EP2293790A2 - Combination of a nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition containing same and use thereof in the treatment of cognitive disorders - Google Patents
Combination of a nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition containing same and use thereof in the treatment of cognitive disordersInfo
- Publication number
- EP2293790A2 EP2293790A2 EP09769521A EP09769521A EP2293790A2 EP 2293790 A2 EP2293790 A2 EP 2293790A2 EP 09769521 A EP09769521 A EP 09769521A EP 09769521 A EP09769521 A EP 09769521A EP 2293790 A2 EP2293790 A2 EP 2293790A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- partial agonist
- alpha
- acetylcholinesterase inhibitor
- type
- nicotinic receptors
- 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- Withdrawn
Links
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- 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
- A61P25/28—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to the combination of a partial agonist of alpha 7 nicotinic receptors and an acetylcholirvestera.se inhibitor, to a pharmaceutical composition comprising the combination of the invention and its use in the treatment of cognitive disorders, and more particularly cognitive disorders related to Alzheimer 's disease.
- the aim of the invention is to answer this technical problem by proposing a combination of a partial agonist of nicotinic receptors of alpha 7 type and of an acetylcholinesterase inhibitor.
- Partial nicotinic alpha7-type agonists have been described as possessing pro-cognitive properties in several animal models that interrogate different types of memory or cognitive functions (Biton et al., Neuropsychopharmacology, 2007, 32. 1-16, Pichat et al., Neuropsychopharmacology, 2007, 32: 17-34).
- a first subject of the invention relates to a combination of a partial agonist of nicotinic type alpha 7 receptors and an acetylcholinesterase inhibitor.
- a second subject of the invention relates to a pharmaceutical composition comprising, as active ingredient, such an association.
- a third subject of the invention relates to the use of such an association for the treatment of cognitive disorders of various origins, and more particularly cognitive disorders related to Alzheimer's disease.
- partial agonists of the nicotinic receptors of alpha 7 type of the invention mention may be made of the agonists partial nicotinic receptors alpha 7 type of general formula (I)
- n represents the number 0, 1 or 2
- R 1 , R 2 , R 3 , R 4 and R 5 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxy group,
- R 2 and R 3 together form a group of formula -OCH 2 O- or -CH 2 CH 2 CH 2 CH 2 -, in the form of a base or of a salt of addition to an acid, hydrate or solvate.
- t and z can take the values from 1 to 6: a carbon chain may have from t to 2 carbon atoms, for example C 1 -C 3 a carbon chain which may have from 1 to 3 atoms of carbon ;
- halogen atom a fluorine, chlorine, bromine or iodine atom
- alkyl group a saturated linear or branched aliphatic group.
- an alkoxy group an -O-alkyl radical whose group alkyl is as previously defined.
- salts of the compounds of general formula (I) that can be used according to the invention can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) , are also part of the invention.
- the compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
- a first group of compounds of formula (I) that can be used according to the invention is that in which X represents an oxygen atom.
- a second group of compounds of formula (I) that can be used according to the invention is that in which n represents the number 0.
- a third group of compounds of formula (I) that can be used according to the invention is that in which R 1 , R 2 , R 3 , R 4 and R 5 each represent, independently of one another, a hydrogen atom. or halogen.
- the fourth group of compounds of formula (I) that can be used according to the invention is that in which R 1 , R 2 , R 4 and R 5 each represent a hydrogen atom and R 3 represents a halogen atom.
- a fifth group of compounds of formula (I) that can be used according to the invention is that in which X represents an oxygen atom; n represents the number 0; R 1 , R 2 , R 4 and R 5 each represent a hydrogen atom and R 3 represents a halogen atom.
- An example of a salt of 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate which can be used according to the invention is the fumarate salt ((2E) -but-2-enedioate).
- the acetylcholinesterase inhibitor may be chosen from all the acetylcholinesterase inhibitors known in the literature.
- combination according to the invention is the combination consisting of (2E) -but-2-enedioate 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxyléite and donepezil.
- the pharmaceutical composition contains a minimum active dose of each active ingredient present in the combination according to the invention.
- the invention also relates to a pharmaceutical composition containing a sub-active dose of each active ingredient present in the combination according to the invention.
- a pharmaceutical composition containing a sub-active dose of each active ingredient present in the combination according to the invention.
- the use of such sub-active doses may make it possible to avoid the side effects of one or more active ingredients present in the combination according to the invention.
- the excipients are selected according to the desired pharmaceutical form and method of administration from among the usual excipients which are known to those skilled in the art.
- the composition may be administered orally, parenterally or rectally.
- Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intra-muscular or intravenous administration forms, rectal administration forms and implants.
- the active ingredients according to the invention can be used in creams, gels, ointments or lotions.
- the two active ingredients are administered in the same way, for example the oral route, or one of the active ingredients is administered according to a first route, for example the oral route, and the other active ingredient is administered in a different way, for example the parenteral route.
- the active ingredients are mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
- pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
- the doses depend on the desired effect, the duration of treatment and the route of administration used.
- the daily doses of each of the active ingredients of the combination according to the invention are as follows: partial agonists of nicotinic receptors of alpha 7 type: between 0.5 and 500 mg per day and per person, in particular between 1 and 100 mg per day and per person; acetylcholinesterase inhibitor: between 3 and 200 mg per day and per person, in particular between 5 and 100 mg per day and per person,
- a unitary form of administration of the alpha 7-type nicotinic receptor-type partial agonist in the form of a tablet comprises the following ingredients:
- a unitary form of administration of the acetylcholinesterase inhibitor in the form of a tablet may comprise 10 mg of the acetylcholinesterase inhibitor and of the usual excipients, for example microcrystalline cellulose, silica colloidal, talc, croscarmellose sodium, magnesium stearate.
- the two active ingredients can be combined in a single pharmaceutical composition, comprising the two active ingredients, such as a tablet or a capsule.
- the two active ingredients may also, whether administered simultaneously or not, be present in separate pharmaceutical compositions.
- the combination according to the invention may be in the form of a kit comprising, on the one hand, at least one partial agonist of nicotinic receptors of alpha 7 type as defined above and, on the other hand at least one acetylcholinesterase inhibitor as hereinbefore defined, the alpha 7 nicotinic receptor partial agonist and the acetylcholinesterase inhibitor being in separate compartments and intended to be administered simultaneously, separately or spread over time (sequential administration).
- Another subject of the invention relates to the use of an association as described above for the preparation of a medicinal product intended for the treatment of cognitive disorders, and more particularly cognitive disorders related to Alzheimer 's disease.
- the invention also relates to a method for treating cognitive disorders, and more particularly cognitive disorders related to Alzheimer's disease, which comprises administering to a patient a minimum active or sub-active dose of a alpha-type nicotinic receptor partial agonist as defined above, and a minimum active or sub-active dose of an acetylcholinesterase inhibitor as defined above, said doses being administered simultaneously, separately or separately. sequential, as described above.
- the aim is to highlight the superior effect of the association on the amplitude of the pro-cognitive pharmacological effect compared to the effect produced by the two active ingredients taken individually in the treatment of these cognitive disorders.
- a first study aimed at demonstrating in the adult rat a procognitive synergy of the combination according to the invention in an episodic visual memory task, using a spontaneous forgetfulness protocol in the object recognition test.
- Phase of habituation Given this protocol, the animals are first subjected to a session of habituation to the environmental context (a wooden enclosure of 65 x 45 x 45 cm) for a duration of 2 minutes. The time spent in active locomotion is measured using a stopwatch.
- Reminder session The reminder session takes place after 24h for all groups.
- the rats are confronted with a pair of objects consisting of the object encountered during the learning phase, and an unknown object.
- the rats are deposited in the same way as for the learning session.
- the exploration of an object is counted if the animal orients its muzzle towards the object, within a perimeter of 2 centimeters around it, or he touches him with his muzzle or paws. If the rat turns around the object or sits above, these behaviors are not considered exploratory.
- test compounds are administered orally 60 minutes (rat study) before each of the three sessions of the protocol.
- the exploration times of the two objects expressed in seconds and the recognition index (exploration duration of the new object / total exploration time new and familiar objects) are measured.
- Similar exploration times vis-à-vis the familiar object and the new object reflect an oblivion of the familiar object and therefore a deficiency of episodic visual memory.
- a longer duration of exploration of the new object than of the familiar object reflects a significant rernemoration of the familiar object and thus an improvement of the episodic visual memory.
- a low recognition index indicates an oblivion of the familiar object and therefore a deficiency of the episodic visual memory.
- Figure 1 and Table 1 show the time spent in locomotion during the session of accommodation for each of the experimental groups.
- Table 2 and Figures 2 and 3 show: the duration of exploration (in seconds) of the two objects, new and familiar; and the recognition index as defined above; during the booster session for each of the experimental groups.
- amyloid peptide A ⁇ 25-35 is dissolved in distilled water at a final concentration of 3 mg / ml. It is then incubated at 37 ° C for A days to form aggregates of toxic peptide.
- the control animals receive the mixed peptide ("scrambled peptide"), consisting of the same amino acids, but organized in a random sequence. This mixed peptide has no neuronal (non-toxic) toxicity.
- the behavioral experimental protocol used is comparable to that used in the test of spontaneous forgetfulness in rats, described above.
- mice Phase getting used; In this protocol, the mice are first subjected to a session of habituation to the environmental context ⁇ a light gray PVC enclosure of 52 x 52 x 40 cm, lighting at 6 Lux) for a duration of 10 minutes. The time spent in active locomotion is measured using a stopwatch.
- Reminder session The reminder session takes place after a 1-hour forget-out period for all groups. This short period of forgetfulness induces good booster performance in control animals and makes it possible to demonstrate a deficit induced by the injection of toxic peptide in the other animals.
- the mice are confronted with a pair of objects consisting of the object encountered during the learning phase, and an unknown object. The mice are deposited in the anceinte in the same way as for the learning session. This test lasts 5 minutes during which we measure the time spent exploring each of the 2 objects.
- An animai control will present, for this period of short forgetfulness, a more important exploration of the new object, translating a significant remembrance of the familiar object.
- deficit animals will have exploration durations of the two objects that are not statistically different.
- the exploration of an object is counted if the animal orients its muzzle towards the object, within a perimeter of 2 centimeters around it, or 'he touches him with his snout or his paws' If the rat turns around the object or sits on it, these behaviors are not considered exploratory.
- the raw data is expressed in seconds.
