COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE.

Abstract

The invention relates to certain chromanol, quinone, or hydroquinone compounds and derivatives thereof for the treatment of Alzheimer's disease and / or for improving memory function and / or reducing plaque burden. Specifically, the present invention relates to chromanol compounds selected from (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1,5-yl)methanone, ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride, and S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone, and pharmaceutically acceptable salts thereof.

Description

COMPOUNDS FOR THE TREATMENT OF ALZHEIMER'S DISEASE I. FIELD OF THE INVENTION The invention relates to compounds for the treatment of Alzheimer's disease. The invention also relates to chromanol compounds and derivatives thereof for improving memory function. II. DESCRIPTION OF THE BACKGROUND OF THE TECHNIQUE Alzheimer's disease is a progressive neurodegenerative disorder and the leading cause of dementia in the elderly. EP 2994160 B1 describes a method for treating Alzheimer's disease in patients who have moderate Alzheimer's disease and / or who carry an ApoE4 allele by administering pooled immunoglobulin G. EP 2892563 B1 describes methods for treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of N-(2-(6-fluoro-1 H-indol-3-yl)ethyl)-3-(2,2, 3,3-tetrafluopropropoxy)benzylamine or a pharmaceutically acceptable salt to a patient requiring such treatment, wherein the effective daily dose administered to the patient is between approximately 30 and approximately 60 mg. EP 2937085 B1 describes that a combination of 6-[4-(1-cyclohexyl-1H-tetrazol-5,5yl)butoxy]-3,4-dihydrocarbostyryl (cilostazol) or a salt thereof and donepezil or a salt thereof exhibits a synergistic action for treating Alzheimer's disease. Document WO2002 / 043666 prophetically suggests that the use of antioxidants can prevent or reduce mental decline. While antioxidants can indeed reduce the oxidative load in mitochondria, no clear effect has been found in the treatment of Alzheimer's disease. Cay et al. in ACS Chemical Neuroscience (2017) 8:2496-2511 describe drugs based on donepezil substituted with a Trolox moiety, suggested for use in the treatment of Alzheimer's disease. Numerous in vitro tests suggest some activity for certain Alzheimer's biomarkers. Beta amyloid (Aβ or Abeta) denotes peptides of 36 to 43 amino acids that are the main component of amyloid plaques found in the brains of people with Alzheimer's disease. Peptides are derived from amyloid precursor protein (APP), which is cleaved by beta-secretase and gamma-secretase to produce Aβ. Aβ molecules can aggregate to form flexible, soluble oligomers that can exist in numerous forms. It is now believed that certain misfolded oligomers (known as seeds) can induce other Aβ molecules to also adopt the misfolded oligomeric form, leading to a chain reaction that results in plaque formation. Soluble oligomers are toxic to nerve cells, and plaques form from these soluble oligomers. ML / a / zuzz / uu / zz / There remains a need for new compounds for the treatment of Alzheimer's disease and similar diseases related to impaired mitochondrial function and health, particularly those with fewer side effects, or preferably no side effects at all within the dosage range of such compounds. It is an object of the present invention to provide compounds for the treatment of Alzheimer's disease. A further object of the present invention is to provide compounds to improve memory function. It is a further object of the present invention to provide compounds to reduce the development of beta plaque burden in a patient experiencing Alzheimer's disease. III. BRIEF DESCRIPTION OF THE INVENTION One or more of the above objectives are met by providing certain chromanol, quinone, or hydroquinone compounds for one or more of these treatments. The foregoing objectives are achieved by the present invention by providing compounds according to formula (I), (II), the hydroquinone analogue of formula (II) or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease or to improve memory function and / or to reduce plaque burden in a patient with Alzheimer's disease; MA / a / ZUZZ / UU / zz / wherein R1 represents a hydrogen or a prodrug portion that can be eliminated in living tissue and wherein either R2 and R3 together with the N atom to which they are attached form a 5-8 membered, saturated or unsaturated, non-aromatic, optionally substituted ring having one to four N atoms, wherein R2 and R3 together contain 3-12 carbon atoms; oo R2 is a hydrogen atom, or an alkyl group with 1-6 carbon atoms, and R3 is an alkyl group, optionally substituted with