Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• the invention relates to the field of neurodegenerative diseases.
• the invention relates more particularly to compositions comprising a synergistic combination of 3(2-Fluoroethyl)tricyclo [3.3.1.13.7]decan-1-amine (Fluoroethylnormemantine, FENM) with at least one acetylcholinesterase inhibitor.
• the invention also relates to these combinations or compositions comprising them for their use in the treatment of neurodegenerative pathologies and, more particularly, in the prevention and/or treatment of the cognitive disorders of these pathologies.
• the World Health Organization estimates that by 2050 the number of people aged over 60 will reach two billion. This unprecedented aging of the world population suggests a strong pressure of chronic diseases related to aging on health systems. Dementia is one of these. Thus, the WHO estimates that the total number of people with dementia should exceed 150 million people by 2050.
• Dementia is characterized by a degradation of cognitive functions, in particular memory and reasoning, which impacts the patient's behavior and his ability to perform everyday tasks.
• Dementia is a syndrome that covers pathologies with very diverse etiologies that affect different areas of the brain and/or other regions of the central nervous system and involve in particular neurodegeneration and the death of neuronal cells. Directly linked to aging, mitochondrial dysfunction and oxidative stress play a crucial role in the pathogenesis of neurodegenerative diseases.
• pathologies and syndromes are also often related to an abnormal accumulation of certain proteins and/or the accumulation of mutated and/or abnormally folded proteins as observed in Ap amyloidosis, tauopathies, synucleinopathies, aggregation of superoxide dismutase-1 (SOD1), polyglutamine, protein TDP-43.
• SOD1 superoxide dismutase-1
• Alzheimer's disease is the most common cause of dementia and is thought to be the cause of 60-70% of cases (source WHO).
• Alzheimer's disease Today, several molecules are authorized in the symptomatic treatment of Alzheimer's disease. It is the anticholinesterases such as donepezil, rivastigmine, or galantamine which benefit from marketing authorizations, in monotherapy, at the mild, moderate or moderately severe stage of the disease.
• Memantine a voltage antagonist non-competitive dependent on NMDA receptors, is allowed in moderate and severe stages of the disease and is not allowed in the mild stage of the disease.
• These compounds are not recommended in the early stage of the disease, due to a lack of clinical efficacy.
• their effects are symptomatic and limited and have only been demonstrated in the short term (on average 6 months) in nearly two thirds of the patients included in the clinical studies (source, Haute Autorotti de Santé, France) .
• AMM European Medicines Agency
• EMA European Medicines Agency
• the supposed efficacy of anticholinesterases in the early stage of the disease is based on a single study performed specifically on patients at this stage in which a modest benefit was observed only in patients who tolerated doses of 10 mg per day. of donepezil.
• the health authorities in France consider that this study does not make it possible to conclude that there is an interest in starting this treatment at the mild stage of the disease (Source Haute Autorotti de Santé, France, 2012).
• Acetylcholinesterase inhibitors are also associated with a risk of serious or potentially life-threatening adverse effects and/or necessitating discontinuation of treatment. These may be digestive disorders (diarrhea, vomiting), cardiovascular disorders (bradycardia, syncope), or even neuropsychiatric disorders (dizziness, mental confusion) which are counterproductive in the case of treatment of dementia.
• Application WO 2014/191424 describes MENM labeled with 18 F for the labeling of NMDA receptors and their visualization by positron emission tomography to study the distribution of these receptors and their reaction to drug treatments.
• Application WO 2019/115833 describes FENM in the treatment of disorders related to anxiety and depression.
• WO 2013/064579 describes a combination of a connexin blocking agent (such as meclofenamic acid) with an acetylcholine esterase inhibitor (such as donepezil) for their use in the treatment of cognitive disorders.
• a connexin blocking agent such as meclofenamic acid
• an acetylcholine esterase inhibitor such as donepezil
• Aducanumab is an anti-amyloid monoclonal antibody whose use is aimed at decreasing the amyloid load in the brain.
• Aducanumab received marketing authorization issued by the FDA in 2021, for the treatment of early-stage or prodromal Alzheimer's disease with proven presence of amyloid deposits. Faced with unreproduced results concerning less cognitive decline in the patients treated, and taking into account the fact of the absence of therapeutic solutions, the marketing authorization was conditional on a reassessment of the product to confirm its clinical benefit ( ⁇ www.fda. gov>). Approximately 35% of the patients treated presented cerebral microhemorrhages and cerebral edemas (source France Alzheimer, ⁇ www.francealzheimer.org>). The cost of the treatment, which requires monthly intravenous administration, is estimated at $56,000 per year.
• the object of the invention is to remedy the drawbacks of the prior art.
• the aim of the invention is to propose a new therapy for cognitive damage in neurodegenerative pathologies and in particular Alzheimer's disease (AD).
• This new therapy is based on the combined action of fluoroethylnormemantine (FENM) and at least one acetylcholinesterase inhibitor.
