WO1999025363A1 - Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia - Google Patents

Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia Download PDF

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Publication number
WO1999025363A1
WO1999025363A1 PCT/FR1998/002384 FR9802384W WO9925363A1 WO 1999025363 A1 WO1999025363 A1 WO 1999025363A1 FR 9802384 W FR9802384 W FR 9802384W WO 9925363 A1 WO9925363 A1 WO 9925363A1
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Prior art keywords
trifluoromethylphenyl
ethyl
tetrahydropyridine
biphenylyl
alkyl
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PCT/FR1998/002384
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French (fr)
Inventor
Jean-Pierre Maffrand
Philippe Soubrie
Jean-Paul Terranova
Original Assignee
Sanofi-Synthelabo
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Priority claimed from FR9714322A external-priority patent/FR2771007B1/en
Priority claimed from FR9714324A external-priority patent/FR2771006B1/en
Priority to EEP200000290A priority Critical patent/EE04235B1/en
Priority to IL13612298A priority patent/IL136122A0/en
Priority to JP2000520796A priority patent/JP2001523642A/en
Priority to HU0100098A priority patent/HUP0100098A3/en
Priority to NZ504420A priority patent/NZ504420A/en
Priority to AU11609/99A priority patent/AU743228B2/en
Priority to SK711-2000A priority patent/SK286040B6/en
Priority to CA002309966A priority patent/CA2309966A1/en
Application filed by Sanofi-Synthelabo filed Critical Sanofi-Synthelabo
Priority to EA200000412A priority patent/EA003255B1/en
Priority to BR9814035-3A priority patent/BR9814035A/en
Priority to KR1020007005231A priority patent/KR100599350B1/en
Priority to EP98954538A priority patent/EP1030671A1/en
Priority to PL98340500A priority patent/PL194597B1/en
Publication of WO1999025363A1 publication Critical patent/WO1999025363A1/en
Priority to IS5482A priority patent/IS5482A/en
Priority to NO20002450A priority patent/NO20002450L/en
Priority to IL136122A priority patent/IL136122A/en
Priority to US11/070,351 priority patent/US20050148614A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/64Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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 subject of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a new combination of active principles, for the treatment of senile dementia of the Alzheimer type, consisting of derivatives of 1,2,3,6-tetrahydropyridines, optionally in the form of one of their pharmaceutically acceptable salts and of a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts and its use for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.
  • Senile dementia of the Alzheimer type hereinafter called DAT (from English
  • Impairia of Alzheimer's type is a neurodegenerative disease clinically characterized by the progressive decline of cognitive functions occurring in the elderly with an incidence that increases in relation to age. Given demographic trends, TAD will become an increasingly widespread disease.
  • the only treatment for DAT currently available on the market consists of administering by acetylcholinesterase inhibitors which by reducing the hydrolysis of acetylcholine thus increase its bioavailability. It is therefore a symptomatic treatment.
  • Tacrine sold under the brand COGNEX ®
  • donepezil sold under the brand ARICEPT
  • acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate forms of DAT.
  • Other products for the symptomatic treatment of TAD are being studied. Some of them also act on the availability of acetylcholine, others improve the symptomatic framework of patients affected by TAD by other mechanisms. So far, no drug available on the market has been able to slow the progression of the disease.
  • EP-458696 describes the use of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine, known in the literature SR 57746, for the preparation drugs to fight neurodegenerative conditions, including senile dementia and Alzheimer's disease.
  • the neurotrophic action of SR 57746 on the nervous system is similar to that of certain endogenous neurotrophins, such as, for example, nerve growth factor (NGF).
  • NGF nerve growth factor
  • WO 97/01536 describes new 4-substituted l-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity similar to that of certain endogenous neurotrophins. Thanks to this activity, the compounds described in This patent application is said to be useful in the treatment of several pathologies of the central nervous system, including Alzheimer's disease.
  • the activity in the treatment of nervous pathologies such as the DAT of the compound SR57746 and of the compounds described in WO 97/01536 is not intended to treat the symptoms but, by protecting the neurons, to modify the course of the disease and to reduce the progression.
  • the subject of the present invention is a pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3 , 6-tetrahydropyridine and a compound of formula (I),
  • Ri represents hydrogen, a halogen, a CF 3 group, or (C1-C4) - dcoxyl
  • R2 represents hydrogen, a halogen, a hydroxyl, a group CF 3 , (C3-C4) - alkyl or (Ci-C ⁇ alkoxyle;
  • R3 and R4 each represent hydrogen or a (C ⁇ -C3) alkyl;
  • a particularly advantageous component (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form one of its pharmaceutically acceptable salts.
  • SR 57746 A is a particularly preferred salt.
  • An advantageous method for the preparation of SR 57746A provides for the reaction between 2- (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and the isolation of l- hydrochloride (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine which is subsequently crystallized from an ethanol / water mixture by heating and cooling to 5 ° C with a cooling rate of 10 ° C / hour and a stirring speed of 400 revolutions / minute, so as to obtain a mixture of two crystalline forms in a ratio of about 66/34.
  • SR 57746A is preferably used in microparticulate form, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by micronization.
  • Another particularly advantageous component (a) is 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tet.ahydropyridine, in particular its hydrochloride salt.
  • the expression “active compound in the symptomatic treatment of DAT” designates a product which is capable of improving the symptomatological framework of patients suffering from DAT without intervening in the causes of the disease.
  • Such compounds are for example acetylcholinesterase inhibitors, muscarinic agonists Mi, nicotinic agonists, receptor antagonists
  • N-methyl-D-aspartate N-methyl-D-aspartate (NMDA), nootropics, acetylcholinesterase inhibitors being particularly advantageous.
  • the invention relates to a pharmaceutical composition containing as active ingredient, a component (a), optionally in the form of one of its pharmaceutically acceptable salts, and a component (b) chosen from inhibitors of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts.
  • acetylcholinesterase inhibitors are tacrine and donepezil.
  • acetylcholinesterase inhibitors which can be used are, for example, rivastigmine (SDZ-ENA-713), galanth.amine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5) : 752-768; The Merck
  • acetylcholinesterase inhibitors are also 5,7-dihydro-3- [2- [l-
  • acetylcholinesterase inhibitors are, for example, those described in patent applications JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95 -21822, EP 637 586, US 5,401,749, EP 742 207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP 07-133274, EP 649 846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272, EP 627400.
  • Agonists of the Mi receptor are, for example, milamelin, besipiridine, talsaclidine, xanomelin, YM-796 and YM-954 (Eur. J. Pharmacol ., 1990, 187: 479-486), 3- [N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl] -pyridazinamine, also named SR-46559 (Biorg. Med. Chem.
  • nicotinic agonists are, for example, MKC-231 (Biorg. Med. Chem. Let., 1995, 5 (14): 1495-1500), T-588 (Japan J. Pharmacol., 1993, 62: 81- 86), ABT-418 (Br. J. Pharmacol., 1997, 120: 429-438).
  • NMDA receptor antagonist for example memantine (Arzneim. Forsch., 1991, 41: 773-780).
  • the present invention relates to the use of the compositions of the invention for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.
  • the present invention also relates to a method of treating senile dementia of the Alzheimer type which consists in administering to a patient suffering from this disease an effective dose of component (a) above, possibly in the form one of its pharmaceutically acceptable salts and an effective dose of a component (b), in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, said administrations being simultaneous, sequential or spread over time and the effective doses of the active principles which can be contained in separate unit administration forms or, when the active principles are administered simultaneously, the two active principles advantageously being contained in a single pharmaceutical form.
  • the active ingredients according to the present invention are preferably administered orally.
  • the active ingredients can be administered in unit forms administration, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions.
  • Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.
  • 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.
  • 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.
  • the amount of active ingredient to be administered depends, as always, on the degree of progression of the disease as well as on the age and weight of the patient.
  • the doses of the two active ingredients are analogous to those normally used in the art for the isolated administration of each of these active ingredients.
  • compositions according to the invention therefore contain doses recommended for non-combined treatments, for example from 0.5 to 700 mg of component (a) or of a pharmaceutically acceptable salt thereof and 0.1 to 50 mg of component ( b) or a pharmaceutically acceptable salt thereof or lower doses, since the combination exerts a synergistic effect.
