particular cardiovascular.
Dans le cadre de la présente invention, on préfère les compositions comprenant la nicotine ou un ligand des récepteurs nicotiniques et un inhibiteur réversible de la monoamine oxydase .In the context of the present invention, preferred are compositions comprising nicotine or a nicotinic receptor ligand and a reversible monoamine oxidase inhibitor.
Dans le cadre de la présente invention, l'inhibiteur de la monoamine oxydase peut être un inhibiteur de la monoamine oxydase A réversible, un inhibiteur de la monoamine oxydase B réversible ou irréversible ou un inhibiteur de la monoamine oxydase A,B mixte réversible.In the context of the present invention, the monoamine oxidase inhibitor can be a reversible monoamine oxidase A inhibitor, a reversible or irreversible monoamine oxidase B inhibitor or an inhibitor of the reversible mixed monoamine oxidase A, B.
Plus particulièrement à titre d' IMAO A réversible on peut citer : la béfloxatone, le moclobémide, la brofaromme, la phenoxathme, l'esuprone, le befol, le RS 8359 (Sankyo), le T794 (Tanabé) , le KP 9 (Krenitsky, USA) , le E 2011 (Eisai) , la toloxatone, le pirlmdole, l'amiflamme, la sercloremme , la baz aprme,More particularly, as reversible MAOI, we can cite: befloxatone, moclobemide, brofaromme, phenoxathme, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 (Krenitsky , USA), E 2011 (Eisai), toloxatone, pirlmdole, amiflamme, sercloremme, la baz aprme,
A titre d'IMAO B réversible on peut citer : le lazabemide, le milacémide, la caroxazone, l'IFO, A titre d' IMAO B irréversible on peut citer : leAs reversible MAOI B we can cite: lazabemide, milacemide, caroxazone, IFO, As irreversible MAOI B we can cite:
L-deprényl, la mofégilme, la rasagél e, la pargylme.L-deprenyl, mofegilme, rasagél e, pargylme.
A titre d' IMAO on peut encore citer les composés décrits :By way of MAOI, the compounds described can also be cited:
- dans la demande de brevet W096/38444, c'est à dire des dérivés d' oxazolιdm-2 -one et par exemple la- In patent application W096 / 38444, that is to say derivatives of oxazolιdm-2 -one and for example the
( S) -5-méthoxyméthyl-3- [6- (4,4, 4-trιfluorobutoxy) -1,2- benzιsoxazol-3-yl] oxazolιdm-2-one,(S) -5-methoxymethyl-3- [6- (4,4, 4-trιfluorobutoxy) -1,2- benzιsoxazol-3-yl] oxazolιdm-2-one,
- dans la demande de brevet EP 0 699 680, c'est à dire des dérivés de 3 , 3a, 4 , 5-tétrahydro-lH-oxazolo [3 , 4-a] qumolém- 1-one et par exemple la [3 ( S) , 3a ( S) ] -3 -méthoxyméthyl -7-- in patent application EP 0 699 680, that is to say derivatives of 3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] qumolém-1-one and for example the [3 (S), 3a (S)] -3 -methoxymethyl -7-
(4,4, 4-trιfluoro-3 (R) -hydroxybutoxy) -3 , 3a, 4, 5-tétrahydro- IH-oxazolo [3 , 4-a] qumolém-1-one et la [3 (S) , 3a (S) ] - 3-méthoxyméthyl-7- [4,4, 4 -trifluorobutoxy] -3 , 3a, 4, 5- tétrahydro-lH-oxazolo [3 , 4-a] qumoléme-1-one, - dans la demande de brevet W097/13768, c'est à dire des dérivés d' oxazolιdm-2 -one et par exemple la (R) -5- (méthoxyméthyl) -3- [6- (4,4, 4 -trifluorobutoxy) benzofuran-3-yl] oxazolιdm-2-one et la (R) -5 -méthoxyméthyl - 3 - (6-cyclopropylméthoxybenzofuran-3-yl) oxazolιdm-2-one, - dans la demande de brevet W097/17347, c'est à dire des composés dérivés d' oxazolιdm-2-one et par exemple la (-) 3- [2- (3,3,3-trιfluoropropyl) -3 , 4-dιhydro-2H-l- benzopyran-6-yl] -5 (R) -méthoxyméthyloxazolιdm-2-one et la 3- [2- (3,3, 3-trιfluoropropyl) -2 , 3-dιhydrobenzofuran-5-yl] - 5 (R) -méthoxyméthyloxazolιdm-2-one,(4,4, 4-trιfluoro-3 (R) -hydroxybutoxy) -3, 3a, 4, 5-tétrahydro- IH-oxazolo [3, 4-a] qumolém-1-one and the [3 (S), 3a (S)] - 3-methoxymethyl-7- [4,4,4-trifluorobutoxy] -3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] qumoleme-1-one, - in patent application WO97 / 13768, that is to say derivatives of oxazolιdm-2 -one and for example (R) -5- (methoxymethyl) -3- [6- (4,4, 4 -trifluorobutoxy) benzofuran-3-yl] oxazolιdm-2-one and (R) -5 -methoxymethyl - 3 - (6-cyclopropylmethoxybenzofuran-3-yl) oxazolιdm-2-one, - in patent application W097 / 17347, c ' ie compounds derived from oxazolιdm-2-one and for example (-) 3- [2- (3,3,3-trιfluoropropyl) -3, 4-deιhydro-2H-l- benzopyran-6-yl ] -5 (R) -methoxymethyloxazolιdm-2-one and 3- [2- (3,3, 3-trιfluoropropyl) -2, 3-deιhydrobenzofuran-5-yl] - 5 (R) -methoxymethyloxazolιdm-2-one ,
- dans la demande de brevet W097/17346, c'est à dire des composés dérivés de 3- (benzofuran-5-yl) oxazolιdm-2-one et par exemple la 3 - [2 - (3 , 3 , 3 -trifluoropropyl) benzofuran- 5-yl] -5 ( S) -méthoxyméthyloxazolιdm-2-one, la 3- (2 -propylbenzofuran-5-yl ) -5 ( R) -méthoxyméthyloxazolidm- 2-one et la 3 - (2 -phénylbenzofuran-5-yl) -5 (S) - méthoxyméthyloxazolιdιn-2 -one ,- In patent application WO97 / 17346, that is to say compounds derived from 3- (benzofuran-5-yl) oxazolιdm-2-one and for example 3 - [2 - (3, 3, 3 -trifluoropropyl ) benzofuran- 5-yl] -5 (S) -methoxymethyloxazolιdm-2-one, the 3- (2 -propylbenzofuran-5-yl) -5 (R) -methoxymethyloxazolidm- 2-one and 3 - (2 -phenylbenzofuran-5-yl) -5 (S) - methoxymethyloxazolιdιn-2 -one,
- dans la demande de brevet EP 0 655 445, c'est à dire des dérivés de 1 , 3 , 4 -oxadιazol-2 ( 3 H) -one et par exemple la 5- [4 - (4,4,4 -trifluorobutoxy) phényl] -3 - (2 -méthoxyéthyl ) - 1,3, 4-oxadιazol-2 (3H) -one .- in patent application EP 0 655 445, that is to say derivatives of 1, 3, 4 -oxadιazol-2 (3 H) -one and for example 5- [4 - (4,4,4 - trifluorobutoxy) phenyl] -3 - (2-methoxyethyl) - 1,3,4-oxadιazol-2 (3H) -one.
