NEW SYNERGISTIC COMBINATIONS BASED ON FENM

Abstract

The invention relates to a composition comprising a synergistic combination of fluoroethylnormemantine (FENM) and at least one agonist or positive modulator of the sigma-1 receptor.More particularly, the invention relates to said composition for its use as a medicinal product, even more particularly for its use in the treatment of a selected pathology from among neurogenetic diseases of metabolic origin such as GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy, or 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. Figure to be published with the abbreviation: FIGURE 5.

Description

Title of the invention: NEW SYNERGISTIC COMBINATIONS BASED ON FENM

[0001] The invention relates to the field of neurodegenerative diseases.

[0002] The invention relates more particularly to compositions comprising a synergistic combination of 3(2-fluoroethyl)tricyclo[3.3.1.13,7]decan-l-amine (fluoroethylnormemantine, FENM) with at least one agonist or positive modulator of the sigma-1 receptor.

[0003] The invention also relates to these combinations or compositions comprising them for their use in the treatment of neurodegenerative diseases and, more particularly, in the prevention and / or treatment of cognitive disorders of these diseases. Previous technique

[0004] The World Health Organization (WHO) estimates that by 2050 the number of people over the age of 60 will reach two billion. This unprecedented aging of the world's population suggests that chronic age-related diseases will place significant pressure on healthcare systems. Dementia is one such disease. The WHO estimates that the total number of people living with dementia will exceed 150 million by 2050.

[0005] Dementia is characterized by a decline in cognitive functions, particularly memory and reasoning, which impacts the patient's behavior and their ability to perform everyday tasks. Dementia is a syndrome encompassing pathologies with highly 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.These pathologies and syndromes are also often linked to an abnormal accumulation of certain proteins and / or the accumulation of mutated and / or abnormally folded proteins such as observed in A[3] amyloidosis, tauopathies, synucleinopathies, aggregation of superoxide dismutase-1 (SOD1), polyglutamine, TDP-43 protein.

[0006] Alzheimer's disease is the most common cause of dementia and is thought to be responsible for 60-70% of cases (source WHO).

[0007] Today, several molecules are authorized for the symptomatic treatment of Alzheimer's disease. These are anticholinesterases such as donepezil, the Rivastigmine and galantamine have marketing authorizations (MAs) for use as monotherapy in mild, moderate, or moderately severe disease. Memantine, a non-competitive voltage-dependent NMDA (N-methyl-D-aspartate) receptor antagonist, is authorized for moderate and severe disease but not for mild disease. These compounds are not recommended in the early stages of the disease due to a lack of clinical efficacy. Furthermore, their effects are symptomatic and limited, and have only been demonstrated in the short term (on average, 6 months) in approximately two-thirds of patients included in clinical trials (source: French National Authority for Health).

[0008] Endoplasmic reticulum (ER) chaperones are known to regulate the cellular response to misfolded proteins and ER-induced stress. Within membrane contact domains between the ER and mitochondria, known as MAMs (mitochondrial-associated membranes), they modulate exchanges between the two organelles. Among them, the sigma-1 receptor is a chaperone protein highly enriched in these MAM domains. Through protein-protein interactions, activation of the sigma-1 receptor directly affects not only calcium transfer to the mitochondria but also numerous cellular pathways (Maurice et al., 2016). Ligands that selectively activate the sigma-1 receptor exhibit potent neuroprotective properties in several animal models of neurodegenerative diseases (Maurice, 2021).In particular, sigma-1 receptor agonists modulate cholinergic and glutamatergic systems. Research into potential additive or synergistic effects of sigma-1 receptor agonists in combination with cholinergic or glutamatergic modulators has shown synergy with anticholinesterases such as donepezil but no synergy with NMDA receptor antagonists such as memantine (Maurice et al., 2016). Application WO 2017 / 191034 describes a phosphinolactone-derived sigma-1 receptor positive modulator for use in the treatment of neurodegenerative diseases. Application WO 2017 / 137600 describes neuroprotective effects of igmesin, a sigma-1 receptor agonist, on cognitive impairment induced by oligomerized amyloid A[325 35] peptide, a pharmacological model of Alzheimer's disease.In this model, WO 2017 / 137600 describes the absence of synergy of igmesin with memantine to counteract the effects of peptide A[325 35- Maurice (2016) also describes the effect of PRE-084 in the A[325 35- peptide injection model. WO 2014 / 155138 describes the synergy between donepezil and blarcamesin in the same model.

[0009] Application WO 2014 / 191424 describes 18F-labeled FENM for labeling NMDA receptors and visualizing them by positron emission tomography to study the distribution of these receptors and their response to drug treatments. Application WO 2019 / 115833 describes FENM in the treatment of anxiety and depression-related disorders. Application WO 2021 / 234324 identifies neuroprotective effects of FENM.

[0010] Application WO 2013 / 064579 describes a combination of connexin blocking agents (such as meclofenamic acid) with an acetylcholinesterase inhibitor (such as donepezil) for use in the treatment of cognitive disorders.

[0011] Aducanumab is an anti-amyloid monoclonal antibody used to reduce amyloid burden in the brain. Aducanumab received marketing authorization from the FDA (Food and Drug Administration) in 2021 for the treatment of early or prodromal Alzheimer's disease with confirmed amyloid deposits. Given the lack of replicated results regarding reduced cognitive decline in treated patients, and considering the absence of therapeutic solutions, the marketing authorization was made conditional upon a re-evaluation of the product to confirm its clinical benefit (<www.fda.gov> ). Approximately 35% of treated patients experienced cerebral microhemorrhages and cerebral edema (source: France Alzheimer).<www.francealzheimer.org> The cost of the treatment, which requires monthly intravenous administrations, is estimated at $56,000 per year.

[0012] The diagnosis of dementia associated with a neurodegenerative disease or Alzheimer's disease at an early stage leads to a significant demand for treatment from the patient and their family, with the aim of stopping or slowing the progression of the disease as early as possible. Thus, while research avenues are currently being explored, this need remains unmet. There is also a significant need for more effective treatments, both in terms of symptom relief and the duration of treatment efficacy, for patients in the more advanced stages of the disease. [Technical problem]

[0013] The invention aims to overcome the drawbacks of the prior art. In particular, the invention aims to provide a new therapy for cognitive impairment in neurodegenerative diseases, especially Alzheimer's disease (AD). This new therapy is based on the combined action of fluoroethylnormemantine (FENM) and at least one agonist or positive modulator of the sigma-1 receptor. The synergistic action identified is surprising between These molecules allow, on the one hand, for particularly effective effects in preserving cognitive abilities, on the other hand, for the development of new compositions that were not possible with memantine, and on the other hand, for a reduction in the doses used for these compounds. This reduction eliminates the risk of adverse effects and even increases the possible duration of treatment while achieving greater improvement with particularly low doses. This improved efficacy makes it possible to consider using this treatment, including in the early stages of the disease. [Brief description of the invention]

[0014] The applicants have discovered, quite surprisingly, that the combined effects of 3-(2-fluoroethyl)adamantan-l-amine (FENM) with those of sigma-1 receptor agonists have a synergistic effect in treating cognitive symptoms in a mouse model intoxicated by intracerebral administration of amyloid peptide oligomers P25 35 (A[325 35]-). This synergistic action is observed in cognitive tests of short-term working memory, but also of long-term contextual memory. Such synergistic effects suggest the possibility of new treatments for neurodegenerative diseases that are more effective than those currently used.

[0015] Accordingly, an object of the present invention relates to a synergistic combination of FENM or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts.

[0016] In a particular embodiment of said synergistic combination, said at least one agonist or positive modulator of a sigma-1 receptor is selected from 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane;2-(Pyrimidin-2-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(Pyrimidin-5-yl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-; oxazaphosphinane; 2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane, PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-l-carboxylate), (+)-pentazocin, (+)-SKF10,047, cutamesin, fluvoxamine, igmesin, OPC-14523, BD737, BHDP, pridopidine, ANAVEXl-41, FANAVEX2-73, FANAVEX3-71, SDHEA, selegiline, fluoxetine, citalopram, amitriptyline, L-687384, dipentylamine, dextromethorphan, dimethyltryptamine, opipramol or one of its Pharmaceutically acceptable salts, these compounds are known agonists or positive modulators of the sigma-1 receptor.

[0017] Said synergistic combination may comprise one or more of the following characteristics, alone or in combination: - at least one agonist of a sigma-1 receptor selected from PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-l-carboxylate), cutamesine (l-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine) and Figmesine ((5E)-N-(cyclopropylmethyl)-N-methyl-3,6-diphenyl-5-hexen-3-amine), - at least one positive modulator of a sigma-1 receptor is 2-(3-chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane or one of its pharmaceutically acceptable salts, - a molar ratio of agonist or positive modulator of a sigma-1 receptor / FENM less than or equal to 7, said molar ratio being greater than or equal to 0.5.

[0018] Said synergistic combination is particularly effective in counteracting the cognitive effects caused by the administration of AP25-35 amyloid peptide. The synergistic combination according to the invention therefore constitutes a new treatment of interest for neurodegeneration and associated dementia. Thus, the synergistic combination according to the invention is of particular interest for its use as a drug.

[0019] More particularly, the synergistic combination according to the invention is particularly suitable for use in the treatment of a pathology selected from among neurogenetic diseases of metabolic origin, 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, GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy.

[0020] As shown in the experimental part, the synergistic combination according to any one of the claims is suitable for use in the treatment, prevention, reduction or slowing of the progression of cognitive impairments in a subject suffering from, suspected of suffering from or considered at risk of suffering from a neurodegenerative pathology.