  • compositions include, for example, 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts.
  • Preferred compositions include 0.5 to 5 mg of SR 57746 or a pharmaceutically acceptable salt thereof, especially the hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.
  • the doses indicated in the present description refer to the active ingredients in non-salified form.
  • composition according to the invention has been demonstrated using a specific model for the septo-hyppocampal cholinergic system, on lesions caused by the injection of vincristine.
  • this model we evaluate the effects of the products tested on amnesia induced by the injection of vincristine which induces biochemical alterations similar to the alterations present in Alzheimer's disease.
  • the rats have stable and lasting amnesia.
  • the rats are divided into two groups, one group receiving solvent and the other group receiving SR 57746A at a dose of 5 mg / kg po, a dose which is not sufficient to allow functional recovery in terms of memory in rats subjected to this test (the effective dose being 10 mg / kg as described in EP 655247).
  • the dose of 1 mg / kg i.p. tacrine is then administered to the two groups of rats.
  • the control group having received solvent and tacrine, shows no recovery of memory while the group having been treated with SR 57746A (sub-effective dose) and tacrine shows a significant recovery of memory deficits.
  • the results of this test make it possible to recognize a synergistic action with the association of the present invention.
  • the composition of the invention allows a effective treatment of DAT in all its forms.

Abstract

The invention concerns a pharmaceutical composition containing as active principles: a constituent (a) selected between 1-(2-napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin and a compound (I) in which: Y represents -CH- or -N-; R1 represents hydrogen, a halogen, a hydroxyl, a CF3, a (C3-C4)alkyl or (C1-C4) alkoxyl group; R2 represents hydrogen, a halogen, a hydroxyl, a CF3, (C3-C4) alkyl or( C1-C4)alkoxyl group; R3 and R4 represent each hydrogen or a (C1-C4)alkyl; X represents (a) a (C3-C6)alkyl; a (C3-C6)alkoxyl; a (C3-C7)carboxyalkyl; a (C1-C4)alkoxycarbonyl(C3-C6-)alkyl; a (C3-C7)carboxyalkoxyl; or a (C1-C4)alkoxycarbonyl(C3-C6)alkoxyl; (b) a radical selected among a (C3-C7)cycloalkyl, (C3-C7)cycloalkyloxy, (C3-C7)cycloalkylmethyl, (C3-C7)cycloalkylamino and cyclohexenyl, said radical capable of being substituted by a halogen, hydroxy, (C1-C4)alkoxy, carboxy, (C1-C4)alkoxycarbonyl, amino, mono- or di-(C1-C4)alkyamino or (c) a group selected among phenyl, phenoxy, phenylamino, N-(C1-C3)alkyl-phenyl-amino, phenylmethyl, phenylethyl, p henylcarbonyl, phenylthio, phenylsulphonyl, phenylsulphinyl and styryl, said group capable of being mono- or polysubstituted on the phenyl group by a halogen, CF3, (C1-C4)alkyl, (C1-C4)alkoxy, cyano, amino, mono- or di-(C1-C4)alkylamino, (C1-C4)acylamino, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, mono- or di-(C1-C4)alkylaminocarbonyl, amino(C1-C4)alk yl, hydroxy(C1-C4)alkyl, or halogeno(C1-C4)alkyl; optionally in the form of one of its pharmaceutically acceptable salts; and an constituent (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when constituent (a) is other than 1-(2napht-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin or one of its pharmaceutically acceptable salts, the constituent (b) is an acetylcholinesterase inhibiting agent.

Description

ASSOCIATION DE PRINCIPES ACTIFS, NOTAMMENT DE TETRAHYDROPYRIDINES ET D'AGENTS INHIBITEURS DE L'ACETYLCHOLINESTERASE, POUR LE TRAITEMENT DE LA DEMENCE SENILE DU TYPE ALZHEIMERCOMBINATION OF ACTIVE INGREDIENTS, IN PARTICULAR TETRAHYDROPYRIDINES AND ACETYLCHOLINESTERASE INHIBITORS, FOR THE TREATMENT OF SENILE ALZHEIMER DEMENTIA
La présente invention a pour objet une composition pharmaceutique comprenant une nouvelle association de principes actifs, pour le traitement de la démence sénile du type Alzheimer, constituée de dérivés de 1,2,3,6-tétrahydropyridines, éventuellement sous la forme de l'un de leurs sels pharmaceutiquement acceptables et d'un composé actif dans le traitement symptomatique de la démence sénile du type Alzheimer, notamment d'un inhibiteur de l'acétylcholinestérase, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables et son utilisation pour la préparation de médicaments destinés au traitement de la démence sénile du type Alzheimer. La démence sénile du type Alzheimer ci-après dénommée DAT (de l'anglaisThe subject of the present invention is a pharmaceutical composition comprising a new combination of active principles, for the treatment of senile dementia of the Alzheimer type, consisting of derivatives of 1,2,3,6-tetrahydropyridines, optionally in the form of one of their pharmaceutically acceptable salts and of a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts and its use for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type. Senile dementia of the Alzheimer type hereinafter called DAT (from English
"dementia of Alzheimer's type") est une maladie neurodégénérative caractérisée cliniquement par la déchéance progressive des fonctions cognitives se présentant chez les personnes âgées avec une incidence qui augmente en relation avec l'âge. Compte tenu des tendences démographiques, la DAT va devenir une maladie de plus en plus répandue."dementia of Alzheimer's type") is a neurodegenerative disease clinically characterized by the progressive decline of cognitive functions occurring in the elderly with an incidence that increases in relation to age. Given demographic trends, TAD will become an increasingly widespread disease.
Chez les patients atteints par la DAT, une réduction des taux de plusieurs neurotransmetteurs a été constatée, notamment de l'acétylcholine.In patients with DAT, a reduction in the levels of several neurotransmitters has been seen, including acetylcholine.
Le seul traitement de la DAT actuellement disponible sur le marché consiste à administer par les inhibiteurs de l'acétylcholinestérase qui en réduisant l'hydrolyse de l'acétylcholine en augmentent ainsi la biodisponibilité. Il s'agit donc d'un traitement symptomatique.The only treatment for DAT currently available on the market consists of administering by acetylcholinesterase inhibitors which by reducing the hydrolysis of acetylcholine thus increase its bioavailability. It is therefore a symptomatic treatment.
La tacrine, commercialisée sous la marque COGNEX®, et le donepezil, commercialisé sous la marque ARICEPT , sont des inhibiteurs de l'acétylcholinestérase indiqués pour le traitement symptomatique des formes faibles à modérées de DAT. D'autres produits pour le traitement symptomatique de la DAT sont à l'étude. Certains d'entre eux agissent ég ement sur la disponibilité de l'acétylcholine, d'autres améliorent le cadre symptomatique des patients atteints par la DAT par d'autres mécanismes. Jusqu'à présent, aucun médicament disponible sur le marché n'est en mesure de ralentir la progression de la maladie. EP-458696 décrit l'utilisation de la l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)- 1,2,3,6-tétr.ahydropyridine, dénommée en littérature SR 57746, pour la préparation de médicaments destinés à combattre les états neurodégénératifs, y compris la démence sénile et la maladie d'Alzheimer. L'action neurotrophique du SR 57746 sur le système nerveux est semblable à celle de certaines neurotrophines endogènes, telles que par exemple le facteur de croissance nerveuse (NGF).Tacrine, sold under the brand COGNEX ® , and donepezil, sold under the brand ARICEPT, are acetylcholinesterase inhibitors indicated for the symptomatic treatment of mild to moderate forms of DAT. Other products for the symptomatic treatment of TAD are being studied. Some of them also act on the availability of acetylcholine, others improve the symptomatic framework of patients affected by TAD by other mechanisms. So far, no drug available on the market has been able to slow the progression of the disease. EP-458696 describes the use of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine, known in the literature SR 57746, for the preparation drugs to fight neurodegenerative conditions, including senile dementia and Alzheimer's disease. The neurotrophic action of SR 57746 on the nervous system is similar to that of certain endogenous neurotrophins, such as, for example, nerve growth factor (NGF).