La béfloxatone et la moclobémide sont tout particulièrement préférés à titre d'inhibiteur de la monoamine oxydase A réversible ainsi que la ( - ) 3 - [2- (3 , 3 , 3 -trifluoropropyl ) -Befloxatone and moclobemide are most particularly preferred as a reversible monoamine oxidase A inhibitor, as is (-) 3 - [2- (3, 3, 3 -trifluoropropyl) -
3 , 4-dιhydro-2H-l-benzopyran-6-yl] -5 (J?) - méthoxyméthyloxazolιdm-2 -one .3, 4-dιhydro-2H-1-benzopyran-6-yl] -5 (J?) - methoxymethyloxazolιdm-2 -one.
La (S) -5 -méthoxyméthyl -3- [6- (4,4, 4 -trifluorobutoxy) -1,2- benzιsoxazol-3-yl] oxazolιdm-2-one est tout particulièrement préféré à titre d'inhibiteur de la monoamine oxydase B réversible.(S) -5 -methoxymethyl -3- [6- (4,4,4-trifluorobutoxy) -1,2- benzιsoxazol-3-yl] oxazolιdm-2-one is most particularly preferred as an inhibitor of reversible monoamine oxidase B.
La [3 ( S) , 3a ( S) ] -3-méthoxyméthyl-7- [4, 4 , 4 -trifluorobutoxy] -[3 (S), 3a (S)] -3-methoxymethyl-7- [4, 4, 4 -trifluorobutoxy] -
3 , 3a, 4 , 5-tétrahydro-lH-oxazolo [3 , 4-a] qumoléme-1-one est tout particulièrement préféré à titre d'inhibiteur de la monamme oxydase A,B mixte réversible, ainsi que la3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] qumoleme-1-one is very particularly preferred as an inhibitor of reversible mixed monamme oxidase A, B, as well as
(R) -5- (méthoxyméthyl) -3- [6- (4 , 4 , 4 -trifluorobutoxy) benzofuran-3 -yl] oxazolιdm-2-one et la (R) -5 -méthoxyméthyl -(R) -5- (methoxymethyl) -3- [6- (4, 4, 4 -trifluorobutoxy) benzofuran-3 -yl] oxazolιdm-2-one and (R) -5 -methoxymethyl -
3- (6-cyclopropylméthoxybenzofuran-3-yl) oxazolιdm-2-one .3- (6-cyclopropylmethoxybenzofuran-3-yl) oxazolιdm-2-one.
Parmi les différentes classes d' IMAO citées, on préférera, pour les compositions selon la présente invention, les IMAOAmong the various classes of MAOIs mentioned, the MAOIs will be preferred for the compositions according to the present invention
A et A,B mixtes réversibles.A and A, B reversible mixed.
Un autre objet de la présente invention consiste en une composition pharmaceutique comprenant de la nicotine ou ligand des récepteurs nicotiniques et un inhibiteur de la monoamine oxydase comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps destiné au sevrage tabagique.Another object of the present invention consists of a pharmaceutical composition comprising nicotine or nicotinic receptor ligand and a monoamine oxidase inhibitor as a combination product for simultaneous, separate or spread over time intended for smoking cessation.
On entend par "utilisation simultanée" l'administration des composés de la composition selon l'invention compris dans une seule et même forme pharmaceutique. On entend par "utilisation séparée" l'administration, en même temps, des deux composés de la composition selon l'invention chacun compris dans une forme pharmaceu ique distincte . On entend par "utilisation étalée dans le temps" l'administration successive, du premier composé de la composition selon l'invention, compris dans une forme pharmaceutique, puis, du deuxième composé de la composition selon l'invention, compris dans une forme pharmaceutique distincte.The term “simultaneous use” is understood to mean the administration of the compounds of the composition according to the invention included in one and the same pharmaceutical form. By "separate use" is meant the administration, at the same time, of the two compounds of the composition according to the invention each included in a separate pharmaceutical form. The term “use spread over time” is understood to mean the successive administration of the first compound of the composition according to the invention, included in a pharmaceutical form, then of the second compound of the composition according to the invention, included in a pharmaceutical form separate.
Dans le cas de cette "utilisation étalée dans le temps", le laps de temps écoulé entre l'administration du premier composé de la composition selon l'invention et l'administration du deuxième composé de la même composition selon l'invention n'excède généralement pas 24 heures.In the case of this "use spread over time", the period of time between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention does not exceed usually not 24 hours.
Les formes pharmaceutiques, comprenant soit un seul des composés constitutifs de la composition selon l'invention soit l'association des deux composés, qui peuvent être mises en oeuvre dans les différents types d'utilisations décrites ci -dessus, peuvent par exemple être appropriées à l'administration orale, nasale, parentérale ou transdermique .The pharmaceutical forms, comprising either only one of the constituent compounds of the composition according to the invention or the combination of the two compounds, which can be used in the different types of uses described above, can for example be suitable for oral, nasal, parenteral or transdermal administration.
Aussi, dans le cas d'une "utilisation séparée" et d'une "utilisation étalée dans le temps", les deux formes pharmaceutiques distinctes peuvent être destinées à la même voie d'administration ou à une voie d'administration différente (orale et transdermique ou orale et nasale ou parentérale et transdermique etc) .Also, in the case of a "separate use" and a "use spread over time", the two separate pharmaceutical forms can be intended for the same route of administration or for a different route of administration (oral and transdermal or oral and nasal or parenteral and transdermal etc).
Toutes ces formes pharmaceutiques font également partie de 1 ' invention.All these pharmaceutical forms are also part of the invention.
Parmi les formes pharmaceutiques adaptées à l'administration orale, on peut citer les comprimés, gélules, pilules et les gommes à mâcher à libération immédiate ou prolongée. Pour l'administration parentérale, les formes galéniques telles que suspensions ou solutions injectables conviennent .Among the pharmaceutical forms suitable for oral administration, mention may be made of tablets, capsules, pills and chewing gums with immediate or prolonged release. For parenteral administration, dosage forms such as suspensions or injectable solutions are suitable.
La composition selon l' invention peut alors être administrée en une dose journalière unique ou en doses journalières fractionnées. Dans ce dernier cas la composition peut être administrée en 2 à 3 prises par jour.The composition according to the invention can then be administered in a single daily dose or in divided daily doses. In the latter case, the composition can be administered in 2 to 3 doses per day.
Les timbres transdermiques ou patchs sont par exemple adaptés pour l'administration transdermique. Pour l'administration locale, des gels ou émulsions sont également adaptés.The transdermal patches or patches are for example suitable for transdermal administration. For local administration, gels or emulsions are also suitable.
