DERIVES DE FLUOROETHYLNORMEMANTINE

Abstract

The invention relates to a compound of formula I or II (I), (II), A- being a counteranion selected from the following ions: chloride, bromide, iodide, acetate, methane sulfonate, benzene sulfonate, camphosulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, tosylate, and X being a 3-carbon alkyl group. The invention also relates to this compound for its use as a medicinal product, particularly in the treatment of neuropsychiatric disorders. Figure to be published with the abstract: Figure 1

Description

Title of the invention: FLUOROETHYLNORMEMANTINE DERIVATIVES

[0001] The present invention relates to a compound derived from fluoroethylnormemantine (3-(2-fluoroethyl)adamantan-l-amine, FENM), particularly for its use as a medicinal product. More specifically, the invention relates to this derivative for its use in the treatment of neuropsychiatric disorders. Previous technique

[0002] FENM is known as a potent neuroprotective drug in the murine model of intracerebroventricular (icv) injection of A[325_35] oligomers, with efficacy superior to that of memantine (MEM) and no direct amnesic effect at higher doses (WO2021 / 234324).

[0003] FENM notably demonstrates superior protection of cognitive functions compared to MEM in this icv injection model of A[325 35] oligomers (WO2021 / 234324). However, application WO2014 / 191424 describes an affinity of FENM for NMDA receptors of a comparable, or even lower, order of magnitude than that of MEM. Generally speaking, NMDA receptor antagonists are used in a wide variety of therapeutic applications, due to the diversity of their mechanisms of action on NMDA receptors related to the diversity of their structures. Moreover, small structural variations of these compounds have a major impact on the activity of these molecules and, ultimately, their biological effect, so that it is difficult to predict the effects of one antagonist to another (e.g. analgesic, anxiolytic, or neuroprotective), from one type of pathology (e.g. anxiety, neurodegeneration) to another, even for molecules with a similar structure.

[0004] Although authorized by several health agencies for the symptomatic treatment of moderate to advanced Alzheimer's disease (AD), MEM has a limited duration of action, delaying the progression of symptoms by a few months. The condition of treated patients eventually deteriorates rapidly, potentially even reaching a state that would have been achieved without any treatment. These limited effects have led some authorities to withdraw coverage of MEM from health systems for symptomatic treatment.

[0005] Notwithstanding the recent discovery of the interesting and unexpected properties of FENM, patients today face the absence of a proven therapeutic solution capable of inducing neuroprotection, particularly in the context of neurodegeneration but also in the context of acute neuronal damage. There are Therefore, there is a need for the supply of treatment candidates in an area where the failure rate of drug development is significant. [Technical problem]

[0006] There is therefore currently a need for drug candidates with neuroprotective properties capable of effectively modifying the course of neurodegenerative diseases in the long term, with an improved neuroprotective effect compared to the simple transient symptomatic effects of MEM.

[0007] The applicant has developed a specific test which has enabled it to identify a compound with properties equal to or even superior to those of FENM, and which constitute promising candidates, with FENM, for the treatment of neuropsychiatric pathologies including neurodegenerative pathologies such as tauopathies, synucleinopathies, amyloidopathies, including in particular AD, 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, Korsakoff's syndrome, and / or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke.This test makes it possible to differentiate between molecules with limited-time symptomatic effects, such as MEM, and molecules that provide long-lasting protection of neurological function, such as that of the present invention. [Brief description of the invention]

[0008] Based on this test, the applicant was therefore able to differentiate and characterize the compound of the invention, which exhibits superior neuroprotective properties to FENM, among compounds with very similar structures. This compound, when administered orally, demonstrates stable protective activity over time in the tested animal models of neuropsychiatric diseases, and thus has the potential to modify the course of these diseases.

[0009] Thus, a first object of the invention is therefore composed of formula (I):

[0010] [Chem.l]

[0011]

[0012] or one of its salts of formula (II):

[0013] [Chem.2]

[0014] (II)

[0015] A being a counter union chosen from the following ions: chloride, bromide, iodide, acetate, methane sulfonate, benzene sulfonate, camphosulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, tosylate, or any other pharmaceutically acceptable salt.

[0016] The superior neuroprotective effect compared to FENM discovered for the compound of the invention makes it a particularly suitable candidate for the treatment of various diseases.

[0017] Consequently, a second object relates to said compound of formula (I) or one of its salts of formula (II) for its use as a medicinal product.

[0018] The compound of the invention or one of its pharmaceutically acceptable salts tested are particularly effective in various neuropsychiatric pathologies in the treatment of which, without being bound by any theory, they exert neuroprotective effects superior to FENM, particularly beneficial in maintaining cognitive abilities.

[0019] Thus, a third object relates to said compound of formula (I) or one of its salts of formula (II) for its use in the prevention, stabilization or reduction of alterations in cognitive abilities in a subject suffering, suspected of suffering or considered at risk of suffering from a neuropsychiatric pathology.

[0020] According to an optional feature, said neuropsychiatric pathology is selected from stress, post-traumatic stress disorder (PTSD), depression or anxiety in a subject suffering or suspected of suffering from one of these pathological conditions.

[0021] The compound of the invention or one of its pharmaceutically acceptable salts is particularly effective in inducing neuroprotection under conditions of A[325_35] oligomer-induced neurodegeneration.

[0022] A fourth object of the invention therefore relates to said compound of formula (I) or one of its salts of formula (II) for its use in the prevention or treatment of a neurodegenerative disease in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative disease.

[0023] According to an optional feature of this object, the invention relates to the compound of formula (I) or one of its salts of formula (II), for its use in the prevention or reduction of alterations in cognitive abilities in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative pathology.

[0024] According to another optional feature of this object, the invention relates to the compound of formula (I) or one of its salts of formula (II), for its use to induce neuroprotection in a subject suffering from, suspected of suffering from, or considered at risk of suffering from a neurodegenerative disease.

[0025] In a particular embodiment, said neurodegenerative pathology is 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, Korsakoff's syndrome, neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke, preferably Alzheimer's disease.

[0026] A fifth object relates to a pharmaceutical composition comprising said compound of formula (I) or one of its salts of formula (II), and, according to an optional feature, comprising from 0.5 to 30 mg of said compound or one of its pharmaceutically acceptable salts. Brief description of the drawings

[0027] [Fig. 1] [Fig. 1], Spontaneous alternation in the Y-maze of animals during 42 days of oral treatment. Animals received an injection of A[325_35] on day 1 and were subsequently treated in their drinking water at a dose of 1 mg / kg / day until day 42. The spontaneous alternation test was performed weekly. The results show the pooled means ± SEM for all weeks of analysis. * p < 0.05, *** p < 0.001 vs. group injected with A[325_35], untreated (black bar); # p < 0.05, ## p < 0.01, ### p < 0.001 vs. group injected with A[325_35] treated with MEM (dark gray bar labeled MEM). Bonferroni test.

[0028] [Fig.2] [Fig.2], Reaction scheme A for the synthesis of the compound according to the invention. This synthetic process includes the early introduction of the amine function onto the adamatane ring, before fluorination.

[0029] [Fig.3] [Fig.3], reaction scheme B for the synthesis of the compound according to the invention. This synthesis process involves the introduction of the amine function onto the adamatane ring, after fluorination. [Description of the invention]

[0030] The present invention relates to a compound derived from fluoroethylnormemantine of formula (I) or its salts of formula (II) as mentioned above. The invention also relates to this compound for its use as a medicinal product. Indeed, a new test developed by the applicant has made it possible to identify and select a compound with long-term neuroprotective properties and a potential ability to modify the course of neuropsychiatric diseases. Definitions

[0031] In the context of the present invention, a reference to a specific drug or compound includes not only the specifically named drug or compound, but also any corresponding pharmaceutically acceptable salt, hydrate, derivative, isomer, racemate, enantiomerically pure composition, conjugate, or prodrug of the active molecule of the drug or compound. Preferably, a reference to a compound includes the specifically named compound, as well as any pharmaceutically acceptable salt, hydrate, isomer, racemate, isomer, enantiomerically pure composition of the compound. More preferably, the designation of a compound is intended to designate the compound as specifically designated in itself, as well as any pharmaceutically acceptable salt thereof.

[0032] Unless otherwise specified, the mention of a physical measurement value in the form of an interval is understood to include bounds.