[0021] Another object of the present invention relates to a pharmaceutical composition comprising the aforementioned synergistic combination. Brief description of the drawings

[0022] [Fig-1] (A) Symptomatic effect of FENM, PRE-084, or the FENM+PRE-084 combination on memory impairment induced by oligomerized A[>2335] peptide in the Y-maze test; Data: mean ± standard deviation from mean. ANOVA: F(n>204) = 2.513, p = 0.0055, n = 10-39 per group; test performed on day 8, 24 hours after the last administration of the compound or combination; * p < 0.05, ** p < 0.01, *** p < 0.001 vs. (V+V) treated group; # p < 0.05, ### p < 0.001 vs. (A[>2333+V] treated group; Dunnett's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), PRE-084 (P), or the FENM+PRE-084 combination (m). 100% corresponds to the performance level of mice not intoxicated with A[325 35] and treated with the vehicle. 0% protection corresponds to the performance level of mice treated with (A[325 35]+V). S: synergistic effect with an IC50 less than 1; V: vehicle solution.

[0023] [Fig.2] (A) Symptomatic effect of FENM, PRE-084 or the combination FENM+PRE-084 on memory impairment induced by oligomerized A[325 35] peptide in the passive avoidance test. Training took place on day 9, 48 hours after the last treatment. Retention was tested on day 10, 24 hours after training. Data: mean + standard deviation from mean. Kruskal-Wallis ANOVA: H = 48.69, p < 0.0001, n = 11-41; *p < 0.05, **p < 0.01, ***p < 0.001 vs. (V+V) treated group; #p < 0.05, ###p < 0.001 vs. (A[325 35 +V] treated group); Dunn's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), PRE-084 (P), or the FENM+PRE-084 combination (m). 100% corresponds to the performance level of mice treated with (V+V). 0% protection corresponds to the performance level of mice treated with (A[325 35+V]. S: synergistic effect with an IC50 less than 1; V: vehicle solution.

[0024] [Fig.3] (A) Symptomatic effect of FENM, igmesine or the combination FENM+igmesine on memory impairment induced by oligomerized A[325 35 peptide in the Y-maze test; Data: mean + standard deviation from mean. ANOVA: F(10,153) = 2.902, p = 0.0024, n = 10-20 per group; the test is performed on day 8, 24 hours after the last administration of the compound or the combination; * p < 0.05, ** p < 0.01, *** p < 0.001 vs. (V+V) treated group; # p < 0.05, ## p < 0.01, ### p < 0.001 vs. (A[325 35+V] treated group); Dunnett's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), igmesin (I), or the FENM+igmesin combination (m). 100% corresponds to the performance level of mice treated with (V+V). 0% protection corresponds to the performance level of mice treated with (A[325 35+V]. S: synergistic effect with an IC50 less than 1; V: vehicle solution.

[0025] [Fig.4] (A) Symptomatic effect of FENM, igmesine or the combination FENM+igmesin on the effect of oligomerized A[325 35]-induced memory impairment in the passive avoidance test. Training took place on day 9, 48 hours after the last treatment. Retention was tested on day 10, 24 hours after training. Data: mean + standard deviation from mean. Kruskal-Wallis ANOVA: H = 28.99, p = 0.0013, n = 10⁻²⁴; *p < 0.05, **p < 0.01, ***p < 0.001 vs. (V+V) treated group; Dunn's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), igmesin (I), or the FENM+igmesin combination (m). 100% corresponds to the performance level of (V+V) treated mice. 0% protection corresponds to the performance level of mice treated with (A[325 35+V]. S: synergistic effect; V: vehicle solution.

[0026] [Fig. 5] (A) Symptomatic effect of FENM, cutamesin or the combination FENM+cutamesin on memory impairment induced by oligomerized A[325 35] peptide in the Y-maze test; Data: mean + standard deviation from mean. ANOVA: F(i0>i6i) = 3.144, p = 0.0011, n = 11-23 per group; the test is performed on day 8, 24 hours after the last administration of the compound or combination; * p < 0.05, *** p < 0.001 vs. (V+V) treated group; ## p < 0.01, ### p < 0.001 vs. (A[>23 33+V] treated group; Dunnett's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), cutamesin (C), or the FENM+cutamesin combination (m). 100% corresponds to the performance level of mice treated with (V+V). 0% protection corresponds to the performance level of mice treated with (A[>2333+V]. S: synergistic effect; V: vehicle solution.

[0027] [Fig.6] (A) Symptomatic effect of FENM, cutamesin or the combination FENM+cutamesin on the impairment of memory induced by oligomerized A[325 35] peptide in the passive avoidance test. Training took place on day 9, 48 hours after the last treatment. Retention was tested on day 10, 24 hours after training. Data: mean + standard deviation from the mean. Kruskal-Wallis ANOVA: H = 36.49, p < 0.0001, n = 12-21; * p < 0.05, ** p < 0.01, *** p < 0.001 vs. group treated with (V+V); # p < 0.05, ## p < 0.01 vs. group treated with (A[325 35]+V); Dunn's test. (B) Protection scale showing the level of protection (PP) conferred by FENM (F), cutamesin (C), or the FENM+cutamesin combination (m). 100% corresponds to the performance level of mice treated with (V+V). 0% protection corresponds to the performance level of mice treated with (A[325 35+V]. S: synergistic effect; V: vehicle solution. [Description of the invention]

[0028] Definitions

[0029] 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, 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.Unless otherwise stated, however, the mention in units of mass or in units of mass per day of the quantity of a compound of the composition or combination according to the invention, refers to the compound designated in itself.

[0030] For the purposes of this invention, "pharmaceutically acceptable salts" refer to 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 saline 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 in question, 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 in question 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. Although most salts of a given active ingredient are bioequivalent, some... They may have, among other things, enhanced solubility or bioavailability properties. Salt selection is now a standard operation in the drug development process, as taught by Stahl and Wermuth in their manual (Stahl and Wermuth).

[0031] Examples of compounds that can be used to implement a combination of FENM with at least one agonist of a sigma-1 receptor according to the invention are listed respectively in Tables 1 and 2 below.

[0032] [Tables 1] Compound Reference Number CAS1 FENM 1639210-26-6 FENM HBr NA FENM HCl NA

[0033] 1 Chemical Abstracts database registration number Service. NA: Not available

[0034] A preferred FENM salt is FENM hydrochloride.

[0035] A particularly preferred salt of FENM is FENM hydrobromide.

[0036] [Tables2] Compound IUPAC Name CAS1 Reference Number PRE-084 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate 138847-85-5 PRE-084 (chlorhydrate) 2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate; hydrochloride 75136-54-8 pentazocine l,13-dimethyl-10-(3-methylbut-2-enyl)-10-azatricycl o [7.3.1.02'7] tridec a-2(7) ,3,5-trien-4-ol 7361-76-4; 35 9-83-1 (+)SKF 10047 14-methyl-12-prop-2-enyl-12-azatctracyclo|7.5.0.011 3.03'8]tetradeca-3(8),4,6-trien-6-ol 133005-41-1 cutamesin l-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl l)piperazine 165377-43-5 cutamesin (dichlor hydrate) l-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl )piperazine ;dichlor 165377-44-6 ANAVEX 2-73 (or blarcamesin hydro chloride) l-(2,2-diphenyloxolan-3-yl)-A,A-dimethylmethanamin ;hy drochloride 195615-84-0 ANAVEX 1-41 l-(5,5-diphenyloxolan-3-yl)-N,N-dimethylmethanamine 99761-13-4 ANAVEX 3-71 l-(2,8-dimethyl-l-thia-3,8-diazaspiro[4.5]decan-3-yl)-3-(lH-indol-3-yl)propan-l-one 1235733-73-9 fluvoxamine 2-[(E)-[5-methoxy-l-[4-(trifluoromethyl)phenyl]pentylidene]amino] oxyethanamine 54739-18-3 4-IBP N-(l-benzylpiperidin-4-yl)-4-iodobenzamide 155798-08-6 igmesine (E)-N-(cyclopropylmethyl)-N-methyl-3,6-diphenyl ex-5-en-3-amine 140850-73-3 igmesin (hydrochloride) (E)-N-(cyclopropylmethyl)-N-methyl-3,6-diphenylh ex-5-en-3-amine;hydrochloride 130152-35-1 OPC-14523 l-(3-(4-(3-Chlorophenyl)-l-piperazinyl)propyl)-5-m ethoxy-3,4-dihydro-2-quinolinone 145969-30-8 BD-737 [2-(3,4-Dichloro-phenyl)-ethyl]-methyl-(2-pyrrolidin-1-y 1-cyclohexy 1)-amine NA BHDP 6-[(4-benzylpiperazin-l-yl)methyl]-2,3-dimethoxyphenol NA pridopidine 4-(3-methylsulfonylphenyl)-l-propylpiperidine 346688-38-8 SDHEA [(3S,8R,9S,10R,13S,14S)-10,13-dimethyl-17-oxo-l, 2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-y1] hydrogen sulfate 651-48-9 selegiline N-methyl-N-(l-phenylpropan-2-yl)prop-2-yn-l-amine 14611-51-9 fluoxetine N-methyl 1-3-pheny 1-3-[4-(trifluoromethyl l)phenoxy]-propan-1-amine 54910-89-3 ; 1 00568-02-3 ; 1 00568-03-4 citalopram l-[3-(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3 -dihy dro [3,4] benzofuran- 5 -c arbonitrile 59729-33-8; 1 28196-01-0; 1 28196-02-1 L-687384 l'-benzylspiro[2,3-dihydro-lH-naphthalene-4,4'-pipe ridine] 95417-67-7 dipentylamine N-pentylpentan-1 - amine 2050-92-2; dextromethorphan (1S,9S,10S)-4-methoxy-17-methyl-17-azatetracyclo [7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene 125-71-3 dimethyltryptamine 2-(lH-indol-3-yl)-N,N-dimethylethanamine 61-50-7 opipramol 2-[4-(3-benzo[b][l]benzazepin-ll-ylpropyl)piperazi nl-yl]ethanol 909-39-7

[0037] 1 Chemical Abstracts database registration number Service. NA: Not available

[0038] A preferred salt of PRE-084 is PRE-084 hydrochloride.