On préfère particulièrement le patch ou timbre transdermique qui permet une administration lente et régulière pour l'un au moins des deux composés de l'association. L'autonomie du patient vis-à-vis de son traitement est ainsi favorisée.Particularly preferred is the transdermal patch or patch which allows slow and regular administration for at least one of the two compounds of the combination. The patient's autonomy vis-à-vis his treatment is thus favored.
Le patch permet d'obtenir une libération de la composition qui peut durer entre 8 et 72 heures.The patch makes it possible to obtain a release of the composition which can last between 8 and 72 hours.
Les compositions pharmaceutiques appropriées à être mises en oeuvre dans un patch ou timbre transdermique peuvent se présenter sous forme de gel, de pommade, de solution, de crème ou d'émulsion. Elles peuvent être préparées selon les procédés conventionnels pour l'homme du métier.The pharmaceutical compositions suitable for use in a patch or patch can be in the form of a gel, ointment, solution, cream or emulsion. They can be prepared according to conventional methods for those skilled in the art.
Les compositions peuvent encore être formulées sous forme de spray nasal, spray pulmonaire ou suppositoire.The compositions can also be formulated as a nasal spray, pulmonary spray or suppository.
De manière préférée l'un au moins des deux composants de l'association est administrée par voie transdermique, par exemple par patch ou timbre transdermique. On pourra par exemple administrer l'IMAO par voie orale et la nicotine ou le ligand des récepteurs nicotiniques par patch ou bien l'inverse ou bien l'IMAO et la nicotine ou le ligand des récepteurs nicotiniques tous les deux par patch ou timbre transdermique .Preferably, at least one of the two components of the combination is administered transdermally, for example by patch or transdermal patch. One could for example administer MAOI orally and nicotine or the nicotinic receptor ligand by patch or the reverse or else MAOI and nicotine or the nicotinic receptor ligand both by patch or transdermal patch.
Habituellement les compositions pharmaceutiques selon la présente invention sont dosées pour permettre une administration journalière de 2 à 20 mg de nicotine ou de ligand des récepteurs nicotiniques et de 1 à 20 mg d'inhibiteur de la monoamine oxydase.Usually the pharmaceutical compositions according to the The present invention is dosed to allow daily administration of 2 to 20 mg of nicotine or of nicotinic receptor ligand and from 1 to 20 mg of monoamine oxidase inhibitor.
Enfin, la présente invention a aussi pour objet l'utilisation de nicotine ou un ligand des récepteurs nicotiniques et d'un inhibiteur de la monoamine oxydase pour la fabrication d'un médicament destiné au sevrage tabagique.Finally, the present invention also relates to the use of nicotine or a ligand for nicotinic receptors and a monoamine oxidase inhibitor for the manufacture of a medicament intended for smoking cessation.
L'effet de l'association d'un inhibiteur de la monoamine oxydase à la nicotine sur la pression artérielle moyenne et sur la fréquence cardiaque a fait l'objet d'une étude qui a mis en évidence l'intérêt de cette association dans le sevrage tabagique.The effect of the association of a monoamine oxidase inhibitor with nicotine on average blood pressure and on heart rate was the subject of a study which highlighted the interest of this association in the smoking cessation.
MATERIEL ET METHODESMATERIAL AND METHODS
L'étude a été réalisée sur des rats mâles de souche Sprague-Dawley pesant de 277 à 345 g le jour du traitement.The study was carried out on male Sprague-Dawley rats weighing from 277 to 345 g on the day of treatment.
On met en suspension dans un véhicule (Tween 80 0,5% w/v, méthylcellulose 0,5% w/v dans l'eau pour préparation injectable) de la béfloxatone ou du moclobémide. On met en solution dans l'eau de la nicotine pour une préparation injectable.Befloxatone or moclobemide is suspended in a vehicle (Tween 80 0.5% w / v, methylcellulose 0.5% w / v in water for injection). Nicotine is dissolved in water for an injectable preparation.
Schéma expérimentalExperimental design
Les animaux ont subi, sous anesthésie générale par injection mtrapéπtonéale de kétamme (116 mg/kg ι.p.), un cathétéπsme de la carotide et de la veine jugulaire avec extériorisation des cathéters en région dorso-scapulaire . Le jour suivant l'implantation, les animaux ont été connectés à des appareils de mesure permettant l'enregistrement en continu de la pression artérielle et de la fréquence cardiaque. Après une période de stabilisation de 30 minutes environ, les animaux ont reçu le traitement par voie orale, puis 45 minutes plus tard, trois doses croissantes de nicotine, administrées par voie intraveineuse à 5 minutes d' intervalle .The animals underwent, under general anesthesia by mtrapéπtonéale injection of ketamme (116 mg / kg ι.p.), a cathétéπsme of the carotid and the jugular vein with exteriorization of the catheters in dorsoscapular region. The day after implantation, the animals were connected to measuring devices allowing the continuous recording of blood pressure and heart rate. After a stabilization period of approximately 30 minutes, the animals received the oral treatment, then 45 minutes later, three increasing doses of nicotine, administered intravenously at an interval of 5 minutes.
Les animaux ont ensuite été euthanasiés par injection mtra-cardiaque de Doléthal .The animals were then euthanized by mtra-cardiac injection of Doléthal.
TraitementTreatment
Deux groupes d'animaux ont été constitués (n=7/groupe) . L'un a été traité avec la béfloxatone à la dose de 1 mg/kg p.o., sous un volume de 5 ml/kg. L'autre groupe a reçu dans les mêmes conditions un volume équivalent de véhicule. D'autre part, deux autres groupes d'animaux ont été constitués (n=6/groupe) . L'un a été traité avec le moclobémide à la dose de 10 mg/kg p.o., soit un volume de 5 ml/kg. L'autre a reçu dans ces mêmes conditions un volume équivalent de véhicule. Chaque animal a reçu la nicotine aux doses de 30, 50 etTwo groups of animals were formed (n = 7 / group). One was treated with befloxatone at a dose of 1 mg / kg p.o., in a volume of 5 ml / kg. The other group received an equivalent volume of vehicle under the same conditions. On the other hand, two other groups of animals were formed (n = 6 / group). One was treated with moclobemide at a dose of 10 mg / kg p.o., i.e. a volume of 5 ml / kg. The other received under these same conditions an equivalent volume of vehicle. Each animal received nicotine at doses of 30, 50 and
100 μg/kg, successivement, sous forme de bolus intraveineux sur 30 secondes environ.100 μg / kg, successively, in the form of an intravenous bolus over approximately 30 seconds.
Paramètres mesurésMeasured parameters
La pression artérielle moyenne et la fréquence cardiaque ont été mesurées avant traitement, avant chaque administration de nicotine, ainsi qu'à l'acmé de l'effet de ces administrations.Average blood pressure and heart rate were measured before treatment, before each administration of nicotine, and at the peak of the effect of these administrations.