[0033] For the purposes of this invention, "pharmaceutically acceptable" means a pharmaceutically acceptable and relatively non-toxic inorganic or organic acid addition salt of a compound of the present invention. The formation of a pharmaceutical salt consists of 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 principal compound, acting 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, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, or citric acid.Pharmaceutically acceptable salts of the invention also include those. in which the main compound functions as an acid and reacts with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium, or choline salts. Although most salts of a given active ingredient are bioequivalent, some may have, among other things, enhanced solubility or bioavailability properties. Salt selection is now a standard procedure in the drug development process, as taught by Stahl and Wermuth in their textbook (Stahl and Wermuth).

[0034] The term "neuroprotection," as used in the invention, refers to the prevention or slowing of the progression of a disease affecting the central nervous system that results in neurodegeneration and / or peripheral nervous system that results in neurodegeneration. Neurodegeneration is characterized by the loss of functionality of nerve cells, particularly at the synapses, and therefore specifically in their ability to exchange information with each other or with the somatic cells they innervate, particularly muscle cells. This can result in a decrease in cognitive abilities and / or somatic disorders, which may be transient or permanent and potentially progressive. The degeneration of nerve cells, the loss of synapses, and the death of cells in these systems, particularly neurons, lead in particular to cognitive decline and / or somatic disorders such as muscle atrophy.This muscle atrophy linked to neurodegeneration affects the motor skills of the upper or lower limbs and can lead to disorders such as respiratory and / or cardiac dysfunction, balance and / or coordination problems, and tremors. These cognitive or somatic disorders can vary in intensity depending on the specific neurodegenerative disease, and also vary in intensity between individuals with the same disease. The relative importance of somatic and cognitive impairments can also vary significantly from one disease to another, especially since the two are interdependent. Indeed, it is well known that in Alzheimer's disease, patients whose cognitive function is primarily affected are prone to balance problems and falls.In many neurodegenerative diseases, hormonal imbalances and muscle wasting associated with neurodegeneration result in changes in body mass. For example, in Huntington's disease, which primarily affects the central nervous system (CNS), patients experience significant weight loss, and this symptom is taken into account by doctors in their diagnosis. Conversely, in diseases involving motor neuron degeneration, such as amyotrophic lateral sclerosis (ALS), patients may... exhibit significant cognitive symptoms, particularly in the advanced stages of the disease.

[0035] Neurodegeneration can be observed in neuropsychiatric pathologies, including neurodegenerative pathologies. Neurodegenerative pathologies are, for example, pathologies such as tauopathies, synucleopathies or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy. Other neurodegenerative diseases include Huntington's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, epilepsy, vascular dementia, Korsakoff's syndrome, or acute neuronal diseases such as alcohol withdrawal, ischemia, neonatal ischemia, head trauma, and stroke, which can result in neurodegeneration or be a risk factor for it.The compound according to the invention induces neuroprotection, specifically aimed at preventing neurodegeneration and thus the associated cognitive, nervous, and / or somatic consequences. Cognitive impairment, linked to transient or permanent neurodegeneration, can also be associated with other neuropsychiatric conditions such as depression, anxiety, post-traumatic stress disorder (PTSD), and stress, which are known to have structural neuronal components such as hippocampal atrophy. In these conditions, this can result in transient impairment of cognitive abilities. In some cases, these other neuropsychiatric conditions can also lead to somatic impairments related to damage to the peripheral nervous system (PNS), such as respiratory or cardiac function deficits, balance and coordination problems, and tremors.

[0036] Thus, "neuropsychiatric pathology" encompasses, within the meaning of the invention: neurodegenerative pathologies such as tauopathies, synucleopathies, or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, Huntington's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, epilepsy, vascular dementia, Korsakoff's syndrome, or acute neuronal pathologies such as alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke, and also disorders such as depression, anxiety, post-traumatic stress disorder (according to its (Anglo-Saxon acronym, PTSD), stress, which can include impairments in cognitive performance.

[0037] The term "subject" here refers to any member of the animal kingdom, preferably mammals and even more preferably humans. In another preferred embodiment, bees, insects which also possess an NMDA system controlling memory generation, are also included.

[0038] “A beta peptides,” also known as “A[3], “beta-amyloid peptides,” “amyloid peptides,” or “beta-amyloid,” result from the cleavage of the APP (Amyloid Protein Precursor) protein, located in the neuronal membrane, by gamma and beta secretases. In humans, they can vary in size (primarily 38 to 42 amino acids) and exist as oligomeric assemblies of varying size and solubility. Each type of oligomer is potentially toxic, leading to impaired synaptic plasticity that ultimately results in neuronal death (Pike et al., 1991). This synaptic alteration causes dysfunction in regions involved in memory and learning processes. These fragments are also found in amyloid plaques, which accumulate with age or in certain diseases.In vivo, in humans, A[3X 42] has a strong propensity to self-aggregate; familial forms of Alzheimer's disease are accompanied by an increase in the relative level of the A[3i_42 / A[3i_40] peptide, and it is this relative level that is more indicative of the diagnosis of the pathology than the accumulation of A[3i 42] and / or A[3i 40] peptides. A[3i] is a fragment toxic to neuronal cells in vitro. In mice and rats, intravascular injection of A[3] 25-35 peptide oligomers is one of the models used to study neurodegeneration induced by A[3] oligomers, particularly in the context of Alzheimer's disease, and to test drug candidates for this disease (Maurice et al., 1996).Neurotoxicity of "beta A peptides", or "A[3]" or "beta-amyloid peptides", or "amyloid peptides", or even "beta-amyloid", is therefore understood, in the sense of the invention, as neurotoxicity induced by any oligomer and / or aggregate formed of one or more peptide(s) resulting from the cleavage of the APP protein.

[0039] Unless otherwise stated, the doses mentioned for treatments which include the administration of the compound according to the invention shall be understood as the total mass of said compound not including that of the anion with which it is associated, in other words, as an equivalent dose of the amine (i.e. the compound according to the invention of formula (I)).

[0040] With regard to the cognitive or motor abilities of a subject, an "alteration" or an "impairment" means a qualitative and / or quantitative decrease in the cognitive or motor performance measured in said subject.

[0041] The applicant discovered that the compound of formula (I) or one of its salts of formula (II) makes it possible to prevent, in an effective and stable manner over time, the Cognitive deficits induced by intravenous (ICV) intoxication with A[>25] oligomers. Such a level of neuroprotection is no longer observed for MEM, whose activity disappears after 42 days of treatment in the murine model, demonstrating a therapeutic effect that goes beyond simple symptomatic treatment of the type conferred by MEM, one of the few treatments authorized for AD, yet with insufficient therapeutic benefit. Such a stable and lasting effect is also observed in models of other neuropsychiatric diseases as described above.

[0042] Thus, a first object of the invention is a compound of formula (I):

[0043] [Chem.l]

[0044] (I)

[0045] designated according to international nomenclature as 3-(fluoromethyl)adamantan-l-amine,

[0046] or one of its salts of formula (II):

[0047] [Chem.2]

[0048] (II)

[0049] A being a counter anion selected from the following ions: chloride, bromide, iodide, acetate, methane sulfonate, benzene sulfonate, camphosulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, tosylate, or any other pharmaceutically acceptable salt.

[0050] Experimental data show that this compound exhibits superior properties to MEM, which persist over time, and properties preventing memory damage induced by A[325_35] oligomers that are in line with Disease-modifying properties. This represents a crucial advance because until now, only symptomatic treatments existed for neurodegenerative diseases, including Alzheimer's disease. This activity is entirely unexpected. Furthermore, it is worth noting that this compound behaves differently from other compounds that are structurally very similar. This underscores the highly unpredictable nature of the activity and effects of NMDA receptor antagonists.

[0051] In a particular embodiment, in the salt of formula (II), the counter anion is chloride.

[0052] In a particular embodiment, in the salt of formula (II), the counter anion is the bromide.

[0053] A second object of the invention is the compound of formula (I) or one of its salts of formula (II) as described above for use as a medicinal product. Indeed, the data obtained show a statistically significant effect in tested models of neuropsychiatric pathologies. In particular, the experimental data provided below show a statistically significant effect of preventing memory impairment in an acute model of neuronal intoxication in animals treated with the compound of formula (I) or its salt of formula (II) according to the invention.

[0054] A third object of the invention is the compound of formula (I) or its salt of formula (II) for its use in the prevention or treatment of a neurodegenerative pathology in a subject suffering, suspected of suffering or considered at risk of suffering from a neuropsychiatric pathology.

[0055] Said neuropsychiatric pathology may be chosen from: tauopathies, synucleopathies or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, or pathologies such as Huntington's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, epilepsy, vascular dementia, Korsakoff's syndrome, or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke.