• FENM fluoroethylnormemantine
• FENM fluoroethylnormemantine
• acetylcholinesterase inhibitor acetylcholinesterase inhibitor.
• the synergy of action identified between these molecules makes it possible, on the one hand, to obtain particularly effective effects in the preservation of cognitive abilities and/or to reduce the doses used for these compounds.
• This decrease makes it possible to reduce the risk of adverse effects or even to increase the possible duration of treatment while obtaining a greater improvement for particularly low doses.
• This improved efficacy makes it possible to envisage the use of this treatment, including at
• an object of the present invention relates to a composition
• a composition comprising a synergistic combination of 3-(2-fluoroethyl)adamantan-1-amine (FENM) or any of its pharmaceutically acceptable salts and at least one inhibitor of acetylcholinesterase or any of its pharmaceutically acceptable salts.
• FENM 3-(2-fluoroethyl)adamantan-1-amine
• said at least one acetylcholine esterase inhibitor is selected from donepezil, galantamine, rivastigmine, tacrine, or any of their pharmaceutically acceptable salts.
• these molecules benefit from an MA or have already been tested in humans and their pharmacokinetic and pharmacodynamic properties are already known, which is a particular advantage.
• the compounds are formulated together or separately.
• the FENM and/or said at least one acetylcholinesterase inhibitor is mixed with a pharmaceutically acceptable excipient.
• the dose of FENM is compatible with a dosage of FENM less than or equal to 20 mg/day
• said at least one acetylcholinesterase inhibitor is donepezil which is present at a dose compatible with a dosage less than or equal to 10 mg/day
• said at least one acetylcholinesterase inhibitor is rivastigmine which is present at a dose compatible with a dosage less than or equal to 3 mg/day
• / or said at least one acetylcholinesterase inhibitor is galantamine which is present at a dose compatible with a dosage less than or equal to 16 mg/day.
• the molar ratio FENM/at least one acetylcholine esterase inhibitor is lower or equal to 4, less than or equal to 3, preferably less than or equal to 2, preferably less than or equal to 1.
• a particular object of the present invention relates to the composition as described above, in any one of its embodiments, for its use as a medicament.
• the composition comprising a synergistic combination of FENM and of at least one acetylcholinesterase inhibitor is particularly effective in countering cognitive damage in a model of neurodegenerative pathology.
• a pathology selected from tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease , Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, sclerosis amyotrophic side.
• the FENM and the at least one acetylcholinesterase inhibitor are administered separately, concomitantly or sequentially.
• this can be done by the use of specific formulations of FENM on the one hand and of at least one acetylcholinesterase inhibitor on the other hand resulting in differentiated infusion kinetics for each of the compounds included in a unit composition; alternatively, according to another example, the at least FENMs on the one hand and the at least one acetylcholinesterase inhibitor of the combination on the other hand are formulated and administered in individualized dosage forms.
• Another object of the invention resides in FENM, or a pharmaceutically acceptable salt thereof, in synergistic combination with at least at least one acetylcholinesterase inhibitor selected from donepezil, galantamine, rivastigmine, tacrine or any of their pharmaceutically acceptable salts, for use in the treatment of a pathology selected from tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease , posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, Lewy body dementia, amyotrophic lateral sclerosis. tricks
• Fig 2 (A) Symptomatic effect of donepezil FENM (DPZ) or FENM-DPZ combination on memory impairment induced by oligomerized peptide AP25-35 intoxication in the passive avoidance test.
• reference to a specific drug or compound includes not only the specifically named drug or compound, but also any salt, hydrate, derivative, isomer, racemate, enantiomerically pure composition, conjugate or corresponding pharmaceutically acceptable prodrug of the active molecule of the drug or of said compound.
• the mention of a compound includes the specifically named compound, as well as any pharmaceutically acceptable salt, hydrate, isomer, racemate, isomer, enantiomerically pure composition of said compound.
• designation of a compound is intended to designate the compound as specifically designated per se, as well as any pharmaceutically acceptable salt thereof. Unless otherwise stated, however, the mention in mass unit or in mass unit per day of the quantity of a compound of the composition or the combination according to the invention, means the designated compound per se.
• salts are meant, within the meaning of the invention, a pharmaceutically acceptable and relatively non-toxic inorganic or organic acid addition salt of a compound of the present invention.
• Pharmaceutical salt formation involves coupling an acidic, basic, or zwitterionic drug molecule with a counterion to create a salt version of the drug.
• a wide variety of chemical species can be used in the neutralization reaction.
• the pharmaceutically acceptable salts of the invention therefore include those obtained by reacting the compound concerned, when it functions as a base, with an inorganic or organic acid to form a salt, for example, salts of acetic acid, nitric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid or citric acid.
• the pharmaceutically acceptable salts of the invention also include those in which, when the compound concerned functions as an acid, said compound is reacted with a suitable base to form, for example, salts of sodium, potassium, calcium, magnesium, ammonium or choline.