Expression des résultatsExpression of results
L'homogénéité des valeurs de base (pour la pression artérielle moyenne et la fréquence cardiaque) entre les groupes avant chaque administration (traitement ou nicotine) a été vérifiée par une analyse de vaπance à 2 facteurs (groupe x temps) avec mesures répétées sur le temps . Les valeurs obtenues avant traitement, avant la première injection de nicotine et à l'acmé de l'effet de chaque dose de nicotine ont été relevées et présentées sous forme de moyennes + ESM. Les groupes traités avec la béfloxatone et le moclobémide ont été comparés aux groupes témoins respectifs par une analyse de variance à 2 facteurs (groupe x dose de nicotine) avec mesures répétées sur la dose de nicotine, suivie d'un test de Dunnett à niveau fixé de dose de nicotine.The homogeneity of the basic values (for mean arterial pressure and heart rate) between the groups before each administration (treatment or nicotine) was verified by a 2-factor variance analysis (group x time) with repeated measurements on the time . The values obtained before treatment, before the first nicotine injection and at the peak of the effect of each dose of nicotine were noted and presented in the form of means + ESM. The groups treated with befloxatone and moclobemide were compared to the respective control groups by a 2-factor analysis of variance (group x nicotine dose) with repeated measurements on the nicotine dose, followed by a Dunnett test at fixed level nicotine dose.
RESULTATS ET CONCLUSIONSRESULTS AND CONCLUSIONS
Dans ces conditions expérimentales, la nicotine provoque chez les animaux témoins une élévation de la pression artérielle moyenne et une légère augmentation de la fréquence cardiaque.Under these experimental conditions, nicotine causes an increase in average blood pressure in the control animals and a slight increase in heart rate.
La béfloxatone à 1 mg/kg p.o. et le moclobémide à 10 mg/kg p.o. réduisent les augmentations de pression artérielle et de fréquence cardiaque induites, entre 45 min et 60 min après le traitement, par des administrations intraveineuses de nicotine. (TAB.l à 4). Befloxatone 1 mg / kg po and moclobemide 10 mg / kg po reduce the increases in blood pressure and heart rate induced, between 45 min and 60 min after treatment, by intravenous administration of nicotine. (TAB.l to 4).
TAB.l : Pression artérielle moyenne (mm Hg) , rat vigileTAB.l: Average blood pressure (mm Hg), awake rat
Figure imgf000017_0001
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0002
TAB .3 : Pression artérielle moyenne (mm Hg) , rat vigileTAB .3: Average blood pressure (mm Hg), awake rat
Figure imgf000017_0003
Figure imgf000017_0003
Figure imgf000018_0002
moyenne ± ESM
Figure imgf000018_0002
mean ± ESM
NS : non significativement différent du groupe véhicule (P>0,05, test de Dunnett après analyse de variance à deux facteurs avec mesures répétées)NS: not significantly different from the vehicle group (P> 0.05, Dunnett test after two-factor analysis of variance with repeated measurements)
* : significativement différent du groupe véhicule (P<0,05, test de Dunnett après analyse de variance à 2 facteurs avec mesures répétées)*: significantly different from the vehicle group (P <0.05, Dunnett test after 2-factor analysis of variance with repeated measurements)
** : significativement différent du groupe véhicule (P<0,01, test de Dunnett après analyse de variance à 2 facteurs avec mesures répétées)**: significantly different from the vehicle group (P <0.01, Dunnett test after 2-factor analysis of variance with repeated measurements)
*** : significativement différent du groupe véhicule (P<0,001, test de Dunnett après analys de variance à 2 facteurs avec mesures répétées)***: significantly different from the vehicle group (P <0.001, Dunnett test after 2-factor analysis of variance with repeated measurements)
Figure imgf000018_0001
Figure imgf000018_0001
EXEMPLES DE COMPOSITIONS PHARMACEUTIQUESEXAMPLES OF PHARMACEUTICAL COMPOSITIONS
Exemple 1 : comprimé contenant de la béfloxatone et patch transdermique contenant de la nicotineEXAMPLE 1 Tablet Containing Befloxatone and Transdermal Patch Containing Nicotine
On fabrique des comprimés contenant 10 mg de béfloxatone selon la composition suivanteTablets containing 10 mg of befloxatone are manufactured according to the following composition
béfloxatone 5,0 %befloxatone 5.0%
10 lactose 150 mesh 66,0 % cellulose microcristalline 20,0 % povidone 4,0 % crospovidone 4,0 % stéarate de magnésium 1,0 %
Figure imgf000019_0002
Figure imgf000019_0001
10 lactose 150 mesh 66.0% microcrystalline cellulose 20.0% povidone 4.0% crospovidone 4.0% magnesium stearate 1.0%
Figure imgf000019_0002
Figure imgf000019_0001
Les cinq premiers composants sont mél
Figure imgf000019_0003
gés, granulés avec de l'eau, séchés et calibrés. Les granulés sont ensuite mélangés au stéarate de magnésium et compressés pour former des comprimés de 200 mg en masse, à l'aide d'une presse rotative.The first five components are mel
Figure imgf000019_0003
aged, granulated with water, dried and graded. The granules are then mixed with the magnesium stearate and compressed to form tablets of 200 mg by mass, using a rotary press.
On prépare un patch transdermique d'une surface de 20 cm2 capable de libérer 14 mg en 24 heures selon la composition suivante :A transdermal patch with an area of 20 cm 2 capable of delivering 14 mg in 24 hours is prepared according to the following composition:
Couche matricielle :Matrix layer:
- S (-) nicotine 35 mg- S (-) nicotine 35 mg
- polymère acrylique Duro-Tak 387-2353 - acrylic polymer Duro-Tak 387-2353
Les granulés sont préparés par granulation humide selon les compositions suivantes :The granules are prepared by wet granulation according to the following compositions:
GRANULE 1GRANULE 1
5 béfloxatone 5 % lactose 150 mesh 66 % cellulose microcπstallme 20 % povidone 4 % crospovidone 4 %5 befloxatone 5% lactose 150 mesh 66% cellulose microcπstallme 20% povidone 4% crospovidone 4%
10 stéarate de magnésium 1 %10 magnesium stearate 1%
GRANULE 2 nicotine polacrylix qsp 5% nicotine lactose 150 mesh qsp 100 %GRANULE 2 nicotine polacrylix qs 5% nicotine lactose 150 mesh qs 100%
15 cellulose microcristallme 20 % povidone 4 % hydroxypropylméthylcellulose 25 % stéarate de magnésium 1 %15 microcrystalline cellulose 20% povidone 4% hydroxypropyl methylcellulose 25% magnesium stearate 1%
Les cinq premiers composants de chaque granulé sont mélangés, granulés avec de l'eau, puis les granulés obtenus sont séchés et calibrés. Le stéarate de magnésium est ensuite ajouté et mélangé. Des comprimés bicouches sont préparés par compression en utilisant une presseThe first five components of each granule are mixed, granulated with water, then the granules obtained are dried and calibrated. The magnesium stearate is then added and mixed. Bilayer tablets are prepared by compression using a press
Manesty BL . Chaque couche contient 100 mg de granulé si bien que chaque comprimé contient 5 mg de béfloxatone et 5 mg de nicotine.Manesty BL. Each layer contains 100 mg of granules so that each tablet contains 5 mg of befloxatone and 5 mg of nicotine.