[0056] According to a fourth object, the invention relates to a compound of formula (I) or its salt of formula (II) for use in the prevention or treatment of a neurodegenerative disease. In a particular embodiment, the subject suffers from, is suspected of suffering from, or is considered at risk of suffering from a neuropsychiatric disease selected from: tauopathies, synucleopathies, or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, degeneration corticobasal, Pick's disease, frontotemporal dementia, posterior cortical atrophy, or pathologies such as Huntington's disease, amyotrophic lateral sclerosis, epilepsy, vascular dementia, Korsakoff's syndrome, or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke, stress, post-traumatic stress disorder (PTSD), anxiety, or depression.

[0057] The experimental data provided show a statistically significant effect in preventing memory impairment in an acute model of Alzheimer's disease. This compound provides protection against the toxicity of A

[325] oligomers injected directly into the brains of mice, which results in a rapid decline in the animals' memory capacity within 7 days. The data presented here in the test developed by the inventors confirm the merely symptomatic effect of MEM, which does not persist over time. Mice treated with the compound of the invention perform significantly better than MEM over time, preventing cognitive impairment induced by A

[325] oligomers for up to 42 days. The molecules of formula (I) or (II) tested also show efficacy in the treatment of other neuropsychiatric disorders listed above.

[0058] The neurotoxicity mechanisms of A[325_35 are shared by many neurodegenerative diseases. In one embodiment of the invention, therefore, said subject suffers, is suspected of suffering or is considered at risk of suffering from a neurodegenerative pathology selected from among tauopathies, synucleopathies or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, or pathologies such as Huntington's disease, amyotrophic lateral sclerosis, epilepsy, vascular dementia, Korsakoff's syndrome, or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke.

[0059] In another particular embodiment, the subject may have been diagnosed as having a neurodegenerative disease as mentioned above. This diagnosis is based on behavioral, cognitive, biological, and / or medical imaging analyses well known to a person skilled in the art.

[0060] In another particular embodiment, the subject may also be suspected of suffering from a pathology such as the one mentioned above. In other words, the diagnosis established for this subject is uncertain, that is to say, for example, that the subject does not present a level of symptoms (in their intensity), or all of the different symptoms or signs of the clinical picture that would allow for a formal diagnosis. of the pathology. However, in this subject, the symptoms or signs observed are relevant within the context of the pathology. This may involve, for example, patients at the beginning of the disease's development who are then only exhibiting a few precursor signs, potentially of low intensity.More specifically, the subject presents relevant symptoms or signs in the context of a tauopathy, synucleopathy or amyloidopathy such as sporadic or genetic Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, or relevant symptoms or signs in the context of pathologies such as Huntington's disease, amyotrophic lateral sclerosis, epilepsy, vascular dementia, Korsakoff's syndrome, or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke.

[0061] The relevant symptoms or signs can be detected by behavioral, cognitive, biological and / or medical imaging analyses well known to the person skilled in the art and commonly used in the diagnosis of these pathologies.

[0062] For example, tests commonly used for the cognitive assessment of human subjects include 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 General Practitioner Assessment of Cognition), 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 Alzheimer's Disease Cooperative Study - Activities of Daily Living), according to their English name.

[0063] More specifically, the MMSE allows for the screening of individuals suffering from major neurocognitive impairment (dementia) without linking it to a specific pathology. The MMSE is also used to monitor the cognitive status of individuals and to measure the decline in cognitive functions in those suffering from neurocognitive impairment. This test assesses orientation, registration, attention and calculation, memory retention, language, and constructional praxis. CERAD (Consortium to Establish a Registry for Alzheimer's Disease) has developed a dementia severity scale linked to MMSE scores. A score between 19 and 24 is associated with mild dementia, between 10 and 18 with moderate dementia, and a score below 10 with severe dementia, with a maximum score of 30.

[0064] The ADAS-Cog is a cognitive subscale of the Alzheimer's Disease Assessment Scale and therefore only addresses the cognitive aspects of dementia. Thus, it can be used to assess (i.e., score) and monitor the progression of any type of dementia. The ADAS-Cog assesses orientation, memory, executive function, visuospatial ability, language, and practical skills, with a score range of 0 to 70, a higher score indicating greater impairment. The ADAS-Cog is considered more sensitive than the MMSE. It is one of the most commonly used tests for the clinical evaluation of compounds applying for Marketing Authorization in the context of anti-dementia treatments and also for measuring the progression of cognitive impairment.

[0065] Medical imaging can identify structural or functional damage to specific brain areas, and thus aid in the diagnosis of some of these neurodegenerative diseases. For example, ioflupane brain scintigraphy can characterize damage to dopaminergic neurons in Parkinson's disease or Lewy body dementia. 18F-labeled FENM is being considered as a marker for NMDA receptors by positron emission tomography (PET) and is the subject of a pilot study in humans (Beaurain et al., 2019). MRI or PET can, for example, diagnose frontotemporal dementia (by identifying atrophy of the frontal and temporal lobes) or Alzheimer's disease (cortical atrophy and / or hippocampal atrophy).Thus, in a particular embodiment, the "subject suffering, suspected of suffering or considered at risk of suffering" presents with damage to dopaminergic neurons, fronto- and / or temporal atrophy, or cortical atrophy and / or atrophy of one or both hippocampi.

[0066] Analysis of the presence of certain proteins in the CSF can help establish the diagnosis of, for example, Alzheimer's disease, whose typical profile combines a decrease in the concentration of the A

[342] peptide and an increase in Tau proteins and their phosphorylated forms P-Tau. In some cases, the measurement of A

[31] 40 and the A

[31] 42 / A

[31] 40 ratio can improve the diagnosis. Imaging and CSF markers allow for early diagnosis of diseases, in some cases before the onset of cognitive symptoms. Thus, in one embodiment In particular, the "subject suffering, suspected of suffering or considered at risk of suffering" presents an abnormal profile of the levels of peptides A[3X 42 and / or A[3i 40 and / or Tau protein and / or its phosphorylated forms and / or the ratio Ap42 / Ap40.

[0067] Also, the study of event-related potential (ERP) recordings is of great application in the evaluation of cognitive processes because the results are independent of the stimulus used. ERPs are observed in response to a discordant stimulus and represent the activated cognitive phenomena such as perception, attention, decision-making, memory, language, etc. ERPs are recorded, for example, by electroencephalography (EEG) or magnetoencephalography (MEG). ERPs provide information on the brain's processing of the stimulus even when no change in behavior is perceptible. The characteristics of the ERP can vary depending on various factors such as the relevance of the stimulus, the task performed, lesions of the nervous system, or the use of medication.

[0068] ERPs are known in the state of the art as useful cognitive biomarkers for the diagnosis of dementia, monitoring disease progression, and evaluating the pro-cognitive effect of treatments. Thus, ERPs are found to be altered in patients with Alzheimer's disease, vascular dementia, or dementia associated with parkinsonian symptoms, such as Lewy body dementia. More specifically, ERP measurements allow for the detection of cognitive impairment at an early stage, particularly in the early or mild stages of Alzheimer's disease. The most frequently examined ERP in clinical practice is the P300 (or P3) wave, which is a large centroparetal positivity that occurs with a latency of approximately 300 ms after the discordant stimulus. The P300 wave can be divided into two subcomponents, P3a and P3b.P3a is generally considered to be related to the degree of focused attention, while P3b is thought to index the updating of working memory. The amplitude of Fonde's P300 refers in particular to motivation (related to task difficulty) and vigilance as a function of the probability of stimulus occurrence. Latency refers to the time required for decision-making. An increase in the latency of P300 (or its subcomponents) and a decrease in its amplitude (or its subcomponents) are observed in patients with dementia, particularly Alzheimer's disease. Thus, in a particular embodiment, the "subject suffering, suspected of suffering, or considered at risk of suffering" presents with an altered ERP in one or more, or even all, of its components.The study of latency evolution is also useful for monitoring the progression of dementia, particularly Alzheimer's disease, and for assessing the response to treatment in AD.

[0069] Preferably, the subject suffers from a neurodegenerative disease but does not present with cognitive symptoms or does not present with significant cognitive symptoms. Thus, due to the neuroprotective properties described in the experimental part, it will be possible to prevent, delay, or slow the onset of these symptoms and consequently maintain the patients' quality of life and avoid the occurrence of other pathologies associated with neurodegenerative diseases, particularly psychiatric pathologies such as depression.