• salt selection is now a common standard operation in the drug development process as taught by Stahl and Wermuth in their textbook (Stahl and Wermuth).
• a preferred donepezil salt is donepezil hydrochloride.
• a preferred galantamine salt is galantamine hydrobromide.
• a preferred rivastigmine salt is rivastigmine tartrate.
• a preferred salt of FENM is FENM hydrochloride.
• a particularly preferred salt of FENM is FENM hydrobromide.
• the term “combination”, within the meaning of the present invention, designates a treatment in which at least FENM and at least one acetylcholinesterase inhibitor is co-administered to a subject to cause a biological effect.
• these at least two compounds can be administered together or separately, at the same time or sequentially.
• the FENM and said at least one acetylcholinesterase inhibitor can be administered by following different administration routes and/or protocols. Accordingly, although they can be formulated together, the compounds as part of a combination within the meaning of the invention can also be formulated separately.
• the FENM can be administered orally and said at least one acetylcholinesterase inhibitor of the combination according to the invention can be injected into said subject, for example, intravenously, subcutaneously or even transdermally.
• the FENM can be administered orally and said at least one inhibitor of acetylcholinesterase may also be administered orally to said subject concomitantly or in a time-shifted manner.
• the sequence of administration of the active principles of the combination is such that the said active principles or their active metabolite(s) exert their biological effects at the same time, so that the subject benefits from the maximum effect of said combination.
• the FENM and the said at least one acetylcholinesterase inhibitor are administered so as to reach their maximum concentration in the plasma or the cerebrospinal fluid, preferably the cerebrospinal fluid, at the same time.
• synergy applied to the combinations according to the invention means combinations for which the pro-mnesic or anti-amnesic effects observed or known for each of the active principles of the said combination add up or multiply when used in such a way as to that their physiological effects interact.
• This synergistic effect makes it possible in particular to obtain pro-mnesic or anti-amnesic effects at doses at which the active principles applied in monotherapies would have no effect or a limited effect, which can make it possible to reduce the side effects and/ or to avoid or shorten the duration of dose-escalation protocols.
• this synergy between the effects of the compounds of the combination according to the invention also makes it possible to potentiate these pro-mnesic or anti-amnesic effects or to improve complex types of memory as shown in the experimental part.
• the methods for analyzing the interaction between two molecules and for determining the synergistic effect of a combination of compounds are well known to those skilled in the art.
• a non-limiting example is the analysis of isobolograms and the determination of the combination index according to the principles set out by Fraser (1872) and as implemented, for example, by Martin et al. (2020).
• a presence of synergy can be detected by applying the mathematical method illustrated in the experimental part.
• Synergy can be demonstrated in vivo in animal models of a pathology, for example via tests to assess cognitive performance or morphological alterations associated with the pathology.
• the synergy can be demonstrated in vitro, for example, within the framework of in vitro tests on cells, in models recognized by the scientific community such as for example cytotoxicity tests, by measuring various parameters relating to cell viability, and in the case of neuronal cells, the growth of neurites, the formation of synapses, etc.
• Concerning dementia and/or AD illustrations of these tests are given, for example, by Chumakov et al. (2015).
• subject is meant herein to describe any member of the animal kingdom, preferably mammals and even more preferably humans.
• a subject in need of the combinatorial treatments of the invention is defined as a subject suffering from, being suspected of suffering from or being considered at risk of suffering from a neurodegenerative pathology leading to a dementia and associated cognitive disorders.
• pathologies are, for example, tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy , vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.
• compositions, combinations and methods of the present invention are particularly suitable for the treatment of cognitive disorders associated with Alzheimer's disease at its early, moderate or advanced stage.
• said subject suffers from, is suspected of suffering from or is considered at risk of suffering from Alzheimer's disease at its early, moderate or advanced stage.
• said subject suffers, is suspected of suffering or is considered at risk of suffering from cognitive disorders associated with the early, moderate or advanced stages of Alzheimer's disease, preferably cognitive disorders associated with the early stage of Alzheimer's disease.
• treatment includes therapy, prevention, prophylaxis, delay or reduction of symptoms caused by or causes of the above diseases or disorders.
• treatment includes in particular the control of the progression of the disease and the associated symptoms.
• treatment includes, in particular, protection against the effects of toxicity caused by amyloid p, or a reduction or delay of these effects in the subjects treated.
• treatment particularly designates an improvement, an arrest or a delay in the evolution of the cognitive symptoms of the diseases mentioned.
• amyloid A 25-35 poisoning The protective effect of this combination against the cognitive decline caused by amyloid A 25-35 peptide intoxication is observed for both short-term working memory and long-term memory.
• the invention relates to a synergistic combination of MENM or any of its pharmaceutically acceptable salts and at least one acetylcholinesterase inhibitor or any of its pharmaceutically acceptable salts .
• said at least one acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine or else tacrine.