[0039] A preferred igmesine salt is igmesine hydrochloride. The preferred enantiomer is +(E)-N-(cyclopropylmethyl)-N-methyl-3,6-diphenylhex-5-en-3-amine.

[0040] A preferred salt of cutamesin is cutamesin dihydrochloride.

[0041] Examples of positive modulators of a sigma-1 receptor usable in the synergistic combination according to the invention are listed in application WO 2017 / 191034 and are incorporated herein by reference to that application. These are in particular 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphin ane; 2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane;2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyrimidin-2-yl)-2-o xo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(Pyrimidin-5-yl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane, or one of its pharmaceutically acceptable salts.

[0042] For the purposes of the invention, a sigma-1 receptor is a subtype of sigma receptor, which is a transmembrane chaperone protein of the endoplasmic reticulum such as that encoded in humans by the SIGMAR1 gene (ENSG00000147955). The sigma-1 receptor is expressed in many types of tissue. It is particularly concentrated in certain regions of the central nervous system. It has been implicated in Several phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, and cancer, are affected. Thus, a sigma-1 receptor agonist, as defined in the invention, is understood to be a compound that binds to the protein encoded by the human SIGMAR1 gene mentioned above, or one of its homologs, or any other orthologous protein, for example, in mice or rats. A sigma-1 receptor agonist compound can be readily identified using methods known to those skilled in the art. For example, a sigma-1 receptor agonist, as defined in the invention, includes compounds that competitively displace the binding of a sigma-1 radioligand and induce sigma-1 receptor activity, such as the dissociation of the BiP / sigma-1 receptor complex in a cell line (Hayashi & Su, Cell, 2007).In one particular embodiment, a sigma-1 receptor agonist is capable of competitively displacing carbon-11 radiolabeled cutamesin. This competition can be identified and quantified in vivo by dynamic positron emission tomography (PET scan), a technique well-known to those skilled in the art. A positive modulator of the sigma-1 receptor does not displace the binding of a sigma-1 radioligand but induces an increase in the activity of this receptor, and, for example, dissociation of the BiP / sigma-1 receptor complex can be detected. Thus, those skilled in the art can easily identify a sigma-1 receptor agonist or positive modulator suitable for combination with FENM. A sigma-1 receptor agonist can have a Ki ranging from 0.1 nM to 2000 nM. Preferably the agonist of a sigma-1 receptor has a Ki less than 1000 nM, less than 500 nM, less than 100 nM, and even more preferably less than 50 nM for the sigma-1 receptor.Preferably, a positive agonist or modulator of a sigma-1 receptor suitable for combination with FENM exhibits selective activity at said sigma-1 receptor. Thus, a positive agonist or modulator of a sigma-1 receptor suitable for combination with FENM exhibits significant affinity or modulatory activity at a sigma-1 receptor that is at least 1, 2, 3, 4, or even 5 orders of magnitude greater than, or more than, another agonist or modulator. In particular, a positive agonist or modulator of a sigma-1 receptor suitable for combination with FENM does not exhibit significant affinity or modulatory activity for any other receptor or enzyme of the central nervous system. Even more particularly, within the synergistic combination according to the invention, said positive agonist or modulator of a sigma-1 receptor is not donepezil.

[0043] Particularly preferred agonists or positive modulators of the sigma-1 receptor are selected from: 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl- [1,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphos phinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaph osphinan; 2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tetramethyl[l,4,2]-oxazaphosphinane; 2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tetramethyl[l,4,2]-oxazaphosphinane; 2-(Pyrimidin-2-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(Pyrimidin-5-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane;2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane, PRE-084, (+)-pentazocine, (+)-SKF10,047, cutamesin, fluvoxamine, igmesin, OPC-14523, BD-737, BHDP, pridopidine, ANAVEX1-41, ANAVEX 2-73, ANAVEX 3-71, dehydroepiandrosterone sulfate (DHEA-S), selegiline, fluoxetine, citalopram, amitriptyline, L-687384, dipentylamine, dextromethorphan, dimethyltryptamine, opipramol or one of their pharmaceutically acceptable salts. ;

[0044] The term "combination," as used in the present invention, refers to a treatment in which at least one FENM and at least one sigma-1 receptor agonist are co-administered to a subject to produce a combined biological effect. In a combination therapy according to the invention, these at least two compounds may be administered together or separately, simultaneously or sequentially. In particular, FENM and said at least one sigma-1 receptor agonist may be administered via different routes and / or administration protocols. Consequently, although they may be formulated together, the compounds as components of a combination as defined in the invention may also be formulated separately. For example, FENM may be administered orally, and said at least one sigma-1 receptor agonist of the combination according to the invention may be injected into said subject, for example, intravenously, subcutaneously, or transdermally.In another embodiment, for example, FENM may be administered orally and said at least one sigma-1 receptor agonist may also be administered orally to said subject concomitantly or at a time-separated interval. Preferably, the administration sequence of the active ingredients of the combination (FENM and said at least one sigma-1 receptor agonist) is such that said active ingredients 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. Thus, particularly preferably, FENM and said at least one agonist of a sigma-1 receptor are administered so as to reach their maximum concentration in the plasma or cerebrospinal fluid, preferably cerebrospinal fluid, at the same time.

[0045] The term "synergy," as applied to the combinations according to the invention, refers to combinations in which the observed physiological or behavioral effects, for example, pro-amnesic or anti-amnesic effects, or effects known for each of the active ingredients in said combination, are additive or multiplied when used in such a way that their physiological effects interact. This synergistic effect makes it possible, in particular, to obtain pro-amnesic or anti-amnesic effects at doses at which the active ingredients applied in monotherapies would have no effect or a limited effect, which can reduce side effects and / or avoid or shorten the duration of dose escalation protocols. Furthermore, this synergy between the effects of the compounds in the combination according to the invention also makes it possible to potentiate these pro-amnesic or anti-amnesic effects or to improve complex types of memory, as shown in the experimental portion.The methods for analyzing the interaction between two molecules and determining the synergistic effect of a combination of compounds are well known to those skilled in the art. An example is the analysis of isobolograms and the determination of the combination index according to the principles set forth by Fraser (1872) and as implemented, for example, by Martin et al. (2020).

[0046] The term "subject" here refers to any member of the animal kingdom, preferably mammals and even more preferably humans. A subject requiring the combination treatments of the invention is defined as a subject suffering from, suspected of suffering from, or considered at risk of suffering from a neurodegenerative disease leading to dementia and associated cognitive impairment.These pathologies include, for example, neurogenetic diseases of metabolic origin such as GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy, 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, and amyotrophic lateral sclerosis. The compositions, combinations, and methods of the present invention are particularly suited to the treatment of cognitive disorders associated with Alzheimer's disease in its early, moderate, or advanced stages. Thus, in a particular embodiment, the subject suffers, or is suspected of suffering. or is considered at risk of suffering from Alzheimer's disease in its early, moderate or advanced stages. In another particular embodiment, said subject suffers, is suspected of suffering from or is considered at risk of suffering from cognitive impairment associated with the early, moderate or advanced stages of Alzheimer's disease, preferably cognitive impairment associated with the early stage of Alzheimer's disease.

[0047] As used herein, the term "treatment" includes therapy, prevention, prophylaxis, delay, or reduction of symptoms caused by or from the causes of the above-mentioned diseases or disorders. The term "treatment" includes, in particular, control of disease progression and associated symptoms. The term "treatment" includes, in particular, protection against the effects of amyloid toxicity [3], or a reduction or delay of these effects in treated subjects. The term "treatment" specifically refers to improvement, cessation, or delay in the progression of cognitive symptoms of the aforementioned diseases.

[0048] Combination of FENM and at least one agonist or positive modulator of a sigma-1 receptor

[0049] As shown by the experimental data presented below, a synergistic interaction of the neuroprotective effects of FENM and sigma-1 receptor agonists was discovered, resulting in an improvement of cognitive symptoms in a pharmacological animal model of Alzheimer's disease. The protective effect of this combination against cognitive decline induced by the administration of amyloid peptide A[325_35] is observed for both short-term working memory and long-term memory.

[0050] Thus, in a first aspect, the invention relates to a synergistic combination of FENM or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts.

[0051] The sigma-1 agonists tested in the experimental part are of very different structures; therefore, the data presented illustrate that a synergy of the effects of FENM and sigma-1 receptor agonists can be obtained regardless of the nature of the sigma-1 agonist involved. Furthermore, since positive modulators of the sigma-1 receptor behave in vivo, particularly in model A[325 35], like agonists (Maurice et al. 2019), they can be substituted for agonists.

[0052] In a particular embodiment, the synergistic combination of FENM or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts comprises at least one agonist of a sigma-1 receptor selected from: 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5- tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyrimidin-2-yl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(Pyrimidine-5-yl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane;2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane, PRE-084, (+)-pentazocin, (+)-SKF10,047, cutamesin, fluvoxamine, igmesin, OPC-14523, BD-737, BHDP, pridopidine, ANAVEX1-41, ANAVEX 2-73, ANAVEX 3-71, SDHEA, selegiline, fluoxetine, citalopram, amitriptyline, L-687384, dipentylamine, dextromethorphan, dimethyltryptamine, opipramol or one of their pharmaceutically acceptable salts, or one of their mixture.