[0070] Finally, in a particular embodiment, said subject may be at risk of suffering from a neuropsychiatric condition as described above. In other words, said subject does not present any symptoms or signs associated with said condition, but has an increased risk of developing this condition compared to the general population, because they have risk factors related to their lifestyle, genetic predispositions or family history, the presence of comorbidities and / or their age.More specifically, the subject has a lifestyle, presents genetic predispositions or has a family history, suffers from comorbidities and / or is of an age which increases their risk (compared to the general population) of developing a tauopathy, a synucleopathy or an amyloidopathy such as AD, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, Huntington's disease, amyotrophic lateral sclerosis, epilepsy, vascular dementia, Korsakoff's syndrome, or neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke.

[0071] For example, and without being limiting, age is the primary risk factor for dementias, including AD, since 5 to 8% of people over 60 years of age are affected. Regarding genetic predispositions to diseases of the central nervous system (CNS) and / or peripheral nervous system (PNS), one can cite, for example, the presence of the e4 allele of apolipoprotein E (ApoE), which is known to be associated with an increased risk of developing several dementias, and in particular AD (Liu et al.2013); also, for example, mutations in the genes SNCA (alpha-synuclein), PRKN (parkin), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced putative kinase 1), DJ-1, ATP13A2 or in the 11 loci of the PARK1-PARK11 genes are associated with an increased risk of Parkinson's disease for the subject carrying such genetic predispositions or mutations; the mutation of the SOD1 gene and its link with amyotrophic lateral sclerosis or mutations in the gene encoding huntingtin are also examples of genetic predisposition to diseases of the CNS and PNS.

[0072] Thus, in one embodiment, the subject presents a risk factor for a neurodegenerative disease. More specifically, the subject does not present any other symptoms of the disease. Preferably, the subject does not present any cognitive symptoms of the disease. In a preferred embodiment, the subject has a genetic predisposition for said disease, in particular the genetic predispositions listed above.

[0073] Thus, in a particular embodiment, the invention relates to the compound of formula (I) for its use in the treatment of dementia, in particular Alzheimer's disease, in a subject presenting the e4 allele of apolipoprotein E (ApoE).

[0074] In another particular embodiment, the invention relates to the compound of formula (II) for its use in the treatment of dementia, in particular Alzheimer's disease, in a subject presenting the e4 allele of apolipoprotein E (ApoE).

[0075] In another particular embodiment, the invention relates to the compound of formula (I) for its use in the treatment of Parkinson's disease, in a subject with mutations in the genes SNCA (alpha-synuclein), PRKN (parkin), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced putative kinase 1), DJ-1, ATP13A2 or in the 11 loci of the PARK1-PARK11 genes in connection with a predisposition for this pathology.

[0076] In another particular embodiment, the invention relates to the compound of formula (II) for its use in the treatment of Parkinson's disease, in a subject with mutations in the genes SNCA (alpha-synuclein), PRKN (parkin), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced putative kinase 1), DJ-1, ATP13A2 or in the 11 loci of the PARK1-PARK11 genes in connection with a predisposition for this pathology.

[0077] In another particular embodiment, the invention relates to the compound of formula (I) for its use in the treatment of amyotrophic lateral sclerosis, in a subject with a mutation of the SOD1 gene linked to a predisposition for this pathology.

[0078] In another particular embodiment, the invention relates to the compound of formula (II) for its use in the treatment of amyotrophic lateral sclerosis, in a subject with a mutation of the SOD1 gene linked to a predisposition for this pathology.

[0079] In another particular embodiment, the invention relates to the compound of formula (I) for its use in the treatment of Huntington's disease, in a subject with one or more mutations in the gene encoding huntingtin linked to a predisposition for this pathology.

[0080] In another particular embodiment, the invention relates to the compound of formula (II) for its use in the treatment of Huntington's disease, in a subject with one or more mutations in the gene encoding huntingtin linked to a predisposition for this pathology.

[0081] In another preferred embodiment, the subject has a condition associated with an increased risk of developing a neurodegenerative disease. Among the comorbidities associated with an increased risk of developing these conditions are, for example, Down syndrome, post-traumatic stress disorder (PTSD), depression, hypertension, diabetes, traumatic brain injury, or stroke. Furthermore, these comorbidities, such as stress, PTSD, anxiety, or depression, are well known to impair the cognitive abilities of affected individuals. Excessive alcohol consumption is associated with an increased risk of dementia.Exposure to certain metals such as manganese, copper, lead, or certain chemical compounds such as paraquat, rotenone, or maneb is associated with an increased risk of developing Parkinson's disease.

[0082] Administration of the compound of formula (I) or one of its salts of formula (II) in these subjects defined as at risk makes it possible to prevent or delay the occurrence of neurodegenerative diseases and / or their symptoms, in particular cognitive symptoms.

[0083] Thus, in one embodiment, the invention relates to the compound of formula (I) for its use in preventing or delaying the onset of neurodegenerative diseases and / or their symptoms in a subject with trisomy 21, post-traumatic stress disorder (PTSD), depression, high blood pressure, diabetes, or who has suffered a head injury or stroke.

[0084] In another embodiment, the invention relates to the compound of formula (II) for its use in preventing or delaying the onset of neurodegenerative diseases and / or their symptoms in a subject with trisomy 21, post-traumatic stress disorder (PTSD), depression, high blood pressure, diabetes, or who has suffered a head injury or stroke.

[0085] In another embodiment the invention relates to the compound of formula (I) or one of its salts of formula (II) for its use to prevent, delay, reduce or stabilize alterations in cognitive abilities related to stress, PTSD, depression or anxiety in a subject suffering or suspected of suffering from one of these pathological conditions.

[0086] In a particular embodiment, the invention relates to the compound of formula (I) for its use in preventing, delaying, or reducing cognitive impairment. related to stress, PTSD, depression or anxiety in a subject suffering or suspected of suffering from one of these pathological conditions.

[0087] In a particular embodiment, the invention relates to the compound of formula (II) for its use in preventing, delaying, reducing or stabilizing alterations in cognitive abilities related to stress, PTSD, depression or anxiety in a subject suffering or suspected of suffering from one of these pathological conditions.

[0088] In a particular embodiment, the subject exhibits a detectable impairment of their cognitive abilities. Preferably, this impairment is measured by the MMSE or the ADAS-Cog. Preferably, the subject has an MMSE score of less than 30, less than or equal to 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or less than or equal to 2. Also preferably, this alteration is measured in the subject by the analysis of the P300 wave of the subject's ERP, the subject showing a decrease in the amplitude and / or latency of the P300 wave or one of its components.

[0089] In another particular embodiment, the subject suffers from mild dementia. In another particular embodiment, the subject suffers from moderate dementia. In yet another particular embodiment, the subject suffers from severe dementia. Most preferably, the subject suffers from mild dementia. Thus, in one particular embodiment, the invention relates to the compound of formula (I) or one of its salts of formula (II), for use in a subject suffering from mild dementia.

[0090] In a particular embodiment, the invention relates to a compound of the invention of formula (I) or (II) for its use in the prevention or reduction of alterations in cognitive abilities in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative pathology.

[0091] In a particular embodiment, the invention relates to a compound of the invention of formula (I) or one of its salts of formula (II) for its use in the prevention or treatment of MA.

[0092] In a particular embodiment, the compound of formula (I), or one of its salts of formula (II), is devoid, at the administered dose, of undesirable cognitive effect, in particular of amnesic or somniferous effect for the patient.

[0093] Preferably, the compound of formula (I), or one of its salts of formula (II), is administered, for their aforementioned uses in particular, to the subject in the form of a pharmaceutical preparation, for example, but not limited to, orally or parenterally (subcutaneously, intranasally, or intravenously). Oral administration is particularly preferred and, as demonstrated in the experimental part, quite effective.

[0094] In one embodiment, the compound of formula (I), or one of its salts of formula (II) is administered to the human subject at an oral dose of between 0.5 and 30 mg per day inclusive, preferably between 0.75 and 15 mg per day, between 1 and 10 mg per day, between 2 and 8 mg per day, between 3 and 6 mg per day, even more preferably at a dose of 4 mg per day.

[0095] In another embodiment, the compound of formula (I), or one of its salts of formula (II) is administered to the human subject at an oral dose of between 8 pg / kg and 400 pg / kg per day inclusive, between 15 pg / kg and 300 pg / kg per day, between 30 pg / kg and 200 pg / kg per day, between 40 pg / kg and 100 pg / kg, between 50 pg / kg and 70 pg / kg per day, even more preferably at a dose of 60 pg / kg per day.

