EP0954311A1 - Use of 1- 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1yl]-2-(6,7-dimethoxynapht-2-yl) ethane for preparing medicines for the treatment of cerebral and neuronal disorders - Google Patents

Use of 1- 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1yl]-2-(6,7-dimethoxynapht-2-yl) ethane for preparing medicines for the treatment of cerebral and neuronal disorders

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Publication number
EP0954311A1
EP0954311A1 EP97902426A EP97902426A EP0954311A1 EP 0954311 A1 EP0954311 A1 EP 0954311A1 EP 97902426 A EP97902426 A EP 97902426A EP 97902426 A EP97902426 A EP 97902426A EP 0954311 A1 EP0954311 A1 EP 0954311A1
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EP
European Patent Office
Prior art keywords
treatment
disorders
dementia
cerebral
trifluoromethylphenyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP97902426A
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German (de)
French (fr)
Inventor
Tiziano Croci
Jacqueline Fournier
Umberto Guzzi
Costantino Palmieri
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Sanofi Aventis France
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Sanofi Synthelabo SA
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Publication date
Application filed by Sanofi Synthelabo SA filed Critical Sanofi Synthelabo SA
Publication of EP0954311A1 publication Critical patent/EP0954311A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of l- [4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyrid-1-yl] -2- (6,7-dimethoxynapht-2-yl) ethane (I ) for the preparation of drugs intended for the treatment and / or prophylaxis of cerebral and neuronal diseases.
  • EP 0 458 696 describes the use of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine for the preparation of medicaments intended for the treatment of neurodegeneration.
  • the compound of formula (I) and its pharmaceutically acceptable salts have the capacity to increase the survival of neurons.
  • the present invention therefore relates to the use of l- [4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyrid-1-yl] -2- (6,7-dimethoxynapht-2-yl) ethane, of formula (I)
  • pharmaceutically acceptable salts of the compound of formula (I) mention may be made of those formed with pharmaceutically acceptable acids, for example, those with mineral acids, such as the hydrochloride, hydrobromide, borate, phosphate, sulphate, hydrogen sulfate, hydrogen phosphate and those with organic acids, such as citrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, the succinate, acetate, tartrate, mesylate, tosylate, isethionate, ⁇ -ketoglutarate, ⁇ -glycerophosphate, glucose-1-phosphate.
  • mineral acids such as the hydrochloride, hydrobromide, borate, phosphate, sulphate, hydrogen sulfate, hydrogen phosphate
  • organic acids such as citrate, benzoate, ascorbate, methyl sulfate, naphthal
  • the septal region was removed from embryos of 17-18 day old rats under a dissecting microscope under sterile conditions, then it was dissociated in a trypsin-ethylenediaminotetraacetic acid (EDTA) medium.
  • EDTA trypsin-ethylenediaminotetraacetic acid
  • neuroblasts are then seeded in the wells of a titration plate at the rate of 17x10 cells / cm ⁇ , in a non-serum culture medium consisting of
  • test compounds are dissolved in dimethylsulfoxide (DMSO) and diluted as required by the culture medium.
  • DMSO dimethylsulfoxide
  • the neuroblasts are kept in plates containing the test compound or the corresponding solvent for 4 days without changing the medium.
  • the medium is replaced by a tetrazolium salt dissolved in the culture medium (0.15 mg / ml).
  • the cells are then placed in an oven at 37 ° C for 4 hours.
  • the mitochondrial succinodehydrogenases of living cells reduce the tetrazolium salt to formazan blue, which, after dissolution in DMSO, measures the optical density at 540nm, a density which is linearly correlated with the number of living cells (Manthorpe et al., Dev. Brain Res ., 1988, 25: 191-198).
  • the compound of formula (I) as well as its pharmaceutically acceptable addition salts and its solvates can be used for the preparation of pharmaceutical compositions indicated in the treatment and / or prophylaxis of all diseases which involve neuronal degeneration. More particularly, the compounds of the invention can be used, alone or in co-administration or association with other active ingredients acting on the CNS, for example selective M1 cholinomimetics, antagonists
  • nootropics such as piracetam, in particular in the following indications: memory disorders, vascular dementia, post-encephalitic disorders, post-apoplectic disorders, post-traumatic syndromes due to a cranial trauma, disorders deriving from cerebral anoxia, Alzheimer's disease, senile dementia, subcortical dementia, such as Huntington's chorea and Parkinson's disease, dementia caused by AIDS, neuropathies derived from morbidity or damage to the sympathetic or sensory nerves, and brain diseases, such as edema cerebral, and the spinocerebellar degenerations, the degenerations of the motor neurons, like for example amiotrophic lateral sclerosis.