[0053] In a particular embodiment, the synergistic combination of FENM or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts comprises at least two agonist(s) or positive modulator(s) of a sigma-1 receptor selected from: 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane;2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tétraméthyl [l,4,2]-oxazaphosphinane ; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tétraméthyl [1,4,2]-oxazaphosphinane ; 2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tétraméthyl-[l,4,2]-oxazaphosphinane ; 2-(Pyrimidin-2-yl)-2-oxo-3,3,5,5- ; tetramethyl-[l,4,2]-oxazaphosphinane; 2-(Pyrimidine-5-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane, PRE-084, (+)-pentazocin, (+)-SKF10,047, cutamesin, fluvoxamine, igmesin, OPC-14523, BD-737, BHDP, pridopidine, ANAVEXl-41, ANAVEX 2-73, ANAVEX 3-71, SDHEA, selegiline, fluoxetine, citalopram, amitriptyline, L-687384, dipentylamine, dextromethorphan, dimethyltryptamine, opipramol or one of their pharmaceutically acceptable salts.

[0054] In a particular embodiment, said at least one agonist of a sigma-1 receptor is selected from PRE-084 (IUPAC name: 2-morpholin-4-ylethyl 1-phenylcyclohexane-l-carboxylate), igmesine (IUPAC name: (E)-N-(cyclopropylm ethyl)-N-methyl-3,6-diphenylliex-5-en-3-amine), cutamesine (IUPAC name: 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine), or any of their pharmaceutically acceptable salts.

[0055] In a particular embodiment, said at least one positive modulator of a sigma-1 receptor is 2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane or any of their pharmaceutically acceptable salts.

[0056] As mentioned, the synergistic effect observed for the combinations of the invention makes it possible to consider using, in humans, the minimum doses or even doses lower than the doses at which sigma-1 inhibitors are used or have been tested in humans.

[0057] Thus, in a particular embodiment, in the synergistic combination according to the invention, at least one agonist of a sigma-1 receptor is igmesin and is administered at a dose less than or equal to 20 mg per day, less than or equal to 15 mg per day, less than or equal to 10 mg per day, less than or equal to 8 mg per day, less than or equal to 6 mg per day, less than or equal to 5 mg per day, less than or equal to 4 mg per day, less than or equal to 3 mg per day, or even less than or equal to 2 mg per day, but always sufficient to observe a beneficial effect of the combination on the cognitive abilities of the subject.In another particular embodiment, in the synergistic combination according to the invention, at least one agonist of a sigma-1 receptor is cutamesin and is administered at a dose less than or equal to 50 mg per day, less than or equal to 25 mg per day, less than or equal to 10 mg per day, or even less than 5 mg per day, but still sufficient to observe a beneficial effect of the combination on the subject's cognitive abilities. In a . Another particular embodiment, in the synergistic combination according to the invention, at least one acetylcholinesterase inhibitor is PRE-084 and is administered at a dose less than or equal to 50 mg per day, less than or equal to 25 mg per day, less than or equal to 10 mg per day or even less than 5 mg per day, but still sufficient to observe a beneficial effect of the combination on the subject's cognitive abilities.

[0058] In one particular embodiment of the synergistic combination according to the invention, at least one sigma-1 receptor agonist is igmesin and is administered at a dose of between 0.030 mg / kg per day and 0.14 mg / kg per day, between 0.06 mg / kg per day and 0.11 mg / kg per day, or even between 0.07 mg / kg and 0.09 mg / kg per day, considering a human subject with an average weight of 70 kg, as considered in the guidelines of health authorities. In another particular embodiment of the synergistic combination according to the invention, at least one sigma-1 receptor agonist is cutamesin and is administered at a dose of between 0.071 mg / kg per day and 0.71 mg / kg per day, considering a human subject with an average weight of 70 kg.In another particular embodiment, in the synergistic combination according to the invention, at least one acetylcholinesterase inhibitor is PRE-084 and is administered at a dose of between 0.071 mg / kg per day and 0.71 mg / kg per day, considering a human subject with an average weight of 70 kg, as considered in the guidelines of the health authorities.

[0059] In a particular embodiment, said at least positive modulator of a sigma-1 receptor is 2-(3-chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane and is administered at a dose less than or equal to 50 mg per day, less than or equal to 25 mg per day, less than or equal to 10 mg per day or even less than 5 mg per day, but still sufficient to observe a beneficial effect of the combination on the subject's cognitive abilities.

[0060] In a particular embodiment, FENM, in the synergistic combination according to the invention, is used at a dose less than or equal to 80 mg per day, less than or equal to 40 mg per day, less than or equal to 20 mg per day, less than or equal to 15 mg per day, less than or equal to 10 mg per day, less than or equal to 5 mg per day, less than 4 mg per day, less than 3 mg per day, less than 2 mg per day, or even less than or equal to 1 mg, or even lower, but still sufficient to observe a beneficial effect of the combination on the cognitive abilities of the subject.

[0061] In another particular embodiment, FENM, in the synergistic combination according to the invention, is used at a dose less than or equal to 1.1 mg / kg per day, less than or equal to 0.6 mg / kg per day, less than or equal to 0.29 mg per day, less than or equal to 0.21 mg / kg per day, less than or equal to 0.14 mg / kg per day, less than or equal to 0.07 mg / kg per day, less than 0.06 mg / kg per day, less than 0.04 mg / kg per day, less than 0.03 mg / kg per day, or even less than or equal to 0.01 mg / kg per day, or even less, considering a human subject of an average point of 70 kg, as considered in the guidelines of the health authorities, but still sufficient to observe a beneficial effect of the combination on the cognitive abilities of the subject.

[0062] A person skilled in the art will be able to adjust the dose to be administered according to the mass of the subject.

[0063] Thus, in a particular embodiment of the synergistic combination of FENM and at least one agonist or positive modulator of a sigma-1 receptor according to the invention, the molar ratio of sigma-1 agonist (or positive modulator) to FENM is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, preferably less than or equal to 2, said molar ratio of sigma-1 receptor agonist (or positive modulator) to FENM being greater than or equal to 0.5. Particularly preferred, said molar ratio of sigma-1 receptor agonist (or positive modulator) to FENM is less than 2 and greater than or equal to 0.5. In another particular embodiment said agonist of a sigma-1 receptor is igmesin, and the molar ratio igmesin / FENM is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2.Said igmesin / FENM molar ratio being greater than or equal to 0.1. Particularly preferred, said igmesin / FENM molar ratio is less than 2 and greater than or equal to 0.5. In another particular embodiment, said agonist of a sigma-1 receptor is igmesin, and the igmesin / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2, said igmesin / FENM molar ratio being greater than or equal to 0.5. Particularly preferred, said igmesin / FENM molar ratio is less than 2 and greater than or equal to 0.5. In another particular embodiment said agonist of a sigma-1 receptor is PRE-084, and the PRE-084 / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2.The PRE-084 / FENM molar ratio being greater than or equal to 0.1. Most preferably, the PRE-084 / FENM molar ratio is less than 2 and greater than or equal to 0.5. In another particular embodiment, the agonist of a sigma-1 receptor is cutamesin, and the cutamesin / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, preferably less than or equal to 2. The cutamesin / FENM molar ratio being greater than or equal to 0.1. Most preferably, the cutamesin / FENM molar ratio is less than 2 and greater than or equal to 0.5.

[0064] As mentioned previously, preferably, the aforementioned ratios are achieved in plasma or cerebrospinal fluid. Those skilled in the art will be able to determine the appropriate doses of FENM and at least one agonist or positive modulator of a sigma-1 receptor to be administered to the subject so as to achieve these molar ratios, in terms of Cmax, in the target compartment of the body, based on the Cmax of each of the active ingredients in the combination. Separate administration has the advantage of allowing precise consideration of the pharmacokinetic and pharmacodynamic characteristics (PK / PD data) of each of the active ingredients in the combination, particularly in the case of very different properties between the active ingredients in the combination according to the invention.

[0065] The cognitive abilities of human subjects and their evolution can be measured by tests well known to those skilled in the art. Tests commonly used for the cognitive assessment of human subjects include, for example, in Anglo-Saxon terminology, 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 Cognition 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 Alzheimer's Disease Cooperative Study - Activities of Daily Living), according to their English names.

[0066] More specifically, the MMSE makes it possible to screen individuals suffering from major neurocognitive impairment (dementia) without linking it to a specific pathology. The MMSE is also used to monitor individuals' cognitive status and to measure the decline in cognitive functions in people suffering from neurocognitive impairment. This test assesses orientation, registration, attention and calculation, memory retention, language, and construction praxis. CERAD (Consortium to Establish a Registry for Alzheimer's Disease) has established a dementia severity scale associated with MMSE scores. A score between 19 and 24 is associated with mild dementia, between 10 and 18, moderate dementia, and a score below 10 corresponds to severe dementia. severe dementia, the maximum score being 30. A variation of 2 points in the score is generally considered clinically relevant.

[0067] The ADAS-Cog is a cognitive subscale of the Alzheimer's Disease Assessment Scale and therefore only addresses the cognitive aspects of dementia. It can thus 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.

[0068] Thus, a combination with a beneficial effect on the subject's cognitive abilities will show a slowing or stabilization of the deterioration of the subject's cognitive abilities compared to the usual progression established in untreated subjects at the same stage of the disease for a given period of time. In other words, for example, in the case of the ADAS-Cog, a beneficial effect on the subject's cognitive abilities will correspond to a decrease, stabilization, or a smaller increase in the ADAS-Cog score compared to the usual worsening of the score observed in untreated subjects at an equivalent stage and age. Although the worsening of the score depends on the stage of the pathology and the subject's age, an annual increase of 5.82 points in the ADAS-Cog score is generally observed in subjects with untreated Alzheimer's disease (Zhang et al., 2020).Regarding the MMSE, for example, a beneficial effect on the subject's cognitive abilities will correspond to a smaller increase, stabilization, or decrease in the MMSE score compared to the usual worsening of the MMSE score observed in untreated subjects. An annual decrease of 2.28 points in the MMSE score is generally observed in subjects with untreated Alzheimer's disease (Rossetti et al. 2010).

[0069] 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 may vary depending on various factors such as the relevance of the stimulus, the task performed, damage to the nervous system, or the use of medication.