[0096] Obviously, and as recalled in the definitions section, the doses mentioned in the preceding paragraphs are understood to be doses of the amine (i.e. the compound according to the invention of formula (I)).

[0097] With regard to conferring neuroprotection in the case of neurodegenerative diseases selected from among tauopathies, synucleopathies, or amyloidopathies such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, Pick's disease, frontotemporal dementia, posterior cortical atrophy, or pathologies such as Huntington's disease, amyotrophic lateral sclerosis, epilepsy, vascular dementia, Korsakoff's syndrome, it will be readily understood that treatment of the subject with the compound of formula (I) or one of its salts of formula (II) lasts for the subject's entire life, at least as long as the treatment is effective. As demonstrated in the experimental part, unlike memantine, the compound according to the invention is effective for prolonged treatments.

[0098] For acute conditions such as neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head injuries, and stroke, time-limited treatment may be considered. It may last 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, or 4 weeks, or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or 1, 2, 3, 4, 5, or 6 years or even longer, i.e., the duration of the need for neuroprotection. For these acute pathologies, it is desirable that the treatment including the compound of formula (I) or (II) be implemented as early as possible, to best prevent neurodegeneration, for example, on the day of their occurrence, the next day, or even the day after.

[0099] The doses used may be unit doses, that is, administered all at once to the subject. A dose may also be administered in several doses spread throughout the day, the number of doses in the day allowing the desired daily dose to be obtained. Thus, in a particular embodiment, the doses in question may to be administered in one to four daily doses, for example 1 time, for example 2 times, for example 3 times, or even 4 times.

[0100] In a particular embodiment, the compound of formula (I) or one of its salts of formula (II) is packaged so as to provide the dose corresponding to one intake without requiring any handling such as measuring volume, weighing or dividing a tablet, which is particularly advantageous in subjects possibly with cognitive impairments since it avoids any calculation or particular handling.

[0101] In one embodiment, the compound of formula (I) or one of its salts of formula (II) is in tablet form. In a particular embodiment, said tablet is divisible into 2, 3, or even 4 pieces so as to provide the subject with the dose required for administration using 1, 2, or 3 pieces of said tablet. This is particularly advantageous, for example, in cases where treatment requires a dose escalation period to reach the target daily dose, with the pieces corresponding to the escalation increments and the entire tablet to the target dose of the treatment.

[0102] In a particular embodiment, the treatment comprising the administration of the compound of formula (I) or one of its salts of formula (II) includes a dose titration period to allow the subject to become accustomed to the treatment. This period takes place at the beginning of treatment or when resuming treatment after it has been interrupted. During this period, the daily doses are increased regularly until the maximum dose tolerated by the patient or prescribed by the practitioner is reached. For example, the dose titration increments may be 2, 3, 4, 5, 6, 7 days or even longer, preferably 7 days, and the doses may be increased by 0.5 mg per increment, 1 mg per increment, 2 mg per increment, 3 mg per increment, 4 mg per increment, 5 mg or even more, preferably 1 mg.Thus, in one particular embodiment, the doses are increased by 1 mg week by week until the maximum dose tolerated by the subject or the dose prescribed by the practitioner is reached. In another embodiment, the doses are increased by 5 mg week by week until the maximum dose tolerated by the subject or the dose prescribed by the practitioner is reached.

[0103] In another embodiment, the compound of formula (I) or one of its salts of formula (II) is formulated in liquid form. It can then be packaged as a unit dose in containers such as ampoules, or in a container such as a bottle or vial associated with a device allowing the withdrawal and, optionally, the administration of the desired volume to obtain the appropriate dose.

[0104] A fifth object of the invention relates to a pharmaceutical composition adapted for the administration of an effective dose of a compound of formula (I) or one of its salts of formula (II). This composition can be adapted for oral or parenteral (subcutaneous, intranasal or intravenous) administration of said compound.

[0105] In a particular embodiment, said composition comprises between 0.5 and 30 mg inclusive, preferably between 1 and 10 mg, between 2 and 8 mg, between 3 and 6 mg, and even more preferably a 4 mg dose of a compound of formula (I) or one of its salts of formula (II). In a particular embodiment, the pharmaceutical composition suitable for administering an effective dose of a compound of formula (I) or one of its salts of formula (II) is in solid form, in capsule, tablet, or capsule form, for oral administration. In a particular embodiment, said composition in solid form, in capsule, tablet or tablet comprises between 0.5 and 30 mg inclusive, preferably between 1 and 10 mg, between 2 and 8 mg, between 3 and 6 mg, even more preferably a dose of 5 mg of a compound of formula (I) or one of its salts of formula (II).In one particular embodiment, said composition is in a form adapted to provide the compound of formula (I) or one of its salts of formula (II) adapted to provide the dose required by the subject, by several daily doses or to achieve dose escalation steps, as explained above.

[0106] The doses mentioned, as before, are understood to be equivalent doses of the amine (compound of formula (I)). EXAMPLES

[0107] Example 1: Methods for preparing the compound according to the invention

[0108] The FENM and MEM derivative compounds tested were synthesized according to the Two reaction schemes, A ([Fig. 2]) and B ([Fig. 3]), were used. The carboxylic acids derived from the starting adamantane were obtained from Sigma. In the reaction schemes employed, Fischer esterification, reduction to lithium aluminum hydride, and tosylation of the alcohol were carried out using commercially available compounds and according to conventional protocols, notably those described by Smith and March (2001). However, the following steps should be specified: Amination of the adamantane ring

[0109] In both processes, the amination of the adamantane nucleus (synthesis scheme A, step 1, or synthesis scheme B, step 5) is systematically carried out via a Ritter reaction:

[0110] In a round-bottom flask containing the adamantane derivative, HNO3 (1.2-1.4Veq) is added and the mixture is cooled to 0°C for one hour using a mini chiller. H2SO4 (7Veq) is added dropwise for 3 hours using a syringe pump at 0°C. MeCN (7Veq) is then added. The reaction is maintained at 0°C for 2 hours and allowed to warm up overnight. The reaction is then poured The mixture is placed in ice and left to stand for 20 minutes. A saturated bicarbonate solution is then carefully added until gas emission ceases. The mixture is transferred to a settling funnel and extracted four times with DCM. The organic phases are combined, washed with dried Na₂SO₄ brine, filtered, and volatile substances are then removed under vacuum. The resulting residue is then purified by flash chromatography to provide the desired product. [YES] Fluorination of the sulfonate ester (synthesis scheme A, step 5, or synthesis scheme B, step 4)

[0112] A solution of the toluenesulfonic ester from the previous step (synthesis scheme A, step 4, or synthesis scheme B, step 3) dissolved in MeCN (5 Veq) at 70 °C is added to a solution of TB AF (IN) in THF (2 Veq). The reaction is stirred for 18 h before being concentrated under reduced pressure. Diethyl ether (3 Veq) is added, and the resulting mixture is washed with a saturated NaHCO3 solution. The aqueous phase is then extracted with Et2O (twice with 3 Veq), and the combined organic phase is washed sequentially with water and brine, dried over filtered Na2SO4, and the volatiles are removed under vacuum. Purification by flash chromatography provides the fluorinated compound.

[0113] Reduction of the esters to the corresponding alcohol (synthesis scheme B, step 2)

[0114] To an oven-dried Schlenk flask under argon, fitted with a rubber septum and a magnetic stir bar, and loaded with methyl ester derivatives and dry THF (20V / g), LiAlH Na2CO3 (1.2 Veq or 3.5 Veq for a compound bearing an ammonium group) is added in portions at 0°C. After 1 h at 0°C, the reaction is allowed to warm to room temperature for 3 hours. The reaction is then cooled to 0°C and water (IV / g) and NaOH(3N) (IV / g) are added successively. The reaction is allowed to warm to room temperature and stirring is continued until the aluminum salts precipitate. The mixture is then filtered through Celite and washed with EtOAc (3 times). The organic phase is then washed with Na2CO3 and brine, dried with Na2SO4, and concentrated under vacuum to provide the desired alcohol.