nitrogen or oxygen, wherein the alkyl group comprises 3-12 carbon atoms, the alkyl group in R3 comprises one or more non-aromatic cyclic structures and may contain linear and / or branched groups and one or more ethylenic unsaturations. For the present invention, the compound according to formula (II) includes the hydrogenated quinone analogue (i.e., hydroquinone), although the quinone derivative is preferred in view of stability. In a preferred embodiment, the nitrogen can be an amine, quaternary amine, guanidine, or amine, and the oxygen is a hydroxyl, carbonyl, or carboxylic acid; and / or oxygen and nitrogen together can form amide, urea, or carbamate groups. In a preferred embodiment, R1 in formula (I) is hydrogen or forms together with oxygen-6 an ester group with 2-6 carbon atoms. In a preferred embodiment of the compounds according to formula (I) or according to formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring incorporating an additional N atom, the ring of which is unsubstituted or substituted with an alcohol or alkanol group having 1-4 carbon atoms, such as ethylol. In another preferred embodiment, R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4-7 carbon atoms and having a nitrogen atom, the ring of which is unsubstituted or substituted with an alcohol or alkanol group having 1-4 carbon atoms, such as ethylol. According to another preferred embodiment, the compound is (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(piperazin-1-yl)methanone (SUL-121), ((S)-6-hydroxy-2,5,7,8-tetramethyl-N-((R)-piperidin-3-yl)chroman-2-carboxamide hydrochloride (SUL-13) or (6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazin-1-yl)methanone (SUL-109). In a modality with maximum preference, the compound is the S enantiomer of SUL-109, particularly, S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperazine-1-yl)methanone (SUL138). In a preferred embodiment according to the invention, the compound according to formula (I) or according to formula (II) has a molecular weight of less than 500 Da. As such, Trolox derivatives are described, for example in documents WO2014 / 098586, WO2014 / 011047 and WO2017 / 060432. However, memory function or plaque formation, or any other type of in vivo or in vitro test directly relevant to the treatment of Alzheimer's disease, are not investigated. Document WO2019 / 101826 suggests that some compounds comprising a Trolox moiety may act as MPGES inhibitors, which is suggested to be advantageous in the treatment of inflammatory diseases. Document WO2019 / 101826 suggests that Alzheimer's disease may act through MPGES; however, our research has found no difference in expression in wild-type mice versus APP / PS1 mice, indicating that MPGES is not relevant to Alzheimer's disease. Memory function and plaque formation caused by amyloid-P polymerization are considered the main problems in Alzheimer's disease. Although some antioxidants may reduce the underlying oxidation mechanisms, no evidence has been provided that they can actually improve memory function. The present findings show that specific Trolox derivatives may be a valuable new treatment option for Alzheimer's disease. IV. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows how chronic treatment with SLJL-138 increases memory (% immobility) in WT and APP mice Figure 2 shows how SUL-138 increases LTP maintenance in WT and APP mice. Figure 3 shows that treatment with SUL-138 reduces the number and size of plaques in APP / PS1 mice. V. DETAILED DESCRIPTION OF THE INVENTION The present invention fulfills one or more of the foregoing objects by providing compounds according to formula (I) or (II), as shown above, or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer's disease or for improving memory function and / or reducing plaque burden in a patient experiencing Alzheimer's disease. Preferably, memory function is improved, while also reducing plaque formation, thus enabling even better treatment of Alzheimer's disease. Insofar as memory enhancement is not considered a medical treatment, the present invention further provides for the use of the defined compounds for memory enhancement in a mammal. The mammal is preferably a human being. R1 can be a substituent that is readily eliminated from the human body, making the compound a prodrug. R1 can be, for example, an amino acid derivative or an ester derivative and generally has a molecular weight of less than 100 Daltons. In a preferred embodiment, R1 in formula (I) is hydrogen or forms, together with oxygen-6, an ester group with 2-6 carbon atoms. The ester may comprise one or more ether or alcohol groups. Suitable esters are acetate, butyrate, 3-hydroxybutyrate, and the like. In a