- the compounds to be tested are administered intraperitoneally, 60 minutes before each of the three sessions of the protocol.
- the index of recognition (duration of exploration of the new object / total duration of exploration of new and familiar objects) is also measured.
- a low recognition index reflects an omission of the familiar object and therefore a complete abolition of short-term recall performance.
- the set of results obtained in the two series of experiments above demonstrates the superior effect of the combination according to the invention in terms of efficacy with respect to each of the active ingredients administered in isolation and at the same dosage. on visual episodic memory disorders in a task of object recognition in rodents. This superior effect is observed not only in non-deficient animals whose performance is improved, but also in a pathophysiological model of Alzheimer's disease, using intracerebral injections of toxic amyloid peptide.
- This higher effect is representative of the effectiveness of the combination according to the invention on cognitive disorders, and more particularly on the cognitive disorders related to Alzheimer's disease, a pathology for which this type of cognitive function is known to be particularly impaired.
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Abstract
The present invention relates to the combination of an alpha-7 nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor. The invention also relates to a pharmaceutical composition comprising the combination according to the invention and to the use thereof in the treatment of cognitive disorders.
Description
ASSOCIATION D'UN AGONISTE PARTIEL DES RECEPTEURS NICOTINIQUES ET D'UN INHIBITEUR D'ACETYLCHOLINESTERASE, COMPOSITION PHARMACEUTIQUE LA CONTENANT ET SON UTILISATION DANS LE TRAITEMENT DES TROUBLES COGNITIFS. ASSOCIATION OF A PARTIAL NICOTINIC RECEPTOR AGONIST AND AN ACETYLCHOLINESTERASE INHIBITOR, A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND USE THEREOF IN THE TREATMENT OF COGNITIVE DISORDERS
L'invention se rapporte à l'association d'un agoniste partiel des récepteurs nicotiniques de type alpha 7 et d'un inhibiteur d' acetylcholirvestera.se, à une composition pharmaceutique comprenant l'association de l'invention et à son utilisation dans le traitement des troubles cognitifs, et plus particulièrement des troubles cognitifs liés à la maladie d' Alzheimer .The invention relates to the combination of a partial agonist of alpha 7 nicotinic receptors and an acetylcholirvestera.se inhibitor, to a pharmaceutical composition comprising the combination of the invention and its use in the treatment of cognitive disorders, and more particularly cognitive disorders related to Alzheimer 's disease.
Par troubles cognitifs, on entend les déficits des fonctions intellectuelles supérieures qui concernent, entre autres, les troubles de la mémoire à court terme et à long terme, de la mémoire de travail, des processus attentionnels et de la vigilance, de la mémoire sémantique, de la mémoire spatiale, les troubles des fonctions executives supérieures (abstraction et planification, jugement) .Cognitive disorders are defined as deficits of higher intellectual functions which concern, among others, short-term and long-term memory disorders, working memory, attentional processes and vigilance, semantic memory, of spatial memory, disorders of higher executive functions (abstraction and planning, judgment).
Les patients atteints de troubles cognitifs liés à la maladie d'Alzheimer sont actuellement traités par l'administration d'inhibiteurs de l'acétylcholinestérase.Patients with cognitive impairment related to Alzheimer's disease are currently treated with acetylcholinesterase inhibitors.
L'une des difficultés des traitements des troubles cognitifs liés à la maladie d'Alzheimer par les inhibiteurs de l'acétylcholinestérase réside dans le fait que de nombreux patients traités développent progressivement des effets secondaires indésirables avec la répétition des administrations. Ainsi, 10% à 15% des patients traités sont obligés d'arrêter les traitements du fait des effets secondaires de type gastro-intestinaux (nausées,
vomissements, diarrhées) et 40% des patients traités ne peuvent recevoir une dose thérapeutique optimale du fait de ces effets secondaires. En outre, seuls 30% à 50% des patients traités répondent au traitement et les effets thérapeutiques observés ne consistent souvent qu'en une simple stabilisation modérée des symptômes {voir pour revue le rapport Alzheimer's disease, Décision Resourcea, USA, June 2006) .One of the difficulties in treating cognitive disorders related to Alzheimer's disease by acetylcholinesterase inhibitors lies in the fact that many treated patients progressively develop undesirable side effects with the repetition of administrations. Thus, 10% to 15% of the treated patients are obliged to stop the treatments because of the gastrointestinal side effects (nausea, vomiting, diarrhea) and 40% of treated patients can not receive an optimal therapeutic dose because of these side effects. In addition, only 30% to 50% of treated patients respond to treatment and the observed therapeutic effects often consist only of a simple mild stabilization of symptoms (see review Alzheimer's disease report, Resourcea Decision, USA, June 2006).
II est par conséquent nécessaire de trouver des médicaments plus efficaces pour traiter les patients souffrants de troubles cognitifs, et plus particulièrement des troubles cognitifs liés à la maladie d'Aizheimer, qui de plus présenteraient moins d'effets secondaires indésirables.It is therefore necessary to find more effective drugs to treat patients suffering from cognitive disorders, and more particularly cognitive disorders related to Aizheimer's disease, which furthermore have less undesirable side effects.
L'invention vise à répondre à ce problème technique, en proposant une association d'un agoniste partiel des récepteurs nicotiniques de type alpha 7 et d'un inhibiteur d' acétylcholinestérase,The aim of the invention is to answer this technical problem by proposing a combination of a partial agonist of nicotinic receptors of alpha 7 type and of an acetylcholinesterase inhibitor.
Les agonistes partiels des récepteurs nicotiniques de type alpha 7 (α7-nAChRs) ont été décrits comme possédant des propriétés pro-cognitives dans plusieurs modèles animaux interrogeant différents types de mémoire ou de fonctions cognitives (Biton et al., Neuropsychopharmacology, 2007, 32 .1-16 ; Pichat et al., Neuropsychopharmacology, 2007, 32 :17-34) .Partial nicotinic alpha7-type agonists (α7-nAChRs) have been described as possessing pro-cognitive properties in several animal models that interrogate different types of memory or cognitive functions (Biton et al., Neuropsychopharmacology, 2007, 32. 1-16, Pichat et al., Neuropsychopharmacology, 2007, 32: 17-34).
L'utilisation d'un agoniste partiel et non d'un agoniste complet représente une avancée technologique significative. En effet, le récepteur nicotinique alpha 7 est connu pour présenter des phénomènes de désensibilisation rapide et prononcée. Un agoniste partiel, contrairement à un agoniste complet, ne désensibilisera que très peu le récepteur, ce qui se traduira par une persistance des effets thérapeutiques avec la répétition des traitements.
L'association de l'invention présente une action améliorée par rapport à l'action des deux principes actifs pris individuellement. En effet, on observe un effet supérieur de l'association sur l'amplitude de l'effet pharraacologique pro-cogn.itif par rapport a l'effet produit par les deux principes actifs pris individuellement. Cet effet supérieur de l'association permettrait :The use of a partial agonist and not a complete agonist represents a significant technological advance. Indeed, the nicotinic receptor alpha 7 is known to exhibit rapid and pronounced desensitization phenomena. A partial agonist, unlike a complete agonist, will desensitize very little receptor, which will result in persistence of therapeutic effects with the repetition of treatments. The combination of the invention has an improved action compared to the action of the two active ingredients taken individually. Indeed, we observe a higher effect of the association on the amplitude of the pharraacological pro-cognitive effect compared to the effect produced by the two active ingredients taken individually. This superior effect of the association would allow:
- de diminuer la dose prescrite et donc permet une meilleure tolérance du traitement (diminution des effets secondaires gastro-intestinaux) ;- to reduce the prescribed dose and therefore allows a better tolerance of treatment (reduction of gastrointestinal side effects);
- la possibilité d'une durée de traitement des patients plus longue, du fait de la meilleure tolérance ;the possibility of a longer patient treatment time, because of the better tolerance;
- l'augmentation du pourcentage do patients répondeurs au traitement associatif par rapport au traitement par les inhibiteurs de l'acétyleholinestérase seuls.the increase in the percentage of patients responding to the associative treatment compared with the treatment with the acetyl cholinesterase inhibitors alone.
Un premier objet de l'invention concerne une association d'un agoniste partiel des récepteurs nicotiniques de type alpha 7 et d'un inhibiteur d' acétyleholinestérase.A first subject of the invention relates to a combination of a partial agonist of nicotinic type alpha 7 receptors and an acetylcholinesterase inhibitor.
Un deuxième objet de l'invention concerne une composition pharmaceutique comprenant, à titre de principe actif, une telle association.A second subject of the invention relates to a pharmaceutical composition comprising, as active ingredient, such an association.
Un troisième objet de l'invention se rapporte à l'utilisation d'une telle association pour le traitement des troubles cognitifs d'origines variées, et plus particulièrement des troubles cognitifs liés à la maladie d'Alzheimer .A third subject of the invention relates to the use of such an association for the treatment of cognitive disorders of various origins, and more particularly cognitive disorders related to Alzheimer's disease.
Ainsi, un premier objet de l'invention se rapporte é l'association d'un agoniste partiel des récepteurs nicotiniques de type alpha 7 et d'un inhibiteur d' acétyleholinestérase.Thus, a first object of the invention relates to the combination of a partial agonist of nicotinic receptors of alpha 7 type and of an acetylcholinesterase inhibitor.
Parmi, les agonistes partiels des récepteurs nicotiniqυes de type alpha 7 de l'invention, on peut citer les agonistes
partiels des récepteurs nicotiniques de type alpha 7 de formule générale (I)Among the partial agonists of the nicotinic receptors of alpha 7 type of the invention, mention may be made of the agonists partial nicotinic receptors alpha 7 type of general formula (I)
dans laquelle
X représente un atome d'oxygène ou un groupe de formule KZ dans laquelle Z représente un atome d'hydrogène ou un groupein which X represents an oxygen atom or a group of formula KZ in which Z represents a hydrogen atom or a group
(C1-C6) alkyle, n représente le nombre 0, 1 ou 2, et(C 1 -C 6 ) alkyl, n represents the number 0, 1 or 2, and
R1, R2, R3, R4 et R5 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, trif.luorométhoxy, cyano, hydroxy,R 1 , R 2 , R 3 , R 4 and R 5 each represent, independently of one another, a hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxy group,
(C1-C6) alkyle, (C1-C6)alcoxy, phénoxy ou phényie éventuellement substitué par un atome d'halogène ou un groupe trifluorométhyle, cyano, hydrσxy, (C1-C6) alkyle ou (C1-C6) alcoκy, ou bien encore R2 et R3 forment ensemble un groupe de formule -OCH2O- ou -CH2CH2CH2CH2-, à l'état de base ou de sel d'addition à un acide, d'hydrate ou de solvate.(C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, phenoxy or phenyl optionally substituted by a halogen atom or a trifluoromethyl, cyano, hydrσxy, (C 1 -C 6 ) alkyl or (C 1) -C 6 ) alcoκy, or alternatively R 2 and R 3 together form a group of formula -OCH 2 O- or -CH 2 CH 2 CH 2 CH 2 -, in the form of a base or of a salt of addition to an acid, hydrate or solvate.