WO 97/01536 décrit de nouvelles l-phénylalkyl-l,2,3,6-tétrahydropyridines 4- substituées ayant une activité neurotrophique et neuroprotectrice semblable à celle de certaines neurotrophines endogènes. Grâce à cette activité, les composés décrits dans cette demande de brevet sont censés être utiles dans le traitement de plusieurs pathologies du système nerveux central, y compris la maladie d'Alzheimer.WO 97/01536 describes new 4-substituted l-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity similar to that of certain endogenous neurotrophins. Thanks to this activity, the compounds described in This patent application is said to be useful in the treatment of several pathologies of the central nervous system, including Alzheimer's disease.
L'activité dans le traitement des pathologies nerveuses telles que la DAT du composé SR57746 et des composés décrits dans WO 97/01536 ne vise pas à traiter les symptômes mais, en protégeant les neurones, à modifier la marche de la maladie et en réduire la progression.The activity in the treatment of nervous pathologies such as the DAT of the compound SR57746 and of the compounds described in WO 97/01536 is not intended to treat the symptoms but, by protecting the neurons, to modify the course of the disease and to reduce the progression.
Il a été maintenant trouvé que l'association des composés ci-dessus, éventuellement sous la forme de l'un de leurs sels pharmaceutiquement acceptables avec un composé actif dans le traitement symptomatique de la démence sénile du type Alzheimer, notamment d'un inhibiteur de l'acétylcholinestérase, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, permet un traitement complet et très efficace de la DAT, l'association exerçant un effet rapide et complémentaire.It has now been found that the combination of the above compounds, optionally in the form of one of their pharmaceutically acceptable salts with a compound active in the symptomatic treatment of senile dementia of the Alzheimer type, in particular of an inhibitor of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts, allows a complete and very effective treatment of DAT, the combination exerting a rapid and complementary effect.
Ainsi, la présente invention a pour objet une composition pharmaceutique contenant en tant que principes actifs un composant (a) choisi parmi la l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétrahydropyridine et un composé de formule (I),Thus, the subject of the present invention is a pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3 , 6-tetrahydropyridine and a compound of formula (I),
Figure imgf000004_0001
dans laquelle Y représente -CH- ou -N-;
Figure imgf000004_0001
in which Y represents -CH- or -N-;
Ri représente l'hydrogène, un halogène, un groupe CF3,
Figure imgf000004_0002
ou (C1-C4)- dcoxyle;
Ri represents hydrogen, a halogen, a CF 3 group,
Figure imgf000004_0002
or (C1-C4) - dcoxyl;
R2 représente l'hydrogène, un halogène, un hydroxyle, un groupe CF3, (C3-C4)- alkyle ou (Ci-C^alcoxyle; R3 et R4 représentent chacun l'hydrogène ou un (Cι-C3)alkyle;R2 represents hydrogen, a halogen, a hydroxyl, a group CF 3 , (C3-C4) - alkyl or (Ci-C ^ alkoxyle; R3 and R4 each represent hydrogen or a (Cι-C3) alkyl;
X représenteX represents
(a) un (C3-C, )alk le; un (C3-C6).alcoxyle; un (C3-C7)carboxyalkyle; un (C1-C4)- alcoxycarbonyl(C3-C6)alkyle; un (C3-C7)carboxyalcoxyle; ou un (Cι-C4).alcoxy- carbonyl(C3-C6)alcoxyle; (b) un radical choisi parmi un (C3-G7)cycloalkyle, (C3-C7)cycloalkyloxy, (C3-C7)- cycloalkylméthyle, (C3-C7)cycloalkylamino et cyclohexényle, ledit radical pouvant être substitué p.ar un halogène, hydroxy, (Cι-C4)alcoxy, carboxy, (Cι-C4)alcoxycarbonyle, amino, mono- ou ώ-(Cι-C4).alkylamino; ou (c) un groupe choisi parmi phényle, phénoxy, phénylamino, N-(Cι-C3)alkyl-phényl- amino, phénylméthyle, phényléthyle, phénylcarbonyle, phenylthio, phénylsulfonyle, phénylsulfinyle et styryle, ledit groupe pouvant être mono- ou polysubstitué sur le groupe phényle par un halogène, CF3, (Cj-C4)alkyle, (C[-C4)alcoxy, cyano, amino, mono- ou di-(Cι-C4)alkylamino, (Cι-C4)acylamino, carboxy, (Cι-C4)alcoxyc.arbonyle, aminocarbonyle, mono- ou di-(Cι-C4)alkylaminocarbonyle, amino(Cι-C4)alkyle, hydroxy(Cι-C4)alkyle ou halogéno(Cι-C4)alkyle; éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables et - un composant (b) actif dans le traitement symptomatique de la DAT, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, à la condition que lorsque le composant (a) est autre que la l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétrahydropyridine ou l'un de ses sels pharmaceutiquement acceptables, le composant (b) est un agent inhibiteur de l'acétylcholinestérase.(a) a (C3-C,) alk le; a (C3-C6) .alkoxyl; a (C3-C7) carboxyalkyl; a (C1-C4) - alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxyl; or a (Cι-C4) .alkoxycarbonyl (C3-C6) alkoxyl; (b) a radical chosen from a (C3-G7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by halogen, hydroxy, (Cι-C4) alkoxy, carboxy, (Cι-C4) alkoxycarbonyl, amino, mono- or ώ- (Cι-C4) .alkylamino; or (c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C 3 ) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group with a halogen, CF3, (Cj-C4) alkyl, (C [-C4) alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, ( C1-C4) alkoxyc.arbonyl, aminocarbonyl, mono- or di- (C1-C4) alkylaminocarbonyl, amino (C1-C4) alkyl, hydroxy (C1-C4) alkyl or halo (C1-C4) alkyl; optionally in the form of one of its pharmaceutically acceptable salts and - a component (b) active in the symptomatic treatment of DAT, optionally in the form of one of its pharmaceutically acceptable salts, provided that when the component (a) is other than 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine or one of its pharmaceutically acceptable salts, the component (b ) is an acetylcholinesterase inhibitor.
La l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine (SR 57746) a été décrit dans EP 101 381 et les composés de formule (I) ci-dessus sont décrits dans WO 97/01536.1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746) has been described in EP 101 381 and the compounds of formula (I) ci above are described in WO 97/01536.
Un composant (a) particulièrement avantageux est la l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétrahydropyridine (SR 57746), éventuellement sous la forme l'un de de ses sels pharmaceutiquement acceptables.A particularly advantageous component (a) is 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine (SR 57746), optionally in the form one of its pharmaceutically acceptable salts.
Parmi les sels pharmaceutiquement acceptables du SR 57746, le chlorhydrate ci- après dénommé SR 57746 A est un sel particulièrement préféré.Among the pharmaceutically acceptable salts of SR 57746, the hydrochloride hereinafter called SR 57746 A is a particularly preferred salt.
Une méthode avantageuse pour la préparation du SR 57746A prévoit la réaction entre le 2-(2-bromoéthyl)naphtalène et la 4-(3-trifluorométhylphényl)- 1,2,3,6- tétrahydropyridine et l'isolement du chlorhydrate de l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétr.ahydropyridine qui est p.ar la suite cristallisé dans un mélange éthanol/eau par chauffage et refroidissement à 5 °C avec une vitesse de refroidissement de 10° C/heure et une vitesse d'agitation de 400 tours/minute, de façon à obtenir un mélange de deux formes cristallines dans un rapport d'environ 66/34.An advantageous method for the preparation of SR 57746A provides for the reaction between 2- (2-bromoethyl) naphthalene and 4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and the isolation of l- hydrochloride (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine which is subsequently crystallized from an ethanol / water mixture by heating and cooling to 5 ° C with a cooling rate of 10 ° C / hour and a stirring speed of 400 revolutions / minute, so as to obtain a mixture of two crystalline forms in a ratio of about 66/34.
Le SR 57746A est utilisé de préférence sous forme microparticul re, p.ar exemple sous une forme essentiellement amorphe obtenue par atomisation ou sous une forme microcristalline obtenue par micronisation.SR 57746A is preferably used in microparticulate form, for example in an essentially amorphous form obtained by atomization or in a microcrystalline form obtained by micronization.