  • the administration of the compounds of the invention can be suitably carried out by oral, parenteral, sublingual or transdermal route.
  • the quantity of active principle to be administered in the treatment of cerebral and neuronal disorders according to the method of the present invention depends on the nature and the gravity of the affections to be treated as well as on the weight of the patients. Nevertheless, the preferred unit doses will generally comprise from 0.5 to 700 mg, advantageously from 2 to 300 mg, preferably from 5 to 150 mg, for example between 5 and 50 mg, namely 1, 2, 5, 10, 15 , 20, 25, 30, 40 or 50 mg of product.
  • unit doses will normally be administered one or more times a day, for example 2, 3, 4, or 5 times a day, preferably one to three times a day, the overall dose in humans being variable between 0.5 and 1400 mg per day, advantageously between 1 and 1000 mg per day, for example from 2 to 500 mg, more suitably from 5 to 200 mg per day.
  • the active principle can be administered in unit administration forms, either as it is, for example in lyophilized form, either in admixture with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions.
  • Suitable unit administration forms include oral forms such as optionally scored tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, administration forms under - cutaneous, intramuscular or intravenous, forms of local administration and forms of rectal administration.
  • the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.
  • the tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
  • a preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
  • a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color.
  • Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
  • Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.
  • the active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
  • the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention concerns the use of 1-[4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1yl]-2-(6,7-dimethoxynapht-2-yl) ethane (I) for preparing medicines for the treatment and/or prevention of cerebral and neuronal disorders

Description

UTILISAΉON DU l-[4-(3-TRIFLUOROMETIiYLPHENYL)-l,2,3,6-TETRAI γOROPYRm-lYL]-2-(6,7-USE OF 1- [4- (3-TRIFLUOROMETIiYLPHENYL) -l, 2,3,6-TETRAI γOROPYRm-lYL] -2- (6,7-
DΓMETH0XYNAPHT-2-YL)ETΗANE POUR LA PREPARAΗON DE MEDICAMENTS DESTINES AUX TRAITEMENTS DE TROUBLES CEREBRAUX ET NEURONAUX neurotrophique.DΓMETH0XYNAPHT-2-YL) ETΗANE FOR THE PREPARATION OF MEDICINAL PRODUCTS FOR THE TREATMENT OF Neurotrophic CEREBRAL AND NEURAL DISORDERS.
La présente invention concerne l'utilisation du l-[4-(3-trifluorométhylphényl)- l,2,3,6-tétrahydropyrid-l-yl]-2-(6,7-diméthoxynapht-2-yl)éthane (I) pour la préparation de médicaments destinés au traitement et/ou à la prophylaxie des maladies cérébrales et neuronales.The present invention relates to the use of l- [4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyrid-1-yl] -2- (6,7-dimethoxynapht-2-yl) ethane (I ) for the preparation of drugs intended for the treatment and / or prophylaxis of cerebral and neuronal diseases.
EP 0 458 696 décrit l'utilisation de la l-[2-(2-naphtyl)éthyl]-4-(3-trifluoro- méthylphényl)-l,2,3,6-tétrahydropyridine pour la préparation de médicaments destinés au traitement de la néurodégénérescence.EP 0 458 696 describes the use of 1- [2- (2-naphthyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine for the preparation of medicaments intended for the treatment of neurodegeneration.
Le composé (I), ses sels ainsi que leur préparation sont décrits dans EP 0 458 697. Dans cette demande de brevet on décrit également l'activité anticonstipante du composé de formule (I) et de ses sels pharmaceutiquement acceptables.The compound (I), its salts and their preparation are described in EP 0 458 697. In this patent application, the anticonstipant activity of the compound of formula (I) and of its pharmaceutically acceptable salts is also described.
On a maintenant trouvé, de façon surprenante, que parmi les produits décrits dans EP 0 458 697, le composé de formule (I) et ses sels et solvates pharmaceutiquement acceptables exercent des effets neurotrophiques au niveau du système nerveux, effets qui se sont révélés similaires à ceux du facteur de croissance nerveuse (NGF, de l'anglais "Nerve Growth Factor").It has now been surprisingly found that, among the products described in EP 0 458 697, the compound of formula (I) and its pharmaceutically acceptable salts and solvates exert neurotrophic effects on the nervous system, effects which have been found to be similar to those of the nerve growth factor (NGF, from the English "Nerve Growth Factor").