Les composés de formule générale (I) sont décrits dans le document WO 00/58311.The compounds of general formula (I) are described in WO 00/58311.
Dans le cadre de la présente invention, on entend parIn the context of the present invention, the term
- Ct-Cz où t et z peuvent prendre les valeurs de 1 à 6 : une chaîne carbonée pouvant avoir de t à 2 atomes de carbone, par exemple C1-C3 une chaîne carbonée qui peut avoir de 1 à 3 atomes de carbone ;- C t -C z where t and z can take the values from 1 to 6: a carbon chain may have from t to 2 carbon atoms, for example C 1 -C 3 a carbon chain which may have from 1 to 3 atoms of carbon ;
- un atome d'halogène : un atome de fluor, de chlore, de bromes ou d ' iode ; - un groupe alkyle : un groupe aliphatique saturé linéaire ou ramifié. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, isobutyle, tertbutyle, pentyle, etc ;a halogen atom: a fluorine, chlorine, bromine or iodine atom; an alkyl group: a saturated linear or branched aliphatic group. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like;
- un groupe alcoxy : un radical -O-alkyle dont le groupe
alkyle est tel que précédemment défini.an alkoxy group: an -O-alkyl radical whose group alkyl is as previously defined.
Les composés de formule générale (I) définis ci-dessus ont été décrits dans le document WO 00/58311 en tant qυ'agonistes partiels des récepteurs nicotiniques de type alpha 7.The compounds of general formula (I) defined above have been described in WO 00/58311 as partial agonists of alpha 7 nicotinic receptors.
Les sels des composés de formule générale (I) utilisables selon l'invention peuvent être préparés avec des acides pharmaceutiguement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés de formule (I), font également partie de l'invention.The salts of the compounds of general formula (I) that can be used according to the invention can be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds of formula (I) , are also part of the invention.
Les composés de formule générale (I) peuvent exister sous forme d'hydrates ou de soivates, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et soivates font également partie de l'invention.The compounds of general formula (I) can exist in the form of hydrates or soivates, namely in the form of combinations or combinations with one or more water molecules or with a solvent. Such hydrates and soivates are also part of the invention.
Les composés de formule générale (I) peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastèréoisomères. Ces énantiomèrea, diastèréoisomères, ainsi que leurs mélanges, y compris les mélanges racémiques, font partie de l' invention .The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, form part of the invention.
Un premier groupe de composés de formule (I) utilisables selon l'invention est celui dans lequel X représente, un atome d'oxygène.A first group of compounds of formula (I) that can be used according to the invention is that in which X represents an oxygen atom.
Un second groupe de composés de formule (I) utilisables selon l'invention est celui dans lequel n représente le nombre 0.A second group of compounds of formula (I) that can be used according to the invention is that in which n represents the number 0.
Un troisième groupe de composés de formule (I) utilisables selon l'invention est celui dans lequel R1, R2, R3, R4 et R5 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène.
On quatrième groupe de composés de formule (I) utilisables selon l'invention est celui dans lequel R1, R2, R4 et R5 représentent chacun un atome d'hydrogène et R3 représente un atome d'halogène.A third group of compounds of formula (I) that can be used according to the invention is that in which R 1 , R 2 , R 3 , R 4 and R 5 each represent, independently of one another, a hydrogen atom. or halogen. The fourth group of compounds of formula (I) that can be used according to the invention is that in which R 1 , R 2 , R 4 and R 5 each represent a hydrogen atom and R 3 represents a halogen atom.
Un cinquième groupe de composés de formule (I) utilisables selon l'invention est celui dans lequel X représente un atome d'oxygène ; n représente le nombre 0 ; R1, R2, R4 et R5 représentent chacun un atome d'hydrogène et R3 représente un atome d'halogène.A fifth group of compounds of formula (I) that can be used according to the invention is that in which X represents an oxygen atom; n represents the number 0; R 1 , R 2 , R 4 and R 5 each represent a hydrogen atom and R 3 represents a halogen atom.
Parmi les composés de formule (I) utilisables dans le cadre de l'invention, on peut citer notamment le 1,4- diazabicyclo[3.2.2]nonane-4-carboxylate de 4-bromophényle, à l'état de base ou de sel d'addition à un acide, d'hydrate ou de solvate.Among the compounds of formula (I) that may be used in the context of the invention, mention may in particular be made of 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate, in the base or acid addition salt, hydrate or solvate.
Un exemple de sel du 1, 4-diazabicyclo[3.2.2]nonane-4- carboxylate de 4-bromophényIe utilisable selon l'invention est le sel de fumarate ( (2E) -bυt-2 -ènedioate) .An example of a salt of 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate which can be used according to the invention is the fumarate salt ((2E) -but-2-enedioate).
Conformément à l'invention, on peut préparer les composés de formule générale (I) selon le procédé décrit dans la demande WO 00/58311.According to the invention, the compounds of general formula (I) can be prepared according to the process described in application WO 00/58311.
Exemple ; Préparation du (2E)-but-2-ènedioate de 1,4- diazabicyclol'3.2.2)nonane-4-carboxylate de 4-bromophényleExample; Preparation of (2E) -but-2-ènedioate 1,4 diazabicyclol '3.2.2) nonane-4-carboxylate 4-bromophenyl
Dans un réacteur double enveloppe de 6 L,. on place 232,45 g de 1, 4-diazabicyclo[3,2,2]nonane-4-carboxylate de 4- bromophényle (WO 00/58311) dans 2331 mL d'éthanol. Le milieu réactionnel est porté à 60βC. Une solution de 87,17 g d'acide fumarique dans un 1000 mL d'éthanol et 97 mL d'eau, préalablement chauffée à 60°C, est alors ajoutée. On distille ensuite 1900 mL de solvant puis le milieu réactionnel est refroidi à 20°C en 2,5h. Après 2,5h de contact à 20°C, le (2E) -but-2-ènedioate de 1,4-
diazabicyclo(3.2.2]nonane-4-carboxylate de 4-bromophényle est filtré, lavé par 2 fois 400 mL d'éthanol puis séché sous vide à 50°C.In a 6 L jacketed reactor ,. 232.45 g of 4-bromophenyl 1,4-diazabicyclo [3,2,2] nonane-4-carboxylate (WO 00/58311) are placed in 2331 ml of ethanol. The reaction medium is brought to 60βC. A solution of 87.17 g of fumaric acid in a 1000 ml of ethanol and 97 ml of water, previously heated to 60 ° C., is then added. 1900 ml of solvent are then distilled off and the reaction medium is then cooled to 20 ° C. in 2.5 hours. After 2.5 hours of contact at 20 ° C., the (2E) -but-2-enedioate of 4-bromophenyl diazabicyclo (3.2.2] nonane-4-carboxylate is filtered, washed with twice 400 ml of ethanol and then dried under vacuum at 50 ° C.
Point de fusion (DSC) ; 175°CMelting point (DSC); 175 ° C
RMN 1H (400MHz, DMSO-d6) δ(ppm) : 1.80 (si (a), 2H), 2,10 (sl, 2H), 3.10 (sl, 6H), 3.71 (sl, 1H), 3.84 (sl, 1H), 4.25 (sl, 0.5H), 4.40 (sl, 0.5J4), 6.58 (s, 2H) , 7.14 (m, 2H), 7.57 (m, 2H), 11 (sl, 2H) . (a) si ≈ singulet large. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 1.80 (si (a), 2H), 2.10 (sl, 2H), 3.10 (sl, 6H), 3.71 (sl, 1H), 3.84 ( sl, 1H), 4.25 (ss, 0.5H), 4.40 (ss, 0.54), 6.58 (s, 2H), 7.14 (m, 2H), 7.57 (m, 2H), 11 (ss, 2H). (a) if ≈ singlet wide.
Au sens de la présente invention, l'inhibiteur d'acétylcholinestérase peut être choisi parmi tous les inhibiteurs d'acétylcholinestérase connus dans la littérature. A titre d'exemple, on peut citer notamment la rivastigmine (Exelon®) et le donepezil (Aricept®) .For the purpose of the present invention, the acetylcholinesterase inhibitor may be chosen from all the acetylcholinesterase inhibitors known in the literature. By way of example, mention may in particular be made of rivastigmine (Exelon®) and donepezil (Aricept®).
Ainsi, un exemple d'association selon l'invention est l'association constituée du (2E) -but-2-ènedioate de 1,4- diazabicyclo[3.2.2]nonane-4-carboxylate de 4-bromophényle et de la rivastigraine.Thus, an example of an association according to the invention is the combination consisting of (2E) -but-2-enedioate of 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate and rivastigrain .
Un autre exemple d'association selon l'invention est l'association constituée du (2E) -but-2-ènedioate de 1,4- diazabicyclo[3.2.2]nonane-4-carboxyléite de 4-bromophényle et du donepezil.Another example of combination according to the invention is the combination consisting of (2E) -but-2-enedioate 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxyléite and donepezil.
Un second objet de l'invention concerne une composition pharmaceutique comprenant, à titre de principe actif, une association telle que définie précédemment, et un ou plusieurs excipients pharmaceutiquement acceptables.A second subject of the invention relates to a pharmaceutical composition comprising, as active principle, an association as defined above, and one or more pharmaceutically acceptable excipients.
La composition pharmaceutique contient une dose minimale active de chaque principe actif présent dans l'association selon l'invention.The pharmaceutical composition contains a minimum active dose of each active ingredient present in the combination according to the invention.
L'invention concerne également une composition pharmaceutique contenant une dose sub-active de chaque
principe actif présent dans l'association selon l'invention. L'emploi de telles doses sub-actives peut permettre d'éviter les effets secondaires d'un ou des principes actifs présents dans l'association selon l'invention.The invention also relates to a pharmaceutical composition containing a sub-active dose of each active ingredient present in the combination according to the invention. The use of such sub-active doses may make it possible to avoid the side effects of one or more active ingredients present in the combination according to the invention.