[0115] Example! : Tests in animal models of neurodegenerative diseases and prevention of cognitive impairment induced by A[325_35] oligomers

[0116] All procedures on animals were carried out in strict compliance with the European Union Directive of 22 September 2010 (2010 / 63) and the ARRIVE guidelines (Kilkenny et al., 2010). Test compounds, reference compounds

[0117]

[0118]

[0119]

[0120] Memantine (MEM) is sourced from Sigma-Aldrich® (Saint-Quentin-Fallavier, France). Fluoroethylnormemantine (FENM) is sourced from M2i Life Sciences® (Saint-Cloud, France). Amyloid peptide [25-35] (A[325_35, GENEPEP® (Saint-Jean-De-Védas, France)) was solubilized in preparation water at a concentration of 3 mg / ml and stored at -20°C until use. Before injection, the peptide was incubated at 37°C for 4 days to oligomerize it. The compounds tested are listed in Table 1 below: [Table 1 Compound te sté Formula Name lUPAC / NMR data memantine 3,5-dimethyladamantan-1-amine FENM F 3-(2-fluoroethyl 1)adamantan-1-amine riluzole H2N—jj jrp 6-(trifluoromethoxy)benzothiazol-2-amine 1 13, F r' ,À2 IV 8,--4-(2 Se 1, ' 4 ô (1 HNMR, CDCL 3,500 MHz): 8.05 (3H, br s) (NH 3 ); 4.39 (2H, dt, J = 6.2Hz, JHF=47.3 Hz) ( H 13 ); 2.27-2.19 (2H, m) (H s,3 ); 2.09-1.94 (4H, 2m) (H 6.10); 1.78 (2H, s) (H 8 ); 1.71-1.56 (4H, m) (H 12)4 ); 1.51-1.41 (4H, m) (H 9.2); 1.31-1.28 (2H, m) (H u ). ô (13 C, CDCL 3.125 MHz): 84.3 (j^ = 165 Hz, d) (C b); 54.5 (C 7 ); 45.1 (C 8 ); 40.1 (C 10 + C 6 ); 40.0 (C 9 +C 2 ); 38.13(^ = 3.75 Hz, d) (C u) ; 34.6 (C 4 ); 34.3 (C t ); 29.0(C 3 +C s ); 23.7 (j2f = 20 Hz) (C 12). ô (19 FNMR, CDCL 3,470 MHz):217.81, (tt, ŸHP = 47 Hz, = 23.5 Hz). HRMS : - for Ci3H23NF: Calculated mass 212.18 14; found :212.1815 2 s-s g 2 '&" y-^. t> " <t ô (1 HNMR, CDCL 3,500 MHz) : 8.08 (3h, brs) NH 3 ; 4.03 (2H, d, fHF = 47.6 Hz) ; (H u ) ;2.32-2.21(2H, m) (H s,3 ) ;2.14-2.01 (4H, 2m) (H 6)10 ) ; 1.91 (2H, s) (H 8 ) ; 1.74-1.63 (2H, m) (H 4 ) ; 1.6 1-1.53 (4H, m) (H 9,2). ô (13 C, CDCL 3,125 MHz) : 90.9, (¾ = 172.5 Hz, d) (C n ) ; 54.2 (C 7 ) ; 41.4 (¾ = 3.75Hz, d) (C s ); 41.3(C io+ C 6 ) ; 36.7 (j|,F= 17.5 Hz, d)(C i ) ; 36.3 tfCJ= 5 Hz, d)(C 9+ C 2 ) ;34.7 (C 4 );23 • 8(C 3-5 ) ô (19 FNMR, CDCL 3,470 MHz) : 229.87(t, J^= 47.6Hz). HRMS : -for Cn Hi9 N F Calculated mass 184.15 12 found : 184.1502 Cn H19 N F 3 R J' lïf" S V-- : 2 -?[ M-, Br' b - 4 ô (1 HNMR, CDCL 3,500 MHz) : 8.09 (3H,brs ) (NH 3 ) ; 4.22 (1H, dq, = 10Hz, J^=45 Hz) (H u ) ; 2.29(2H, s) (H s,3 ) ; 2.12-2.02 (4H, 2m) ( H 6)10 ) ;2.00-1.79 (2H, m)(H 8 ) ; 1.73-1.44 (6H, m ) (H 9,2,4 ) ; 1.28-1.19 (3H, dd, ^F = 10 Hz, ^F= 2 5 Hz) (H 12 ) ô (13 CNMR, CDCL 3,125 MHz) : 95.8(¾ = 1 85.15 Hz, d) (C u );54.5 (C 7 );40.8 (C 6 ) ;40.7 ( C 10 ) ;40.3 (C 8) ;39.2,(j2.f= 18.75Hz, d)(C 1 ) ;3 5.6, (j’F= 3.75Hz, d)(C 9 ) ;35.3(j|f= 3.75Hz, d) (C 2 ) ;34.9(C 4 ) ; 28.8(C 3.5 ) ; 14.5,(¾ = 23.75 Hz, d)(C 12 ). ô (19 FNMR, CDCL 3,470 MHz) :185.31 ppm ( dq4F = 47 Hz,4f = 23.5 Hz) HRMS : -ForCn H2i N F Calculated mass 198.16 58 found: 198.1658 . 4 .z f * ' S / '4— \ ©2 f‘"\ s : 2 ÉQ ô (1 HNMR, CDC13,500 MHz) : 8.03 (3H, brs) NH 3 ;4.30-4.54 (2H, ABX) (H 13 ) ; 2.27-2.25(2 H, m) (H S3 ) ;2.10-2.01 (4H, m) (H 6,10 ) ; 1.90 (2 H, s) (H 8 ) ; 1.69-1.49 (7H, m) (H 9A4)11 ) ;0.96 (3 H, d) (H 12). ô (13 C, CDCL 3,125 MHz) : 85.3 (j^ = 165.25 Hz, d) (C 13 ) ; 54.8 (C 7 ) ; 43.2 (C 8 ) ; 43.1 (C x i ) ; (j2f= 17.5 Hz, d) 40.3(C 10+ C 6 ) ;38.0 (C 9 ) ; 37.6(C 2 ) ;36.6(t* = 2.5 Hz, d) (C x ) ; 34.9(C Lr 4 ) ;29.2(C s ) ; 29.1(C 3 ) ;10.7(C 12 ) ;(j^= 7.5 Hz). ô (19 FNMR, CDCL 3,470 MHz) :222.08, (td, 1^ = 56.4 Hz, J^F = 32.9 Hz) HRMS : -for C13H23NF : Calculated mass 212.18 14; found :212.1815 5 OB ...--12 i¥ v4;4 Sr , b J 4 ô (1 HNMR, D 2 O, 500 MHz) : 3.72( ABX. J t«= 10.834Hz,2H) (H 12 ) ;2.17-2.13(2H, m) (H 53);! .78-1.67 (4H, m) (H 6,10 ) ; 1.62-1.35 (8H, m) (H 8,4 ,9,2 ) ;1.26 (1H, m) (H u ) ; 1.51-1.36(2H, J = 10H z, d) (H 13). ô (13 C, D 2 0,125 MHz):63.2 (C 12 );53.1 (C 7 ); 43.98 (C u ); 42.24(C 8 );39.52 (C 6 ); 39.50 (C 10 ); 37.20 (C 8 ); 36.87(C 2 ); 36.07(C x ); 34.33(C 4 ); 28.84(C 3 );28.82(C s );10.42(C X3 ) 6 GH h r g.,^4-_2 .7^ 35 U Br V***?**^. $ ô (1 HNMR, D 2 O, 500 MHz) : 3.61(2H, dt, J = 5.0Hz) (H X2 ) ;2.16-2.12(2H, m) (H S3 ) ; 1.78-1.6 8 (4H, m) (H 6,X0 ) ; 1.59-1.53 (4H, m (H 8.4 ), 1.51-1.36(6H, m) (H xw ). ô (13 C, D 2 0,125 MHz):57.4 (C X2 ) ;52.8 (C 7 ) ; 44.7 (C 8 ); 44.17(C xx );39.8(C 6.10 ); 39.36 (C 9. 2 ); 34.14(C 4 ); 33.4 (C x ); 28.8 (C 3+ C s ). HRMS :-for C12H22NO Calculated mass 196.1704 found: 196.1701 . 7 Cl 8 2 ô (1 HNMR, CDCL 3,300 MHz) : 8.33, (3H, Br s)NH 3, 3.53(2H, m) (H 12 );2.26(2H, s) (H s,3 );2. 08-1.92 (4H, m) (H 6,10 ); 1.84 (2H, s (H 8 ); 1.78-1.61 (4H, m) (H 4 ); 1.51-1.36(2H, m) (H 11)9,2 ). ô (13 C, CDCL 3,75 MHz) :ô 53.44(C 7 ); 45.92, 44.94, 40.18, 39.97, 39.78, 35.01, 34.69, 29.00. HRMS : for Ci2H2iNC1 Calculated mass 214.137 3 found :214.1701 8 ...F ô (1 HNMR, CDCL 3,500 MHz): 8.12 (3H, brs) 8 2 (NH 3 ); 4.05 (2H, d, J^ = 47.3 Hz) (H u ) ; 2.35 -2.28(1H, m) (H s );1.99 (2H, m) (H 6 ); 1.91-1.73 (4H, m) (H 8)10 ); 1.56-1.39 (4H, m) (H 4,9 ); 1.36- $ 4 1.26 (2H, m) (H2). ô (13 C, CDCL 3,125 MHz) : 90.6, (j^ = 172.5 Hz, d)(C u );54.9 (C 7 ); 46.8(C 10 ); 43.5¾ = 3 .75 Hz, d) (C 2 ); 41.9(C 4 ); 40.8 (¾ = 5 Hz, d)( C 8 ); 39.6(C 6 ); 37.4 (j^ = 17.5 Hz, d) (C 4 ); 3 5.7¾ = 3.7 Hz, d)(C 9 );29.6(C s ); 29.1(C 12 ). ô (19 FNMR, CDCL 3,470 MHz): 229.87(t, = 47.6Hz) Animaux et modèles modèles