Un autre composant (a) particulièrement avantageux est la l-[2-(4- biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1 ,2,3,6-tétr.ahydropyridine, notamment son sel chlorhydrate. D'autres composés avantageux sont les suivants: l-[2-(3'-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétra- hydropyridine; l-[2-(2'-chloro-4-biphénylyl)éthyl]-4-(3-triπuorométhyl-phényl)-l,2,3,6- tétrahydropyridine; l-[2-(4'-chloro-4-biρhénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétra- hydropyridine; l-[2-(4'-fluoro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(3'-trifluorométhyl-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(4-cyclohexylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[-2-(4-biphénylyl) éthyl]-4-(4-fluorophényl)-l,2,3,6-tétrahydropyridine; l-t2-(4-biphénylyl)-2-méthylpropyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(4-phénoxyphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-benzylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-n-butylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-n-butoxyphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-(4-éthoxycarbonylpropoxy)phényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(4-biphénylyl)éthyl]-4-(6-chloropyrid-2-yl)-l,2,3, 6-tétrahydropyridine; l-[2-(2,3'-dichloro-4-biphenylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6,- tétrahydropyridine; l-[2-(3-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1 ,2,3 ,6- tétr.ahydropyridine; l-[2-(3',5'-dichloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(2',4,-dichloro-4-biphénylyl)éthyl]-4-(3-trifluorométhyl-hényl)-l,2,3,6- tétrahy dropyridine ; l-[2-(2-chloro-4-biρhénylyl)éthyl]-4-(3-trifluorométhylρhényl)-l,2,3,6- tétr.ahydropyridine; l-[2-(3'chloro-4-biρhénylyl)-2-méthylpropyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(2-fluoro-4-biphénylyl)ρroρyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétr.ahydropyridine; l-[2-(4-méthoxy-3-biphénylyl)éthyl]-4-(3-trifluorométhylphé nyl)- 1 ,2,3,6-tétrahydropyridine; l_[2-(4'-méthoxy-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l.[2-(4'-hydroxy-4-biphénylyl)éthyl]-4-(3-trifluorométhyl-phényl)-l,2,3,6- tétrahydropyridine; l-[2-(4'-éthoxycarbonylbutoxy-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(3-biphénylyl)-éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydroρyridine; l-[2-(3'chloro-4'-fluoro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahy dropyridi ne ; l-[2-(2'trifluorométhyl-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1,2,3,6- tétrahydropyridine;Another particularly advantageous component (a) is 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tet.ahydropyridine, in particular its hydrochloride salt. Other advantageous compounds are the following: 1- [2- (3'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2'-chloro-4-biphenylyl) ethyl] -4- (3-triπuoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-chloro-4-biρhenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3'-trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-cyclohexylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1 - [- 2- (4-biphenylyl) ethyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydropyridine; 1-t2- (4-biphenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-phenoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-benzylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-n-butylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-n-butoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4- (4-ethoxycarbonylpropoxy) phenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-biphenylyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; 1- [2- (2,3'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6, - tetrahydropyridine; 1- [2- (3-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (3 ', 5'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2 ', 4 , -dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-hényl) -1,2,3,6-tetrahy dropyridine; 1- [2- (2-chloro-4-biρhenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3'chloro-4-biρhenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; l- [2- (2-fluoro-4-biphenylyl) ρroρyl] -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetr.ahydropyridine; 1- [2- (4-methoxy-3-biphenylyl) ethyl] -4- (3-trifluoromethylphé nyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (4'-methoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1. [2- (4'-hydroxy-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-ethoxycarbonylbutoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3-biphenylyl) -ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (3'chloro-4'-fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahy dropyridi ne; 1- [2- (2'trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine;
1 - [2-(3 ,4-diisobutylphény l)éthy 1] -4-(3-trifluorométhylphényl)- 1 ,2,3 ,6- tétrahydropyridine; l-[2-(3,4-dipropylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-cyclohexylphényl)éthyl]-4-(6-chloropyrid-2-yl)-l,2,3,6-tétrahydropyridine; l-[2-(4-isobutylphényl)-propyl]-4-(6-chloropyrid-2-yl)-l,2,3,6-tétrahydropyridine; et leurs sels pharmaceutiquement acceptables.1 - [2- (3, 4-diisobutylpheny 1) ethyl 1] -4- (3-trifluoromethylphenyl) - 1, 2,3, 6-tetrahydropyridine; 1- [2- (3,4-dipropylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-cyclohexylphenyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-isobutylphenyl) -propyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; and their pharmaceutically acceptable salts.
Dans la présente description, l'expression "composé actif dans le traitement symptomatique de la DAT" désigne un produit qui est capable d'améliorer le cadre symptomatologique des patients atteints par la DAT sans intervenir sur les causes de la maladie.In the present description, the expression “active compound in the symptomatic treatment of DAT” designates a product which is capable of improving the symptomatological framework of patients suffering from DAT without intervening in the causes of the disease.
De tels composés sont par exemple les inhibiteurs de l'acétylcholinestérase, les agonistes muscariniques Mi, les agonistes nicotiniques, les antagonistes du récepteurSuch compounds are for example acetylcholinesterase inhibitors, muscarinic agonists Mi, nicotinic agonists, receptor antagonists
N-méthyl-D-aspartate (NMDA), les nootropiques, les inhibiteurs de l'acétylcholinestérase étant particulièrement avantageux.N-methyl-D-aspartate (NMDA), nootropics, acetylcholinesterase inhibitors being particularly advantageous.
Selon un aspect préféré, l'invention concerne une composition pharmaceutique contenant en tant que principe actif, un composant (a), éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, et un composant (b) choisi parmi les inhibiteurs de l'acétylcholinestérase, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables.According to a preferred aspect, the invention relates to a pharmaceutical composition containing as active ingredient, a component (a), optionally in the form of one of its pharmaceutically acceptable salts, and a component (b) chosen from inhibitors of acetylcholinesterase, optionally in the form of one of its pharmaceutically acceptable salts.
Des inhibiteurs de l'acétylcholinestérase particulièrement avantageux sont la tacrine et le donepezil.Particularly advantageous acetylcholinesterase inhibitors are tacrine and donepezil.
D'autres inhibiteurs de l'acétylcholinestérase pouvant être utilisés sont par exemple la rivastigmine (SDZ-ENA-713), la galanth.amine, le métrifonate, l'eptastigmine, la velnacrine, la physostigmine (Drugs, 1997, 53(5): 752-768; The MerckOther acetylcholinesterase inhibitors which can be used are, for example, rivastigmine (SDZ-ENA-713), galanth.amine, metrifonate, eptastigmine, velnacrine, physostigmine (Drugs, 1997, 53 (5) : 752-768; The Merck
Index 12 éd.).Index 12 ed.).
D'autres inhibiteurs de l'acétylcholinestérase sont encore la 5,7-dihydro-3-[2-[l-Other acetylcholinesterase inhibitors are also 5,7-dihydro-3- [2- [l-
(phénylméthyl)-4-pipéridinyl]éthyl]-6H-pyrrolo[3 ,2-f]- 1 ,2-benzisoxazol-6-one nommée aussi icopézil (J. Med. Chem., 1995, 38. 2802-2808), le MDL-73J45 ou zifrosilone (Eur. J. Phar acol., 1995, 276: 93-99), le TAK-147 (J. Med. Chem., 1994, 37: 2292- 2299).(phenylmethyl) -4-piperidinyl] ethyl] -6H-pyrrolo [3, 2-f] - 1, 2-benzisoxazol-6-one called also icopezil (J. Med. Chem., 1995, 38. 2802-2808), MDL-73J45 or zifrosilone (Eur. J. Phar acol., 1995, 276: 93-99), TAK-147 (J. Med. Chem., 1994, 37: 2292-2299).