• Donepezil, galantamine and rivastigmine are particularly preferred as they have been licensed for over twenty years, their side effects and properties pharmacological are well known.
• Tacrine because of its hepatotoxicity is less preferred. Nevertheless, the synergistic effect demonstrated here, which concerns protection against cognitive symptoms, may make it possible to consider the use of low doses at which this hepatotoxicity is not observed.
• the synergistic combination of FENM with donepezil is particularly preferred.
• the synergistic effect observed for the combinations of the invention makes it possible to envisage using, in humans, minimum doses or even doses lower than these minimum doses at which acetylcholinesterase inhibitors are used in humans. 'male.
• the at least one acetylcholinesterase inhibitor is donepezil and is administered at a dose less than or equal to 10 mg per day, less than or equal to 5 mg per day, less than or equal to 2.5 mg per day, but still sufficient to observe a beneficial effect of the combination on the subject's cognitive abilities.
• the at least one acetylcholinesterase inhibitor is galantamine and is administered at a dose less than or equal to 16 mg per day, less than or equal to 8 mg per day, less than or equal to 4 mg per day or even less than 2 mg per day, but still sufficient to observe a beneficial effect of the combination on the subject's cognitive abilities.
• the at least one acetylcholinesterase inhibitor is rivastigmine and is administered at a dose less than or equal to 3 mg per day, less than or equal to 1, 5 mg per day, or even less than or equal to 1 mg per day, but still sufficient to observe a beneficial effect of the combination on the cognitive abilities of the subject.
• the FENM in the synergistic combination according to the invention, is used at a dose less than or equal to 20 mg per day, less than or equal to 10 mg per day, or even less than or equal to 5 mg per day. , but still sufficient to observe a beneficial effect of the combination on the cognitive abilities of the subject.
• the cognitive capacities of human subjects and their development can be measured by tests well known to those skilled in the art.
• Commonly used tests for the cognitive assessment of human subjects are, for example, the Mini-Mental State Examination (MMSE or Folstein test), Modified Mini-Mental State Examination (or 3MS scale), Abbreviated Mental Test Score (AMTS or Abbreviated mental test), Dementia questionnaire for persons with Mental Retardation (or DMR questionnaire), Cognitive Abilities Screening Instrument (CASI or Cognitive Abilities Screening Instrument), Trail-making test, Clock drawing test, Alzheimer's disease assessment scale - Cognition (ADAS -Cog or Cognitive subscale of the Alzheimer's disease assessment scale), General Practitioner Assessment of Cognition (GPCOG or Cognitive Practitioner Assessment), Montreal Cognitive Assessment (MoCA or Montreal Cognitive Assessment), or Rowland Universal Dementia Assessment Scale (RUDAS or Rowland Universal Dementia Assessment Scale), or Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL or cooperative study of Alzheimer's disease
• the MMSE makes it possible to screen people suffering from major neurocognitive impairment (dementia) without linking it to a particular pathology.
• the MMSE is also used to monitor the cognitive state of people and to measure the decline of cognitive functions in people who suffer from neurocognitive impairment. This test assesses orientation, registration, attention and calculation, memory retention, language and construction praxis.
• the CERAD in its English name Consortium to Establish a Registry for Alzheimer's Disease or Consortium to establish a registry of Alzheimer's disease
• a score between 19 and 24 is associated with mild dementia, between 10 and 18 with moderate dementia, and a score below 10 corresponds to severe dementia, the maximum score being 30.
• a change of 2 points in the score is generally considered clinically relevant.
• the ADAS-Cog is a cognitive subscale of the Alzheimer's Disease Rating Scale and therefore only addresses cognition-related aspects of dementia. Thus it can be used to assess (/.e. score) and follow the evolution of any type of dementia.
• the ADAS-Cog assesses orientation, memory, executive function, visuospatial ability, language, or practice, with a score range of 0 to 70, with a higher score indicating greater impairment.
• ADAS-Cog is considered more sensitive than MMSE. It is one of the most commonly used tests for the clinical evaluation of candidate compounds for obtaining a Marketing Authorization in the context of anti-dementia treatments and also in the measurement of the evolution of the attacks. cognitive.
• a combination with a beneficial effect of the combination on the cognitive capacities of the subject will show a slowing down, or a stabilization of the deterioration of the cognitive capacities of the subject with regard to the usual evolution established in untreated subjects at the same stage of the disease. for a given period of time.
• a beneficial effect on the cognitive abilities of the subject will correspond to a decrease, stabilization or a lower intensity increase in the ADAS- score.
• Cog compared to the usual worsening of the score observed in untreated subjects at an equivalent stage and of an equivalent age.
• the synergy between FENM and at least one acetylcholinesterase inhibitor is observed for a very low FENM/acetylcholinesterase inhibitor molar ratio.
• the molar ratio tested for memantine and donepezil in the state of the art is greater than 4, if we consider the combinations based on 20 mg of memantine and 10 mg of donepezil) it is in particular the ratio contained in NAMZARIC® authorized by the FDA, based on donepezil hydrochloride and memantine hydrochloride.