De plus, le composé de formule (I) et ses sels pharmaceutiquement acceptables possèdent la capacité d'augmenter la survie des neurones.In addition, the compound of formula (I) and its pharmaceutically acceptable salts have the capacity to increase the survival of neurons.
La présente invention a donc pour objet l'utilisation du l-[4-(3- trifluorométhylphényl)-l,2,3,6-tétrahydropyrid-l-yl]-2-(6,7-diméthoxynapht-2- yl) éthane, de formule (I)The present invention therefore relates to the use of l- [4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyrid-1-yl] -2- (6,7-dimethoxynapht-2-yl) ethane, of formula (I)
et ses sels et solvates pharmaceutiquement acceptables, pour la préparation de médicaments destinés au traitement et/ou à la prophylaxie des maladies associées à une dégénérescence neuronale. and its pharmaceutically acceptable salts and solvates, for the preparation of medicaments intended for the treatment and / or prophylaxis of diseases associated with neuronal degeneration.
Parmi les sels pharmaceutiquement acceptables du composé de formule (I), on peut citer ceux formés avec les acides pharmaceutiquement acceptables, par exemple, ceux avec les acides minéraux, tels que le chlorhydrate, le bromhydrate, le borate, le phosphate, le sulfate, l'hydrogénosulfate, l'hydrogénophosphate et ceux avec les acides organiques, tels que le citrate, le benzoate, l'ascorbate, le méthylsulfate, le naphtalene-2-sulfonate, le picrate, le fumarate, le maléate, le malonate, l'oxalate, le succinate, l'acétate, le tartrate, le mésylate, le tosylate, l'iséthionate, α-cétoglutarate, l'α-glycérophosphate, le glucose- 1 -phosphate.Among the pharmaceutically acceptable salts of the compound of formula (I), mention may be made of those formed with pharmaceutically acceptable acids, for example, those with mineral acids, such as the hydrochloride, hydrobromide, borate, phosphate, sulphate, hydrogen sulfate, hydrogen phosphate and those with organic acids, such as citrate, benzoate, ascorbate, methyl sulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate, malonate, oxalate, the succinate, acetate, tartrate, mesylate, tosylate, isethionate, α-ketoglutarate, α-glycerophosphate, glucose-1-phosphate.
Cette découverte est particulièrement surprenante car le composé de formule (I) semble être les seul composé, parmi ceux de la classe décrite dans EP 0 458 697, qui possède cette activité neurotrophique.This discovery is particularly surprising because the compound of formula (I) seems to be the only compound, among those of the class described in EP 0 458 697, which has this neurotrophic activity.
L'activité du composé de formule (I) et de ses sels pharmaceutiquement acceptables sur le système nerveux a été démontrée par des essais conduits en utilisant des neurones isolés à partir de dissections de la région septale d'embryons de rats.The activity of the compound of formula (I) and of its pharmaceutically acceptable salts on the nervous system has been demonstrated by tests carried out using neurons isolated from dissections of the septal region of rat embryos.
Plus particulièrement on a prélevé la région septale d'embryons de rats âgés de 17- 18 jours sous microscope à dissection dans des conditions stériles, puis on l'a dissociée dans un milieu trypsine-acide éthylènediaminotétraacétique (EDTA). La suspension de cellules a été placée dans un flacon de culture dans un milieuMore particularly, the septal region was removed from embryos of 17-18 day old rats under a dissecting microscope under sterile conditions, then it was dissociated in a trypsin-ethylenediaminotetraacetic acid (EDTA) medium. The cell suspension was placed in a culture flask in medium
DME/Ham's F12 (v.v) (Dulbecco Modified Eagle Médium/ Nutrient Mixture Ham'sDME / Ham's F12 (v.v) (Dulbecco Modified Eagle Medium / Nutrient Mixture Ham's
F12 - R.G. Ham, Proc. Nat. Sci, 1965, 53:288) contenant du sérum de veau à 5% et du sérum de cheval à 5% et maintenue à 37*C pendant 90 minutes. Ce traitement permet l'élimination des cellules non-neuronales.F12 - R.G. Ham, Proc. Nat. Sci, 1965, 53: 288) containing 5% calf serum and 5% horse serum and maintained at 37 ° C for 90 minutes. This treatment eliminates non-neuronal cells.