[0121] • for tests to prevent cognitive impairment induced by AP 25-35 oligomers or anxiety measurement tests

[0122] Six-week-old male c57bl / 6 mice were used (weight 22 ± 2 g, Janvier labs (St Berthevin, France)). The animals were housed in groups of 8 to 10 individuals with access to food / water ad libitum in a temperature / humidity controlled facility (12 h / 12 ​​h light / dark cycle; lights on, 7 h; behavioral experiments, between 9 h and 17 h), in a soundproofed and air-controlled experimental room.

[0123] Intravenous injections of AfL were performed as described in Maurice et al. (1996). Control (vehicle) injections were performed with only preparation water. 3 µL of AfL oligomer solution or vehicle were administered to the mice. The mice were tested for their cognitive abilities in the Spontaneous Alternation Test in the Y-maze. The animals received an injection d'A[325 3sle day 1 and were treated with the test compounds, FENM and MEM thereafter in drinking water at a dose of Img / kg / day until day 42.

[0124] The level of anxiety in mice is assessed in open field and / or light-dark box tests as described below.

[0125] The test and reference compounds (MEM and FENM) were dissolved in the animals' drinking water in a volume dependent on the weight of the animals present in the cage and the amount of water consumed in 24 hours by that same cage. The quantities correspond to an oral dose of 1 mg / kg / day. The bromine salts of the compounds according to the invention are administered. • Mouse model of SLA#

[0126] The experiments are carried out on male mice. The transgenic male mice B6SJL-Tg(SODl)2Gur / J and their control (respectively SN2726 and SN2297 from Jackson Laboratories®, Ben Harbor, USA and distributed by Charles River® in France) are chosen in this series of experiments to mimic ALS.

[0127] Diseased mice express the SOD1-G93A transgene, engineered with a mutant human SOD1 gene (a single amino acid substitution of glycine to alanine at codon 93) driven by its endogenous human SOD1 promoter. Control mice express the human SOD1 gene.

[0128] Mice receive the candidate drug diluted in the vehicle from no earlier than 3 weeks and no later than 15 weeks after birth until death. Diluted solutions of the test compounds are prepared with water at room temperature just before the start of administration.

[0129] Riluzole (positive control) is added to drinking water at a final concentration of 6 mg / ml (adjusted for the average body weight of each group). Since a mouse drinks approximately 5 ml / day, the estimated administered dose is 30 mg / kg / day, a dose that has been shown to increase mouse survival.

[0130] The test compounds are solubilized in the drinking water of the animals in a volume dependent on the weight of the animals present in the cage and the amount of water consumed in 24h00 for that same cage.

[0131] Behavioral tests and analyses are performed after prolonged administration of the test compounds for 1 to 3 weeks and repeated regularly until the animals die.

[0132] Mice are tested for their grip strength in the grip test (grip test in Anglo-Saxon terminology). • Murine model of Huntington's disease#

[0133] The C57BL / 6J R6 / 2 transgenic mouse line expresses the 5' end of the human huntingtin (HTT; HD or Hdh) gene with -168 CAG repeat expansions. These B6J.R6 / 2 mice (CAG 168, Jackson Laboratories, Ben Harbor, USA) are used to study Huntington's disease.

[0134] Mice receive the candidate drug diluted in the vehicle from no earlier than 8 weeks and no later than 15 weeks after birth until death. Diluted solutions of the test compounds are prepared with water at room temperature just before the start of administration.

[0135] Behavioral tests and analyses are carried out after prolonged administration of the test compounds for 1 to 4 weeks and repeated regularly until the animals die.

[0136] The mice are tested for their activity and motor skills in the so-called open field test (open field in Anglo-Saxon terminology). • Murine model of Parkinson's disease and alpha-synucleinopathies#

[0137] TetP-hA53T a-syn transgenic mice (line 4360, Jackson Laboratories, Ben Harbor, USA) express the human mutant alpha-synuclein A53T under the control of the mouse prion protein gene promoter (Prnp) and the tetracycline-sensitive regulatory element tetO. When mated with a mutant strain expressing tTA, the expression of the SNCA*A53T protein is controlled by doxycycline in the offspring of the double mutant (Brahmachari et al., 2019). These mice are used to study human neuronal alpha-synucleinopathies, including familial Parkinson's disease.

[0138] Mice receive the candidate drug diluted in the vehicle no earlier than 3 weeks and no later than 10 weeks after doxycycline induction, from birth until death. Diluted solutions of the test compounds are prepared with water at room temperature just before the start of administration.

[0139] Behavioral tests and analyses are performed after prolonged administration (at least 4 weeks) of the test compounds and repeated regularly until the animals die.

[0140] The mice are tested for their activity and motor skills in the so-called open field test (open field in Anglo-Saxon terminology). • Genetic mouse model of Alzheimer's disease #

[0141] The APPswePSldE9 transgenic mouse model of Alzheimer's disease (Jackson Laboratories®, Ben Harbor, USA) expresses two human mutations, one in the APP gene and the other in the PSL gene. These mice exhibit amyloid plaque deposition that increases with age, as well as deficits in cognitive tasks and episodic memory tasks. These mice are used in research to study neurological brain disorders, particularly Alzheimer's disease, amyloid plaque formation, and aging.

[0142] Mice receive the candidate drug diluted in the vehicle from 3 months post-birth until death. Diluted solutions of the test compounds are prepared with water at room temperature just before the start of administration.

[0143] Behavioral tests and analyses are performed after prolonged administration (at least 3 weeks) of the test compounds.

[0144] Mice are tested for their cognitive abilities in the spontaneous alternation test in the Y maze. • Spontaneous alternation test in the Y-maze#

[0145] The animals were tested for their spontaneous alternation performance in the Y-maze, an index of spatial working memory (Maurice et al., 1994; 1998; Maurice, 2016). Made of gray polyvinyl chloride, the Y-maze has arms measuring 40 cm x 13 cm; 3 cm at the bottom, 10 cm at the top, converging at equal angles. Each mouse was placed at the end of an arm and allowed to move freely for 8 minutes. Entries into the arm, including possible returns into the same arm, were recorded. An alternation was defined as a successive entry into all three different branches. The percentage of alternation was calculated as follows: maximum number of alternations = total number of entries into arms minus 2, and percentage of alternation = (actual alternations / maximum alternations) x 100. Animals with fewer than 10 entries in 8 minutes or a percentage of alternation > 90% or < 20% were excluded from the calculations. • Open field test #

[0146] The open field test is a comprehensive test that measures the movements of an animal introduced into a new environment using an infrared tracking system (Activity Monitor, Sandown Scientific, United Kingdom). This test assesses the baseline activity of rodents. The variables measured in this test are total ambulatory activity, the number of entries, and the time spent in the central area (a virtual area represented by a 12.3 cm square), as well as righting movements. Depending on the model, this test can be used to detect motor impairment (measurements taken over a longer period, e.g., 2 hours) but also anxious behavior (measurements taken over a shorter period). • Grip test #

[0147] The assessment of grip strength (grip) makes it possible to detect subtle differences in gripping performance composed of muscle strength, state of sensitivity (for example, painful tactile sensations can modify the measured values ​​of strength), behavior and attitude.