[0070] ERPs are known in the prior art as useful cognitive biomarkers for the diagnosis of dementia, monitoring disease progression, and evaluating the pro-cognitive effect of treatments. ERPs are altered, for example, 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 the P300 wave relates to motivation (in connection with task difficulty) and vigilance, depending on the probability of stimulus occurrence. Latency refers to the time required for decision-making. An increase in P300 latency (or its subcomponents) and a decrease in its amplitude (or its subcomponents) are observed in patients with dementia, particularly Alzheimer's disease. Studying changes in latency is useful for monitoring the progression of dementia, especially Alzheimer's disease, and for evaluating the response to Alzheimer's treatment.

[0071] Thus, the study of ERPs can make it possible to monitor the evolution of cognitive symptoms and thereby control the neuroprotection conferred by the combination of the invention. An increase in the latency of the Fonde P300 wave and / or a decrease in its amplitude is indicative of a decline in the cognitive abilities of the individual tested. Thus, a decrease in the latency of the P300 wave and / or an increase in its amplitude will be a sign of neuroprotection.

[0072] The in vivo efficacy of a synergistic combination according to the invention can therefore easily be evaluated by any of the aforementioned tests.

[0073] Composition according to the invention comprising a synergistic combination of FENM and of at least one agonist of a sigma-L receptor

[0074] In another aspect, the invention relates to a composition comprising a synergistic combination as described above. More particularly, according to this aspect, the invention relates to a pharmaceutical composition comprising, or capable of reconstituting in the body of the subject to whom it is administered, the synergistic combination according to the invention as described above.

[0075] In this composition, FENM or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts are formulated together or separately, in quantities and with excipients suitable for reproducing the effects of said synergistic combination in the target organism.

[0076] In a particular mode, FENM and at least one agonist or positive modulator of a sigma-1 receptor are the only active ingredients of said composition. In other words, FENM and at least one agonist or positive modulator of a sigma-1 receptor are the only compounds within the composition having therapeutic or preventative activity.

[0077] In another particular embodiment, the composition according to the invention comprises other active ingredients. Without a further particular embodiment, these other active ingredients are selected from the compounds listed in Table 3 below.

[0078] [Tables3] Compound Reference Number CAS T donepezil 120014-06-4; 120011-70-3 galantamine 357-70-0; 1953-04-4; 5072-47-9 rivastigmine 123441-03-2; 129101-54-8 tacrine 321-64-2; 1684-40-8; 7149-50-0 memantine 19982-08-2; 41100-52-1

[0079] 1 Chemical Abstracts database registration number Service.

[0080] A preferred salt of donepezil is donepezil hydrochloride.

[0081] A preferred galantamine salt is galantamine hydrobromide.

[0082] A preferred rivastigmine salt is rivastigmine tartrate.

[0083] These molecules are known as symptomatic treatments, sometimes with limited effects, for certain degenerative diseases. The use of some of these molecules is further limited by their adverse effects, or even their toxicity. Combining them with the synergistic combination of the invention can increase their efficacy and / or avoid or reduce adverse effects or toxicity by allowing for lower doses. Thus, in another particular embodiment, the composition according to the invention further comprises, as an active ingredient, at least one compound selected from donepezil, galantamine, rivastigmine, and tacrine, or one of their pharmaceutically acceptable salts or a mixture thereof. More particularly, the composition according to the invention comprises In addition, it may contain 10 mg, 7.5 mg, 5 mg, or even 2.5 mg of donepezil. In another particular embodiment, the composition according to the invention further comprises 16 mg, 8 mg, 4 mg, or even 2 mg of galantamine. In yet another particular embodiment, the composition according to the invention further comprises 3 mg, 1.5 mg, or even 1 mg of rivastigmine.

[0084] Preferably, the composition is administered to the subject in the form of a pharmaceutical preparation, for example, but not limited to, orally, locally (cutaneous, buccal, sublingual) or parenterally (subcutaneous, intramuscular or intravenous). Oral administration is particularly preferred.

[0085] The quantities of the active ingredients in this composition, that is to say at least FENM and at least one agonist or positive modulator of a sigma-1 receptor, are compatible with the doses as determined above for the synergistic combinations of the invention. In other words, when said composition is presented in the form of a unit dose (in the form of a tablet, capsule, powder, emulsion, solution), said dose comprises quantities of FENM or at least one agonist or positive modulator of a sigma-1 receptor that 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.In one particular embodiment, the composition according to the invention comprises 10 mg of igmesine, 9 mg of igmesine, 8 mg of igmesine, 7 mg of igmesine, 6 mg of igmesine, 5 mg of igmesine, 4 mg of igmesine, 3 mg of igmesine, or even 2 mg of igmesine. In another particular embodiment, the composition according to the invention comprises 50 mg of PRE-084, 25 mg of PRE-084, 10 mg of PRE-084, or even 9 mg of PRE-084, 8 mg of PRE-084, 7 mg of PRE-084, 6 mg of PRE-084, 5 mg of PRE-084, 4 mg of PRE-084, 3 mg of PRE-084, or even 2 mg of PRE-084. In another particular embodiment, the composition according to the invention comprises 50 mg of cutamesin, 25 mg of cutamesin, 10 mg of cutamesin, or even 9 mg of cutamesin, 8 mg of cutamesin, 7 mg of cutamesin, 6 mg of cutamesin, 5 mg of cutamesin, 4 mg of cutamesin, 3 mg of cutamesin, or even 2 mg of cutamesin.

[0086] In a particular embodiment, the composition according to the invention comprises 80 mg of FENM, 40 mg of FENM, 20 mg of FENM, 15 mg of FENM, 10 mg of FENM, 5 mg of FENM, 5 mg of FENM, 4 mg of FENM, 3 mg of FENM, or even 2 mg of FENM.

[0087] In another embodiment, in the composition according to the invention, the molar ratio of a sigma-1 / FENM agonist (or positive modulator) receptor is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, less than or equal to 3, preferably less than or equal to 2, said molar ratio of a sigma-1 / FENM receptor. positive) of a sigma-1 receptor / FENM being greater than or equal to 0.5. Particularly preferred, said agonist (or positive modulator) molar ratio of a sigma-1 receptor / FENM is less than 2 and greater than or equal to 0.5. In another particular embodiment, said agonist of a sigma-1 receptor is igmesin, and the igmesin / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2. Said igmesin / FENM molar ratio being greater than or equal to 0.1. Particularly preferred, said igmesin / FENM molar ratio is less than 2 and greater than or equal to 0.5.In another particular embodiment, said agonist of a sigma-1 receptor is igmesin, and the igmesin / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2, said igmesin / FENM molar ratio being greater than or equal to 0.5. Particularly preferred, said igmesin / FENM molar ratio is less than 2 greater than or equal to 0.5. In another particular embodiment, said agonist of a sigma-1 receptor is PRE-084, and the PRE-084 / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2. Said PRE-084 / FENM molar ratio being greater than or equal to 0.1. Particularly preferred, said PRE-084 / FENM molar ratio is less than 2 and greater than or equal to 0.5.In another particular embodiment, said agonist of a sigma-1 receptor is cutamesin, and the cutamesin / FENM molar ratio is less than or equal to 7, less than or equal to 6, less than or equal to 5, less than or equal to 4, is less than or equal to 3, preferably less than or equal to 2. Said cutamesin / FENM molar ratio being greater than or equal to 0.1. Particularly preferred, said cutamesin / FENM molar ratio is less than 2 and greater than or equal to 0.5.

[0088] The dose can 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 can be administered in one to four daily doses, for example 1 time, for example 2 times, for example 3 times, or even 4 times.

[0089] In a preferred embodiment, in said composition, the combination of FENM or at least one agonist or modulator of a sigma-1 receptor is conditioned so as to provide the dose corresponding to one intake without requiring manipulation such as volume measurement, weighing or division of a tablet, which is particularly advantageous in subjects with cognitive impairments since it avoids any calculation or special manipulation.

[0090] For example, FENM or at least one agonist or positive modulator of a sigma-1 receptor are formulated separately in the form of powder, micro-granules, granules or even separate tablets and then combined in a capsule to facilitate taking.

[0091] Pharmaceutical 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. Typically, in compositions according to the invention, FENM and / or said at least one agonist or positive modulator of a sigma-1 receptor is mixed with a pharmaceutically acceptable excipient.

[0092] In one embodiment, said composition is in the form of a tablet. Said tablet may be scored into 1, 2, 3, or even 4 pieces so as to provide the subject with the dose required for administration using 1, 2, 3, or even 4 pieces of said tablet. This is particularly useful, for example, when treatment requires a dose escalation period to reach the target daily dose, as the pieces can correspond to the incremental doses, and the entire tablet to the target dose of the treatment.

[0093] In one embodiment, in said composition, FENM and at least one agonist or positive modulator of a sigma-1 receptor are mixed within the same tablet or tablet with the same excipient(s). In a particular embodiment, FENM and at least one agonist or positive modulator of a sigma-1 receptor are present in different compartments of said tablet or tablet with excipients specific to them, and which are determined by their physicochemical or pharmacokinetic properties.

[0094] In another embodiment, particularly advantageous for molecules with different PK / PD profiles, FENM and at least one agonist or positive modulator of a sigma-1 receptor are present separately within this tablet. Thus, in a particular embodiment, FENM and at least one agonist or positive modulator of a sigma-1 receptor are present in different compartments of said tablet, for example, one compound being located outside and the other compound inside said tablet, which allows for separate and time-staggered administration of these compounds.