D'autres inhibiteurs de l'acétylcholinestérase sont par exemple ceux qui sont décrits dans les demandes de brevet JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95-21822, EP 637 586, US 5,401,749, EP 742 207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP 07-133274, EP 649 846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272, EP 627400. Des agonistes du récepteur Mi sont par exemple la milaméline, la bésipiridine, la talsaclidine, la xanoméline, le YM-796 et le YM-954 (Eur. J. Pharmacol., 1990, 187: 479-486), le 3-[N-(2-diéthylamino-2-méthylpropyl)-6-phényl-5-propyl]-pyridazinamine, nommée aussi SR-46559 (Biorg. Med. Chem. Let., 1992, 2: 833:838), le AF-102, le CI- 979, le L-689, 660, le LU 25-109, le S-99 77-2, le SB 202,026, la thiopilocarpine, le WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).Other acetylcholinesterase inhibitors are, for example, those described in patent applications JP 09-095483, WO 97/13754, WO 97/21681, WO 97/19929, ZA 96-04565, US 5,455,245, WO 95 -21822, EP 637 586, US 5,401,749, EP 742 207, US 5,547,960, WO 96/20176, WO 96/02524, EP 677 516, JP 07-188177, JP 07-133274, EP 649 846, EP 648 771, JP 07-048370, US 5,391,553, WO 94/29272, EP 627400. Agonists of the Mi receptor are, for example, milamelin, besipiridine, talsaclidine, xanomelin, YM-796 and YM-954 (Eur. J. Pharmacol ., 1990, 187: 479-486), 3- [N- (2-diethylamino-2-methylpropyl) -6-phenyl-5-propyl] -pyridazinamine, also named SR-46559 (Biorg. Med. Chem. Let., 1992, 2: 833: 838), AF-102, CI-979, L-689, 660, LU 25-109, S-99 77-2, SB 202.026, thiopilocarpine, WAL 2014 (Pharmacol. Toxicol., 1996, 78: 59-68).
Des agonistes nicotiniques avantageux sont par exemple le MKC-231 (Biorg. Med. Chem. Let., 1995, 5 (14): 1495-1500), le T-588 (Japan J. Pharmacol., 1993, 62: 81-86), le ABT-418 (Br. J. Pharmacol., 1997, 120: 429-438).Advantageous nicotinic agonists are, for example, MKC-231 (Biorg. Med. Chem. Let., 1995, 5 (14): 1495-1500), T-588 (Japan J. Pharmacol., 1993, 62: 81- 86), ABT-418 (Br. J. Pharmacol., 1997, 120: 429-438).
Un antagoniste des récepteurs NMDA avantageux est par exemple la mémantine (Arzneim. Forsch., 1991, 41: 773-780).An advantageous NMDA receptor antagonist is for example memantine (Arzneim. Forsch., 1991, 41: 773-780).
Selon un aspect ultérieur, la présente invention concerne l'utilisation des compositions de l'invention pour la préparation des médicaments destinés au traitement de la démence sénile du type Alzheimer.According to a further aspect, the present invention relates to the use of the compositions of the invention for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type.
Selon un aspect ultérieur, la présente invention concerne aussi une méthode de traitement de la démence sénile du type Alzheimer qui consiste à administrer à un patient atteint de cette maladie une dose efficace d'un composant (a) ci-dessus, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables et une dose efficace d'un composant (b), notamment d'un inhibiteur de l'acétylcholinestérase, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, lesdites administrations étant simultanées, séquentielles ou étalées dans le temps et les doses efficaces des principes actifs pouvant être contenues dans des formes d'administration unitaires séparées ou bien, lorsque les principes actifs sont administrés simultanément, les deux principes actifs étant avantageusement contenus dans une forme pharmaceutique unique. Les principes actifs selon la présente invention sont de préférence administrés par voie orale.According to a further aspect, the present invention also relates to a method of treating senile dementia of the Alzheimer type which consists in administering to a patient suffering from this disease an effective dose of component (a) above, possibly in the form one of its pharmaceutically acceptable salts and an effective dose of a component (b), in particular of an acetylcholinesterase inhibitor, optionally in the form of one of its pharmaceutically acceptable salts, said administrations being simultaneous, sequential or spread over time and the effective doses of the active principles which can be contained in separate unit administration forms or, when the active principles are administered simultaneously, the two active principles advantageously being contained in a single pharmaceutical form. The active ingredients according to the present invention are preferably administered orally.
Dans les compositions pharmaceutiques de la présente invention pour l'administration orale, les principes actifs peuvent être administrés sous formes unitaires d'administration, 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 par exemple les comprimés éventuellement sécables, les gélules, les poudres, les granules et les solutions ou suspensions orales.In the pharmaceutical compositions of the present invention for oral administration, the active ingredients can be administered in unit forms administration, mixed with conventional pharmaceutical carriers, animals and humans for the treatment of the above conditions. Suitable unit dosage forms include, for example, possibly scored tablets, capsules, powders, granules and oral solutions or suspensions.
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'élixir 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.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.
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.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.
Le principe actif peut être formulé également sous forme de microcapsules, éventuellement avec un ou plusieurs supports ou additifs.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.
La quantité de principe actif à administrer dépend, comme toujours, du degré de progression dé la maladie ainsi que de l'âge et du poids du patient.The amount of active ingredient to be administered depends, as always, on the degree of progression of the disease as well as on the age and weight of the patient.
Les doses des deux principes actifs sont analogues à celles normalement retenues dans la technique pour l'administration isolée de chacun de ces principes actifs.The doses of the two active ingredients are analogous to those normally used in the art for the isolated administration of each of these active ingredients.
Les compositions selon l'invention contiennent donc des doses recommandées pour les traitements non combinés, par exemple de 0,5 à 700 mg du composant (a) ou d'un de ses sels pharmaceutiquement acceptables et 0,1 à 50 mg du composant (b) ou d'un de ses sels pharmaceutiquement acceptables ou bien des doses inférieures, étant donné que l'association exerce un effet synergique.The compositions according to the invention therefore contain doses recommended for non-combined treatments, for example from 0.5 to 700 mg of component (a) or of a pharmaceutically acceptable salt thereof and 0.1 to 50 mg of component ( b) or a pharmaceutically acceptable salt thereof or lower doses, since the combination exerts a synergistic effect.
Des compositions avantageuses comprennent par exemple 0,5 à 5 mg de SR 57746 ou d'un de ses sels pharmaceutiquement acceptables et 0,1 à 50 mg d'un inhibiteur de l'acétylcholinestérase ou d'un de ses sels pharmaceutiquement acceptables. Des compositions préférées comprennent 0,5 à 5 mg de SR 57746 ou d'un de ses sels pharmaceutiquement acceptables, notamment du chlorhydrate, et 2 à 10 mg de donepezil ou d'un de ses sels pharmaceutiquement acceptables.Advantageous compositions include, for example, 0.5 to 5 mg of SR 57746 or one of its pharmaceutically acceptable salts and 0.1 to 50 mg of an acetylcholinesterase inhibitor or one of its pharmaceutically acceptable salts. Preferred compositions include 0.5 to 5 mg of SR 57746 or a pharmaceutically acceptable salt thereof, especially the hydrochloride, and 2 to 10 mg of donepezil or one of its pharmaceutically acceptable salts.
Les doses indiquées dans la présente description se réfèrent aux principes actifs sous forme non-salifiée.The doses indicated in the present description refer to the active ingredients in non-salified form.
L'activité de la composition selon l'invention a été mise en évidence en utilisant un modèle spécifique pour le système cholinergique septo-hyppocampique, sur des lésions causées par l'injection de vincristine. Dans ce modèle, on évalue les effets des produits testés sur l'amnésie induite par l'injection de vincristine qui induit des altérations biochimiques similaires aux altérations présentes dans la maladie d'Alzheimer.The activity of the composition according to the invention has been demonstrated using a specific model for the septo-hyppocampal cholinergic system, on lesions caused by the injection of vincristine. In this model, we evaluate the effects of the products tested on amnesia induced by the injection of vincristine which induces biochemical alterations similar to the alterations present in Alzheimer's disease.