Les excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaités, parmi les excipients habituels qui sont connus de l'homme du métier. La composition peut être administrée par voie orale, parentérale ou rectale. Les formes unitaires d'administration appropriées comprennent les formes par voie orale telles que les comprimés, les gélules molles ou dures, les poudres, les granules et les solutions ou suspensions orales, les formes d'administration sublinguale, buccale, intrachéale, intraoculaire, intranasale, par inhalation, les formes d'administration topique, transdermique, sous-cutanée, intra-muscυlaire ou intraveineuse, les formes d'administration rectale et les implants. Pour l'application topique, on peut utiliser les principes actifs selon l'invention dans des crèmes, gels, pommades ou lotions.The excipients are selected according to the desired pharmaceutical form and method of administration from among the usual excipients which are known to those skilled in the art. The composition may be administered orally, parenterally or rectally. Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intra-muscular or intravenous administration forms, rectal administration forms and implants. For topical application, the active ingredients according to the invention can be used in creams, gels, ointments or lotions.
Selon l'invention, les deux principes actifs sont administrés selon la même voie, par exemple la voie orale, ou l'un des principes actifs est administré selon une première voie, par exemple la voie orale, et l'autre principe actif est administré selon une voie différente, par exemple la voie parentérale.According to the invention, the two active ingredients are administered in the same way, for example the oral route, or one of the active ingredients is administered according to a first route, for example the oral route, and the other active ingredient is administered in a different way, for example the parenteral route.
Lorsqu'on prépare une composition sous forme de comprimé, on mélange les ingrédients actifs avec un ou plusieurs excipients pharmaceutiques, tels que la gélatine, l'amidon, le lactose, le stéarate de magnésium, le talc, la silice, la gomme arabique, le mannitol, la cellulose microcristalline, l'hypromellose ou analogues.When preparing a composition in tablet form, the active ingredients are mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hypromellose or the like.
On peut nnrober les comprimés de saccharose, d'un dérivé cellulosique ou d'autres matières adaptées à l'enrobage. Les comprimés peuvent être réalisés par différentes techniques, telles que la compression directe, la granulation sèche ou humide ou la fusion a chaud.
On peut également obtenir une composition pharmaceutique sous forme de gélule en mélangeant les ingrédients actifs avec un diluant et en versant le mélange obtenu dans des gélules molles ou dures. Pour une administration parentérale, on utilise des suspensions aqueuses, des solutions salines isotoniques ou des solutions stériles et injectables qui contiennent des agents pharmacologiquement compatibles, par exemple le prσpylèneglycol ou le butylèneglycol.Saccharose tablets, a cellulose derivative or other materials suitable for coating may be coated. The tablets may be made by various techniques, such as direct compression, dry or wet granulation or hot melt. A pharmaceutical capsule composition can also be obtained by mixing the active ingredients with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible agents, for example propylene glycol or butylene glycol, are used.
Selon la pratique habituelle, le dosage approprié à chaque patient est déterminé par le médecin selon le mode d'administration, l'âge, le poids et la réponse dudit patient.According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the age, the weight and the response of said patient.
Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée.The doses depend on the desired effect, the duration of treatment and the route of administration used.
Par exemple par voie orale, les doses journalières de chacun des principes actifs de l'association selon l'invention sont les suivantes : agonistes partiels des récepteurs nicotiniques de type alpha 7: entre 0,5 et 500 mg par jour et par personne, notamment entre 1 et 100 mg par jour et par personne ; inhibiteur d'acétylcholinestérase : entre 3 et 200 mg par jour et par personne, notamment entre 5 et 100 mg par jour et par personne,For example, orally, the daily doses of each of the active ingredients of the combination according to the invention are as follows: partial agonists of nicotinic receptors of alpha 7 type: between 0.5 and 500 mg per day and per person, in particular between 1 and 100 mg per day and per person; acetylcholinesterase inhibitor: between 3 and 200 mg per day and per person, in particular between 5 and 100 mg per day and per person,
II peut y avoir des cas particuliers où des dosages plus élevés ou plus faibles sont appropriés. De tels dosages ne sortent pas du cadre de l'invention.There may be special cases where higher or lower dosages are appropriate. Such dosages are not outside the scope of the invention.
Les doses respectives de l'agoniste partiel des récepteurs nicotiniques de type alpha 7 et de l'inhibiteur d'acétylcholiπestérase sont généralement sensiblement identiques entre elles ou bien peuvent différer l'une de l'autre.The respective doses of the partial agonist of the nicotinic receptors of type alpha 7 and of the acetylcholinesterase inhibitor are generally substantially identical to each other or may differ from one another.
A titre d'exemple, une forme unitaire d'administration de l'agoniste partiel des récepteurs nicotiniques de type alpha 7 sous forme de comprimé comprend les ingrédients suivants :
By way of example, a unitary form of administration of the alpha 7-type nicotinic receptor-type partial agonist in the form of a tablet comprises the following ingredients:
Egalement a titre d'exemple, une forme unitaire d'administration de l'inhibiteur d' acétylcholinestérase sous forme de comprimé peut comprendre 10 mg de l'inhibiteur d' acétylcholinestérase et des excipients usuels, par exemple de la cellulose microcristalline, de la silice colloïdale, du talc, de la croscarmellose sodique, du stéarate de magnésium.By way of example, a unitary form of administration of the acetylcholinesterase inhibitor in the form of a tablet may comprise 10 mg of the acetylcholinesterase inhibitor and of the usual excipients, for example microcrystalline cellulose, silica colloidal, talc, croscarmellose sodium, magnesium stearate.
L'administration de chacun des principes actifs peut également être effectuée de façon simultanée, séparée ou de manière étalée dans le temps (administration séquentielle) .The administration of each of the active ingredients can also be carried out simultaneously, separately or in a manner spread over time (sequential administration).
Lorsque l'administration est effectuée de façon simultanée, les deux principes actifs peuvent être réunis au sein d'une composition pharmaceutique unique, comprenant les deux principes actifs, telle qu'un comprimé ou une gélule.When the administration is carried out simultaneously, the two active ingredients can be combined in a single pharmaceutical composition, comprising the two active ingredients, such as a tablet or a capsule.
Les deux principes actifs peuvent également, que leur administration soit simultanée ou non, être présents dans des compositions pharmaceutiques distinctes. A cet effet, l'association selon l'invention peut se présenter sous forme de kit comprenant, d'une part, au moins un agoniste partiel des récepteurs nicotiniques de type alpha 7 tel que défini dans ce qui précède et, d'autre part, au moins un inhibiteur d' acétylcholinestérase tel que défini dans ce qui précède, l' agoniste partiel des récepteurs nicotiniques de type alpha 7 et l'inhibiteur d' acétylcholinestérase étant dans des compartiments distincts et étant destinés à être administrés de façon simultanée, séparée ou étalée dans le temps (administration séquentielle) .The two active ingredients may also, whether administered simultaneously or not, be present in separate pharmaceutical compositions. For this purpose, the combination according to the invention may be in the form of a kit comprising, on the one hand, at least one partial agonist of nicotinic receptors of alpha 7 type as defined above and, on the other hand at least one acetylcholinesterase inhibitor as hereinbefore defined, the alpha 7 nicotinic receptor partial agonist and the acetylcholinesterase inhibitor being in separate compartments and intended to be administered simultaneously, separately or spread over time (sequential administration).
Un autre objet de l'invention concerne l'utilisation d'une association telle que décrite précédemment pour la préparation d'un médicament destiné au traitement des
troubles cognitifs, et plus particulièrement des troubles cognitifs liés â Ia maladie d' Alzheimer .Another subject of the invention relates to the use of an association as described above for the preparation of a medicinal product intended for the treatment of cognitive disorders, and more particularly cognitive disorders related to Alzheimer 's disease.
L'invention a également pour objet une méthode de traitement des troubles cognitifs, et plus particulièrement des troubles cognitifs liés à la maladie d'Alzheimer, qui comprend l'administration à un patient d'une dose minimale active ou sub-active d'un agoniste partiel des récepteurs nicotiniques de type alpha 7 tel quie défini précédemment, et d'une dose minimale active ou sub-active d'un inhibiteur d' acétylcholinestérase tel que défini dans ce qui précède, lesdites doses étant administrées de façon simultanée, séparée ou séquentielle, comme cela est décrit précédemment .The invention also relates to a method for treating cognitive disorders, and more particularly cognitive disorders related to Alzheimer's disease, which comprises administering to a patient a minimum active or sub-active dose of a alpha-type nicotinic receptor partial agonist as defined above, and a minimum active or sub-active dose of an acetylcholinesterase inhibitor as defined above, said doses being administered simultaneously, separately or separately. sequential, as described above.
Les effets de l'association sur les troubles cognitifs ont été évalués grâce à deux tests de psychopharmacologie comportementale chez le rongeur (rat et souris) , Ces tests visent un des principaux types de troubles cognitifs que sont les troubles de la mémoire et plus particulièrement les troubles de la mémoire épisodique visuelle.The effects of the association on cognitive disorders were evaluated thanks to two tests of behavioral psychopharmacology in rodents (rats and mice), These tests target one of the main types of cognitive disorders that are the memory disorders and more particularly the visual episodic memory disorders.
Le but est de mettre en évidence l'effet supérieur de l'association sur l'amplitude de l'effet pharmacologique pro-cognitif par rapport à l'effet produit par les deux principes actifs pris individuellement dans le traitement de ces troubles cognitifs.The aim is to highlight the superior effect of the association on the amplitude of the pro-cognitive pharmacological effect compared to the effect produced by the two active ingredients taken individually in the treatment of these cognitive disorders.
1. Test de l'oubli spontané che2 le rat non déficitaire1. Spontaneous forgetfulness test che2 non-deficient rat
Une première étude a visé à mettre en évidence chez le rat adulte une synergie procognitive de l'association selon l'invention dans une tâche de mémoire visuelle épisodique, utilisant un protocole d'oubli spontané dans le test de reconnaissance d'objet.A first study aimed at demonstrating in the adult rat a procognitive synergy of the combination according to the invention in an episodic visual memory task, using a spontaneous forgetfulness protocol in the object recognition test.