Exemple 3 : Capsule contenant de la béfloxatone et spray nasal contenant de la nicotineExample 3 Capsule Containing Befloxatone and Nasal Spray Containing Nicotine
Les comprimés contenant 10 mg de béfloxatone sont préparés selon la composition suivante :The tablets containing 10 mg of befloxatone are prepared according to the following composition:
béfloxatone 6,25 lactose 150 mesh 84,15 povidone 4,00 crospovidone 5,00befloxatone 6.25 lactose 150 mesh 84.15 povidone 4.00 crospovidone 5.00
40 stéarate de magnésium 0,50 silice colloïdale 0,10 Les cinq premiers composants de chaque granulé sont mélangés, granulés avec de l'eau, séchés et calibrés. Les granulés sont ensuite mélangés avec le stéarate de magnésium et la silice colloïdale puis on remplit des capsules en gélatine de taille 2 de 160 mg des granulés ainsi préparés.40 magnesium stearate 0.50 colloidal silica 0.10 The first five components of each pellet are mixed, pelletized with water, dried and graded. The granules are then mixed with magnesium stearate and colloidal silica and then gelatin capsules of size 2 of 160 mg of the granules thus prepared are filled.
On prépare une solution pour administration nasale contenant 50 mg de nicotine, 900 mg de chlorure de sodium, 10 mg de chlorure de benzalkonium, 100 mg de EDTA sodium et 100 mg d'eau stérilisée. Cette solution est filtrée et distribuée dans des ampoules. A solution for nasal administration containing 50 mg of nicotine, 900 mg of sodium chloride, 10 mg of benzalkonium chloride, 100 mg of EDTA sodium and 100 mg of sterilized water is prepared. This solution is filtered and distributed in ampoules.

Claims

Revendications claims
1. Composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotiniques et un inhibiteur de la monoamine oxydase comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps destiné au sevrage tabagique.1. Pharmaceutical composition comprising nicotine or a nicotinic receptor ligand and a monoamine oxidase inhibitor as a combination product for simultaneous, separate or spread over time intended for smoking cessation.
2. Composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotiniques et un inhibiteur de la monoamine oxydase A ou A,B mixte réversible comme produit de combinaison pour une utilisation simultanée, séparée ou étalée dans le temps destinée au sevrage tabagique .2. Pharmaceutical composition comprising nicotine or a nicotinic receptor ligand and a reversible mixed monoamine oxidase A or A, B inhibitor as a combination product for simultaneous, separate or spread over time intended for smoking cessation.
3. Composition pharmaceutique selon l'un quelconque des revendications 1 ou 2, caractérisée en ce que l'inhibiteur de la monoamine oxydase est choisi dans le groupe constitué par : - parmi les IMAO de type A : la béfloxatone, le moclobémide, la brofaromine, la phénoxathine, l'esuprone, le befol, le RS 8359 (Sankyo), le T794 (Tanabé), le KP 9 (Krenitsky, USA) , le E 2011 (Eisei) , la toloxatone, le pirlindole, l' amiflamine, la sercloremine, la bazinaprine, la (-) 3- [2- ( 3, 3, 3-trifluoropropyl) -3, 4-dihydro-2H-l- benzopyran-β-yl] -5 ( R) -méthoxyméthyloxazolidin-2-one, la 3- (2-propylbenzofuran-5-yl) -5 (R) -méthoxyméthyloxazolidin- 2-one et la 3- [2- (3, 3, 3-trifluoropropyl) -2 , 3- dihydrobenzofuran-5-yl] -5 ( R) -méthoxyméthyloxazolidin-2-one, - parmi les IMAO de type B : le lazabemide, le milacémide, la caroxazone, l'IFO, le L-deprényl, la mofégiline, la rasagéline, la pargyline, la (S) -5-méthoxyméthyl-3- [6- (4,4, 4-trifluorobutoxy) -1,2- benzisoxazol-3-yl] oxazolidin-2-one et la 5- [4- (4,4,4- trifluorobutoxy) phényl] -3- (2-méthoxyéthyl) -1,3, 4-oxadiazol- 2 (3H) -one,3. Pharmaceutical composition according to any one of claims 1 or 2, characterized in that the monoamine oxidase inhibitor is chosen from the group consisting of: - from MAOIs of type A: befloxatone, moclobemide, brofaromine , phenoxathine, esuprone, befol, RS 8359 (Sankyo), T794 (Tanabé), KP 9 (Krenitsky, USA), E 2011 (Eisei), toloxatone, pirlindole, amiflamine, sercloremine, bazinaprine, (-) 3- [2- (3, 3, 3-trifluoropropyl) -3, 4-dihydro-2H-1- benzopyran-β-yl] -5 (R) -methoxymethyloxazolidin-2 -one, 3- (2-propylbenzofuran-5-yl) -5 (R) -methoxymethyloxazolidin- 2-one and 3- [2- (3, 3, 3-trifluoropropyl) -2, 3- dihydrobenzofuran-5 -yl] -5 (R) -methoxymethyloxazolidin-2-one, - among MAOIs type B: lazabemide, milacemide, caroxazone, IFO, L-deprenyl, mofegiline, rasageline, pargyline, (S) -5-methoxymethyl-3- [6- (4,4,4-trifluorobutoxy) -1,2- benzisoxazol-3-yl ] oxazolidin-2-one and 5- [4- (4,4,4,4-trifluorobutoxy) phenyl] -3- (2-methoxyethyl) -1,3,4-oxadiazol- 2 (3H) -one,
- parmi les IMAO de type A,B mixte : la [3 ( S) , 3a (S) ] -3- méthoxyméthyl-7- (4,4, -trifluoro-3 ( R) -hydroxybutoxy) - 3, 3a, 4, 5-tétrahydro-lH-oxazolo [3, 4-a] quinoléin-1-one, la [3 (S) , 3a ( S) ] 3-méthoxyméthyl-7-[4, 4, -trifluorobutoxy] - 3, 3a, 4, 5-tétrahydro-lH-oxazolo[3, -a]quinoléine-l-one, la ( R) -5- (méthoxyméthyl) -3- [6- (4, 4, 4-triflurobutoxy) benzofuran-3-yl ] oxazolidin-2-one, le ( R) -5-méthoxyméthyl-3- ( β-cyclopropylméthoxybenzofuran-3-yl) oxazolidin-2-one, la 3- [2- (3, 3, 3-trifluoropropyl) benzofuran-5-yl] -5 (S) - méthoxyméthyloxazolidin-2-one et la- among mixed MAOIs of type A, B: [3 (S), 3a (S)] -3- methoxymethyl-7- (4,4, -trifluoro-3 (R) -hydroxybutoxy) - 3, 3a, 4,5-tetrahydro-1H-oxazolo [3, 4-a] quinoline-1-one, the [3 (S), 3a (S)] 3-methoxymethyl-7- [4, 4, -trifluorobutoxy] - 3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, -a] quinoline-1-one , (R) -5- (methoxymethyl) -3- [6- (4, 4, 4-triflurobutoxy) benzofuran-3-yl] oxazolidin-2-one, (R) -5-methoxymethyl-3- ( β-cyclopropylmethoxybenzofuran-3-yl) oxazolidin-2-one, 3- [2- (3, 3, 3-trifluoropropyl) benzofuran-5-yl] -5 (S) - methoxymethyloxazolidin-2-one and
3- (2-phénylbenzofuran-5-yl) -5 (S) -méthoxyméthyloxazolidin- 2-one .3- (2-phenylbenzofuran-5-yl) -5 (S) -methoxymethyloxazolidin- 2-one.