Les modes opératoires de ce modèle, lésions causées par la vincristine ainsi que l'évaluation de la mémoire sociale, sont décrits dans EP 655247. Test de l'évaluation de la mémoire sociale chez le rat. Après avoir causé des lésions par injection de vincristine comme décrit dans EPThe operating modes of this model, lesions caused by vincristine as well as the evaluation of social memory, are described in EP 655247. Test of the evaluation of social memory in rats. After causing injury by injection of vincristine as described in EP
655247 les rats présentent une amnésie stable et durable. Les rats sont divisés en deux groupes, un groupe recevant du solvant et l'autre groupe recevant du SR 57746A à la dose de 5 mg/kg p.o., dose qui n'est pas suffisante pour permettre une récupération fonctionnelle en terme de mémoire chez les rats soumis à ce test (la dose efficace étant de 10 mg/kg comme décrit dans EP 655247). La dose de 1 mg/kg i.p. de tacrine est administrée ensuite aux deux groupes de rats. Le groupe témoin, ayant reçu du solvant et de la tacrine, ne montre aucune récupération de la mémoire alors que le groupe ayant été traité par le SR 57746A (dose subefficace) et la tacrine montre une récupération significative des déficits mnésiques. Les résultats de ce test permettent de reconnaître une action synergique à l'association de la présente invention.655247 rats have stable and lasting amnesia. The rats are divided into two groups, one group receiving solvent and the other group receiving SR 57746A at a dose of 5 mg / kg po, a dose which is not sufficient to allow functional recovery in terms of memory in rats subjected to this test (the effective dose being 10 mg / kg as described in EP 655247). The dose of 1 mg / kg i.p. tacrine is then administered to the two groups of rats. The control group, having received solvent and tacrine, shows no recovery of memory while the group having been treated with SR 57746A (sub-effective dose) and tacrine shows a significant recovery of memory deficits. The results of this test make it possible to recognize a synergistic action with the association of the present invention.
Grâce à l'effet complémentaire et synergique des composants de l'association, assurant en même temps la protection voire la guérison des neurones atteints par la maladie ainsi que l'amélioration immédiate des symptômes chez le patient, la composition de l'invention permet un traitement efficace de la DAT dans toutes ses formes. Thanks to the complementary and synergistic effect of the components of the association, ensuring at the same time the protection or even the healing of the neurons affected by the disease as well as the immediate improvement of the symptoms in the patient, the composition of the invention allows a effective treatment of DAT in all its forms.

Claims

REVENDICATIONS 1. Composition pharmaceutique contenant en tant que principes actifs un composant (a) choisi entre la l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétrahydropyridine et un composé (I) CLAIMS 1. Pharmaceutical composition containing as active principles a component (a) chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine and a compound (I)
Figure imgf000011_0001
dans laquelle
Figure imgf000011_0001
in which
Y représente -CH- ou -N-;Y represents -CH- or -N-;
Ri représente l'hydrogène, un halogène, un groupe CF3, (C3~C4)alkyle ou (C1-C4)- alcoxyle; R2 représente l'hydrogène, un halogène, un hydroxyle, un groupe CF3, (C3-C4)- alkyle ou (C1-C )alcoxyle;Ri represents hydrogen, a halogen, a CF 3 group, (C3 ~ C4) alkyl or (C1-C4) - alkoxyl; R2 represents hydrogen, halogen, hydroxyl, CF 3 , (C3-C 4 ) - alkyl or (C 1 -C) alkoxyl;
R3 et R4 représentent chacun l'hydrogène ou un (Cι-C3)alkyle; X représenteR3 and R4 each represent hydrogen or a (Cι-C3) alkyl; X represents
(a) un (C3-C6)alkyle; un (C3-C, )alcoxyle; un (C3-C7)carboxyalkyle; un (C1-C4)- alcoxycarbonyl(C3-C6)alkyle; un (C3-C7)carboxyalcoxyle; ou un (Cι-C4)alcoxy- carbonyl(C3-C6)alcoxyle;(a) a (C3-C6) alkyl; a (C3-C,) alkoxyl; a (C3-C7) carboxyalkyl; a (C1-C4) - alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxyalkoxyl; or a (Cι-C4) alkoxycarbonyl (C3-C6) alkoxyl;
(b) un radical choisi parmi un (C3-C7)cycloalkyle, (C3-C7)cycloalkyloxy, (C3-C7)- cycloalkylméthyle, (C3-C7)cycloalkylamino et cyclohexényle, ledit radical pouvant être substitué par un halogène, hydroxy, (C1-C4)alcoxy, carboxy, (C1-C4)alcoxycarbonyle, amino, mono- ou di-(Cι-C4)alkylamino; ou(b) a radical chosen from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by a halogen, hydroxy, (C 1 -C4) alkoxy, carboxy, (C 1 -C4) alkoxycarbonyl, amino, mono- or di- (Cι-C4) alkylamino; or
(c) un groupe choisi parmi phényle, phénoxy, phénylamino, N-(Cι-C3) kyl-phényl- amino, phénylméthyle, phényléthyle, phénylcarbonyle, phenylthio, phénylsulfonyle, phénylsulfinyle et styryle, ledit groupe pouvant être mono- ou polysubstitué sur le groupe phényle p.ar un halogène, CF3, (Cι-C4)alkyle, (Cι-C4)alcoxy, cyano, amino, mono- ou di-(Cι-C4)alkylamino, (Cι-C4)acylamino, carboxy, (Cι-C4)alcoxycarbonyle, .aminocarbonyle, mono- ou c -(Cι-C4)alkylaminocarbonyle, amino(Cι-C4)alkyle, hydroxy(Cι-C4) kyle ou h£ilogéno(Cι-C4) kyle; éventuellement sous la forme de l'un de ses sels ph-armaceutiquement acceptables, et - un composant (b) actif dans le tr∑ tement symptomatique de la DAT, éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, à la condition que lorsque le composant (a) est autre que la l-(2-napht-2-yléthyl)-4-(3- trifluorométhylphényl)-l,2,3,6-tétπιhydropyridine ou l'un de ses sels pharmaceutiquement acceptables, le composant (b) est un agent inhibiteur de l'acétylcholinestérase.(c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C3) kyl-phenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group by halogen, CF3, (Cι-C4) alkyl, (Cι-C4) alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, ( Cι-C4) alkoxycarbonyl, .aminocarbonyl, mono- or c - (Cι-C4) alkylaminocarbonyl, amino (Cι-C4) alkyl, hydroxy (Cι-C4) kyle or h £ ilo (Cι-C4) kyle; optionally in the form of one of its ph-armaceutically acceptable salts, and - a component (b) active in the highly symptomatic of DAT, optionally in the form of one of its pharmaceutically acceptable salts, with the provided that when component (a) is other than l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tétπιhydropyridine or one of its salts pharmaceutically acceptable, component (b) is an acetylcholinesterase inhibitor agent.
2. Composition selon la revendication 1 caractérisée en ce qu'elle contient en tant que principes actifs la l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables en association avec un composé actif dans le traitement symptomatique de la démence sénile du type Alzheimer éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables.2. Composition according to claim 1 characterized in that it contains as active principles l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6-tetrahydropyridine optionally in the form of one of its pharmaceutically acceptable salts in association with a compound active in the symptomatic treatment of senile dementia of the Alzheimer type optionally in the form of one of its pharmaceutically acceptable salts.