[0148] The grip strength test measures the force with which an animal grips a handle with its forepaws or hind paws. A dynamometer is placed on a handle to measure the force (FG-5000A dynamometer). The mouse is held by The experimenter positions the mouse so that it grasps the handle either with its front paws or its hind paws, and gently pulls the mouse backward until it releases its grip. The force measured when the animal releases its grip is recorded. • Light-dark box test#

[0149] The light-dark box test is a test for measuring anxiety levels that relies on the aversive properties of an open space for rodents and on comparing exploratory activity in a lit compartment and in a dark compartment under the influence of anxiolytic substances. This test is based on rodents' innate aversion to light and their spontaneous exploratory behavior in response to stressful environments (novel environment or light). The test apparatus is divided into two compartments: one is small and dark, the other is large, bright, and therefore stressful. The test detects the anxiolytic or anxiogenic effects of drugs in mice. The passages between each compartment are an indicator of exploratory activity, while the time spent in each compartment reflects aversion.Anxiolytics, effective in humans such as benzodiazepines, have been detected as having anxiolytic activity in this model. Results

[0150] • Prevention of cognitive impairment induced by AP 25J5 oligomers

[0151] The data relating to the spontaneous alternation test observed for the tested compounds are reported in Table 2 below.

[0152] [Tables2] Injection ic VVA[325 35 treatment VV ME M FEN M 1 2 3 4 5 6 7 8 n 54 54 71 70 70 71 67 68 71 72 72 71 Min 50 33 35 36 44 44 38 44 31 29 35 27 Max 89 71 86 88 89 88 86 88 88 88 86 88 Avg 71.1 55 59.5 65.9 65.2 67.4 60.8 66 59 57.2 56.4 57.5 SEM 1.2 1.3 1.3 1.3 1.2 1.2 1.4 1.4 1.4 1.4 1.2 1.3

[0153] V: vehicle, n: number of tests, Min: minimum number of alternations observed, Max: maximum number of alternations observed, Moy: mean, SEM: standard error of measure

[0154] The weekly data from day 7 to day 42 were pooled and analyzed together for each group after verifying that the data followed a normal distribution (Shapiro-Wilk test). This pooled analysis method allows us to confirm the sustained and long-term protective effect observed and conferred by the tested molecules.

[0155] A Bonferroni test (multiple comparison test) was then performed to statistically differentiate the groups from one another by adjusting the data specific to this test. The statistical significance levels considered were p < 0.05, p < 0.01 and p < 0.001.

[0156] After 42 days of treatment, while the memory performance of the animals treated with MEM was found to be significantly different from the control animals (V / V), FENM continued to significantly prevent the learning deficit induced by 1'A[325 35. A significant difference was also observed between the animals treated with MEM and those treated with FENM, reflecting a loss of efficacy of MEM after 42 consecutive days of treatment by oral route at a dose of 1 mg / kg / day.

[0157] Animals treated with the compound of the invention (compound 2) demonstrate statistically different memory performance compared to animals treated with MEM, indicating efficacy as good as, or even better than, FENM ([Fig. 1]) in preventing cognitive deficits. This compound is, however, very similar structurally to the other compounds tested, such as compounds 3 and 8, which do not appear to confer a superior or different effect from that of memantine. Thus, compound 3 exhibits a protective effect similar to memantine, but this effect is short-lived. Compound 8, for its part, confers no memory-protective effect. In general, this demonstrates the unpredictability of the effect and efficacy of molecules selected based solely on their structural similarity and intended to interact with NMDA receptors.

[0158] The test developed by the inventors thus made it possible to identify and select the compound of the invention (compound 2) exhibiting disease-modifying properties in the Alzheimer's disease model of intravascular injection of 1'A[325 35] oligomers, beyond their mere structural similarity to FENM. Indeed, these compounds allow for the prevention of cognitive deficits induced in this acute model of AD in the long term. • Genetic mouse model of ALS#

[0159] The compounds are tested in this model.

[0160] Compound 2 is tested for its improvement in grip strength compared to the other compounds tested.

[0161] Furthermore, in animals sacrificed after treatment, motor neuron counting with Nissl staining, the level of nitrosylated proteins (Apolloni and al., 2021) and / or the level of neuroinflammation (Julien and Kriz; 2006) is analyzed to detect a superior protective effect for the tested compounds. • Genetic mouse model of Huntington's disease#

[0162] Compounds are tested in this model.

[0163] Compound 2 is tested in the improvement of behavioral variables of the open field test associated with the motor activity of animals.

[0164] Furthermore, in animals sacrificed after treatment, the counting of neurons in cresyl violet staining at the level of the superior striatum, the measurement of the level of BDNF in the brain (marker of neuronal atrophy, Ellrichmann et al., (2019)) and / or the measurement of neuroinflammation (Etxeberria-Rekalde et al., 2021) is analyzed to detect a superior protective effect for the compounds tested. • Genetic mouse model of Parkinson’s disease#

[0165] The compounds are tested in this model.

[0166] Compound 2 is tested in the improvement of behavioral variables of the open field test associated with the motor activity of animals.

[0167] Furthermore, in animals sacrificed after treatment, measurement of tyrosine hydroxylase expression at the level of the striatum, measurement of pro-inflammatory neuroinflammation markers such as TNFa or IL6 and / or measurement of alpha synuclein (pSyn) phosphorylation (Hack et al., 2024) shows a superior protective effect for the compounds tested. • Genetic mouse model of Alzheimer's disease#

[0168] Compounds are tested in this model.

[0169] Compound 2 is tested in the improvement of the memory capacities of animals in the spontaneous alternation test.

[0170] Furthermore, in animals sacrificed after treatment, measurement of the amyloid load of tyrosine hydroxylase expression at the level of the striatum, measurement of pro-inflammatory markers (TNFa, IL6 ...), measurement of astrocytic and microglial activation (GFAP, IBA1) and / or measurement of reactive oxygen species (Ruan et al.', 2009) shows a superior protective effect for the compounds tested. • Anxiety reduction #

[0171] Compound 2 is tested in the light-dark box experimental model to detect a positive effect on anxiety measured in animals, references

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[0175] Ellrichmann G, Blusch A, Fatoba O, Brunner J, Reick C, Hayardeny L, Hayden M, Sehr D, Winklhofer KF, Saft C, Gold R. Author Correction: Laquinimod treatment in the R6 / 2 mouse model. Sci Rep. 2019 Mar 15;9(l):4960.

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[0177] Hack W, Gladen-Kolarsky N, Chatterjee S, Liang Q, Maitra U, Ciesla L, Gray NE. Gardenin A treatment atténuâtes inflammatory markers, synuclein pathology and déficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-a-syn mice. Biomed Pharmacother. 2024 Apr;173:l 16370..

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Claims

Demands

1. Compound of formula I: -F (i) or one of its salts of formula II: a" (ii) A being a counter anion selected from the following ions: chloride, bromide, iodide, acetate, methane sulfonate, benzene sulfonate, camphosulfonate, tartrate, dibenzoate, ascorbate, fumarate, citrate, phosphate, salicylate, oxalate, bromohydrate, tosylate, or any other pharmaceutically acceptable salt.

2. The compound or one of its salts according to claim 1, for its use as a medicinal product.

3. The compound or one of its salts according to claim 1, for its use in the prevention, reduction or stabilization of alterations in cognitive abilities in a subject suffering, suspected of suffering or considered at risk of suffering from a neuropsychiatric pathology.

4. The compound or one of its salts according to claim 1, for its use in the prevention or treatment of a neurodegenerative disease in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative disease.

5. The compound or one of its salts according to claim 1, for its use in preventing or reducing cognitive impairment in a subject suffering from, being suspected of suffering from, or being considered at risk of suffering from, a neurodegenerative disease.

6. The compound or one of its salts according to claim 1, for its use in inducing neuroprotection in a subject suffering from, suspected of suffering from, or considered at risk of suffering from a neurodegenerative disease.

7. The compound or one of its salts of formula II for use according to any one of claims 4 to 6, said neurodegenerative pathology being 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, Charcot-Marie-Tooth disease, Korsakoff's syndrome, neurodegeneration related to alcohol withdrawal, ischemia, neonatal ischemia, head trauma, stroke, preferably Alzheimer's disease.

8. The compound of formula I or one of its salts of formula (II) for use according to claim 3, to prevent, delay, reduce or stabilize alterations in cognitive abilities related to stress, PTSD, depression or anxiety in a subject suffering or suspected of suffering from one of these pathological conditions.

9. Pharmaceutical composition comprising the compound of formula (I) or one of its salts of formula (II) according to claim 1.

10. Pharmaceutical composition according to claim 9, comprising from 0.5 mg to 30 mg of the compound of formula I or one of its salts of formula II according to claim 1.

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