preferred embodiment of the compounds according to formula (I) or according to formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring having 3-6 carbon atoms and incorporating an additional N atom, which may be substituted with 1-4 carbon atoms that may comprise an oxygen, carboxylic acid group or amine. ινΐΛ / a / zuzz / uu i ¿¿i Most preferably, R2 and R3 together with the N atom to which they are attached form a 5-7 membered ring comprising an additional amine group, the ring of which is optionally substituted with methyl, ethyl or alcohol-substituted methyl or ethyl. In another preferred embodiment, R2 is a hydrogen atom and R3 comprises a cyclic structure having 3-6 carbon atoms and one nitrogen atom. Most preferably, R2 is a hydrogen atom, and R3 comprises a 5-7 membered ring comprising an additional amine group, the ring being attached to the amide nitrogen, and the ring being optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl. In any case, the ring (the cyclic structure formed by R2 and R3, or of R3 alone) may be unsubstituted or substituted with an alkyl group having 1-4 carbon atoms, an alcohol, or an alkanol group having 1-4 carbon atoms, such as ethylol. In a preferred embodiment according to the invention, the compound according to formula (I) or according to formula (II) has a molecular weight of less than 500 Da. Certain chromanol compounds have been described in WO2014 / 098586. The compounds described in detail are abbreviated as SUL-XXX (where XXX is a 2- or 3-digit number). Many of these compounds are racemic mixtures, although some enantiomers have also been evaluated. Suitable methods for preparing chromanol compounds according to the present invention are described in WO2014 / 098586 or WO2014 / 011047. WO 2017060432 A1 describes amide derivatives of 2-hydroxy-2-methyl-4(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-butanoic acid and methods for manufacturing such compounds. Hydrogenated quinone derivatives can be easily prepared by hydrogenating the quinone structure. According to another preferred embodiment, the compound is (6-hydroxy-2,5,7,8 tetramethylchroman2¡l)(piperaz¡n-1-¡l)methanone (SUL-121), ((S)-6-hydroxy¡-2,5,7,8 tetramethyl-N-((R)-p¡per¡n-3yl)chroman-2-carboxamide hydrochloride (SUL-13) or (6-hydroxy¡-2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxy¡ethyl)p¡peraz¡n-1 il)methanone (SUL-109). In a highest preference embodiment, the compound is the S enantiomer of SUL-109, particularly, S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-1)(4-(2-hydroxyethyl)piperazine-1-1)methanone (SUL138). The counterion in the pharmaceutically acceptable salt may be a counterion as known in the art. Preferably, the compounds have at least one basic nitrogen, an amine, that can be protonated. The counterion is preferably a halogen such as chloride, sulfate, citrate, formate, or the like, and most preferably chloride. The compounds are effective as a racemic mixture or in a substantially pure enantiomeric form. The compounds have one or more chiral centers, usually one or two. Preferably, the compound is substantially enantiomerically pure. Substantially enantiomerically pure means approximately 95% enantiomeric excess or more, more preferably approximately 98% enantiomeric excess, and most preferably approximately 99% enantiomeric excess or more. Furthermore, if the compound contains more than one chiral center, these amounts apply. The compounds are preferably used in effective quantities to achieve an improvement in memory function and / or to achieve the treatment of Alzheimer's disease. The term treatment encompasses reducing the progression of the disease and / or improving the symptoms of the disease. Effects are generally observed at concentrations of approximately 1 μM in body fluid, but higher concentrations are preferred. Preferred concentrations are approximately 10 μM or higher in vivo or in vitro, with a further preference for approximately 20 pM or higher. Generally, a concentration of approximately 200 pM or less in humans should be sufficient and safe. For human use, this would mean, assuming a distribution volume of 30 L, 100% availability, and a concentration of approximately 1 pM, a dosage of approximately 10 mg or more. Preferred amounts would result in a concentration of approximately 10 pM, for which a dosage of approximately 100 mg or more would be suitable. Therefore, dosage forms of approximately 20 mg or more, preferably 50 mg or more, and preferably 100 mg or more are suitable. Generally, solid oral dosage forms contain at most approximately 500 mg of compound, preferably approximately 450 mg or less, to allow for excipients. Larger amounts may be administered with other