[0095] In one embodiment of the composition according to the invention, FENM or at least one agonist or positive modulator of a sigma-1 receptor may be formulated to be released substantially immediately upon administration, at any time, or at a predetermined time period after administration; that is, formulated to be released in a controlled manner in the body. Controlled-release formulations include (i) formulations that create a concentration (ii) formulations that, after a predetermined latency period, create a substantially constant concentration of the compound or its active derivative in the body over a prolonged period; (iii) formulations that maintain the action of the compound or its active derivative for a predetermined period by maintaining a relatively constant and effective level of said compound or its active derivative in the body, further enabling a concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of said compound or its active derivative; (iv) formulations that localize the action of the compound or its active derivative, for example, near or within the diseased tissue or organ, or in a specific body compartment;and (v) formulations that target the action of said compound or its active derivative by using chemical carriers or derivatives to deliver the drug to a particular target cell type.

[0096] In other words, depending on their PK / PD characteristics, the active ingredients of the composition according to the invention can be administered in different dosage forms, which allow an accelerated, slowed, or prolonged release of each of the active ingredients relative to each other so as to achieve the relevant maximum concentrations and / or molar ratios in the target compartment at the same time.

[0097] The 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 harmful effects, side effects, or toxic reactions, and the plasma concentration leading to a therapeutic effect is small; generally, the therapeutic index, TI, is defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED50)); (ii) a narrow absorption window 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. Various strategies can be pursued to achieve a release rate of the compound or its active derivative that is appropriate for the metabolism of the drug in question.Controlled release can be achieved by an 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. Thus, the compound is formulated with suitable excipients into a pharmaceutical composition which, upon administration, releases said compound in a controlled manner (unit compositions or . multiple tablets or capsules, oily solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes).

[0098] In a further particular embodiment, specific technical means such as reservoirs, pumps or transdermal patches (in other words, a self-adhesive patch that dispenses a substance percutaneously) can contribute to the controlled release of at least FENM and / or at least one agonist or positive modulator of a sigma-1 receptor.

[0099] In another embodiment, said composition 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 adequate dose.

[0100] Therapeutic uses of the synergistic combination or composition according to the invention,

[0101] The novel synergistic effect discovered by the inventors for the combination of FENM with at least one agonist or positive modulator of a sigma-1 receptor identified by the inventors constitutes a new therapeutic solution.

[0102] Thus, according to another aspect, the invention relates particularly to the synergistic composition or combination as described above in all their embodiments, for use as a medicinal product. The invention relates to a synergistic combination of FENM and at least one agonist or positive modulator of a sigma-1 receptor for use as a medicinal product. Those skilled in the art can readily determine the agonist or positive modulator activity of a compound on the sigma-1 receptor by detecting, for example, the dissociation of the BiP / sigma-1 receptor complex in a cell line (Hayashi & Su, Cell, 2007) in response to cell exposure to that compound.In one particular embodiment, the invention relates to a synergistic combination of FENM and igmesin, FENM and PRE-084, or FENM and cutamesin, or a composition comprising it, as described above in all their embodiments, for use as a medicinal product.

[0103] According to a further aspect, the invention relates particularly to the synergistic composition or combination, as described above, for use in the treatment of a selected pathology from among tauopathies, synucleinopathies, amyloidopathies, neurogenetic diseases of metabolic origin (for example, GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy), Alzheimer's disease, Parkinson's disease, and multiple system atrophy. Huntington's disease, posterior cortical atrophy, Pick's disease, epilepsy, vascular dementia, frontotemporal dementia, Lewy body dementia, amyotrophic lateral sclerosis. In a particular embodiment, said treatment relates to the treatment of Alzheimer's disease in its early, moderate, or advanced stages, preferably Alzheimer's disease in its early stages. In a particular embodiment, 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, Lewy body dementia, amyotrophic lateral sclerosis.

[0104] A particular embodiment relates to the composition or synergistic combination as described above for their use in the treatment, prevention, reduction or slowing of the progression of cognitive impairments in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative disease.

[0105] A particular embodiment relates to the synergistic composition or combination as described above for use in the treatment of cognitive disorders associated with the early, moderate, or advanced stages of Alzheimer's disease, preferably in the early stages. Indeed, 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 in the early stages of the disease.

[0106] Another particular embodiment relates to the synergistic composition or combination as described above for their use in the treatment of alterations: - of short-term memory, - of medium-term memory, - of spatial memory, or - of recognition and / or learning abilities,

[0107] 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, Lewy body dementia, amyotrophic lateral sclerosis. In a particular manner, said alterations of short-term memory, medium-term memory, spatial memory, or of recognition and / or learning abilities Learning difficulties are associated with the early, moderate, or advanced stage of Alzheimer's disease, preferably in the early stage.

[0108] According to another aspect, the invention relates to a method for treating a pathology selected from among tauopathies, synucleinopathies, amyloidopathies, neurogenetic diseases of metabolic origin (for example, GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy), 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 including administration to a subject in need,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.

[0109] In said method, said synergistic combination is as described above, in all its embodiments. In one embodiment, said method may comprise the administration of a composition according to the invention as described above.

[0110] In one particular embodiment, said method comprises the separate, concomitant, or sequential administration of FENM and at least one agonist or positive modulator of a sigma-1 receptor. In this embodiment, FENM and at least one agonist or positive modulator of a sigma-1 receptor may be administered separately to the subject by the same routes, such as, for example, orally, parenterally, or transdermally. In an alternative embodiment, FENM and at least one agonist or positive modulator of a sigma-1 receptor may be administered to the subject by different routes. For example, one orally and the other transdermally or parenterally. [Examples] [YES] Abbreviations

[0112] A[325-35 fragment del 1 amino acid sequence Nt-GSNKGAIIGLM-Ct (SEQ ID NO 1) of the APP peptide.

[0113] FENM: 3(2-Fluoroethyl)tricyclo[3.3.1.13,7]decan-l-amine hydrobromide (also fluoroethylnormemantine hydrobromide).

[0114] ICV: intracerebroventricular.

[0115] IP: intraperitoneal

[0116] IC: combination index.

[0117] iChE: acetylcholinesterase inhibitor

[0118] PP: percentage of protection.

[0119] CNS: Central Nervous System.

[0120] MA: Alzheimer's Disease 1. Materials and methods

[0121] Animal experiments are conducted in accordance with the provisions of European Union Directive No. 2010 / 63 and have been duly authorized by the French National Consultative Ethics Committee (CCNE) and the ARRIVE guidelines (Kilkenny et al., 2010). 1.1. Animals

[0122] The in vivo experiments were carried out on 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 ad libitum access to food and drink, in a controlled environment (12 h day / night cycle, the light being turned on at 7:00 a.m. and the behavioural experiments taking place between 9:00 a.m. and 5:00 p.m.), under controlled atmosphere and sound environment. 1.2. Test compounds and peptides

[0123] Stock solutions of sigma-1 agonists and FENM

[0124] PRE-084 hydrochloride and cutamesin were obtained from Sigma-Aldrich (Saint-Quentin-Fallavier, France). Igmesin hydrochloride was obtained from Pfizer (France). FENM was supplied by M2i Life Sciences (Saint-Cloud, France). Stock solutions of the compounds were prepared by solubilization in 0.9% NaCl buffer (vehicle) to a concentration of 1 mg / mL, corresponding to a dose of 5 mg / kg. These stock solutions are stored at 4°C for a maximum of 2 weeks. The solutions are administered by intraperitoneal (IP) injection at a volume of 100 µL per 20 g of body weight.

[0125] Amyloid peptide stock solution [25-35]; formation of oligomers

[0126] Amyloid peptide [25-35], noted A[>2335 (Genepep, Saint-jean-de-Vedas, FRANCE), was solubilized in sterile distilled water at a concentration of 3 mg / mL, the stock solution thus formed was aliquoted and stored at -20°C until use.

[0127] The A[325 35] oligomers are formed as described by Maurice et al. (1996), during incubation at 37°C for 4 days prior to injection into the animals. The vehicle solution or the control peptide undergoes the same treatment prior to administration. It has already been demonstrated that injection of the vehicle solution (distilled water) produces the same lack of effect as injection of the control peptide Sc A[3] (control peptide). which includes the same amino acids as A[325 35 in a random order and which does not oligomerize. Animal Administration

[0128] The compounds are administered intraperitoneally (IP) in a volume of 100 pL per 20 g of body weight. The FENM / sigma-1 receptor agonist combinations are administered in a volume of 100 pL per 20 g of body weight. The compound doses mentioned in the experimental section correspond to the doses of the salts of the compounds used and not to the mass equivalent of the compound itself. The administered doses, expressed in moles, are given in Table 4. For each compound, the administered doses are 0.03, 0.1, and 0.3 mg / kg.

[0129] The corresponding doses expressed in mMol / Kg are reported in Table 4 below.

[0130] [Tables4] Active ingredient Dose in mg / kg in 1st experiment Dose in mMol / kg fluoroethylnormemantine 0.01 0.04 0.03 0.11 0.1 0.36 PRE-084 0.03 0.09 0.1 0.28 0.3 0.85 igmesin 0.03 0.08 0.1 0.28 0.3 0.84 cutamesin 0.03 0.07 0.1 0.25 0.3 0.74

[0131] The AP25-35 oligomer solution, the vehicle (sterile distilled water) are administered to mice by ICV injection, as described in Maurice et al. (1996). 1.3. Cognitive / Behavioral Tests

[0132] The ICV injection model of A[325_35] oligomers is a well-known model in the state of the art (Maurice et al., 1996). This model is considered a relevant screening model for the neuroprotective activity of compounds, and more specifically a relevant first-line model of the disease of Alzheimer's. A[325 35] oligomers are known to be cytotoxic to neuronal cells in mice and to induce memory impairment. This deficiency 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.