4. Composition pharmaceutique selon l'une quelconque des revendications 1 à 3, caractérisée en ce qu'elle est destinée à l'administration par voie orale, nasale, parentérale, transdermique ou mixte.4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it is intended for administration by oral, nasal, parenteral, transdermal or mixed route.
5. Composition pharmaceutique selon la revendication 4, caractérisée en ce que l'un au moins ou bien de l'inhibiteur de la monoamine oxydase ou bien de la nicotine ou un récepteur des ligands nicotiniques est destinée à l'administration transdermique.5. Pharmaceutical composition according to claim 4, characterized in that at least one or else of the monoamine oxidase inhibitor or else of nicotine or a receptor for nicotinic ligands is intended for transdermal administration.
6. Composition pharamceutique selon la revendication 5, caractérisée en ce que l'administration transdermique est réalisée par patch ou timbre transdermique.6. pharamceutical composition according to claim 5, characterized in that the transdermal administration is carried out by patch or transdermal patch.
7. Composition pharmaceutique selon l'une quelconque des revendications 1 à 6, caractérisée en ce que le lignand des récepteurs nicotiniques est choisi parmi les agonistes des récepteurs nicotiniques suivants : la cytisine, la lobéline, l'ABT-418, l' épibatidine, le GTS-21, le7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the nicotinic receptor lignand is chosen from the following nicotinic receptor agonists: cytisine, lobelin, ABT-418, epibatidine, the GTS-21, the
AR-R17779, le ABT-594, le ABT-089, mais aussi les agonistes ou antagonistes nicotiniques suivants : le AN-072, l'eperisone, le bromure de rapacuronium, l'altinicline, le conantokin-G, le GW-280430, le RJR-2403, la galantamine, le SIB 1553 A, le A-85380, la métanicotine, le RJR-2531, le RJR-2557, le DBO-83, laAR-R17779, ABT-594, ABT-089, but also the following nicotinic agonists or antagonists: AN-072, eperisone, rapacuronium bromide, altinicline, conantokin-G, GW-280430 , RJR-2403, galantamine, SIB 1553 A, A-85380, metanicotine, RJR-2531, RJR-2557, DBO-83,
9-bromo-l, 2,3,4,5, 6-hexahydro-8H-l, 5-méthanopyrido [1, 2-a] [1, 5] diazocin-8-one, la 11-fluoro-1, 2, 3, , 5, 6-hexahydro- 8H-1, 5-méthanopyrido [1, 2-a] [1, 5] diazocin-8-one, la 9-phényl-l, 2, 3, 4, 5, 6-hexahydro-8H-l, 5- méthanopyrido [ 1 , 2-a] [ 1 , 5 ] diazocin-8-one, la 9-benzyl-l, 2,3,4,5, 6-hexahydro-8H-l, 5-méthanopyrido [1, 2-a] [1 , 5] diazocin-8-one, la 9-acétyl-l, 2, 3, , 5, 6- hexahydro-8H-l, 5-méthanopyrido [1, 2-a] [ 1, 5] diazocin-8-one, la 9- (2-pyridyl) -1,2,3,4,5, 6-hexahydro-8H-l, 5- méthanopyrido [ 1, 2-a] [1,5] diazocin-8-one, 9- (2, 4-difluorophényl)-l,2,3, 4,5, 6-hexahydro-8H-l, 5- méthanopyrido [ 1, 2-a] [ 1, 5] diazocin-8-one, la 9- (2-thiazolyl)-l,2, 3,4,5, 6-hexahydro-8H-l, 5- méthanopyrido [1, 2-a] [1,5] diazocin-8-one, l' endo-6- (3-pyridyl) -2-azabicyclo [2.2.2] octane, l' endo-β- (5-pyrimidinyl) -2-azabicyclo [2.2.2] octane, le 6- (5-bromo-3-pyridyl) -2-azabicyclo [2.2.2] oct-5-ène, le 6- (5-éthynyl-3-pyridyl) -2-azabicyclo [2.2.2] octane, le9-bromo-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido [1,2-a] [1,5] diazocin-8-one, 11-fluoro-1, 2, 3,, 5, 6-hexahydro- 8H-1, 5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one, the 9-phenyl-1,2,3,4,5,5,6-hexahydro-8H-1,5-methanopyrido [1,2-a] [1,5] diazocin-8-one, 9-benzyl-l, 2,3,4,5,6-hexahydro-8H-1,5-methanopyrido [1,2-a] [1,5] diazocin-8-one, 9-acetyl-1,2,3,5,5 , 6-hexahydro-8H-1,5-methanopyrido [1,2-a] [1,5] diazocin-8-one, la 9- (2-pyridyl) -1,2,3,4,5,6 -hexahydro-8H-l, 5-methanopyrido [1, 2-a] [1,5] diazocin-8-one, 9- (2, 4-difluorophenyl) -l, 2,3, 4,5, 6- hexahydro-8H-1,5-methanopyrido [1, 2-a] [1, 5] diazocin-8-one, la 9- (2-thiazolyl) -l, 2, 3,4,5, 6-hexahydro- 8H-1,5-methanopyrido [1, 2-a] [1,5] diazocin-8-one, endo-6- (3-pyridyl) -2-azabicyclo [2.2.2] octane, endo -β- (5-pyrimidinyl) -2-azabicyclo [2.2.2] octane, 6- (5-bromo-3-pyridyl) -2-azabicyclo [2.2.2] oct-5-ene, 6- ( 5-ethynyl-3-pyridyl) -2-azabicyclo [2.2.2] octane, the
(±) -8-méthyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene, le (±) -8- (benzyl) -3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ène, le (±) -3- (6-chloro-3-pyridinyl) -8-méthyl-8- azabicyclo [3.2.1] oct-2-ene, le (±) -3- (8-méthyl-8- azabicyclo [3.2.1] oct-2-en-3-yl) aniline, la spiro [1, 3-benzodioxole-2, 3 ' -quinuclidine] , la 5-méthylspiro [1, 3-benzodioxole-2, 3 ' -quinuclidine] , la 5-tert-butylspiro [1, 3-benzodioxole-2, 3 ' -quinuclidine] , la (±) -3- (5-méthoxy-3-pyridinyl) -9-azabicyclo [3.3.1] non-2-ène, la (±) -3- (5-méthoxy-3-pyridinyl) -9-méthyl-9- azabicyclo [3.3.1] non-2-ène, la (±) -3- ( 9-méthyl-9- azabicyclo [3.3.1] non-2-èn-3-yl) phénylamine, le (±) -3- (3-pyridinyl) -9-azabicyclo [3.3.1] non-2-ène, la (±) -9-méthyl-3- (3-pyridinyl) -9-azabicyclo [3.3.1] non-2-ène, le spiro[l-azabicyclo[2.2.2]octane-3-2' (3'H)- furo [2, 3-b] pyridine] 7 ' -oxide, la 1- ( β-chloro-5- méthoxypyridin-3-yl) perhydro-1, 4-diazépine, la 1- (5-méthoxypyridine-3-yl) perhydro-1, 4-diazépine, la 1- (5-méthoxypyridin-3-yl) perhydro-1, 5-diazocine, la 3- (perhydro-1, 4-diazépin-l-yl) quinoline, la(±) -8-methyl-3- (3-pyridyl) -8-azabicyclo [3.2.1] oct-2-ene, le (±) -8- (benzyl) -3- (3-pyridyl) -8 -azabicyclo [3.2.1] oct-2-ene, le (±) -3- (6-chloro-3-pyridinyl) -8-methyl-8- azabicyclo [3.2.1] oct-2-ene, le ( ±) -3- (8-methyl-8- azabicyclo [3.2.1] oct-2-en-3-yl) aniline, spiro [1, 3-benzodioxole-2, 3 '-quinuclidine], 5- methylspiro [1, 3-benzodioxole-2, 3 '-quinuclidine], 5-tert-butylspiro [1, 3-benzodioxole-2, 3' -quinuclidine], (±) -3- (5-methoxy-3 -pyridinyl) -9-azabicyclo [3.3.1] non-2-ene, la (±) -3- (5-methoxy-3-pyridinyl) -9-methyl-9-azabicyclo [3.3.1] non-2 -ene, (±) -3- (9-methyl-9- azabicyclo [3.3.1] non-2-en-3-yl) phenylamine, (±) -3- (3-pyridinyl) -9- azabicyclo [3.3.1] non-2-ene, la (±) -9-methyl-3- (3-pyridinyl) -9-azabicyclo [3.3.1] non-2-ene, spiro [l-azabicyclo [ 2.2.2] octane-3-2 '(3'H) - furo [2, 3-b] pyridine] 7' -oxide, la 1- (β-chloro-5-methoxypyridin-3-yl) perhydro-1 , 4-diazepine, 1- (5-methoxypyridine-3-y l) perhydro-1, 4-diazepine, 1- (5-methoxypyridin-3-yl) perhydro-1, 5-diazocine, 3- (perhydro-1, 4-diazepin-l-yl) quinoline,