liquid forms for intravenous administration. Examples of dosages that may be used are an effective amount of the compounds of the invention of a dosage of 0.2 mg / kg or higher, such as preferably within the range of approximately 1 mg / kg to approximately 100 mg / kg, or within approximately 2 mg / kg to approximately 40 mg / kg of body weight, or within approximately 3 mg / kg to approximately 30 mg / kg of body weight, or within approximately 4 mg / kg to approximately 15 mg / kg of body weight. The compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times a day. The compounds described in this description can be formulated as pharmaceutical compositions by formulation with additives such as pharmaceutically or physiologically acceptable excipients, carriers and vehicles. Suitable pharmaceutically or physiologically acceptable excipients, carriers, and vehicles include processing agents and drug delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, dextrose, hydroxypropyl-p-cyclodextrin, polyvinylpyrrolidone, low-melting-point waxes, and the like, as well as combinations of two or more of these. Other suitable pharmaceutically acceptable excipients are described in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). MA / a / ¿U¿¿ / UU / / A pharmaceutical composition preferably comprises a unit-dose formulation, where the unit dose is a dose sufficient to produce a therapeutic effect. The unit dose may be a dose administered periodically during a course of treatment or suppression of a disorder. In addition, the unit dose can be a dose administered periodically in a course of treatment to improve native cognitive functions related to memory. The compounds of the invention can be administered enterally, orally, parenterally, sublingually, by inhalation (e.g., as mists or aerosols), rectally, or topically in dosage unit formulations containing pharmaceutically or physiologically acceptable, non-toxic carriers, adjuvants, and vehicles, as desired. The term parenteral, as used herein, includes subcutaneous injection, intravenous injection, intramuscular injection, intratarsal injection, or infusion techniques. The compounds are mixed with pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for the desired route of administration. Oral administration is a preferred route of administration, and formulations suitable for oral administration are the preferred formulations. The compounds described for use herein may be administered in solid, liquid, aerosol, or tablet form, pill, powder mixture, capsule, granule, injectable, cream, solution, suppository, enema, colonic irrigation, emulsion, dispersion, food premix, and other suitable forms. The compounds may also be administered in liposomal formulations. Injectable preparations, such as sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation can also be a sterile solution or suspension for injection in a non-toxic diluent or solvent acceptable for parenteral administration, such as a propylene glycol solution. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending agents. Any soft fixed oil, including synthetic monoglycerides or diglycerides, can be used for this purpose. Furthermore, fatty acids such as oleic acid are also used in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets, and MA / a / ZUZZ / UU l ¿¿I pills, the dosage forms may also comprise buffering agents. Tablets and pills may be further prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may further comprise adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweetening, flavoring, and perfuming agents. The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host to whom the active ingredient is administered and the specific route of administration. The chosen unit dosage is generally manufactured and administered to provide a defined final concentration of drug in the blood, tissues, organs, or other specific body region. The effective amount for a given situation can be readily determined through routine experimentation and is within the skill and judgment of the physician or other expert. The present invention will be further illustrated by the examples below. Reference is made to the figures in the examples. VL EXAMPLES Example 1 The efficacy of the compounds according to the invention for the treatment of Alzheimer's disease was evaluated by two independent tests: one reflecting memory and the other showing synaptic connectivity. Experimental Methods and Details The APP / PS1 mouse model is a widely used A-beta pathology model for Alzheimer's disease (AD) (one of the two major neuropathological features of AD). These mice carry human transgenes for APP (Swedish mutation) and PSEN1 (L166P mutation), which