Les neuroblastes sont ensuite ensemencés dans les puits d'une plaque de titration à raison de 17x10 cellules/cm^, dans un milieu de culture non sérique constitué par duThe neuroblasts are then seeded in the wells of a titration plate at the rate of 17x10 cells / cm ^, in a non-serum culture medium consisting of
DME/Ham's F12 contenant du sélénium (30 nM) et de la transferrine (1,25 μM). Chaque puits a été préalablement traité à la poly-L-lysine. Les plaques ensemencées sont placées dans un incubateur à l'étuve (37*C; 5% CO2).DME / Ham's F12 containing selenium (30 nM) and transferrin (1.25 μM). Each well was previously treated with poly-L-lysine. The inoculated plates are placed in an incubator in the oven (37 ° C; 5% CO2).
Les composés à tester sont dissouts dans du diméthylsulfoxyde (DMSO) et dilués comme requis par le milieu de culture.The test compounds are dissolved in dimethylsulfoxide (DMSO) and diluted as required by the culture medium.
Les neuroblastes sont maintenus dans des plaques contenant le composé à tester ou le solvant correspondant pendant 4 jours sans changer le milieu.The neuroblasts are kept in plates containing the test compound or the corresponding solvent for 4 days without changing the medium.
Après 4 jours le milieu est remplacé par un sel de tétrazolium dissout dans le milieu de culture (0,15 mg/ml). Les cellules sont ensuite placées à l'étuve à 37*C pendant 4 heures. Les succinodéhydrogénases mitochondriales des cellules vivantes réduisent le sel de tétrazolium en bleu formazan dont, après dissolution dans le DMSO, on mesure la densité optique à 540nm, densité qui est linéairement corrélée au nombre de cellules vivantes (Manthorpe et al., Dev. Brain Res., 1988, 25:191- 198).After 4 days the medium is replaced by a tetrazolium salt dissolved in the culture medium (0.15 mg / ml). The cells are then placed in an oven at 37 ° C for 4 hours. The mitochondrial succinodehydrogenases of living cells reduce the tetrazolium salt to formazan blue, which, after dissolution in DMSO, measures the optical density at 540nm, a density which is linearly correlated with the number of living cells (Manthorpe et al., Dev. Brain Res ., 1988, 25: 191-198).
La différence entre les groupes contenant les composés à tester et les témoins a été évaluée par analyse statistique en utilisant le test t bilatéral de Dunnett ("two-tailed Dunnett t-test"). Dans ce test, le composé de formule (I) s'est montré plus actif que les composés décrits dans EP 0 458 696, l'activité significative se manifestant à partir de concentrations très faibles, dès 2,5 nM.The difference between the groups containing the test compounds and the controls was evaluated by statistical analysis using the Dunnett bilateral t-test ("two-tailed Dunnett t-test"). In this test, the compound of formula (I) was more active than the compounds described in EP 0 458 696, the significant activity being manifested from very low concentrations, from 2.5 nM.
En outre, le composé de formule (I) et ses sels et solvates pharmaceutiquement acceptables, présentent des avantages par rapport aux composés décrits dansIn addition, the compound of formula (I) and its pharmaceutically acceptable salts and solvates have advantages over the compounds described in
EP 0 458 696, par la présence des groupes méthoxy. En effet, cette substitution prévient la formation de métabolites dus à l'oxydation sur le groupe naphtalène.EP 0 458 696, by the presence of methoxy groups. Indeed, this substitution prevents the formation of metabolites due to oxidation on the naphthalene group.