1- (β-bromopyridin-3-yl) perhydro-1, -diazépine, la 1- (5-propoxypyridin-3-yl) perhydro-1, -diazépine, la 4- (3-pyridinyloxy) perhydroazépine, la 2-méthyl-1, 2,3,5,6,7,8, 9-octahydro-5, 9-méthanopyrrolo [3,4-h] [3] benzazépine-1, 3-dione, la1- (β-bromopyridin-3-yl) perhydro-1, -diazepine, 1- (5-propoxypyridin-3-yl) perhydro-1, -diazepine, 4- (3-pyridinyloxy) perhydroazepine methyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanopyrrolo [3,4-h] [3] benzazepine-1, 3-dione, the
1, 3-diméthyl-l, 2,3,5,6,7,8, 9-octahydro-5, 9-méthanoimidazo1,3-dimethyl-1,2,3,5,6,7,8,9-octahydro-5,9-methanoimidazo
[4 , 5-h] [ 3] benzazépin-2-one, la[4, 5-h] [3] benzazepin-2-one, the
1,2,3,5,6,7,8, 9-octahydro-5, 9-méthanopyrrolo [3,4-h] [3] benzazépine-1, 3-dione, la 7 , 8-difluoro-2, 3, 4 , 5- tétrahydro-lH-1, 5-méthano-3-benzazépine, le1,2,3,5,6,7,8, 9-octahydro-5, 9-methanopyrrolo [3,4-h] [3] benzazepine-1, 3-dione, la 7, 8-difluoro-2, 3, 4, 5-tetrahydro-1H-1, 5-methano-3-benzazepine, the
8-éthynyl-2, 3, , 5-tétrahydro-lH-l, 5-méthano-3-benzazépme-78-ethynyl-2,3,5,5-tetrahydro-1H-1,5-methano-3-benzazepme-7
-carbonitrile, la 7-chloro-8- (trifluorométhyl) --carbonitrile, 7-chloro-8- (trifluoromethyl) -
2,3,4, 5-tétrahydro-lH-l, 5-méthano-3-benzazépme, le 8- (trifluorométhyl) -2,3,4, 5-tétrahydro-lH-l, 5- méthano-3-benzazépine-7-carbonitrile, les composés2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepme, 8- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-1,5-methano-3-benzazepine -7-carbonitrile, the compounds
{ R, R) f { S, S) , ( R, S) et ( S, R) de la 2-pyrrolidin-2-yl-2 , 3- dihydrofuro [3, 2-b] pyridine et de la 6-pyrrolidin-2-yl-6, 7-dihydro-5fl-2-pyrindine ainsi que{R, R) f {S, S), (R, S) and (S, R) of 2-pyrrolidin-2-yl-2, 3-dihydrofuro [3, 2-b] pyridine and 6 -pyrrolidin-2-yl-6, 7-dihydro-5fl-2-pyrindine as well as
- les composés répondant à la formule générale (I)- the compounds corresponding to the general formula (I)
Figure imgf000025_0001
dans laquelle l'un des symboles X, Y et Z représente un atome d'azote, un autre représente un groupe de formule C-R3 et le troisième représente un atome d'azote ou un groupe de formule C-R4, R3 et R4 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (C1-C6) alkyle ou (Cj-C6) alcoxy,
Figure imgf000025_0001
in which one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula CR 3 and the third represents a nitrogen atom or a group of formula CR 4 , R 3 and R 4 each represents, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) alkoxy group,
Rx et R2 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (C^Cg) alkyle, (C1-C6)- alcoxy, ou phényle éventuellement substitué par un ou deux atomes d'halogènes, par un ou deux groupes trifluorométhyle, par un groupe cyano, par un groupe nitro, par un groupe hydroxy, par un groupe (C^Cg) alkyle, par un ou deux groupes (Cj-Cg) alcoxy, par un groupe méthylènedioxy, par un groupe acétyle, par un groupe trifluorométhoxy ou par un groupe methylthio,R x and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C ^ Cg) alkyl, (C 1 -C 6 ) - alkoxy, or phenyl optionally substituted by one or two halogen atoms, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a (C ^ Cg) alkyl group, by one or two (Cj-Cg) alkoxy groups, a methylenedioxy group, an acetyl group, a trifluoromethoxy group or a methylthio group,
R représente un atome d' hydrogène ou un groupe (Ci-Cg) alkyle, étant toutefois exclus les composés de formule générale (i; dans laquelle X représente un groupe de formule CH, Y et Z représentent chacun un atome d'azote, et Rx ou R2 ne représente pas un groupe phényle éventuellement substitué, - et les composés répondant à la formule générale (I)R represents a hydrogen atom or a (Ci-Cg) alkyl group, being however excluded the compounds of general formula (i; in which X represents a group of formula CH, Y and Z each represent a nitrogen atom, and R x or R 2 does not represent an optionally substituted phenyl group, - and the compounds corresponding to the general formula (I)
dans laquelle
Figure imgf000026_0001
l'un des symboles X, Y et Z représente un atome d'azote, un autre représente un groupe de formule C-R3 et le troisième représente un atome d'azote ou un groupe de formule C-R4, R3 et R4 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (C^Cg) alkyle ou (C^Cg) alcoxy, Rx et R2 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, cyano, hydroxy, (Ci-Cg) alkyle, (C1-C6)al- coxy, ou phényle éventuellement substitué par un atome d'halogène, par un ou deux groupes trifluorométhyle, par un groupe cyano, par un groupe nitro, par un groupe hydroxy, par un groupe (Ci-Cg) alkyle, par un groupe (Ci-Cg) alcoxy, par un groupe acétyle, par un groupe méthylènedioxy, par un groupe trifluorométhoxy, par un groupe methylthio ou par un groupe phényle.in which