1.) Phase d' habituation ; Dons ce protocole, les animaux sont d'abord soumis à une séance d' habituation au contexte environnemental (une enceinte en bois de 65 x 45 x 45 cm)
pendant une durée de 2 minutes. Le temps passé en locomotion active est mesuré à l'aide d'un chronomètre.1.) Phase of habituation; Given this protocol, the animals are first subjected to a session of habituation to the environmental context (a wooden enclosure of 65 x 45 x 45 cm) for a duration of 2 minutes. The time spent in active locomotion is measured using a stopwatch.
2.) Phase d'apprentissage : 24 heures plus tard, deux objets exactement identiques (soit des triangles en métal, soit des pyramides réalisées en Lego) sont disposés dans le dispositif expérimental. Chaque rat est déposé au milieu de l'enceinte, le museau contre la paroi opposée de celle où sont situés les objets/stimulus. On respecte une alternance équitable dans chacun des groupes de rats, des couples d'objets présentés. Les animaux sont laissés dans l'enceinte expérimentale jusqu'à ce qu'ils atteignent une durée d'exploration des deux objets égale à 20 secondes, sur une durée maximale de 3 minutes. Dés que les 20 secondes d' exploration sont atteintes, le rat est remis dans sa cage de stabuiation. Cette procédure permet d'homogénéiser le niveau d'imprégnation des animaux pour les objets familiers, et donc d'obtenir un niveau d'apprentissage comparable d'un animal à l'autre.2.) Learning phase: 24 hours later, two exactly identical objects (either metal triangles or Lego pyramids) are placed in the experimental setup. Each rat is placed in the middle of the enclosure, the muzzle against the opposite wall of the one where the objects / stimuli are located. We observe a fair alternation in each group of rats, pairs of objects presented. The animals are left in the experimental chamber until they reach a duration of exploration of the two objects equal to 20 seconds, for a maximum duration of 3 minutes. As soon as the 20 seconds of exploration are reached, the rat is put back in its stabuiation cage. This procedure makes it possible to homogenize the level of impregnation of animals for familiar objects, and thus to obtain a comparable level of learning from one animal to another.
3.) Séance de rappel : La séance de rappel a lieu âpres un délai d'oubli de 24h pour tous les groupes. Les rats sont confrontés â un couple d'objets constitué de l'objet rencontré lors de la phase d'apprentissage, et d'un objet inconnu. Les rats sont déposés de la même façon que pour la séance d'apprentissage.3.) Reminder session: The reminder session takes place after 24h for all groups. The rats are confronted with a pair of objects consisting of the object encountered during the learning phase, and an unknown object. The rats are deposited in the same way as for the learning session.
Cet essai dure 3 minutes pendant lesquelles on mesure le temps passé à explorer chacun des 2 objets. Si l'animal présente une remémorat.ton significative de l'objet préalablement mémorisé, il explorera majoritairement l'objet nouveau. A l'inverse, si l'animal a oublié l'objet familier, les durées d'exploration de l'objet nouveau et de l'objet familier seront similaires.This test lasts 3 minutes during which we measure the time spent exploring each of the 2 objects. If the animal presents a significant remembrance of the previously memorized object, it will mainly explore the new object. Conversely, if the animal has forgotten the familiar object, the exploration times of the new object and the familiar object will be similar.
Pour les séances d'apprentissage et de rappel, l'exploration d'un objet est comptabilisée si l'animal oriente son museau vers l'objet, à l'intérieur d'un périmètre de 2 centimètres autour de celui-ci, ou s'il le touche avec son museau ou ses pattes. Si le rat tourne autour de l'objet ou s'assoit
dessus, ces comportements ne sont pas considérés comme exploratoires.For the learning and recall sessions, the exploration of an object is counted if the animal orients its muzzle towards the object, within a perimeter of 2 centimeters around it, or he touches him with his muzzle or paws. If the rat turns around the object or sits above, these behaviors are not considered exploratory.
Les données brutes sont exprimées en secondes.The raw data is expressed in seconds.
Les composés à tester sont administrés par voie orale 60 minutes (étude rats) avant chacun des trois séances du protocole .The test compounds are administered orally 60 minutes (rat study) before each of the three sessions of the protocol.
Quatre groupes expérimentaux sont constitués, recevant respectivement :Four experimental groups are constituted, receiving respectively:
1 - véhicule (Méthyl-cellulose + Tween seul)1 - Vehicle (Methylcellulose + Tween alone)
2 - agoniste partiel des récepteurs nicotiniques de type alpha 7 (dose inactive) 3 - inhibiteur d'acétylcholinestérase (dose inactive)2 - alpha 7 nicotinic receptor partial agonist (inactive dose) 3 - acetylcholinesterase inhibitor (inactive dose)
4 - agoniste partiel des récepteurs nicotiniques de type alpha 7 (dose inactive) +- inhibiteur d'acétylcholinestérase (dose inactive)4 - alpha 7 nicotinic receptor partial agonist (inactive dose) + - acetylcholinesterase inhibitor (inactive dose)
Lors de la séance de rappel, 24 heures après la séance d'apprentissage, les durées d'exploration des deux objets, exprimés en secondes et l'indice de reconnaissance (durée d'exploration de l'objet nouveau/durée total d'exploration des objets nouveau et familier) sont mesurés. - Des durées d'exploration semblables vis-à-vis de l'objet familier et de l'objet nouveau traduisent un oubli de l'objet familier et donc une déficience de la mémoire visuelle épisodique. Au contraire, une durée d'exploration plus importante de l'objet nouveau que de l'objet familier, traduit une rernémoration significative de l'objet familier et donc une amélioration de la mémoire visuelle épisodique. - Un indice de reconnaissance peu élevé traduit un oubli de l'objet familier et donc une déficience de la mémoire visuelle épisodique.During the recall session, 24 hours after the training session, the exploration times of the two objects, expressed in seconds and the recognition index (exploration duration of the new object / total exploration time new and familiar objects) are measured. - Similar exploration times vis-à-vis the familiar object and the new object reflect an oblivion of the familiar object and therefore a deficiency of episodic visual memory. On the contrary, a longer duration of exploration of the new object than of the familiar object, reflects a significant rernemoration of the familiar object and thus an improvement of the episodic visual memory. - A low recognition index indicates an oblivion of the familiar object and therefore a deficiency of the episodic visual memory.
Au contraire, un indice de reconnaissance élevé traduit une remémoration significative de l'objet familier et donc une amélioration de la mémoire visuelle épisodique.
Les résultats qui suivent ont été obtenus en constituant les quatre groupes expérimentaux suivants, recevant respectivement :On the contrary, a high recognition index reflects a significant remembrance of the familiar object and thus an improvement in the episodic visual memory. The following results were obtained by constituting the following four experimental groups, receiving respectively:
- Groupe 1 : véhicule (Méthyl-cellulose + Tween seul) - Groupe 2 ; (2E) -but-2-ènedioate de 1, 4-diazabicyclo-- Group 1: vehicle (Methylcellulose + Tween alone) - Group 2; (2E) -but-2-enedioate of 1,4-diazabicyclo
[3.2.2]nonane-4-carboxylate de 4-bromophényle 0,1 mg/kg, p. o. (dose inactive)[3.2.2] 4-bromophenyl nonane-4-carboxylate 0.1 mg / kg, p. o. (inactive dose)
- Groupe 3 : Rivastigmine 0,03 mg/kg, p.o. (dose inactive)- Group 3: Rivastigmine 0.03 mg / kg, p.o. (inactive dose)
- Groupe 4 : (2E) -but-2-ènediαate de 1, 4-diazabicyclo- [3.2.2]nonane~4-carboxylate de 4-bromophényle 0,1 mg/kg, p.o. + Rivastigmine 0,03 mg/kg, p.o. (dose inactive) Les doses ci -dessus sont exprimées en équivalent base.- Group 4: 4-Bromophenyl 1,4-diazabicyclo- [3.2.2] nonane-4-carboxylate 4-(2E) -but-2-enedieate, po + Rivastigmine 0.03 mg / kg , po (inactive dose) The above doses are expressed in base equivalents.
La figure 1 et le tableau 1 présentent le temps passé en locomotion pendant la séance d'habitυation pour chacun des groupes expérimentaux.Figure 1 and Table 1 show the time spent in locomotion during the session of accommodation for each of the experimental groups.
Tableau 1Table 1
Après une seule administration de chacun des deux composés ou de la combinaison des deux, aucune modification de la locomotion n'est observée lors de la séance d'habituatiσn au contexte environnemental .After a single administration of each of the two compounds or a combination of both, no change in locomotion is observed during the habituation session to the environmental context.
Le tableau 2 et les figures 2 et 3 présentent : la durée d'exploration (en secondes) des deux objets, nouveau et familier ; et l'indice de reconnaissance tel que défini ci-dessus ; pendant la séance de rappel pour chacun des groupes expérimentaux .Table 2 and Figures 2 and 3 show: the duration of exploration (in seconds) of the two objects, new and familiar; and the recognition index as defined above; during the booster session for each of the experimental groups.
Lors de la séance do rappel, 24 heures après la séance d'apprentissage, les animaux traités par le véhicule seul ou
par la dose inactive de chacun des deux composés ((2E)-bυt- 2-énedioate de 1, 4-diazabicyclo [3.2.2] nonane-4-carboxylate ou Rivastigmine) ne présentent aucune discrimination significative entre l'objet familier et l'objet nouveau. Ceci traduit un oubli de l'objet familier.During the recall session, 24 hours after the training session, the animals treated by the vehicle alone or by the inactive dose of each of the two compounds (1,4-diazabicyclo [3.2.2] nonane-4-carboxylate or Rivastigmine (2E) -beta-2-ededioate) do not show any significant discrimination between the familiar object and the new object. This reflects an oversight of the familiar object.
A l'inverse, les animaux traités par la combinaison des doses inactives de chacun des composés testés présentent une très importante exploration de l'objet nouveau par rapport à l'objet familier, traduisant une remémoration significative de l'objet familier. Cet effet est observé sur les durées d'exploration des deux objets, exprimées en secondes, et sur l'indice de reconnaissance (tableau 2 et figures 2 et 3) .Conversely, the animals treated by the combination of the inactive doses of each of the compounds tested show a very important exploration of the new object with respect to the familiar object, reflecting a significant recollection of the familiar object. This effect is observed on the exploration times of the two objects, expressed in seconds, and on the recognition index (Table 2 and Figures 2 and 3).