will lead to pathological amyloid deposition in the brain and alterations in hippocampal-dependent memory and Long-Term Potentiation (LTP) starting at approximately 3 months of age (3 MOA). The efficacy of SLJL-138 ((6-hydroxy-2,5,7,8-tetramethylchroman-2-1)(4-(2-hydroxyethyl)perazin1-1)methanone) in alleviating / preventing common pathology in the APP / PS1 mouse model was evaluated. The effect on memory was assessed using a hippocampus-dependent context test (fear conditioning (FC)), and synaptic connectivity was assessed by electrophysiological measurements of LTP (long-term potentiation). Both are impaired in this mouse model under basal conditions. Additionally, phenotyping tools (Sylics) were used to rule out the possibility that SLJL-138 induced atypical behavior following chronic oral treatment. Wild-type (WT) and APP / PS1 mice were each divided into two groups, receiving either vehicle or SUL-138 via their food. The group size was 12 animals. Based on a mouse weight of ~30 g, a food intake of ~5 g / day, and a desired oral intake of 30 mg / day / kg, food pellets containing SUL-138 were sprayed into water with 0.0145% ethanol at a rate of 1 g of SUL-138 per 5 kg of food. The vehicle feed was prepared by spraying the same volume of water containing 0.0145% ethanol. Mice were chronically treated between 2.5 moa (pre-pathology / memory deficit) and 6 moa (age at which clear neuropathology and memory deficits occur) prior to testing. FC: Mice were exposed to a context for 2 minutes, after which they received a 0.7 mA shock to their paws. 30 seconds after the shock, the mice were returned to their home cage. 24 h later, the mice were placed in the same context and their immobility levels were measured for 2 min. LTP: Acute coronal hippocampal slices were maintained in artificial CSF and LTP was measured after 3x 100 Hz stimulation. Phenotypers (provided by Sylics, Amsterdam, Netherlands): Mice were housed in the phenotypers for 3 days, during which spontaneous behavior was measured: activity, dark / light response, habituation, kinematics, light-dark phase transition pattern, and refuge. Results General welfare was monitored and showed no differences between animals treated with vehicle and SUL-138, and all groups showed a similar increase in body weight. Memory was assessed at 6 moa by measuring immobility after context acquisition. Figure 1 shows how chronic treatment with SUL-138 increases memory (% immobility) in WT and APP mice. Treatment with SUL-138 increased immobility levels (memory) in WT and APP mice. Student's t-test, *: p<0.05 **: p<0.01. APP / PS1 mice showed decreased immobility compared to WT mice when treated with control food, as expected. After chronic treatment with SUL-138, memory in APP / PS1 mice was restored to WT levels. This demonstrates that SUL-138 is effective in preventing or improving Alzheimer's disease and / or its symptoms. Interestingly, the wild-type mice that received SUL-138 also performed better on the memory task. This indicates that SUL-138 is also effective in improving memory function in a healthy mammal. Figure 2 shows how SUL-138 increases LTP maintenance in WT and APP mice. Between 8 and 14 hippocampal slices per group (2A: WT Ctrl, WT SUL-138; 2B: APP Ctrl, APP SUL-138) received LTP induced by 3 x 100 Hz (tetanus) stimulations of 1 second each, separated by 20 seconds. The slope was measured for 60 min. LTP was expressed as a percentage of baseline. All LTP data analyses were performed blinded. LTP maintenance (min 30–60) was significantly higher (p < 0.05) in SUL-138 animals (both WT and APP); Student's t-test,* p < 0.05; 2C. Chronic treatment with SUL-138 did not induce differences in spontaneous behavior: activity, dark / light, habituation, kinematics, light-dark phase transition pattern, and refuge were measured. ινΐΛ / a / zuzz / uu i ¿¿i Conclusions The examples show that SUL-138 increases memory and LTP in WT and APP / PS1 mice, and that it effectively restores memory and LTP in APP / PS1 mice to control levels. The increase in these two parameters reflects an increase in overall plasticity / LTP facilitative process that is stimulated by the use of SUL-138. This finding implies that SUL-138 can be used to alleviate symptoms in neurological diseases that exhibit reduced synaptic strength or plasticity. The effects of SUL-138 appear to be specific to memory enhancement, as the treatment did not induce atypical behavior in mice after 3 months of chronic treatment. Furthermore, no weight differences were measured during 3 months of chronic oral treatment, which could indicate aversive or addictive behavior toward SUL-138-treated food or changes in major physiological functions. Finally, there