Grâce à cette puissante activité neuroprotectrice et à leur faible toxicité, compatible pour une utilisation en tant que médicament, le composé de formule (I) ainsi que ses sels d'addition pharmaceutiquement acceptables et ses solvates sont utilisables pour la préparation de compositions pharmaceutiques indiquées dans le traitement et/ou la prophylaxie de toutes les maladies qui impliquent une dégénérescence neuronale. Plus particulièrement, les composés de l'invention sont utilisables, seuls ou en co-administration ou association avec d'autres principes actifs agissant sur le SNC, par exemple les cholinomimétiques Ml sélectifs, les antagonistesThanks to this powerful neuroprotective activity and to their low toxicity, compatible for use as a medicament, the compound of formula (I) as well as its pharmaceutically acceptable addition salts and its solvates can be used for the preparation of pharmaceutical compositions indicated in the treatment and / or prophylaxis of all diseases which involve neuronal degeneration. More particularly, the compounds of the invention can be used, alone or in co-administration or association with other active ingredients acting on the CNS, for example selective M1 cholinomimetics, antagonists
NMDA, les nootropiques tels que le piracétam, notamment dans les indications suivantes: troubles de la mémoire, démence vasculaire, troubles post-encéphalitiques, troubles post-apoplectiques, syndromes post-traumatiques dus à un traumatisme crânien, troubles dérivant d'anoxies cérébrales, maladie d'Alzheimer, démence sénile, démence subcorticale, telle que la chorée de Huntington et la maladie de Parkinson, démence provoquée par le SIDA, neuropathies dérivées de morbidité ou dommage des nerfs sympatiques ou sensoriels, et maladies cérébrales, telles que l'oedème cérébral, et les dégénérescences spinocérébelleuses, les dégénérescences des motoneurones, comme par exemple la sclérose latérale amiotrophique. L'administration des composés de l'invention peut être convenablement effectuée par voie orale, parenterale, sublinguale ou transdermique. La quantité de principe actif à administrer dans le traitement des troubles cérébraux et neuronaux selon la méthode de la présente invention dépend de la nature et de la gravité des affections à traiter ainsi que du poids des malades. Néanmoins, les doses unitaires préférées comprendront généralement de 0,5 à 700 mg, avantageusement de 2 à 300 mg, de préférence de 5 à 150 mg, par exemple entre 5 et 50 mg, à savoir 1, 2, 5, 10, 15, 20, 25, 30, 40 ou 50 mg, de produit. Ces doses unitaires seront administrées normalement une ou plusieurs fois par jour, par exemple 2, 3, 4, ou 5 fois par jour, de préférence une à trois fois par jour, la dose globale chez l'homme étant variable entre 0,5 et 1400 mg par jour, avantageusement entre 1 et 1000 mg par jour, par exemple de 2 à 500 mg, plus convenablement de 5 à 200 mg par jour. Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique ou rectale, le principe actif peut être administré sous formes unitaires d'administration, soit tel quel par exemple sous forme lyophilisée, soit en mélange avec des supports pharmaceutiques classiques, aux animaux et aux êtres humains pour le traitement des affections susdites. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés éventuellement sécables, les gélules, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale et buccale, les formes d'administration sous- cutanée, intramusculaire ou intraveineuse, les formes d'administration locale et les formes d'administration rectale.NMDA, nootropics such as piracetam, in particular in the following indications: memory disorders, vascular dementia, post-encephalitic disorders, post-apoplectic disorders, post-traumatic syndromes due to a cranial trauma, disorders deriving from cerebral anoxia, Alzheimer's disease, senile dementia, subcortical dementia, such as Huntington's chorea and Parkinson's disease, dementia caused by AIDS, neuropathies derived from morbidity or damage to the sympathetic or sensory nerves, and brain diseases, such as edema cerebral, and the spinocerebellar degenerations, the degenerations of the motor neurons, like for example amiotrophic lateral sclerosis. The administration of the compounds of the invention can be suitably carried out by oral, parenteral, sublingual or transdermal route. The quantity of active principle to be administered in the treatment of cerebral and neuronal disorders according to the method of the present invention depends on the nature and the gravity of the affections to be treated as well as on the weight of the patients. Nevertheless, the preferred unit doses will generally comprise from 0.5 to 700 mg, advantageously from 2 to 300 mg, preferably from 5 to 150 mg, for example between 5 and 50 mg, namely 1, 2, 5, 10, 15 , 20, 25, 30, 40 or 50 mg of product. These unit doses will normally be administered one or more times a day, for example 2, 3, 4, or 5 times a day, preferably one to three times a day, the overall dose in humans being variable between 0.5 and 1400 mg per day, advantageously between 1 and 1000 mg per day, for example from 2 to 500 mg, more suitably from 5 to 200 mg per day. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal or rectal administration, the active principle can be administered in unit administration forms, either as it is, for example in lyophilized form, either in admixture with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions. Suitable unit administration forms include oral forms such as optionally scored tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, administration forms under - cutaneous, intramuscular or intravenous, forms of local administration and forms of rectal administration.
Lorsqu'on prépare une composition solide sous forme de comprimés, on mélange l'ingrédient actif principal avec un véhicule pharmaceutique tel que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la gomme arabique ou analogues. On peut enrober les comprimés de saccharose ou d'autres matières appropriées ou encore on peut les traiter de telle sorte qu'ils aient une activité prolongée ou retardée et qu'ils libèrent d'une façon continue une quantité prédéterminée de principe actif.When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.