[0133] The ability of the compounds and their combination to reduce the cognitive symptoms of neurodegeneration induced by A[325 35 oligomers is tested. For this purpose, the test compounds are administered on the same day as the injection of the A[325 35 oligomers and continue on a daily basis until day 7 after the injection of the A[325 35 oligomers; the mice are then subjected to tests of spontaneous switching, or passive avoidance on day 8 after the injection of the A[325 35 oligomers. Passive avoidance test

[0134] This test measures long-term non-spatial (contextual) memory. The apparatus used for this test is a two-compartment box (15 x 20 x 15 cm high), one compartment illuminated with white PVC walls and the other in darkness with black PVC walls and a wire mesh floor. 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 wire mesh floor via a generator (Lafayette Instruments, Lafayette, USA). The test comprises a training 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 opens. When the mouse enters the dark compartment so that its four paws are in contact with the wire mesh, the door closes and electric shocks are applied for 3 seconds.The time taken by the mouse to enter the dark compartment (transition latency) and the level of shock sensitivity (0 = no reaction; 1 = startles; startle and vocalizations) are recorded. The recall session is performed 24 hours after the learning session. Each mouse is placed back in the illuminated white compartment. After 5 seconds, the door opens, and the transition latency, i.e., the time it takes the mouse to reach the dark compartment, is measured. The maximum duration is 300 seconds. Mice with learning and recall latencies < 10 s and a low level of shock sensitivity are excluded from the test. The attrition rate is usually 5%. A mouse with impaired memory will have a recall latency significantly lower than that of a mouse with normal memory. The results are presented as median values ​​with interquartile ranges (25%-75%).

[0135] Spontaneous alternation test in the Y maze

[0136] The spontaneous alternation test is used to study spatial working memory (very short-term) in rodents. The maze is made of opaque gray polyvinyl chloride (PVC). Each arm is 40 cm long, 13 cm high, and 3 cm wide at its base and 10 cm wide at its apex. The arms converge at equal angles. Each mouse is briefly placed at the end of an arm and allowed to move freely for an 8-minute session. The mouse's entries into each arm, including the arm at the end of which it was placed, are recorded. An alternation is defined as the animal's successive entry into three different arms. The maximum number of alternations is therefore the total number of entries into each arm minus 2, and the percentage of alternation is calculated using the formula:

[0137] [Math.l] %Alt = number of alternations performed / L r • y 100 / vzxii / maximum number of alternations

[0138] Data from animals exhibiting extreme behaviors (alternation percentage < 20% or > 90%) are not included in the calculations. The attrition rate is usually 5%. Under normal conditions, a mouse will spontaneously alternate exploring each arm. A mouse with impaired memory and / or orientation will experience a decrease in its alternation percentage. 1.4. Statistical analyses

[0139] Analyses were performed using Prism v9.0 (GraphPad Software, San Diego, CA, USA). Data were analyzed using one-way analysis of variance (ANOVA, F-value) followed by a Dunnett's test or a non-parametric Kruskal-Wallis ANOVA (H-value) followed by a Dunn's comparison test. The statistical significance levels were p < 0.05, p < 0.01, and p < 0.001. 1.5. Calculation of the combination index (CI)

[0140] The nature of the interaction of two compounds at a given effect level was assessed by isobologram analysis (Martin et al., 2020; Maurice, 2016). The representation of the isobolograms follows the concept of Fraser (1872). The dose-response curves follow a biphasic effect; only the ascending portion of the curve was considered in the calculations. The concentration required to produce a given effect (e.g., where ICx = IC50) is determined for compound A (ICx,A) and compound B (ICx,B) and indicated on the x and y axes of a two-coordinate plot, forming the two points, (ICx,A, 0) and (0, ICx,B). The line connecting these two points is the additivity line. In a mixture of drugs A + B, the concentrations of A and B in the combination that produce the same effect are represented by the coordinates (CA,x, CB,x).

[0141] The combination index (CI) is calculated as follows:

[0142] [Math.2] IC = CA, x / ICx, A+CB, X / ICx, B

[0143] where 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.

[0144] IC is the combined index. ICx,A and ICx,B are the concentrations of compounds A and B required alone to produce x% of the maximum effect. An IC less than / equal to / greater than 1 indicates synergy / additivity / antagonism, respectively. To calculate the IC based on the isobologram representation, the alternation percentages and passive avoidance latencies were expressed as percentage protection (PP) for each treatment group, with PP(V / V) set to 100% and PP(A[325-35 / V]) to 0% (Martin et al., 2020; Maurice, 2016). 2. Results

[0145] 2.1. Synergistic effect of a FENM-PRE-084 combination on the memory of work and long-term memory, in a pharmacological model of AD

[0146] The data confirm the anti-amnesic effects of FENM and PRE-084 on the damage induced by A[325_35 oligomers] on short-term working memory and on long-term memory.

[0147] [Chem.l]

[0148] Chemical formula of PRE-084

[0149] First, sub-effective doses were sought, i.e. doses of compounds at which, when administered alone, an effect on FENM-induced damage at the limit of significance is observed, or doses immediately below the first significantly active dose, then the combination treatment was administered and the presence of synergy of the mnemonic effects of the two molecules.

[0150] In the spontaneous alternation test, an improvement in the performance of mice treated with A[325 35] and administered with FENM alone is observed at doses as low as 0.03 mg / kg ([Fig. 1] A), as their performance is not significantly different from that of untreated mice. Mice treated with 0.3 mg / kg of FENM perform significantly better in this test than mice administered with (A[325 35] + V). Administration of PRE-084 alone also results in an improvement in the animals' memory abilities as measured by this test, which are significantly different. of those in mice administered with 0.1 and 0.3 mg / kg. However, no improvement was observed at 0.03 mg / kg.

[0151] In the passive avoidance test, an improvement in performance was observed in mice intoxicated with A[325 35] and administered FENM alone at 0.3 mg / kg ([Fig. 2] A), as their performance was significantly different from that of the intoxicated mice; however, the observed performance remained significantly different from that of the mice treated with (V+V). Similar results were observed in this test for PRE-084 ([Fig. 2] A).

[0152] The minimum active doses for each of the molecules, 0.01 and 0.03 mg / kg for FENM and 0.03 and 0.1 mg / kg for PRE-084, were tested in combination for each of the behavioral tests. The percentage of protection was calculated from the experimental data ([Fig. 1] B, [Fig. 2] B) and the IC50 was determined from linear regressions and isobologram analysis for each combination (Table 5). IC50s of less than 1 were observed for all combinations tested for the two types of memory assessed ([Fig. 1] and [Fig. 2] B). A synergistic action with a CI particularly less than 1 is identified for the FENM / PRE-084 combination at doses of 0.01 and 0.03 for FENM and 0.03 for PRE-084 (Table 5 and [Fig.1] B, [Fig.2] B) and whether for short- or long-term memory restoration.

[0153] The data relating to the combination index for these experiments are reported in Table 5 below.

[0154] [Tableaux5] Treatment (mg / kg IP) PP (%) Cl Spontaneous Alternation FENM (0) 0.0 ± 16.3 FENM (0.01) 20.3 ± 40.6 FENM (0.03) 58.0 ± 27.5 FENM (0.1) 75 0 x 44.3 FENM (0 3) 103.6 ± 23.7 5 PRE-084 (0) 0.0 ± 16.3 PRE-084 (0.03) -8.9 ± 24 2 PRE-084 (0.1) 67.8 ± 28.5 PRE-084 (03) 75.99 ± 26.26 2 FENM (0.01 ) +PRE-084 (0.03) 20 7 ± 29.0 0.024 ± 0.001 0.071 ± 0.002 0.84 + 0 25 FENM (0.01) +PRE-084 (0.1) 49.5 ± 30.8 0.058 + 0.002 0.170 ±0.004 0.76+0.23 FENM (0.03) + PRE-084 (0.03) 63.1 ± 29.8 0.073 ± 0.002 0.217 + 0.005 0.55 + 0.16 Passive avoidance FENM (0) 0.0 + 8.0 FENM (0.01) 19.3 + 19.1 FENM (0.03) 20 8 ±20 9 FENM H FENM (0.01) + PRE-084 (0.03) 68.9 ± 27.4 0.363 ± 0.086 0.693 + 0.133 0.07 + 0.01 FENM (0.01) +PRE-084 (0.1) 14.7 ± 19.1 0.078 ± 0.018 0.148 ±0.028 0.80+0.13 FENM (0.03) + PRE-084 (0.03) 72.2 ± 24.8 0.380 ± 0.090 0.726 ±0.139 0.12 + 0.02

[0155] The observed IC50s indicate a strong synergistic interaction between FENM and PRE-084, as illustrated by the percentage protection scale ([Fig. 1] B, [Fig. 2] B). This strong synergistic interaction results in improved memory performance in animals treated with AfLv^ct with the FENM + PRE-084 combination, illustrated by the percentage protection not being achieved in mice when administered with the molecules alone, regardless of the dose.

[0156] 2.2. Synergistic effect of a FENM-igmesin combination on memory short- and long-term work, in an Ap 25-35 model

[0157] The experiments and data analyses are carried out in the same way as before.

[0158] [Chem.2]

[0159] Chemical formula of igmesin

[0160] At the tested doses, igmesine was found to be effective in protecting short-term memory ([Fig. 3] A) and less effective in protecting long-term working memory ([Fig. 4] A). In these experiments, FENM produced significant protective effects on short-term memory at doses of 0.03 and 0.1 mg / kg, but little improvement in long-term working memory, as previously observed.

[0161] The percentage of protection was calculated from experimental data ([Fig.3] B, [Fig.4] B) and the IC50 was determined from linear regressions and isobologram analysis for each combination (Table 6). A synergistic effect was identified for the FENM+igmesine combination at the low doses tested (Table 6 and ([Fig.3] B, [Fig.4] B)) for both short- and long-term memory restoration.