Tableau 2Table 2
Les résultats ci-dessus montrent que, dans un test de mémoire visuelle éploodigue, l'association selon l'invention a bien un effet proeognicif supérieur par rapport à l'effet procognitif produit par les deux principes actifs pris individuellement.The above results show that, in an eclectic visual memory test, the association according to the invention has a greater proeognitive effect with respect to the procognitive effect produced by the two active principles taken individually.
2. Test du déficit de mémoire épisodique visuelle à court terme induit par des injections Intra-cérébro-ventriculaires (ICV) de protéine β-amyloïde 25-35 chez la souris.2. Short-term visual episodic memory deficit test induced by intra-cerebroventricular (ICV) injections of β-amyloid 25-35 protein in mice.
Les peptides β-amyloïdes sont les constituants majoritaires des plaques séniles observées dans la maladie d'Alzheimer. Le fragment peptidique Aβ25-35 contient les 11 acides aminés nécessaires et suffisants pour induire une toxicité neurologique. C'est la raison pour laquelle des injections
intra-cérébro-ventriculaire (ICV) de ce peptide sont considérées cormme un modèle pathophysiologique de la maladie d'Alzheimer à forte validité prédictive.The β-amyloid peptides are the major constituents of the senile plaques observed in Alzheimer's disease. The peptide fragment Aβ25-35 contains the 11 amino acids necessary and sufficient to induce neurological toxicity. That's why injections Intracerebroventricular (ICV) of this peptide is considered a pathophysiological model of Alzheimer's disease with high predictive validity.
Le peptide amyloide Aβ25-35 est dissout dans de l'eau distillée à une concentration finale de 3 mg/ml. Il est ensuite incubé à 37°C pendant A jours afin de former des agrégats de peptide toxique. Les animaux contrôles reçoivent le peptide mélangé (« scrambled peptide ») , constitué des mêmes acides aminés, mais organisés selon une séquence aléatoire. Ce peptide mélangé ne présente aucune toxicité neuronale (non toxique) .The amyloid peptide Aβ25-35 is dissolved in distilled water at a final concentration of 3 mg / ml. It is then incubated at 37 ° C for A days to form aggregates of toxic peptide. The control animals receive the mixed peptide ("scrambled peptide"), consisting of the same amino acids, but organized in a random sequence. This mixed peptide has no neuronal (non-toxic) toxicity.
Le peptide est injecté par voie intra-cérébro-ventriculaire à des souris de souche CDl anesthésiées â l'isoflurane. Une micro-seringue équipée d'une aiguille de 28 gauges et de 3 mm de longueur est utilisée. L'aiguille est insérée unilatéralement, 1 mm à droite de la ligne central équidistante de chaque œil et à une égale distance entre l'axe des yeux et l'axe des oreilles. 3 μl du peptide agrégé sont injectés pendant une durée d'une minute. Les souris sont utilisées pour leβ épreuves comportementales entre 6 à 14 jours après l'injection intracérébrale.The peptide is injected intra-cerebroventricularly into CD1 strain mice anesthetized with isoflurane. A micro-syringe equipped with a 28-gauge and 3-mm long needle is used. The needle is inserted unilaterally, 1 mm to the right of the equidistant central line of each eye and at an equal distance between the axis of the eyes and the axis of the ears. 3 μl of the aggregated peptide are injected for a period of one minute. Mice are used for behavioral tests between 6 to 14 days after intracerebral injection.
Le protocole expérimental comportemental utilisé est comparable à celui utilisé dans le test de l'oubli, spontané chez le rat, décrit ci-dessus.The behavioral experimental protocol used is comparable to that used in the test of spontaneous forgetfulness in rats, described above.
1.) Phase s'habituation ; Dans ce protocole, les souris sont d'abord soumis à une séance d'habituation au contexte environnemental {une enceinte en PVC gris clair de 52 x 52 x 40 cm, éclairage à 6 Lux) pendant une durée de 10 minutes. Le temps passé en locomotion active est mesuré à l'aide d'un chronomètre.1.) Phase getting used; In this protocol, the mice are first subjected to a session of habituation to the environmental context {a light gray PVC enclosure of 52 x 52 x 40 cm, lighting at 6 Lux) for a duration of 10 minutes. The time spent in active locomotion is measured using a stopwatch.
2.) Phase d'apprentissage : 24 heures plus tard, deux objets exactement identiques (soit des triangles en métal (5.5 x 3.3 cm), soit une brique carrée Lecjo rouge (3.0 x 3.0 x 3.0 cm)) sont disposés dans le dispositif expérimental. Chaque
souris est déposée au milieu de l' enceinte, le museau contre la paroi opposée de celle où sont situés les objets/stimulus. On respectera une alternance équitable dans chacun des groupes de souris, des couples d'objeta présentés. Les animaux sont laissés dans l'enceinte expérimentale jusqu'à ce qu'ils atteignent une durée d'exploration des deux objets égale à 10 secondes, sur une durée maximale de 3 minutes. Dès que les 10 secondes d'exploration sont atteintes, la souris est remise dans sa cage de stabulat.ton. Cette procédure permet d'homogénéiser le niveau d'imprégnation des animaux pour les objets familiers, et donc d'obtenir un niveau d'apprentissage comparable d'un animal à l'autre.2.) Learning phase: 24 hours later, two exactly identical objects (either metal triangles (5.5 x 3.3 cm) or a red Lecjo square brick (3.0 x 3.0 x 3.0 cm)) are placed in the device. experimental. Each mouse is deposited in the middle of the enclosure, the muzzle against the opposite wall of the one where the objects / stimuli are located. We will observe a fair alternation in each group of mice, pairs of objects presented. The animals are left in the experimental chamber until they reach a duration of exploration of the two objects equal to 10 seconds, for a maximum duration of 3 minutes. As soon as the 10 seconds of exploration are reached, the mouse is put back in its cage of stabulat.ton. This procedure makes it possible to homogenize the level of impregnation of animals for familiar objects, and thus to obtain a comparable level of learning from one animal to another.
3.) Séance de rappel : La séance de rappel a lieu après un délai d'oubli de 1 heure pour tous les groupes. Ce délai d'oubli court induit de bonnes performances de rappel chez les animaux contrôles et permet de mettre en évidence un déficit induit par l'injection de peptide toxique chez les autres animaux. Les souris sont confrontées à un couple d'objets constitué de l'objet rencontré lors de la phase d'apprentissage, et d'un objet inconnu. Les souris sont déposées dans l'anceinte de la même façon que pour la séance d' apprentissage . Cet essai dure 5 minutes pendant lesquelles on mesure le temps passé à explorer chacun des 2 objets. Un animai contrôle présentera, pour ce délai d'oubli court, une exploration plus importante de l'objet nouveau, traduisant une remémoration significative de l'objet familier. A l'inverse, des animaux déficitaires présenteront des durées d'exploration des deux objets non statistiquement différentes .3.) Reminder session: The reminder session takes place after a 1-hour forget-out period for all groups. This short period of forgetfulness induces good booster performance in control animals and makes it possible to demonstrate a deficit induced by the injection of toxic peptide in the other animals. The mice are confronted with a pair of objects consisting of the object encountered during the learning phase, and an unknown object. The mice are deposited in the anceinte in the same way as for the learning session. This test lasts 5 minutes during which we measure the time spent exploring each of the 2 objects. An animai control will present, for this period of short forgetfulness, a more important exploration of the new object, translating a significant remembrance of the familiar object. On the other hand, deficit animals will have exploration durations of the two objects that are not statistically different.
Pour les séances d'apprentissage et de rappel, l'exploration d'un objet est comptabilisée si l'animal oriente son museau vers l'objet, à l'intérieur d'un périmètre de 2 centimètres autour de celui-ci, ou s'il le touche avec son museau ou ses pattes» Si le rat tourne autour de l'objet ou s'assoit dessus, ces comportements ne sont pas considérés comme exploratoires .
Les données brutes sont exprimées en secondes.For the learning and recall sessions, the exploration of an object is counted if the animal orients its muzzle towards the object, within a perimeter of 2 centimeters around it, or 'he touches him with his snout or his paws' If the rat turns around the object or sits on it, these behaviors are not considered exploratory. The raw data is expressed in seconds.
Les composés à tester sont administrés par voie intrapéritonéale, 60 minutes avant chacune des trois séances du protocole.The compounds to be tested are administered intraperitoneally, 60 minutes before each of the three sessions of the protocol.
Cinq groupes expérimentaux ont été constitués, recevant respectiventent : 1 - peptide mélangé contrôle (non toxique) , véhiculeFive experimental groups were constituted, receiving respectively: 1 - controlled mixed peptide (non-toxic), vehicle
2 - Peptide Aβ25-35 (toxique), véhicule2 - Peptide Aβ 25-35 (toxic), vehicle
3 - Peptide Aβ25-35, inhibiteur d'acétylcholinestérase (dose inactive)3 - Peptide Aβ 25-35 , acetylcholinesterase inhibitor (inactive dose)
4 - Peptide Aβ25-35, agoniste partiel des récepteurs nicotiniqυes de type alpha 7 (dose inactive)4-Peptide Aβ 25-35 , partial agonist of nicotinic receptors of alpha 7 type (inactive dose)
5 - Peptide Aβ25-45, inhibiteur d'acétylcholinestérase (dose inactive) + agoniste partiel des récepteurs nicotiniques de type alpha 7 (dose inactive)5-Peptide Aβ 25-45 , acetylcholinesterase inhibitor (inactive dose) + partial agonist of nicotinic receptors of alpha 7 type (inactive dose)
Lors de la séance de rappel, c'est-à-dire 1 heure après la séance d'apprentissage, les durées d'exploration des deux objets, exprimés en secondes sont mesurées.During the recall session, that is to say 1 hour after the training session, the exploration times of the two objects, expressed in seconds are measured.
- Des durées d'exploration semblables vis-à-vis de l' objet familier et de l'objet nouveau traduisent un oubli de l'objet familier et donc une abolition totale des performances de rappel à court terme,- Similar exploration times vis-à-vis the familiar object and the new object translate an omission of the familiar object and thus a total abolition of short-term recall performance,
- Au contraire, une durée d'exploration plus importante de l'objet nouveau que de l'objet familier, traduit une bonne performance de rappel de mémoire à court terme.- On the contrary, a longer duration of exploration of the new object than of the familiar object, reflects a good short-term memory recall performance.
L'indice de reconnaissance (durée d'exploration de l'objet nouveau/durée total d'exploration des objets nouveau et familier) est également mesuré.The index of recognition (duration of exploration of the new object / total duration of exploration of new and familiar objects) is also measured.