were no animal welfare problems or differences between groups throughout the experiment. Example 2 Reduced plate load in APP / PS1 mice after SUL-138 intervention APP / PS1 (n=10) and wild-type (WT, n=10) mice were treated with either vehicle or SUL-138. Mice were treated for 3 months starting at 3 months of age with SUL-138-treated food pellets or vehicle. Mice were sacrificed at 6 months of age, the age at which hippocampal-dependent memory impairment and apparent plaque loading are expected (among other things). Brains perfused with 4% PFA, stored in sucrose, were sliced ​​at 35 pM using a cryostat (−20 °C; Leica). Hippocampal sections (n=2 / animal; 5 animals / group) were washed 3 times for 10 min with 1x PBS and then blocked for 1 h in blocking solution (10 mL 1x PBS + 500 pL of normal goat serum + 0.250 g of bovine serum albumin + 20 pL of Triton-100). The sections were incubated overnight with anti-amyloid beta (6E10) (ITK Diagnostics, 1:400), washed 3 times for 10 min with 1x PBS, and then incubated with goat-generated fluorescent Alexa 488 anti-mouse secondary antibody (Sigma-Aldrich, 1:250) for 2 h. Next, the sections were washed 3x 10 min with 1x PBS and mounted on slides. Images of the sections were taken using a Zeiss Cell Discover 7 high-content microscope with an LSM900 confocal head. Using Fiji, both hippocampi were selected separately for 5 animals per group (yellow line in Figure 3A), and the number and size of plaques were measured (Figure 3B, C). The mean number of plaques and plaque size per animal were used for statistical analysis in GraphPad 8 using a one-tailed Student's t-test. Three months of oral SUL-138 reduced both the number of plaques (Figure 3B; p = 0.0138) and plaque size (Figure 3C; p = 0.0021) in APP / PS1 mice compared to vehicle-treated mice. WT animals treated with SUL-138 and vehicle showed no plaques. These data, together with SUL-138 rescuing memory and increasing synaptic transmission (long-term potentiation) in APP / PS1 mice observed according to Example 1, show that SUL-138 is a potential therapeutic option against Alzheimer's disease. The bioavailability of SUL-138 in the brain appears to be high, thus overcoming the problems of other compounds targeting mitochondria, making it a more suitable treatment option for future clinical applications. Example 3 In vitro tests showing that the compounds according to the present invention are active. Excitotoxicity is the process in which nerve cells are damaged or die when levels of otherwise safe and necessary neurotransmitters become pathologically high, resulting in overstimulation of their receptors. Excitotoxicity may be involved in neurodegenerative diseases of the central nervous system, such as Alzheimer's disease. In vitro assays for investigating excitotoxicity utilize well-characterized inducers of neuronal cell death (e.g., glutamate, dopamine, or NDMA) and quantify the viability of stimulated neuronal-like cells. The human neuroblastoma-derived SH-SY5Y cell line can be differentiated in vitro to resemble mature neurons morphologically and biochemically. Furthermore, differentiated SH-SY5Y neuronal-like cells are sensitive to excitotoxicity induced by, among others, glutamate and dopamine. In this current study, the efficacy of SUL-11, SUL-127, SUL-13, SUL-138 (and its main metabolite SUL-138M2), SUL-150, and SUL-151 in inhibiting glutamate- and dopamine-induced excitotoxicity in human SH-SY5Y neuronal-like cells was investigated. SUL-11 is Trolox, while SUL-127 is the methyl ester of Trolox. These two compounds were used as a reference. The compounds used in this study are shown in Table 1 below: Table 1 Compound Chemical Name Formula Structure MW Reference compounds SUL-11 6-hydroxy¡-2,5,7,8-Ci4HisO4 i 250.3 tetramethylchroman-2carboxylic acid μ s ' Ύ Ό \ SUL-127 6-hydroxy-2,5,7,8-tetramethyl-Ci5H2o04 264.3 3,4-dihydro-2H-1 - HOV ,.Á., O benzopyran-2-carboxylate Ti Ά 1 β methyl A .-V' 'O^ O \ compounds according to the invention ML / a / ZUZZ / UU l ¿¿I SUL-13 (S)-6-hydroxy-2,5,7,8- Ci9H28N2O3 u„, [ 332.4 tetramethyl-N-((R)-piperidine- η V j H 3-yl)croman-2-carboxamide AH SUL-138 (S)-(6-hydroxy-2,5,7,8-H 362.5 tetramethylchroman-2-yl)(4-(2- íj hydroxyet¡l)p¡peraz¡n-1- Js Ax yl)methanone T l ¡ 1 ''θ« SUL- 13 8M2 4-(2,5-dlhydrox¡-3,4,6-C205-H trimeth¡lfen¡l)-2-hydroxy-1-(4- Η°Υτ' / ΧΊ (2-hydroxyethyl)piperazine-1 - J| Ί j / 0H [ I il)-2-methylbutan-1 -ona gA SUL-150 (R)-(6-hydroxy-2,5,8,7,7, 26-N-O tetramethylchroman-2- YY yl)(piperazine-1-¡l)methanone Λ A. jy SUL-151 Ci8H26N2O3 hc i 318.4 (S)-(6-hydroxy-2,5,7,8- / J tetramethylchroman-2- 3⁄4 ( ¡ il)(piperazine-1-¡l)methanone Human SH-SY5Y neuroblastoma cells (ATCC #CRL-2266) were maintained in DMEM medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution (#P4333, Sigma-Aldrich, St. Louis, MO) and were passed when cultures reached 70% confluence. Prior to experiments, SH-SY5Y cells were differentiated by serum reduction (1%) and stimulation with 10 pM retinoic acid (#R7882, Sigma-Aldrich, St. Louis, MO) for 72 hours. Differentiated SH-SY5Y cells were seeded at 0.6–10⁵ cells / cm² for all experiments. Differentiated SH-SY5Y cells were pre-incubated with SUL compounds (dose range 8–10⁴ to 1 × 10⁸ M) under standard culture conditions for 30 min and then stimulated with either 1-glutamate (60 mM; #12843-0, Sigma-Aldrich, St. Louis, MO) or dopamine (100 μM; #H8502, Sigma, St. Louis, MO) for an additional 24 h. Neutral red assay solution (#N2889, Sigma-Aldrich, St. Louis, MO) at a concentration of 10% (v / v) was added to the cultures during the final 4 h of culture. Cells were washed with warm PBS and solubilized with neutral red in acid ethanol (1% acetic acid in 50% EtOH). Absorbances were recorded at 540 nm using a CLARIOStar Plus plate reader (BMG Labtech, Germany). Cell viability was normalized to absorbance measurements of untreated cultures (100% viable) and to absorbance measurements of cell-free samples (0% viable). All experiments were performed in triplicate per condition and averaged. Data from two individual experiments were used for evaluation in GraphPad Prism 8.0 (GraphPad Software Inc., CA). A four-parameter nonlinear regression was used to determine the efficacy and potency of the SUL compounds in reducing 1-glutamate- or dopamine-induced excitotoxicity. The efficacy of the SUL compounds in inhibiting excitotoxicity was calculated as Emax = 100 * V(treated) / (V(vehicle) / (100% - V(vehicle))), where V is the observed viability and Emax is the maximum effect produced by treatment with the SUL compound. No cellular toxicity, such as a decrease in viability, was observed when SUL compounds were used in the molar range shown in the table below. SH-SY5Y neuroblastoma cells were differentiated into neuronal-like cells according to established protocols and stimulated with 60 mM glutamate to induce excitotoxicity. Glutamate decreased SH-SY5Y cell viability from 100 ± 1.63% in vehicle-treated control cells to 55.4 ± 1.7% in SH-SY5Y cells exposed to glutamate for 24 hours (p < 0.0001). Pre-incubation of differentiated SH-SY5Y cells with SEIL compounds (103a 10 ® M) increased the cell viability of glutamate-exposed SH-SY5Y cells in a dose-dependent manner, although to varying degrees. Trolox and Trolox methyl ester were clearly less effective than the other SEL compounds, as shown in Table 2 below. SH-SY5Y neuroblastoma cells were stimulated with 150 pM dopamine to induce excitotoxicity. Dopamine decreased SH-SY5Y cell viability from 100 ± 0.8% in vehicle-treated control cells to 50.5 ± 1.0% in SH-SY5Y cells exposed to dopamine for 24 hours (p < 0.0001). Pre-incubation of SH-SY5Y differentiated cells with SEL compounds (10³ to 10.8M) increased the cell viability of dopamine-exposed SH-SY5Y cells in a dose-dependent manner, although with varying efficacies, as shown in Table 2 below. In this model, all compounds decreased cell viability at the 10³M dose level. ML / a / ZUZZ / UU l ¿¿I Table 2: Glutamate-induced excitotoxicity Dopamine-induced excitotoxicity Compound ECso (M) Emax (%) ECso (M) Emax (%) SEL-11 4.62 10.6 76.7 8.35 10.6 79.5 SUL-127 2.01 10.5 90.4 3.53 10.6 69.5 SUL-13 3.82 10.6 100.0 3.24 10.7 91.9 SUL-138 1.42 10.6 100.0 6.60 10.7 100.0 SUL-138M2 4.43 10.6 100.0 1.69 10.6 94.7 SUL-150 1.22 10.7 100.0 5.55 10'8 100.0 SUL-151 9.61 10'8 100.0 6.92 10'8 100.0 ML / a / ZUZZ / UU l ¿¿I The results in the table show that the SUL compounds according to the present invention exhibit an improved EC50 (i.e., active at lower concentrations) and / or improved Emax (i.e., restoration of toxicity is achieved at a higher level). Thus, this example showed that in addition to SUL-138, other SUL compounds such as those claimed are also likely to exhibit the advantages of improved memory function and / or reduced plaque formation; that is, they are generally favorable in the treatment of Alzheimer's disease. Reference Experiment A Hippocampal tissue from wild-type and APP / PS1 mice was examined to determine the expression of prostaglandin synthase and thromboxane synthase A proteins. Peptides resembling prostaglandin synthases PTGS1, PTGES2, PTGES3, and PTGFS were found in hippocampal tissue in both wild-type and APP / PS1 mice (Table 4). No protein fragments of PTGS2, PTGDS, PTGES1, PTGIS, or TXA were found. Treatment with SUL-138 in both wild-type and APP / PS1 mice did not alter the protein expression of prostaglandin-synthesizing enzymes.