[0162] [Tableauxô] Treatment (mgfcg jp oesc) PP CjfFEW Ci Spontaneous Alternation FENM (0) 0.0 ± 13.1 FENM (0.01) 21.9 ± 20.2 FENM (0.03) 68.5 ± 18.4 FENM (0.1) 95.5 ± 26.4 Igmesin (0) 0.0 ± 13.1 Igmesin (0.03) 54.1 ± 25.1 Igmesin (0.1) 72.1 + 16.9 Igmesin (0.3) 6.1 ± 19.3 FENM (0.01) + Igmesin (0.03) 62.7 ± 19.7 0.058 ± 0.001 0.077 + 0.002 0.56 + 0.11 FENM (0.01) + Igmesin (0.1) 60.S ± 23.7 0.057 ± 0.001 0.075 + 0.002 1.51 ± 0.30 FENM (0.03) + Igmesin (0.03) 49.0 ± 23.7 0.046 ± 0.001 0.061 ± 0.003 1.15 ± 0.23 Passive avoidance FENM (0) 0.0 ± 9.9 FENM (0.01) 13.2 ± 13.3 FENM (0.03) 16 7 + 14.0 FENM (0.1) 24.4 ± 19 3 3 Igmesin (0) 0.0 ± 90 Igmesin (0.03) 9.6 ± 180 Igmesin (0.1) 14.1 ± 23.1 Igmesin (0.3) 42.3 ± 21.94 FENM (0.01) + igmesin (0.03) 20.8 ± 18.6 0.033 ± 0.008 0146 ± 0.045 0.51 + 0.09 FENM (0.01) + Igmesin (0.1) 17.2 ± 18.9 0.027 + 0.006 0.121 + 0.037 1.20 ± 0.20 FENM (0.03) + Igmesin (0.03) 15.8 ± 16.8 0.025 ± 0.006 0.111 + 0.034 1.48 + 0.25

[0163] A synergistic action is identified for the FENM+igmesine combination (Table 6 and ([Fig.3] B, [Fig.4] B) whether for the restoration of short- and long-term memory.

[0164] 2.3. Synergistic effect of a FENM-cutamesin combination on memory of short- and long-term work, in an Ap 25-35 model •

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] The experiments and data analyses are carried out in the same way as in 2.1. [Chem. 3] Cutamesin formula Cutamesin was found to be active at the tested doses in protecting both types of memory against memory impairment induced by the administration of A[325_35] ([Fig.5] A and [Fig.6] A). The results observed for FENM are similar to those observed in 2.2 on working memory. The percentage of protection was calculated from experimental data ([Fig. 5] B, [Fig. 6] B) and the IC50 was determined from linear regressions and isobologram analysis for each combination (Table 7). A synergistic effect was identified for the FENM+cutamesin combination at all tested doses (Table 7 and [Fig. 5] B) for short-term memory restoration. [Tables 7] Treafment (mg / kgip orsc) PP (%) Cx, . Cl Spontaneous Alternation FENM(0) 0.0 ±16.6 FENM (0.01) 33.3 ±29.8 FENM (0.03) 86.1 ± 20.6 FENM (0.1) 102.3 ± 31.4' Cutamesin (0) 0.0 ± 16.6 Cutamesin (0.03) 26.2 ± 25.1 Cutamesin (01) 47.2 ±28.9 Cutamesin (0.3) 119.3 ± 29.52 FENM (0.01) + Cutamesin (0.03) 109.7 ± 26.8 0.092 ± 0.002 0.266 ± 0.007 0.22 + 0.0" FENM (0.01) + Cutamesin (0.1) 106.7 ± 21.5 0.089 ± 0.002 0.260 ± 0.007 0.50 + 0.13 FENM (0.03) + Cutamesin (0.03) 91.9 ± 24.2 0.077 ± 0.002 0.224 ± 0.005 0.52 ±0.14 Passive avoidance FENM (0) 0.0 ± 9.0 FENM (0.01; 13.1 ± 13.9 FENM (0.03) 17.1 ± 14.4 FENM (CI? 22.9 ± 19.03 Cutamesin (0) 0.0 ± 9.0 Cutamesin (0.03) 39.1 ± 14.1 Cutamesin (0.1) 49.9 ± 14.7 Cutamesin (0.3) 53.2 + 15.2 4 FENM (0.01) + Cutamesin (0.03)23.5 ± 15.4 0.037 ± 0.009 0.041 ± 0.011 1.00 + 0.14 FENM (0.01) + Cutamesin (0.1) 45.1 ± 18.7 0.070 ± 0.017 0.080 ± 0.021 1.40 ±0.20 FENM (0.03) + Cutamesin (0.03) 17.5 ± 15.1 0.027 ± 0.007 0.031 ±0.008 2.07 ±0.30 3. Conclusions

[0171] These data show a synergy of the protective effects of FENM combined with those of agonists of the sigma-1 receptor, of very different chemical structures, for both short-term and long-term working memory.

[0172] These results suggest the possibility of using FENM combinations with at least one agonist or positive modulator of a sigma-1 receptor in patients currently without an approved therapeutic solution for the treatment of memory symptoms in Alzheimer's disease or related conditions. Also noteworthy is the observed synergy, which allows for a therapeutic effect at particularly low doses of the compounds, with few or no adverse effects expected. REFERENCES

[0173] Fraser TR. Lecture on the antagonism between the actions of active substances. Br Med J. 1872;2:485-7.

[0174] Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell. 2007 Nov 2;131(3):596-610.

[0175] Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG; NC3Rs Reporting Guidelines Working Group. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160:1577-9.

[0176] Martin P, de Witte PAM, Maurice T, Gammaitoni A, Farfel G, Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors. Epilepsy Behav. 2020; 105:106989.

[0177] Maurice T, Lockhart BP, Privât A (1996) Amnesia induced in mice by centrally administered [3-amyloid peptides involves cholinergic dysfunction. Brain Res. 706:181-93.

[0178] Maurice T. Protection by sigma-1 receptor agonists is synergie with donepezil, but not with memantine, in a mouse model of amyloid-induced memory impairments. Behav Brain Res. 2016;296:270-278.

[0179] Maurice T, Voile JN, Strehaiano M, Crouzier L, Pereira C, Kaloyanov N, Virieux D, Pirat JL. Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer's disease by positive modulation of ol receptors. Pharmacol Res. 2019 Jun;144:315-330.

[0180] Remington: The Science and Practice of Pharmacy (23rd ed.), Ed. A Adeboye Adejare, 2020.

[0181] Rossetti HC, Munro Cullum C, Hynan LS, Lacritz LH. The CERAD Neuropsychologic Battery Total Score and the progression of Alzheimer disease. Alzheimer Dis Assoc Disord. 2010;24(2): 138-142.

[0182] Stahl PH, Wermuth CG. Pharmaceutical Salts: Properties, Sélection, and Use. Wiley, 2011. 388 pages.

[0183] Zhang, N., Zheng, X., Lin, H. et al. Testing whether the progression of Alzheimer’s disease changes with the year of publication, additional design, and geographical area: a modeling analysis of literature aggregate data. Alz Res Therapy 12, 64 (2020).

Claims

Demands

1. Synergistic combination of 3-(2-fluoroethyl)adamantan-l-amine (FENM) or any of its pharmaceutically acceptable salts and at least one agonist or positive modulator of a sigma-1 receptor or any of its pharmaceutically acceptable salts exhibiting selective activity on said receptor, wherein the molar ratio agonist or positive modulator of a sigma-1 receptor / FENM is less than or equal to 7, said molar ratio being greater than or equal to 0.

5.

2. The synergistic combination according to claim 1 wherein said at least one agonist or positive modulator of a sigma-1 receptor is selected from 2-(2-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3,5-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(2,3-Dichlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4-Fluorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(3-Nitrophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(4 benzyloxycarbamoylphenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane; 2-(Pyridin-2-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane; 2-(Pyridin-3-yl)-2-oxo-3,3,5,5-tetrameth yl [1,4,2]-oxazaphosphinane; 2-(Pyridin-4-yl)-2-oxo-3,3,5,5-tetramethyl[1,4,2]-oxazaphosphinane;2-(Pyrimidin-2-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(Pyrimidin-5-yl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(4-aminophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-N-methyl-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-chlorophenyl)-2-thiono-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane; 2-(3-Chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[l,4,2]-oxazaphosphinane, PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-l-carboxylate), (+)-pentazocine, (+)-SKF10,047, cutamesin, fluvoxamine, igmesin, OPC-14523, BD737, BHDP, pridopidine, ANAVEXl-41, ANAVEX2-73, FANAVEX3-71, SDHEA, the; selegiline, fluoxetine, citalopram, amitriptyline, L-687384, dipentylamine, dextromethorphan, dimethyltryptamine, opipramol or one of its pharmaceutically acceptable salts.

3. The synergistic combination according to any one of claims 1 to 2, wherein said at least one agonist of a sigma-1 receptor is selected from PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-l-carboxylate), lacutamesine (1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine) and igmesine ((5E)-N-(cyclopropyhnethyl)-N-methyl-3,6-diphenyl-5-hexen-3-amine).

4. The synergistic combination according to any one of claims 1 to 3, wherein said at least one positive modulator of a sigma-1 receptor is 2-(3-chlorophenyl)-2-oxo-3,3,5,5-tetramethyl-[1,4,2]-oxazaphosphinane or one of its pharmaceutically acceptable salts.

5. The synergistic combination according to any one of claims 1 to 4 for its use as a medicinal product.

6. The synergistic combination according to any one of claims 1 to 5 for its use in the treatment of a pathology selected from among neurogenetic diseases of metabolic origin, 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, GM2 ganliosidosis, Krabbe disease, Fabry disease, sialidosis type I, Gaucher disease, Niemann-Pick disease type C, Refsum disease, cerebrotendinous xanthomatosis, adrenoleukodystrophy.

7. The synergistic combination according to any one of claims 1 to 6 for its use in the treatment, prevention, reduction or slowing of the progression of cognitive impairments in a subject suffering, suspected of suffering or considered at risk of suffering from a neurodegenerative disease.

8. A pharmaceutical composition comprising the synergistic combination according to any one of claims 1 to 7.

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