3. Composition selon la revendication 1 caractérisée en ce qu'elle contient en tant que principes actifs3. Composition according to claim 1 characterized in that it contains as active principles
- un composé de formule (I)- a compound of formula (I)
Figure imgf000012_0001
dans laquelle
Figure imgf000012_0001
in which
Y représente -CH- ou -N-; Rj représente l'hydrogène, un halogène, un groupe CF3, (C3-C4)alkyle ou
Figure imgf000012_0002
Y represents -CH- or -N-; R j represents hydrogen, a halogen, a group CF 3 , (C3-C4) alkyl or
Figure imgf000012_0002
.alcoxyle;.alkoxyl;
R2 représente l'hydrogène, un halogène, un hydroxyle, un groupe CF3, (C3-C4)- alkyle ou (Cι-C4)alcoxyle;R2 represents hydrogen, a halogen, a hydroxyl, a group CF 3 , (C3-C4) - alkyl or (Cι-C 4 ) alkoxyl;
R3 et R4 représentent chacun l'hydrogène ou un (Cι-C3)alkyle; X représenteR3 and R4 each represent hydrogen or a (Cι-C 3 ) alkyl; X represents
(a) un (C3-Cg)alkyle; un (C3-C,5)alcoxyle; un (C3-C7)carboxyalkyle; un
Figure imgf000012_0003
alcoxycarbonyl(C3-C6)alkyle; un (C3-C7)carboxy.alcoxyle; ou un (Cι-C4)alcoxy- carbonyl(C3-C6).alcoxyle;
(a) a (C3-Cg) alkyl; a (C3-C, 5) alkoxyl; a (C3-C7) carboxyalkyl; a
Figure imgf000012_0003
alkoxycarbonyl (C3-C6) alkyl; a (C3-C7) carboxy.alkoxyl; or a (Cι-C4) alkoxycarbonyl (C3-C6) .alkoxyl;
(b) un radical choisi parmi un (C3-C7)cycloalkyle, (C3-C7)cycloalkyloxy, (C3-C7)- cycloalkylméthyle, (C3-C7)cycloalkylamino et cyclohexényle, ledit radical pouvant être substitué p.ar un halogène, hydroxy, (Cι-C4) coxy, carboxy, (Cι-C4)alcoxycarbonyle, amino, mono- ou di-(Cι-C4)alkylamino; ou(b) a radical chosen from a (C3-C7) cycloalkyl, (C3-C7) cycloalkyloxy, (C3-C7) - cycloalkylmethyl, (C3-C7) cycloalkylamino and cyclohexenyl, said radical possibly being substituted by halogen, hydroxy, (Cι-C4) coxy, carboxy, (Cι-C4) alkoxycarbonyl, amino, mono- or di- (Cι-C4) alkylamino; or
(c) un groupe choisi parmi phényle, phénoxy, phénylamino, N-(Cι-C3)alkyl-phényl- amino, phénylméthyle, phényléthyle, phénylcarbonyle, phenylthio, phénylsulfonyle, phénylsulfmyle et styryle, ledit groupe pouvant être mono- ou polysubstitué sur le groupe phényle par un halogène, CF3, (Cι-C4)alkyle, (Cι-C4).alcoxy, cyano, amino, mono- ou di-(Cι-C4)alkylamino, (Cι-C4)acylamino, carboxy, (Cj-C4)alcoxycarbonyle, aminocarbonyle, mono- ou di-(Cι-C4)alkylarninocarbonyle, amino(Cj-C4)alkyle, hydroxy (Cι-C4)dkyle ou h.alogéno(Cι-C4).alkyle; éventuellement sous la forme de l'un de ses sels pharmaceutiquement acceptables, et(c) a group chosen from phenyl, phenoxy, phenylamino, N- (Cι-C3) alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfmyl and styryl, said group possibly being mono- or polysubstituted on the phenyl group by halogen, CF3, (Cι-C4) alkyl, (Cι-C4) .alkoxy, cyano, amino, mono- or di- (Cι-C4) alkylamino, (Cι-C4) acylamino, carboxy, (Cj -C4) alkoxycarbonyl, aminocarbonyl, mono- or di- (Cι-C4) alkylarninocarbonyl, amino (Cj-C4) alkyl, hydroxy (Cι-C4) dkyle or h.alo (Cι-C4) .alkyl; optionally in the form of one of its pharmaceutically acceptable salts, and
- un agent inhibiteur de l'acétylcholinestérase, ou un sel pharmaceutiquement acceptable de celui-ci. - an acetylcholinesterase inhibitor agent, or a pharmaceutically acceptable salt thereof.
4. Composition selon la revendication 3 caractérisée en ce que le composant (a) est la 1-4. Composition according to claim 3 characterized in that the component (a) is 1-
[2-(4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l ,2,3,6-tétrahydropyridine ou son sel chlorhydrate.[2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine or its hydrochloride salt.
5. Composition selon la revendication 3 caractérisée en ce que le composant (a) est choisi parmi les composés suivants: l-[2-(3'-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétra- hydropyridine; l-[2-(2'-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhyl-phényl)- 1 ,2,3 ,6- tétrahydropyridine; l-[2-(4'-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétra- hydropyridine; l-[2-(4'-fluoro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétr.ahy dropyridine ; l-[2-(3'-trifluorométhyl-4-biphénylyl)éthyl]-4-(3-trifluorométhylρhényl)-l,2,3,6- tétr.ahydropyridine; l-[2-(4-cyclohexylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétr^ydropyridine; l-[.2-(4-biphénylyl) éthyl]-4-(4-fluorophényl)-l,2,3,6-tétrahydroρyridine; l-[2-(4-biphénylyl)-2-méthylpropyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétr^y dropyridine ; l-[2-(4-phénoxyphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétr^ydropyridine; l-[2-(4-benzylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrώydropyridine; l-[2-(4-n-butylphényl)éthyl]-4-(3-trifluorométhylρhényl)-l,2,3,6-tétrahydroρyridine; l-[2-(4-n-butoxyphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrώydropyridine; l-[2-(4-(4-éthoxycMbonylpropoxy)phényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(4-biρhénylyl)éthyl]-4-(6-chloropyrid-2-yl)-l,2,3, 6-tétrahydropyridine; l-[2-(2,3'-dichloro-4-biphenylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6,- tétr.ahydropyridine; l-[2-(3-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylρhényl)-l,2,3,6- tétr.ahydropyridine; l-[2-(3',5'-dichloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétr.ahydropyridine; l-[2-(2*,4'-dichloro-4-biphénylyl)éthyl]-4-(3-trifluorométhyl-hényl)-l,2,3,6- tétrahydropyridine ; l-[2-(2-chloro-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1,2,3,6- tétrahydropyridine; l-[2-(3'chloro-4-biρhénylyl)-2-méthylpropyl]-4-(3-trifluorométhylρhényl)-l,2,3,6- tétrahydropyridine; l-[2-(2-fluoro-4-biphénylyl)propyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine ; l-[2-(4-méthoxy-3-biphénylyl)éthyl]-4-(3-trifluorométhylphé nyl)- 1 ,2,3,6-tétrahydropyridine; l.[2-(4'-méthoxy-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(4'-hydroxy-4-biphénylyl)éthyl]-4-(3-trifluorométhyl-phényl)-l,2,3,6- tétrahydropyridine; l-[2-(4'-éthoxycarbonylbutoxy-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine; l-[2-(3-biphénylyl)-éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine;5. Composition according to claim 3 characterized in that component (a) is chosen from the following compounds: l- [2- (3'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -l , 2,3,6-tetrahydropyridine; 1- [2- (2'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-phenyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (4'-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr.ahy dropyridine; 1- [2- (3'-trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-cyclohexylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ ydropyridine; 1 - [. 2- (4-biphenylyl) ethyl] -4- (4-fluorophenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (4-biphenylyl) -2-methylpropyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ y dropyridine; 1- [2- (4-phenoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetr ^ ydropyridine; 1- [2- (4-benzylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrώydropyridine; 1- [2- (4-n-butylphenyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydroρyridine; 1- [2- (4-n-butoxyphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrώydropyridine; 1- [2- (4- (4-ethoxycMbonylpropoxy) phenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-biρhenylyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; 1- [2- (2,3'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6, - tet.ahydropyridine; 1- [2- (3-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3 ', 5'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2 * , 4'-dichloro-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-hényl) -1,2,3,6-tetrahydropyridine; 1- [2- (2-chloro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (3'chloro-4-biρhenylyl) -2-methylpropyl] -4- (3-trifluoromethylρhenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (2-fluoro-4-biphenylyl) propyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-methoxy-3-biphenylyl) ethyl] -4- (3-trifluoromethylphé nyl) - 1,2,3,6-tetrahydropyridine; 1. [2- (4'-methoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-hydroxy-4-biphenylyl) ethyl] -4- (3-trifluoromethyl-phenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4'-ethoxycarbonylbutoxy-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3-biphenylyl) -ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine;
1 -[2-(3 ' chloro-4' -fluoro-4-biphénylyl)éthyl] -4-(3-trifluorométhy lphényl)- 1 ,2,3 ,6- tétrahydropyridine; l-[2-(2'trifluorométhyl-4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine ; l-[2-(3,4-diisobutylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahy dropyridine ; l-[2-(3,4-dipropylphényl)éthyl]-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine; l-[2-(4-cyclohexylphényl)éthyl]-4-(6-chloropyrid-2-yl)-l,2,3,6-tétr^ydropyridine; l-[2-(4-isobutylphényl)-propyl]-4-(6-chloropyrid-2-yl)-l,2,3,6-tétrahydropyridine; et leurs sels pharmaceutiquement acceptables.1 - [2- (3 'chloro-4' -fluoro-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetrahydropyridine; 1- [2- (2'trifluoromethyl-4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (3,4-diisobutylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahy dropyridine; 1- [2- (3,4-dipropylphenyl) ethyl] -4- (3-trifluoromethylphenyl) -1,2,3,6-tetrahydropyridine; 1- [2- (4-cyclohexylphenyl) ethyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetr ^ ydropyridine; 1- [2- (4-isobutylphenyl) -propyl] -4- (6-chloropyrid-2-yl) -1,2,3,6-tetrahydropyridine; and their pharmaceutically acceptable salts.