- Un indice de reconnaissance peu élevé traduit un oubli de l'objet familier et donc une abolition totale des performances de rappel à court terme.- A low recognition index reflects an omission of the familiar object and therefore a complete abolition of short-term recall performance.
- Au contraire, un indice de reconnaissance élevé traduit une remémoration significative de l'objet familier et donc une bonne performance de rappel de mémoire à court terme.
Les résultats qui suivent ont été obtenus en constituant les cinq groupes expérimentaux suivants, recevant respectivement ; 1 - peptide mélangé contrôle (non toxique), véhicule- On the contrary, a high recognition index reflects a significant recollection of the familiar object and therefore a good memory recall performance in the short term. The following results were obtained by constituting the following five experimental groups, respectively receiving; 1 - mixed peptide control (nontoxic), vehicle
2 - Peptide Aβ25-35, (toxique) , véhicule2 - Peptide Aβ 25-35 , (toxic), vehicle
3 - Peptide Aβ25-35, Donepezil, 0,1 mg/kg (dose inactive)3 - Peptide Aβ 25-35 , Donepezil, 0.1 mg / kg (inactive dose)
4 - Peptide Aβ25-35, (2E) -but-2-ènedioate de 1,4- diazabieyclo[3.2.2]nonane-4-carboxylate de 4-bromαphényle, 0,1 mg/kg (dose inactive)4 - Peptide Aβ 25-35 , (2E) -but-2-enedioate of 4-bromiphenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate, 0.1 mg / kg (inactive dose)
5 - Peptide Aβ25-35, Donepezil, 0,1 mg/kg + {23)-but-2- ènedioate de 1, 4-dia2abicyclo(3.2.2]nonane-4-carboxylate de 4-bromophényle, 0,1 mg/kg (dose inactive)5 - Peptide Aβ 25-35 , Donepezil, 0.1 mg / kg + {23) -but-2- decedioate 4-bromophenyl 1,4-dia2abicyclo (3.2.2) nonane-4-carboxylate, 0.1 mg / kg (inactive dose)
Les doses ci-dessus sont exprimées en équivalent base.The above doses are expressed in base equivalent.
Après une seule administration de chacun des deux composés ou de la combinaison des deux, aucune modification de la locomotion n'est observée lors de la séance d'habituation au contexte environnemental. De môme, aucune modification des durées d'exploration des deux objets identiques lors de la séance d'apprentissage n'a été relevée.After a single administration of each of the two compounds or a combination of both, no change in locomotion is observed during the session of habituation to the environmental context. Similarly, no change in the duration of exploration of the two identical objects during the training session was noted.
Le tableau 3 et les figures 4 et 5 présentent :Table 3 and Figures 4 and 5 show:
- la durée d'exploration (en secondes) des deux objets, nouveau et familier ; et l'indice de reconnaissance tel que défini ci-dessus ; pendant la séance de rappel pour chacun des groupes expérimentaux.- the duration of exploration (in seconds) of the two objects, new and familiar; and the recognition index as defined above; during the booster session for each of the experimental groups.
Lors de la séance de rappel, les animaux traités par le peptide contrôle non toxique présentent des performances de rappel de mémoire à court terme intactes, se traduisant par une exploration significativement plus importante de l'objet nouveau que de l'objet familier. A l'inverse, les animaux ayant reçu le peptide toxique montrent une abolition totale des performances de rappel à court terme se traduisant par une exploration identique de l'objet familier et de l'objet nouveau.
La dose de (2E) -but-2-ènedioate de 1,4- diazabicyclo[3.2.2)nonane-4-carboxylate de 4-bromophényle et la dose de Donepezil sont, chacune d'entre elles, inactives par elles-mêmes et ne conduisent pas à une amélioration des performances .In the booster session, animals treated with the nontoxic control peptide exhibit intact short-term memory recall performance, resulting in significantly greater exploration of the novel object than of the familiar object. Conversely, the animals that received the toxic peptide show a complete abolition of the short-term recall performance resulting in an identical exploration of the familiar object and the new object. The dose of 4-bromophenyl 1,4-diazabicyclo [3.2.2) nonane-4-carboxylate (2E) -but-2-enedioate and the dose of Donepezil are, each of them, inactive by themselves and do not lead to improved performance.
En revanche, lorsque ces deux produits sont co-administrés, il est observé un effet promnésique très marqué, se traduisant par un retour à des performances de rappel à court-terme similaires, voire supérieures, à celles des animaux traités par le peptide non toxique (tableau 3 et figures 4 et 5) .On the other hand, when these two products are co-administered, a marked promnesic effect is observed, resulting in a return to similar short-term booster performance, or even greater, than that of animals treated with the non-toxic peptide. (Table 3 and Figures 4 and 5).
Tableau 3Table 3
Les résultats ci-dessus montrent que, dans un test de déficit de mémoire épisodique visuelle à court terme, l'association selon l'invention conduit à un effet promnésique supérieur marqué par rapport à l'effet promnésique produit par les deux principes actifs pris individuellement .The results above show that, in a short-term visual episodic memory deficit test, the combination according to the invention leads to a prominent promnesic effect with respect to the promnesic effect produced by the two active principles taken individually. .
L'ensemble des résultats obtenus dans les deux séries d'expérimentations ci-dessus démontre l'effet supérieur de l'association selon l'invention en terme d'efficacité par rapport à chacun des principes actifs administrés de façon isolée et au même dosage, sur les troubles de la mémoire épisodique visuelle dans une tâche de reconnaissance d'objets chez le rongeur. Cet effet supérieur est observé
non seulement chez des d'animaux non déficitaires dont les performances sont améliorées, mais également dans un modèle pathophysiαlogique de la maladie d'Alzheimer, utilisant des injections intracérébrales de peptide amyloide toxique.The set of results obtained in the two series of experiments above demonstrates the superior effect of the combination according to the invention in terms of efficacy with respect to each of the active ingredients administered in isolation and at the same dosage. on visual episodic memory disorders in a task of object recognition in rodents. This superior effect is observed not only in non-deficient animals whose performance is improved, but also in a pathophysiological model of Alzheimer's disease, using intracerebral injections of toxic amyloid peptide.
Cet effet supérieur est représentatif de l'efficacité de l'association selon l'invention sur les troubles cognitifs, et plus particulièrement sur les troubles cognitifs liés à la maladie d'Λlzheimer, pathologie pour laquelle ce type de fonction cognitive est connue pour être particulièrement altérée.
This higher effect is representative of the effectiveness of the combination according to the invention on cognitive disorders, and more particularly on the cognitive disorders related to Alzheimer's disease, a pathology for which this type of cognitive function is known to be particularly impaired.
Claims
1. Association d'un agon.iste partiel des récepteurs nicotiniques de type alpha 7 et d'un inhibiteur d'acétylcholinestérase.1. Association of an alpha 7-type nicotinic receptor partial agonist and an acetylcholinesterase inhibitor.
2. Association selon la revendication 1, caractérisée en ce que l'agoniste partiel des récepteurs nicotiniqυes de type alpha 7 est un composé de formule générale (I)2. Combination according to claim 1, characterized in that the partial agonist of nicotinic receptors of alpha 7 type is a compound of general formula (I)
dans laquelle in which
X représente un atome d' oxygène ou un groupe de formule NZ dans laquelle Z représente un atome d'hydrogène ou un groupe (C1-C6) alkyle, n représente le nombre 0, 1 ou 2, et R1, R2, R3, R4 et R5 représentent chacun, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène ou un groupe trifluorométhyle, triflυorométhoxy, eyano, hydroxy, (C1-C6) alkyle, (C1-C6) alcoxy, phénoxy ou phényle éventuellement substitué par un atome d'halogène ou un groupe trlfiuorométhyle, cyano, hydroxy, (C1-C6) alkyle ou (C1-C6) a.leoxy, ou bien encore R2 et R3 forment ensemble un groupe de formule -OCH2O- ou -CH2CH2CH2CH2-, à l'état de base ou de sel d'addition à un acide, d'hydrate ou de solvate.X represents an oxygen atom or a group of formula NZ in which Z represents a hydrogen atom or a (C 1 -C 6 ) alkyl group, n represents the number 0, 1 or 2, and R 1 , R 2 R 3 , R 4 and R 5 each independently of one another is hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, phenoxy or phenyl optionally substituted with a halogen atom or a trifluoromethyl, cyano, hydroxy, (C 1 -C 6 ) alkyl or (C 1 -C 6 ) a.leoxy group, or moreover, R 2 and R 3 together form a group of formula -OCH 2 O- or -CH 2 CH 2 CH 2 CH 2 -, in the form of a base or an addition salt with an acid, of hydrate or of solvate.
3. Association selon la revendication 2, caractérisée en ce que3. Association according to claim 2, characterized in that
X représente un atome d'oxygène ; r. représente le nombre 0 ;X represents an oxygen atom; r. represents the number 0;
R1, R2, R4 et R5 représentent chacun un atome d'hydrogène et R3 représente un atome d'halogène. R 1 , R 2 , R 4 and R 5 each represent a hydrogen atom and R 3 represents a halogen atom.
4. Association selon la revendication 2 ou 3, caractérisée en ce que l'agoniste partiel des récepteurs nicotiniqυes de type alpha 7 est le 1, 4-diazabicyclo[3.2.2]nonane-4- carboxylate de 4-bromophényle, à l'état de base ou de sel d'addition à un acide, d'hydrate ou de solvate.4. Association according to claim 2 or 3, characterized in that the partial agonist nicotinic receptors type alpha 7 is 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate, at the basic state or salt of addition to an acid, hydrate or solvate.
5. Association selon la revendication 5, caractérisée en ce que le 1, 4-diazabicyclo[3.2.2]nonane-4-carboxylate de 4- bromophényle est sous forme de sel de (2E) -but-2-ènedioate.5. Combination according to claim 5, characterized in that the 4-bromophenyl 1,4-diazabicyclo [3.2.2] nonane-4-carboxylate is in the form of (2E) -but-2-enedioate salt.
6. Association selon l'une quelconque des revendications 1 à 5, caractérisée en ce que l'inhibiteur d' acétyleholineatérase est choisi parmi la rivastigmine et le donepezil .6. Combination according to any one of claims 1 to 5, characterized in that the acetylholineatase inhibitor is selected from rivastigmine and donepezil.