Figure imgf000026_0001
one of the symbols X, Y and Z represents a nitrogen atom, another represents a group of formula CR 3 and the third represents a nitrogen atom or a group of formula CR 4 , R 3 and R 4 each represent independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (C ^ Cg) alkyl or (C ^ Cg) alkoxy group, R x and R 2 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, cyano, hydroxy, (Ci-Cg) alkyl, (C 1 -C 6 ) alkyl, or phenyl group optionally substituted by a halogen atom, by one or two trifluoromethyl groups, by a cyano group, by a nitro group, by a hydroxy group, by a (Ci-Cg) alkyl group, by a (Ci-Cg) alkoxy group, by a acetyl group, by a methylenedioxy group, by a trifluoromethoxy group, by a methylthio group or by a phenyl group.
8. Composition pharmaceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la monoamine oxydase est la béfloxatone.8. Pharmaceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is befloxatone.
9. Composition pharmaceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la monoamine oxydase est le moclobémide. 9. Pharmaceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is moclobemide.
10. Composition pharmaceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la monoamine oxydase est la (S) -5-méthoxyméthyl-3- [6- (4, 4, 4-trifluorobutoxy) -10. Pharmaceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is (S) -5-methoxymethyl-3- [6- (4, 4, 4-trifluorobutoxy) -
1, 2-benzisoxazol-3-yl] oxazolidin-2-one .1, 2-benzisoxazol-3-yl] oxazolidin-2-one.
11. Composition pharmaceutique selon la revendication 4, carctérisée en ce que l'inhibiteur de la monoamine oxydase est la [3 (S) ,3 (S) ] -3-méthoxyméthyl-7- [4 , 4 , 4- trifluorobutoxy] -3, 3a, 4, 5-tétrahydro-lH-oxazolo [3, 4-a] quinoléine-1-one.11. Pharmaceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is [3 (S), 3 (S)] -3-methoxymethyl-7- [4, 4, 4-trifluorobutoxy] - 3, 3a, 4, 5-tetrahydro-1H-oxazolo [3, 4-a] quinoline-1-one.
12. Composition pharamceutique selon la revendication 4, caractérisée en ce que l'inhibiteur de la monoamine oxydase est la [3 (S) , 3a (S) ] -3-méthoxyméthyl-7- (4,4, 4-trifluoro-3 ( R) -hydroxybutoxy) -3, 3a, 4 , 5-tétrahydro- lf-oxazolo [3, 4-a] quinoléin-1-one .12. pharamceutical composition according to claim 4, characterized in that the monoamine oxidase inhibitor is [3 (S), 3a (S)] -3-methoxymethyl-7- (4,4, 4-trifluoro-3 (R) -hydroxybutoxy) -3, 3a, 4, 5-tetrahydro-lf-oxazolo [3, 4-a] quinoline-1-one.
13. Composition pharmaceutique comprenant de la nicotine ou un ligand des récepteurs nicotiniques et un inhibiteur de la monoamine oxydase.13. Pharmaceutical composition comprising nicotine or a nicotinic receptor ligand and a monoamine oxidase inhibitor.
14. Composition pharmaceutique selon la revendication 13, caractérisée en ce que l'inhibiteur de la monoamine oxydase est de type A ou A,B mixte réversible.14. Pharmaceutical composition according to claim 13, characterized in that the monoamine oxidase inhibitor is of type A or A, B reversible mixed.
15. Composition pharmaceutique selon l'une quelconque des revendications 1 à 14, pour une utilisation simultanée dans le temps, caractérisée en ce qu'elle se présente selon l'une des formes pharmaceutiques suivantes : comprimé, pilules, gélule, gomme à mâcher à libération immédiate ou prolongée, timbre transdermique ou patch, spray nasal ou pulmonaire, solution ou suspension injectable ou bien suppositoire.15. Pharmaceutical composition according to any one of claims 1 to 14, for simultaneous use over time, characterized in that it is in one of the following pharmaceutical forms: tablet, pills, capsule, chewing gum immediate or prolonged release, transdermal patch or patch, nasal or pulmonary spray, solution or suspension for injection or suppository.
16. Utilisation d'une association de nicotine ou un ligand des récepteurs nicotiniques et d'un inhibiteur de la monoamine oxydase pour la fabrication d'un médicament destiné au sevrage tabagique. 16. Use of a combination of nicotine or a ligand for nicotinic receptors and a monoamine oxidase inhibitor for the manufacture of a drug intended for smoking cessation.
PCT/FR2000/000193 1999-02-02 2000-01-28 Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms WO2000045846A1 (en)

Priority Applications (4)

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CA002361437A CA2361437A1 (en) 1999-02-02 2000-01-28 Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms
AU22988/00A AU2298800A (en) 1999-02-02 2000-01-28 Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawalsymptoms
JP2000596965A JP2002536342A (en) 1999-02-02 2000-01-28 Pharmaceutical compositions comprising nicotine or a nicotine receptor ligand and a monoamine oxidase inhibitor, and their use for treating tobacco withdrawal symptoms
EP00901660A EP1150715A1 (en) 1999-02-02 2000-01-28 Pharmaceutical compositions containing nicotine or a ligand of nicotine receptors and a monamine oxydase inhibitor and their use for treating tobacco withdrawal symptoms

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FR9901144A FR2788982B1 (en) 1999-02-02 1999-02-02 PHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE AND THEIR APPLICATION IN SMOKING WITHDRAWAL
FR99/01144 1999-02-02

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JP2002536342A (en) 2002-10-29
CA2361437A1 (en) 2000-08-10
AU2298800A (en) 2000-08-25
EP1150715A1 (en) 2001-11-07

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