6. Composition selon la revendication 1 caractérisée en ce que le composé actif dans le tr tement symptomatique de la démence sénile du type Alzheimer est choisi parmi les inhibiteurs de acétylcholinestérase, les agonistes muscariniques Mi, les agonistes nicotiniques, les antagonistes du récepteur NMDA et les nootropiques6. Composition according to claim 1 characterized in that the active compound in the symptomatic treatment of senile dementia of the Alzheimer type is chosen from acetylcholinesterase inhibitors, Mi muscarinic agonists, nicotinic agonists, NMDA receptor antagonists and nootropics
7. Composition selon la revendication 6 caractérisée en ce que le composant (b) est un agent inhibiteur de l'acétylcholinestérase.7. Composition according to claim 6 characterized in that component (b) is an acetylcholinesterase inhibitor agent.
8. Composition selon la revendication 7 caractérisé en ce que l'inhibiteur de l'acétylcholinestérase est choisi entre la tacrine et le donépezil.8. Composition according to claim 7 characterized in that the acetylcholinesterase inhibitor is chosen between tacrine and donepezil.
9. Composition selon la revendication 7 caractérisé en ce que l'inhibiteur de l'acétylcholinestérase est choisi parmi la rivastigmine, la galanthamine, le métrifonate, l'eptastigmine, la velnacrine, la physostigmine, l'icozépil et le zifrosilone.9. Composition according to claim 7 characterized in that the acetylcholinesterase inhibitor is chosen from rivastigmine, galanthamine, metrifonate, eptastigmine, velnacrine, physostigmine, icoepepil and zifrosilone.
10. Composition selon la revendication 1 caractérisé en ce qu'elle contient de 0,5 à 700 mg du composant (a). 11 Composition selon la revendication 1 caractérisé en ce qu'elle contient de 0,1 à 50 mg du composant (b).10. Composition according to claim 1 characterized in that it contains from 0.5 to 700 mg of component (a). 11 Composition according to claim 1 characterized in that it contains from 0.1 to 50 mg of component (b).
12 Composition selon la revendication 2 caractérisé en ce qu'elle contient de 0,5 à 10 mg de la l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l,2,3,6- tétrahydropyridine.12 Composition according to claim 2 characterized in that it contains from 0.5 to 10 mg of l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tetrahydropyridine.
13 Composition selon la revendication 2 caractérisé en ce qu'elle contient en tant que principes actifs la l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l, 2,3,6- tétr∑ihydropyridine et le donépezil ou leurs sels ph.armaceutiquement acceptables.13 Composition according to claim 2 characterized in that it contains as active principles l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tétr∑ihydropyridine and donepezil or their ph.armaceutically acceptable salts.
14 Composition selon la revendication 3 caractérisé en ce qu'elle contient en tant que principes actifs la l-[2-(4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1,2,3,6- tétrahydropyridine et le donépezil ou leurs sels ph.armaceutiquement acceptables.14 Composition according to Claim 3, characterized in that it contains, as active principles, l- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6- tetrahydropyridine and donepezil or their ph.armaceutically acceptable salts.
15 Composition selon la revendication 2 contenant 0,5 à 5 mg de chlorhydrate de 1- (2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l,2,3,6-tétrahydropyridine et 2 à 10 mg de donépezil. 16 Composition selon l'une quelconque des revendications précédentes pour le traitement de la démence sénile du type Alzheimer.15 Composition according to Claim 2 containing 0.5 to 5 mg of 1- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -1, 2,3,6-tetrahydropyridine hydrochloride and 2 to 10 mg of donepezil. 16 Composition according to any one of the preceding claims for the treatment of senile dementia of the Alzheimer type.
17 Utilisation de la composition selon l'une quelconque des revendications précédentes pour la préparation de médicaments destinés au traitement de la démence sénile du type Alzheimer. 18 Utilisation selon la revendication 17 caractérisée en ce que le composant (a) est choisi parmi la l-(2-napht-2-yléthyl)-4-(3-trifluorométhylphényl)-l,2,3,6- tétr.ahydropyridine et la l-[2-(4-biphénylyl)éthyl]-4-(3-trifluorométhylphényl)- 1,2,3,6- tétr.ahydropyridine.17 Use of the composition according to any one of the preceding claims for the preparation of medicaments intended for the treatment of senile dementia of the Alzheimer type. 18 Use according to claim 17 characterized in that the component (a) is chosen from l- (2-naphth-2-ylethyl) -4- (3-trifluoromethylphenyl) -l, 2,3,6- tet.ahydropyridine and 1- [2- (4-biphenylyl) ethyl] -4- (3-trifluoromethylphenyl) - 1,2,3,6-tetr.ahydropyridine.
19 Utilisation selon la revendication 17 caractérisée en ce que le composant (b) est choisi entre la tacrine et le donépezil. 19 Use according to claim 17 characterized in that the component (b) is chosen between tacrine and donepezil.
PCT/FR1998/002384 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia WO1999025363A1 (en)

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EP98954538A EP1030671A1 (en) 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
PL98340500A PL194597B1 (en) 1997-11-14 1998-11-09 Combination of active ingredients, in particular of tetrahydropyridines and acetylocholinesterases inhibiting agents, useful in treatment of senile dementia of alzheimer type
EA200000412A EA003255B1 (en) 1997-11-14 1998-11-09 Combination of tetrahydropyridin derivatives and acetylcholinesterase inhibiting agents for treating senile dementia such as alzheimer dementia
JP2000520796A JP2001523642A (en) 1997-11-14 1998-11-09 Active ingredients for treating senile dementia such as Alzheimer's dementia, especially the combination of tetrahydropyridines and acetylcholinesterase inhibitors
HU0100098A HUP0100098A3 (en) 1997-11-14 1998-11-09 Pharmaceutical combination of active princeples, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
NZ504420A NZ504420A (en) 1997-11-14 1998-11-09 Combination of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
AU11609/99A AU743228B2 (en) 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as Alzheimer dementia
SK711-2000A SK286040B6 (en) 1997-11-14 1998-11-09 Pharmaceutical composition containing 1-(2-napht-2-ylethyl)-4-(3- trifluoromethylphenyl)-1,2,3,6-tetrahydropyridin hydrochloride and donepezil or tacrine
CA002309966A CA2309966A1 (en) 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
EEP200000290A EE04235B1 (en) 1997-11-14 1998-11-09 Combination of active substances, namely tetrahydropyridines and acetylcholinesterase inhibitors, for the treatment of senile dementia of the Alzheimer's disease type
IL13612298A IL136122A0 (en) 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridines and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
BR9814035-3A BR9814035A (en) 1997-11-14 1998-11-09 Association of active ingredients, notably tetrahydropyridines and acetylcholinesterase inhibiting agents, for the treatment of senile dementia of the alzheimer type.
KR1020007005231A KR100599350B1 (en) 1997-11-14 1998-11-09 Combination of active principles, in particular of tetrahydropyridins and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
IS5482A IS5482A (en) 1997-11-14 2000-05-09 Composition of active ingredients especially of tetrahydropyridine and acetylcholine esterase inhibitory agent for the treatment of dementia such as Alzheimer's dementia
NO20002450A NO20002450L (en) 1997-11-14 2000-05-11 Composition of active ingredients, in particular tetrahydropyridines and acetylcholinesterase inhibitors, for the treatment of senile dementia of Alzheimer's type
IL136122A IL136122A (en) 1997-11-14 2000-05-14 Combination of active principles, in particular of tetrahydropyridines and acetylcholinesterase inhibiting agents, for treating senile dementia such as alzheimer dementia
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AU2018269964B2 (en) * 2017-05-15 2022-07-07 Cognition Therapeutics, Inc. Compositions for treating neurodegenerative diseases

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