• Tmax values in humans for donepezil and memantine when administered orally are comparable: between 3 and 8 hours for memantine (Maekawa et al., 2019) and 4.1 ⁇ 1.5 hours for donepezil (Rogers & Friedoff, 1998).
• the experimental data show that the synergistic effect discovered for the combination of the invention is obtained at a much lower molar ratio, which can even be reversed, indicating the specificity of synergistic combinations based on FENM.
• the FENM/acetylcholinesterase inhibitor molar ratio is less than or equal to 4, less than or equal to 3, less than or equal to 2, preferably less than or equal to 1, less than or equal to 0.8, or even less than or equal to 0.5.
• Said FENM/acetylcholinesterase inhibitor molar ratio being greater than or equal to 0.1.
• said FENM/acetylcholinesterase inhibitor molar ratio is less than 1 and greater than or equal to 0.1.
• said acetylcholinesterase inhibitor is donepezil and the FENM/donepezil molar ratio is less than or equal to 4, is less than or equal to 3, less than or equal to 2, preferably less than or equal to 1 , less than or equal to 0.8, or even less than or equal to 0.5.
• Said FENM/donepezil molar ratio being greater than or equal to 0.1.
• said FENM/donepezil molar ratio is less than 1 greater than or equal to 0.1.
• the invention in another aspect, relates to a composition comprising a synergistic combination as described above.
• the MENM or any of its pharmaceutically acceptable salts and the at least one acetylcholinesterase inhibitor or any of its pharmaceutically acceptable salts are formulated together or separately.
• the FENM and the at least one acetylcholinesterase inhibitor are the only active ingredients of said composition.
• the FENM and the at least one acetylcholinesterase inhibitor are the only compounds within the composition having therapeutic or preventive activity.
• the composition is administered to the subject in the form of a pharmaceutical preparation, for example, without being limiting, orally, topically (cutaneously, buccally, sublingually) or parenterally (subcutaneously, intramuscularly or intravenously). Oral administration is particularly preferred.
• the amounts of the active ingredients within this composition are compatible with the doses as determined above for the synergistic combinations of invention.
• said composition when said composition is in the form of a unit dosage (in the form of a cachet, capsule, powder, emulsion, solution) said dosage comprises quantities of FENM or of the at least one acetylcholinesterase inhibitor which are a multiple or a divisor of the doses determined for the synergistic combinations of the invention, thus making it possible to obtain in one or more doses the appropriate dosage as defined above.
• the composition according to the invention comprises 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil. In another particular embodiment, the composition according to the invention comprises 16 mg of galantamine, 8 mg of galantamine, 4 mg of galantamine, or even 2 mg of galantamine. In another particular embodiment, the composition according to the invention comprises 3 mg of rivastigmine, 1.5 mg of rivastigmine, or even 1 mg of rivastigmine.
• the composition according to the invention comprises 20 mg of FENM, 10 mg of FENM, 7.5 mg of FENM, 5 mg of FENM, or even 2.5 mg of FENM.
• the composition according to the invention comprises 20 mg of FENM and 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil. In another embodiment, the composition according to the invention comprises 10 mg of FENM and 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil. In another embodiment, the composition according to the invention comprises 7.5 mg of FENM and 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil.
• the composition according to the invention comprises 5 mg of FENM and 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil. In another embodiment, the composition according to the invention comprises 2.5 mg of FENM and 10 mg of donepezil, 7.5 mg of donepezil, 5 mg of donepezil, or even 2.5 mg of donepezil.
• the FENM/acetylcholinesterase inhibitor molar ratio is less than or equal to 4, less than or equal to 3, less than or equal to 2, preferably less than or equal to 1, less than or equal to 0.8, or even less than or equal to 0.5. Said ratio is greater than or equal to 0.1. Particularly preferably, said FENM/acetylcholinesterase inhibitor molar ratio is less than 1 and greater than or equal to 0.1.
• said acetylcholinesterase inhibitor is donepezil and the FENM/donepezil molar ratio is less than or equal to 4, is less than or equal to 3, is less than or equal to 2, preferably less than or equal to 1, less than or equal to 0.8, or even less than or equal to 0.5, said ratio being greater than or equal to 0.1.
• said FENM/donepezil molar ratio is less than 1 and greater than or equal to 0.1.
• the dose can be administered in several doses spread over the day, the number of doses during the day making it possible to obtain the desired daily dose.
• the doses in question can be administered in one to four daily doses, for example once, for example twice, for example 3 times, or even 4 times.
• the combination of the FENM or of the at least one acetylcholinesterase inhibitor is packaged so as to provide the dose corresponding to an intake without requiring manipulation such as a measurement of volume, weighing or dividing a tablet, which is particularly advantageous in subjects with cognitive impairment since this avoids any particular calculation or manipulation.