7. Associrition selon l'une quelconque des revendications 1 à 6, caractérisée en ce que l'agoniste partiel des récepteurs nicotiniques de type alpha 7 est le (21) -but-2- énedioate de 1,4-diazabicyclo[3.2.2]nonane-4-carboκylate de 4-bromσphényle et l'inhibiteur d'acétyleholinestérase est la rivastigmine .7. Associrition according to any one of claims 1 to 6, characterized in that the partial agonist nicotinic receptors type alpha 7 is (21) -but-2- ededioate 1,4-diazabicyclo [3.2.2 ] 4-bromaphenyl nonane-4-carbo-kylate and the acetylcholinesterase inhibitor is rivastigmine.
8. Association selon l'une quelconque des revendications 1 à 7, caractérisée en ce que l'agoniste partiel des récepteurs nicotiniques de type alpha 7 est le (2E)-but-2- ènedioate de 1,4-diazabicyclo[3.2,2]nonane-4-carboxylate de 4-bromophényle et l'inhibiteur d'acétyleholinestérase est le donepezil.8. Combination according to any one of claims 1 to 7, characterized in that the partial agonist nicotinic receptors type alpha 7 is (2E) -but-2-enedioate 1,4-diazabicyclo [3.2.2 4-bromophenyl nonane-4-carboxylate and the acetyl cholinesterase inhibitor is donepezil.
9. Composition pharmaceutique comprenant à titre de principes actifs, l'association selon l'une quelconque des revendications 1 à 8, ainsi qu'au moins un excipient pharmaceutiquement acceptable.9. Pharmaceutical composition comprising as active ingredients, the combination according to any one of claims 1 to 8, and at least one pharmaceutically acceptable excipient.
10. kit comprenant, d'une part, un agoniste partiel des récepteurs nicotiniques de type alpha 7 tel que défini dans l'une quelconque des revendications 1 à 5 et, d'autre part, un inhibiteur d'acétyleholinestérase, l'agoniste partiel des récepteurs nicotiniques de type alpha 7 et l'inhibiteur d'acétyleholinestérase étant dans des compartiments distincts et étant destinés à être administrés de façon simultanée, séparée ou étalée dans le temps (administration séquentielle) .10. kit comprising, on the one hand, a partial agonist of nicotinic receptors of alpha 7 type as defined in any one of claims 1 to 5 and, on the other hand, an acetylcholinesterase inhibitor, the partial agonist. nicotinic receptors of the alpha 7 type and the acetylcholinesterase inhibitor being in compartments distinct and intended to be administered simultaneously, separately or spread over time (sequential administration).
11. Utilisation d'une association selon l'une quelconque des revendications 1 à 8, pour la préparation d'un médicament destiné au traitement des troubles cognitifs.11. Use of an association according to any one of claims 1 to 8 for the preparation of a medicament for the treatment of cognitive disorders.
12. Utilisation selon la revendication 11, caractérisée en ce que les troubles cognitifs sont liés à la maladie. d'Alzheimer. 12. Use according to claim 11, characterized in that the cognitive disorders are related to the disease. Alzheimer.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0802996A FR2931677B1 (en) | 2008-06-02 | 2008-06-02 | ASSOCIATION OF A PARTIAL NICOTINIC RECEPTOR AGONIST AND AN ACETYLCHOLINESTERASE INHIBITOR, COMPOSITION CONTAINING THE SAME AND USE THEREOF IN THE TREATMENT OF COGNITIVE DISORDERS |
| PCT/FR2009/051041 WO2009156680A2 (en) | 2008-06-02 | 2009-06-02 | Combination of a nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition containing same and use thereof in the treatment of cognitive disorders |
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| EP2293790A2 true EP2293790A2 (en) | 2011-03-16 |
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| EP09769521A Withdrawn EP2293790A2 (en) | 2008-06-02 | 2009-06-02 | Combination of a nicotinic receptor partial agonist and of an acetylcholinesterase inhibitor, pharmaceutical composition containing same and use thereof in the treatment of cognitive disorders |
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| Country | Link |
|---|---|
| US (1) | US20110136791A1 (en) |
| EP (1) | EP2293790A2 (en) |
| JP (1) | JP2011522017A (en) |
| KR (1) | KR20110021946A (en) |
| CN (1) | CN102046164B (en) |
| AU (1) | AU2009264016B2 (en) |
| BR (1) | BRPI0913236A2 (en) |
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| GB0424564D0 (en) * | 2004-11-05 | 2004-12-08 | Novartis Ag | Organic compounds |
| US8314119B2 (en) | 2006-11-06 | 2012-11-20 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
| MX2013003344A (en) | 2010-09-23 | 2013-06-28 | Abbvie Inc | Monohydrate of an azaadamantane derivative. |
| WO2013152783A1 (en) | 2012-04-14 | 2013-10-17 | Audi Ag | Method, system and vehicle for conducting group travel |
| CN103333163A (en) * | 2013-07-09 | 2013-10-02 | 广州中医药大学 | Coumarone derivative, and preparation method and applications thereof |
| EP3200828B1 (en) * | 2014-10-03 | 2020-08-12 | Lachesis Biosciences Limited | Intranasal compositions for treatment of neurological and neurodegenerative diseases and disorders |
| RU2624978C2 (en) * | 2015-07-27 | 2017-07-11 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Воронежский государственный медицинский университет им. Н.Н. Бурденко" Министерства здравоохранения Российской Федерации | Method for moderate cognitive reduction treatment |
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| WO2008028903A2 (en) * | 2006-09-04 | 2008-03-13 | Neurosearch A/S | Pharmaceutical combinations of a nicotine receptor modulator and a cognitive enhancer |
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| ATE286725T1 (en) * | 1998-10-01 | 2005-01-15 | Novartis Pharma Gmbh | NEW ORAL MEDICINAL PREPARATIONS FOR RIVASTIGMINE WITH CONTROLLED RELEASE OF ACTIVE INGREDIENTS |
| FR2791678B1 (en) * | 1999-03-30 | 2001-05-04 | Synthelabo | 1,4-DIAZABICYCLO [3.2.2] NONANE-4-CARBOXYLATES AND -CARBOXAMIDES DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| US20010036949A1 (en) * | 2000-05-09 | 2001-11-01 | Coe Jotham Wadsworth | Pharmaceutical composition and method of treatment of diseases of cognitive dysfunction in a mammal |
| DE60216830T2 (en) * | 2001-02-06 | 2007-06-14 | Pfizer Products Inc., Groton | Pharmaceutical compositions for the treatment of disorders of the CNS or other diseases |
| WO2002085405A2 (en) * | 2001-04-24 | 2002-10-31 | Merck Patent Gmbh | COMBINATION THERAPY USING ANTI-ANGIOGENIC AGENTS AND TNF$g(a) |
| UA83645C2 (en) * | 2002-10-24 | 2008-08-11 | Мерц Фарма Гмбх Унд Ко. Кгаа | Combination therapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors |
| KR20050085535A (en) * | 2002-12-11 | 2005-08-29 | 파마시아 앤드 업존 캄파니 엘엘씨 | Treatment of diseases with combinations of alpha 7 nicotinic acetylcholine receptor agonists and other compounds |
| BRPI0411891A (en) * | 2003-06-27 | 2006-08-29 | Pfizer Prod Inc | pyrazol [3,4-b] pyridin-6-ones as gsk-3 inhibitors |
| US20050043407A1 (en) * | 2003-08-22 | 2005-02-24 | Pfizer Inc | Pharmaceutical composition for the prevention and treatment of addiction in a mammal |
| US20050228019A1 (en) * | 2004-01-26 | 2005-10-13 | Cortex Pharmaceuticals, Inc. | Enhancement of ampakine-Induced facilitation of synaptic responses by cholinesterase inhibitors |
| TW200533371A (en) * | 2004-04-15 | 2005-10-16 | Dainippon Pharmaceutical Co | Medicament comprising a combination of an acetylcholinesterase inhibitor and a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1h)-one derivative |
| KR20070015607A (en) * | 2004-05-07 | 2007-02-05 | 메모리 파마슈티칼스 코포레이션 | 1H-indazole, benzothiazole, 1,2-benzoisoxazole, 1,2-benzoisothiazole, and chromone and preparation and use thereof |
| US20060194723A1 (en) * | 2005-02-28 | 2006-08-31 | Rabinoff Michael D | Novel medication treatment and delivery strategies for Alzheimer's Disease, other disorders with memory impairment, and possible treatment strategies for memory improvement |
| US20090075983A1 (en) * | 2006-02-14 | 2009-03-19 | Dan Peters | Novel Diazabicycloalkane Derivatives and Their Medical Use |
| EP1977746B8 (en) * | 2007-04-02 | 2014-09-24 | Parkinson's Institute | Methods and compositions for reduction of side effects of therapeutic treatments |
| JP5383788B2 (en) * | 2008-03-19 | 2014-01-08 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Trisubstituted 1,2,4-triazoles as nicotinic acetylcholine receptor modulators |
| AR071763A1 (en) * | 2008-05-09 | 2010-07-14 | Janssen Pharmaceutica Nv | TRISUSTITUTED PIRAZOLS, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND USES OF THE SAME IN THE TREATMENT OF NEUROLOGICAL AND PSYCHIATRIC DISORDERS |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008028903A2 (en) * | 2006-09-04 | 2008-03-13 | Neurosearch A/S | Pharmaceutical combinations of a nicotine receptor modulator and a cognitive enhancer |
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| US20110136791A1 (en) | 2011-06-09 |
| RU2493851C2 (en) | 2013-09-27 |
| FR2931677B1 (en) | 2010-08-20 |
| BRPI0913236A2 (en) | 2016-01-19 |
| WO2009156680A2 (en) | 2009-12-30 |
| WO2009156680A3 (en) | 2010-04-22 |
| AU2009264016A1 (en) | 2009-12-30 |
| KR20110021946A (en) | 2011-03-04 |
| JP2011522017A (en) | 2011-07-28 |
| IL209601A0 (en) | 2011-02-28 |
| MX2010013241A (en) | 2011-01-21 |
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| CN102046164A (en) | 2011-05-04 |
| CA2726291A1 (en) | 2009-12-30 |
| SG191623A1 (en) | 2013-07-31 |
| RU2010154417A (en) | 2012-07-20 |
| HK1155943A1 (en) | 2012-06-01 |
| FR2931677A1 (en) | 2009-12-04 |
| AU2009264016B2 (en) | 2014-09-11 |
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