On obtient une préparation en gélules en mélangeant l'ingrédient actif avec un diluant et en versant le mélange obtenu dans des gélules molles ou dures.A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.
Une préparation sous forme de sirop ou d'elixir peut contenir l'ingrédient actif conjointement avec un édulcorant, acalorique de préférence, du méthylparaben et du propylparaben comme antiseptiques, ainsi qu'un agent donnant du goût et un colorant approprié. Les poudres ou les granules dispersibles dans l'eau peuvent contenir l'ingrédient actif en mélange avec des agents de dispersion ou des agents mouillants, ou des agents de mise en suspension, comme la polyvinylpyrrolidone, de même qu'avec des édulcorants ou des correcteurs du goût.A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate color. Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.
Pour une administration rectale, on recourt à des suppositoires qui sont préparés avec des liants fondant à la température rectale, par exemple du beurre de cacao ou des polyéthylèneglycols.Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
Pour une administration parenterale, on utilise des suspensions aqueuses, des solutions salines ou des solutions stériles et injectables qui contiennent des agents de dispersion et/ou des mouillants pharmacologiquement compatibles, par exemple le propylèneglycol ou le butylèneglycol. Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports ou additifs.For parenteral administration, aqueous suspensions, saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol. The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.
Dans les compositions pharmaceutiques selon la présente invention, le principe actif peut être aussi sous forme de complexe d'inclusion dans des cyclodextrines, leurs éthers ou leurs esters. In the pharmaceutical compositions according to the present invention, the active principle can also be in the form of an inclusion complex in cyclodextrins, their ethers or their esters.

Claims

REVENDICATIONS
Utilisation du l-[4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyrid-l-yl]- 2-(6,7-diméthoxynapht-2-yl) éthane, de formule (I)Use of 1- [4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyrid-1-yl] - 2- (6,7-dimethoxynapht-2-yl) ethane, of formula (I)
et de ses sels et solvates pharmaceutiquement acceptables, pour la préparation de médicaments destinés au traitement et/ou à la prophylaxie des maladies associées à une dégénérescence neuronale. and its pharmaceutically acceptable salts and solvates, for the preparation of medicaments intended for the treatment and / or prophylaxis of diseases associated with neuronal degeneration.
2. Utilisation selon la revendication 1 pour le traitement des troubles de la mémoire, de la démence vasculaire, des troubles post-encéphalitiques, des troubles postapoplectiques, des syndromes post-traumatiques dus à un traumatisme crânien, des troubles dérivant d'anoxies cérébrales, de la maladie d'Alzheimer, de la démence sénile, de la démence subcorticale, telle que la chorée de Huntington et la maladie de Parkinson, de la démence provoquée par le SIDA, des neuropathies dérivées de morbidité ou dommage des nerfs sympatiques ou sensoriels, des maladies cérébrales, telles que l'oedème cérébral, et les dégénérescences spinocérébelleuses, les dégénérescences des motoneurones, comme la sclérose latérale amiotrophique.2. Use according to claim 1 for the treatment of memory disorders, vascular dementia, post-encephalitic disorders, postapoplectic disorders, post-traumatic syndromes due to a cranial trauma, disorders deriving from cerebral anoxia, Alzheimer's disease, senile dementia, subcortical dementia, such as Huntington's chorea and Parkinson's disease, dementia caused by AIDS, neuropathies derived from morbidity or damage to the sympathetic or sensory nerves, brain diseases, such as cerebral edema, and spinocerebellar degenerations, motor neuron degenerations, such as amotrophic lateral sclerosis.
3. Utilisation selon la revendication 2 pour le traitement de la démence vasculaire, de la démence sénile, de la maladie d'Alzheimer. 3. Use according to claim 2 for the treatment of vascular dementia, senile dementia, Alzheimer's disease.
EP97902426A 1997-02-03 1997-02-03 Use of 1- 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyrid-1yl]-2-(6,7-dimethoxynapht-2-yl) ethane for preparing medicines for the treatment of cerebral and neuronal disorders Withdrawn EP0954311A1 (en)

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US5618822A (en) * 1990-05-23 1997-04-08 Sanofi N-substituted trifluoromethylphenyltetrahydropyridines, process for the preparation thereof, intermediates in said process and pharmaceutical compositions containing them
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