• FENM or at least one acetylcholinesterase inhibitor are formulated separately in the form of powder, micro-granules, granules or even distinct cachets then combined in a capsule to make it easier to take.
• compositions can be formulated according to conventional pharmaceutical practice (see, for example, Remington: The Science and Practice of Pharmacy (23rd ed.), ed. A Adeboye Adejare, 2020) and the PK/PD characteristics of the active ingredients.
• conventional pharmaceutical practice see, for example, Remington: The Science and Practice of Pharmacy (23rd ed.), ed. A Adeboye Adejare, 2020
• the FENM and/or said at least one acetylcholinesterase inhibitor is mixed with a pharmaceutically acceptable excipient.
• said composition is in the form of a tablet or tablet.
• Said tablet or tablet may be divisible into 1, 2, 3, or even 4 pieces so as to be able to provide the subject with the dose necessary for taking using 1, 2 or 3 pieces of said tablet.
• the FENM and the at least one acetylcholinesterase inhibitor are mixed within the same lozenge or tablet with the same excipient(s).
• the FENM and the at least one acetylcholinesterase inhibitor are present in different compartments of said tablet or tablet with excipients which are specific to them, and which are a function of their physicochemical properties or of their pharmacokinetic properties.
• the FENM and the at least one acetylcholinesterase inhibitor are present separately within this tablet.
• the FEMM and the at least one acetylcholinesterase inhibitor are present in different compartments of said tablet or tablet, for example one compound being located on the outside and the other compound on the outside. inside said lozenge or tablet, which allows separate and time-shifted administration of these compounds.
• the FENM and/or the at least one acetylcholinesterase inhibitor can be formulated to be released (s) substantially immediately after administration, at any time, or at a period predetermined time after administration that is to say formulated (s) so as to be released in a controlled manner in the body.
• Controlled release formulations include (i) formulations which create a substantially constant concentration of the compound or its active derivative in the body over an extended period of time; (ii) formulations which, after a predetermined lag time, create a substantially constant concentration of the compound or its active derivative in the body over an extended period of time; (iii) formulations which maintain the action of the compound or its active derivative for a predetermined period of time by maintaining a level of said compound or its active derivative relatively, constant and effective in the body further enabling a concomitant minimization of the effects undesirable side effects associated with fluctuations in the plasma level of said compound or its active derivative;
• Administration of compounds in the form of a controlled release formulation is particularly preferred in cases where the compound has (i) a narrow therapeutic index (i.e. the difference between the plasma concentration leading to effects harmful effects, side effects or toxic reactions, and the plasma concentration leading to a therapeutic effect is low; in general, the therapeutic index, Tl, is defined as the ratio of the median lethal dose (LD50) to the median effective dose (DE50)); (ii) a narrow window absorption in the gastrointestinal tract; or (iii) a very short biological half-life such that frequent administrations are necessary to maintain the plasma level at an effective therapeutic level.
• Different strategies can be pursued in order to obtain a release with a rate of release of the compound or of its active derivative adapted to the metabolism of the drug in question.
• Controlled release can be achieved by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled release compositions and coatings known to those skilled in the art.
• the compound is formulated with appropriate excipients into a pharmaceutical composition which, upon administration, releases said compound in a controlled manner (unitary or multiple compositions of tablets or capsules, oily solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes).
• specific technical means such as reservoirs, pumps or transdermal patches (in other words a self-adhesive patch which dispenses a substance percutaneously) can contribute to the controlled release of at least the FENM and / or at least one acetylcholinesterase inhibitor.
• said composition is formulated in liquid form. It can be packaged in the form of a unit dose in containers such as ampoules, or else in a container such as a bottle or a flask associated with a device allowing the collection and, optionally, the administration of the desired volume to obtain the adequate dose.
• the invention relates particularly to the composition or to the synergistic combination as described previously in all their embodiments, for their use as medicament.
• the invention relates to the synergistic combination of FENM and donepezil or a composition comprising it, as described above in all their embodiments, for their use as a medicament.
• the invention relates particularly to the synergistic composition or combination, as described previously, for their use in the treatment of a pathology selected from tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease , Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.
• said treatment relates to the treatment of Alzheimer's disease in its early, moderate or advanced stage, preferably Alzheimer's disease in its early stage.
• said treatment relates to the treatment of cognitive disorders associated with any of the pathologies selected from tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy , Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.
• a particular embodiment relates to the synergistic composition or combination as described previously for their use in the treatment of cognitive disorders associated with the early, moderate or advanced stage of Alzheimer's disease, preferably at the early stage.
• the experimental data show a particularly significant synergistic effect in the treatment of long-term contextual memory impairments, which is of particular advantage in the case of patients at the early stage of the disease.
• Another particular embodiment relates to the synergistic composition or combination as described above for their use of the alterations: of short-term memory, of medium-term memory, of spatial memory, or of recognition capacities and/or learning, associated with any of the pathologies selected from tauopathy, synucleinopathy, amyloidopathy, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis.