Claims

1. A compound according to formula (I) or (II), or a pharmaceutically acceptable salt thereof, for use in the treatment of Alzheimer's disease, to improve memory function and / or to reduce plaque burden in a patient with Alzheimer's disease; wherein R1 represents a hydrogen or prodrug portion that can be eliminated in living tissue and wherein either R2 and R3 together with the N atom to which they are attached form an optionally substituted, non-aromatic, saturated or unsaturated 5-8 membered ring having one to four N, O, or S atoms, wherein R2 and R3 together contain 3-12 carbon atoms;oo R2 is a hydrogen atom, or an alkyl group with 1-6 carbon atoms, and R3 is an alkyl group, optionally substituted with nitrogen or oxygen, wherein the alkyl group comprises 3-12 carbon atoms, the alkyl group in R3 comprises one or more non-aromatic cyclic structures and may contain linear and / or branched groups and one or more ethylenic unsaturations.; 2. Compound for use according to claim 1, wherein R1 is hydrogen or forms together with oxygen-6 an ester group with 2-6 carbon atoms.

3. Compound for use according to any one of claims 1-2, wherein the nitrogen can be amine, quaternary amine, guanidine or amine and the oxygen is hydroxyl, carbonyl or carboxylic acid; and / or oxygen and nitrogen together form amide, urea or carbamate groups.

4. Compound for use according to any one of claims 1-3, wherein in the compounds according to formula (I) or according to formula (II), R2 and R3 together with the N atom to which they are attached form a saturated ring incorporating an additional N atom, the ring being unsubstituted or substituted with an alcohol or alkanol group having 1-4 carbon atoms.

5. Compound for use according to claim 4, wherein the compound is a compound according to formula I.

6. Compound for use according to claim 5, wherein R2 and R3 together with the N atom to which they are attached form a 5-7 membered ring comprising an additional amine group, the ring being optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

7. Compound for use according to any one of claims 1-3, wherein R2 is a hydrogen atom and R3 comprises a saturated cyclic structure having 4-7 carbon atoms and having a nitrogen atom, the ring of which may be substituted with an alkyl group, alcohol group or with a group having 1-4 carbon atoms which may comprise an oxygen, carboxylic acid group or amine.

8. Compound for use according to claim 7, wherein the compound is a compound according to formula II and wherein R2 is a hydrogen atom and R3 comprises a cyclic structure having 4-6 carbon atoms and having a nitrogen atom whose ring is optionally substituted with methyl, ethyl, or alcohol-substituted methyl or ethyl.

9. Compound for use according to claim 1, wherein the compound is (6hydroxy¡-2,5,7,8-tetramethylchroman-2¡l)(p¡peraz¡n-1-yl)methanone (SUL-121), hydrochloride ((S)-6hydroxy¡-2,5,7,8-tetramethyl-N-((R)-piper¡din-3-¡l)chroman-2-carboxamide (SUL-13) or (6-hydroxy2,5,7,8-tetramethylchroman-2-yl)(4-(2-hydroxyethyl)piperaz¡n-1-yl)methanone (SUL-109). ΜΛ / a / ZUZZ / UU l ¿¿I 10. Compound for use according to claim 9, wherein the compound is the S enantiomer of SUL-109: S-(6-hydroxy-2,5,7,8-tetramethylchroman-2-1)(4-(2-hydroxyethyl)piperazin-1-1)methanone (SUL-138).

11. Compound for use according to any of claims 1-8, wherein the compound according to formula (I) or formula (II) has a molecular weight of less than 500 Da.

12. Compound for use according to any of the preceding claims, wherein the use is for treating Alzheimer's disease.

13. Compound for use according to any of claims 1-12, wherein the use is for improving memory function.

14. Compound for use according to any of claims 1-13, wherein the use is for reducing plaque burden in a patient with Alzheimer's disease.

15. Use of a compound as described in any one of claims 1-11 to enhance memory function in a mammal, preferably a human.