• said alterations of short-term memory, medium-term memory, spatial memory, or recognition and/or learning abilities are associated with the early, moderate or advanced stage of the disease of Alzheimer's, preferably at an early stage.
• the invention relates to a method for treating a pathology selected from tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis comprising the administration to a subject in need thereof, of a synergistic combination of FENM or any of its pharmaceutically acceptable salts with at least one acetylcholinesterase inhibitor or any of its pharmaceutically acceptable salts.
• a pathology selected from tauopathies, synucleinopathies, amyloidopathies, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, amyotrophic lateral sclerosis comprising the administration to a subject in need thereof
• said synergistic combination is as previously described, in all its embodiments.
• said method may comprise the administration of a composition according to the invention as described above.
• said method comprises the separate, concomitant or sequential administration of the FENM and at least one acetylcholinesterase inhibitor.
• the FENM and the at least one acetylcholinesterase inhibitor can be administered separately to the subject by identical routes, such as for example by the oral, parenteral or transdermal route.
• the FENM and the at least one acetylcholinesterase inhibitor can be administered to the subject by different routes. For example, one orally and the other transdermally or parenterally.
• a particular example being constituted by the transdermal form of rivastigmine marketed under the name Exelon® or of donepezil (in clinical trials in the United States under the name Adlarity®).
• AP25-35 fragment of 11 amino acids of sequence Nt-GSNKGAIIGLM-Ct (SEQ ID NO 1) of the APP peptide.
• FENM 3(2-Fluoroethyl)tricyclo[3.3.1.13.7]decan-1-amine hydrobromide (also fluoroethylnormemantine hydrobromide).
• YMT Y-maze spontaneous alternation test; "Y-maze test” in English.
• PAT passive avoidance test
• Passive Avoidance Test or “step-through passive avoidance test” in English.
• ICV intracerebroventricular.
• IP intraperitoneal.
• CI combination index.
• iChE acetylcholinesterase inhibitor.
• CNS Central Nervous System.
• AD Alzheimer's disease.
• mice Male Swiss OF-1 mice (Janvier, St Berthevin, France) aged 7 to 9 weeks with a mass of 32 ⁇ 2 g.
• the animals are housed in groups of 8 to 10 individuals in plastic cages with unlimited access to drink and food, in a controlled environment (day/night cycle of 12 hours, the light switching on at 7:00 a.m. and behavioral experiments taking place between 9 a.m. and 5 p.m.), under controlled atmosphere and sound environment.
• DPZ was obtained from Eisai Co. Ltd (Tokyo, Japan).
• the FENM was obtained from M2i Life Sciences ( Saint-Cloud, France).
• the stock solutions of the compounds were obtained by solubilization in NaCl buffer (0.9%, vehicle) at a concentration of 2 mg/mL which corresponds to a dose of 5 mg/Kg. These stock solutions are stored at 4°C for a maximum of 2 weeks.
• amyloid peptide [25-35] denoted AP25-35 (Eurogentec, Angers, France) was dissolved in sterile distilled water at a concentration of 3 mg/mL, the stock solution thus formed is aliquoted and stored at -20°C until use.
• AP25-35 oligomers are formed as described by Maurice et al. (1996), during incubation at 37°C for 4 days before injection into the animals.
• the vehicle solution or the control peptide are subjected to the same treatment before administration. It has already been shown that injection of vehicle solution (distilled water) gives the same lack of effect as injection of control peptide Sc Ap (control peptide), which comprises the same amino acids as AP25-35 in an order random and which does not oligomerize.
• the compounds are administered IP in a volume of 100 ⁇ L per 20 g of body weight.
• the administration of the FENM/DPZ combination is carried out in a volume of 100 pL per 20g of body mass.
• the doses of compounds mentioned in the experimental part correspond to the doses of the salts of the compounds used and not to the mass equivalent of the compound itself.
• the doses administered, expressed in moles, are given in Table 2.
• the doses administered are 0.01; 0.03; 0.1; 0.3 and 1 mg/Kg.
• the doses of donepezil and FENM co-administered were 0.03 and 0.01 mg/Kg, respectively.
• the ICV injection model of AP25-35 oligomers is a well-known model in the state of the art. This model is considered to be a relevant screening model for the neuroprotective activity of compounds, and more particularly a relevant first-line model of Alzheimer's disease.
• AP25-35 oligomers are known to be cytotoxic to neuronal cells in mice and to induce spatial and working memory impairment. This deficit is accompanied by the generation of mitochondrial stress, oxidative stress and cell apoptosis, particularly in the hippocampus, and by inflammation of the central nervous system.
• the ability of the compounds and their combination to reduce the cognitive symptoms of neurodegeneration induced by AP25-35 oligomers is tested.
• the administration of the test compounds takes place on the same day as the injection of the AP25-35 oligomers and continues on a daily basis until day 7 after the injection of the AP25-35 oligomers; the mice are then subjected to the YMT, or PAT tests on day 8 after the injection of the AP25-35 oligomers.
• This test measures non-spatial (contextual) long-term memory.
• the device used for this test is a box with two compartments (15 x 20 x 15 cm high) one lighted with white PVC walls and the other in the dark with black PVC walls and a floor. mesh.
• a guillotine door separates the compartments.
• a 60 W lamp is positioned 40 cm above the box and illuminates the white compartment.
• Electric shocks (0.3 mA for 3 s) can be applied to the floor of the grid via a generator (Lafayette Instruments, Lafayette, USA).
• the test consists of a learning session and a test session. The guillotine door is closed during the training session. Each mouse is placed in the white compartment. After 5 seconds, the door rises.
• the spontaneous alternation test is used to study spatial (very short-term) working memory in rodents.
• the maze is made of gray opaque polyvinyl chloride (PVC).
• PVC gray opaque polyvinyl chloride
• Each of its arms is 40 cm long, 13 cm high and 3 cm wide at its base, 10 cm at its top. The arms converge towards each other, with an equal angle between the different arms.
• each mouse is placed at the end of an arm and is left free to move for an 8 min session. Inputs of the mouse into each of the arms, including the arm on the end of which it was dropped, are recorded.
• An alternation is defined as the successive entry of the animal into three different arms.
• the maximum number of alternations is therefore the total number of entries in each of the arms minus 2 and the percentage of alternation is calculated according to the formula:
• the combination index (CI) is calculated as follows:
• IC CA, x/ICx, A + CB, x/ICx, B
• CA,x and CB,x are the concentrations of compounds A and B used in a combination that generates x% of the maximum combination effect.
• CI is the combined index.
• ICx, A and ICx, B are the concentrations of compounds A and B needed alone to produce x% of maximum effect.
• a CI less than/equal to/greater than 1 indicates synergy/additivity/antagonism respectively.
• alternation percentages and passive avoidance latencies were expressed as percent protection (PP) for each treatment group with PP(V/V) set to 100%. and PP(AP25-3s/V) at 0% (Martin et al., 2020; Maurice, 2016).
• the data support the anti-amnesic effects of FENM and DPZ on AP25-35 oligomer-induced damage to short-term working memory.
• mice intoxicated with AP25-35 and administered with FENM alone is significantly improved compared to the control from 0.03 mg/Kg (FIG. 1).
• the improvement observed for the mice administered with a dose of 0.01 mg/Kg is at the limit of statistical significance. From 0.03 mg/Kg FENM significantly improves the percentage of alternation of mice poisoned with AP25-35; moreover, these performances are not significantly different from those of non-intoxicated mice.
• donepezil alone also allows an improvement in the memory capacities of the animals measured by this test. No improvement is however observed at 0.01 mg/Kg (not shown). Administered at 0.03 mg/kg, DPZ does not confer a statistically significant improvement in the performance of poisoned animals. Administered at 0.1 mg/Kg, DPZ confers an improvement in memory symptoms, since the performances of poisoned and treated animals are not significantly different from those of non-poisoned and untreated animals; however, these performances are not significantly different from those observed in untreated intoxicated mice either.
• the FENM/DPZ molar ratio in this combined treatment is 0.5.
• the data support the anti-amnestic effects of FENM and DPZ on AP25-35 oligomer-induced damage to long-term working memory.
• mice intoxicated with AP25-35 and administered with the doses of 0.3 mg/Kg or 1 mg/Kg of FENM IP show performances that are not significantly different from the untreated, non-intoxicated control mice (FIG. 2); these performances are significantly different from intoxicated untreated mice.
• Administration of FENM at lower doses does not protect mice against memory damage due to AP25-35 intoxication.
• Only the highest dose of DPZ tested (1 mg/Kg) is effective in countering the amnesic effects of AP25-35 oligomer poisoning: the latency time of the animals is significantly different from that of untreated poisoned animals. Nevertheless, the improvement is not sufficient to completely restore the performance of the animals since the latency time for these remains significantly different from the latency time of the non-intoxicated untreated animals.
• Maurice T. Protection by sigma-1 receptor agonists is synergistic with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behav Brain Res. 2016;296:270-278.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pain & Pain Management (AREA)
• Emergency Medicine (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Psychology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=80595290

Family Applications (1)

Country Status (5)

Citations (5)

• 2021
  • 2021-11-08 FR FR2111841A patent/FR3128872B1/fr active Active
• 2022
  • 2022-11-08 US US18/708,355 patent/US20250000818A1/en active Pending
  • 2022-11-08 WO PCT/EP2022/081184 patent/WO2023079187A1/fr not_active Ceased
  • 2022-11-08 JP JP2024549574A patent/JP2025500088A/ja active Pending
  • 2022-11-08 EP EP22817139.3A patent/EP4429648A1/fr active Pending

Patent Citations (5)

Non-Patent Citations (17)

Also Published As

Similar Documents

Legal Events