Application of 4-hydroxymandelic acid compound in preparation of medicine for preventing or treating Alzheimer disease

Abstract

The invention relates to application of a 4-hydroxymandelic acid compound shown in a formula I in preparation of a medicine for preventing or treating Alzheimer's disease. The 4-hydroxymandelic acid compound is expected to be used for improving the learning and memory ability and cognitive impairment of AD patients, so that the 4-hydroxymandelic acid compound is used for preventing or treating AD or assisting in improving the memory function. # imgabs0 # (I)

Description

Technical Field

[0001] The present disclosure belongs to the technical field of Alzheimer's disease treatment, and particularly relates to the use of 4-hydroxymandelic acid compounds for preparing drugs for preventing or treating Alzheimer's disease. Background Art

[0002] Alzheimer's disease (AD), commonly known as senile dementia, is a common neurodegenerative disease of the central nervous system, mainly affecting the elderly. Its onset is insidious and the course of the disease is progressive. The main pathological manifestations of AD are brain tissue atrophy, neurofibrillary tangles, senile plaques formation and a large amount of amyloid protein deposition. The core symptoms are acquired cognitive impairment, involving multiple cognitive domains such as memory, learning, orientation, understanding, judgment, calculation, language and visuospatial, and ultimately progressing to global dementia. Among dementia patients, AD accounts for about 65%. With the aging of the global population, the prevalence of AD is increasing continuously, bringing a heavy burden to society and families.

[0003] Currently, the treatment drugs for AD mainly include cholinesterase inhibitors, N-methyl-D-aspartic acid (NMDA) receptor antagonists, anti-Aβ monoclonal antibodies, etc. In addition, they also include antioxidants, neurotrophic factors, anti-inflammatory drugs, etc. These drugs protect neurons through multiple mechanisms and slow down the progression of the disease. However, the current treatment drugs can only slow down the progression of AD, and the treatment effect is limited.

[0004] It is necessary to develop new drugs for preventing or treating AD. Summary of the Invention

[0005] The inventors of the present disclosure have conducted extensive research on the treatment of AD and unexpectedly found that 4-hydroxymandelic acid (4-HMA) can improve the learning and memory ability of Alzheimer's disease model APP / PS1 / Tau triple transgenic mice, improve cognitive impairment, and thus is expected to become a new drug for preventing or treating AD or be used to assist in improving memory function.

[0006] The present disclosure provides, on the one hand, the use of a compound represented by formula I or its pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph, and the uses are selected from: the use for preparing a drug for preventing or treating AD, the use for preparing a drug for improving the learning and memory ability of AD patients, the use for preparing a drug for improving the cognitive impairment of AD patients, the use for preparing a drug for inhibiting the activation of microglia in brain tissue, the use for preparing a health food for assisting in improving memory function: (I) Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

[0007] On the other hand, the present disclosure provides a compound represented by Formula I, a pharmaceutically acceptable salt, stereoisomer, racemate, solvate or polymorph thereof, which is used for preventing or treating AD, improving the learning and memory ability of AD patients, improving the cognitive impairment of AD patients, inhibiting the activation of microglia in the brain tissue, or improving the memory function.

[0008] On the other hand, the present disclosure provides a pharmaceutical composition for preventing or treating AD, improving the learning and memory ability of AD patients, improving the cognitive impairment of AD patients, inhibiting the activation of microglia in the brain tissue, or assisting in improving the memory function, which comprises a therapeutically effective amount of one or more selected from the group consisting of a compound represented by Formula I, a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof, and an optional pharmaceutically acceptable carrier.

[0009] On yet another aspect, the present disclosure provides a method for preventing or treating AD, improving the learning and memory ability of AD patients, improving the cognitive impairment of AD patients, inhibiting the activation of microglia in the brain tissue, or improving the memory function, which comprises administering to a subject a therapeutically effective amount of one or more selected from the group consisting of a compound represented by Formula I, a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof, or the above-mentioned pharmaceutical composition.

[0010] In an embodiment, the compound represented by Formula I is 4-hydroxymandelic acid.

[0011] In an embodiment, the compound represented by Formula I is (R)-4-hydroxymandelic acid, (S)-4-hydroxymandelic acid.

[0012] In an embodiment, the microglia is Iba1 + cells.

[0013] In an embodiment, the drug comprises a compound represented by Formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof as the sole active ingredient.

[0014] In an embodiment, the drug is administered orally. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1Show the test results of space exploration experiments. Among them, A shows the statistical chart of the comparison of the escape latency duration of each group of mice during training, B shows the statistical chart of the comparison of the escape latency duration of each group of mice on the 5th day of training, C shows the schematic diagram of the movement trajectories of each group of mice during the space exploration experiment, D shows the statistical chart of the number of times each group of mice passed through the target platform during the space exploration experiment, E shows the statistical chart of the percentage of activity time of each group of mice in the target quadrant during the space exploration experiment, and F shows the statistical chart of the swimming speed of each group of mice during the space exploration experiment. "*" indicates p < 0.05 compared with the AD model group, "**" indicates p < 0.01 compared with the AD model group, "#" indicates p < 0.05 compared with the control group, "##" indicates p < 0.01 compared with the control group, and "" indicates p < 0.001 compared with the control group.

[0016] Figure 2 Show the activation of microglia in the cortex and hippocampus of each group of mice. Among them, A shows the fluorescence micrograph of the activation of microglia in the cortex and hippocampus of each group of mice, B shows the statistical results of the fluorescence intensity of the activation of microglia in the hippocampus of each group of mice, and C shows the statistical results of the fluorescence intensity of the activation of microglia in the cortex of each group of mice. Specific implementation manners

[0017] The APP / PS1 / Tau triple transgenic mouse model is established by mutations in the APPswe, PS1, and TauP301L gene lines and is used to study the pathogenesis of AD and related neurodegenerative diseases. This strain simultaneously expresses the Swedish double mutant of human amyloid precursor protein (APP) and the M146L mutant of the Psen1 gene as well as the mutant form of the Tau protein through transgenic technology, mimicking the pathological characteristics of β-amyloid deposition and abnormal Tau protein aggregation in AD. The APP / PS1 / Tau triple transgenic mouse model is currently a transgenic animal model that is relatively close to the pathological characteristics of AD. Abnormal deposition of β-amyloid can be observed in the brains of model mice, forming typical amyloid plaques; abnormal aggregation of Tau protein, forming neurofibrillary tangles and neuropil threads; neuronal degeneration, reduction of synaptic density, and damage to synaptic structure; showing a decline in cognitive and memory functions, including impaired spatial learning and memory. This mouse can be used to evaluate the efficacy of potential therapeutic methods and drugs for AD.

[0018] Experiments on APP / PS1 / Tau triple transgenic mouse models have confirmed that treatment with 4-hydroxy mandelic acid can inhibit the activation of microglia in the brain tissue, significantly improve the learning and memory function of AD mice, and alleviate the cognitive dysfunction of AD mice. Therefore, 4-hydroxy mandelic acid is expected to be used to improve the learning and memory ability and cognitive impairment of AD patients, so as to prevent or treat AD, or to assist in improving memory function.

[0019] On the one hand, the present disclosure provides the use of the compound shown in formula I or its pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph as an active ingredient for preventing or treating AD in the preparation of a drug: (I) Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl, Wherein the use is selected from: the use for preparing a drug for preventing or treating AD, the use for preparing a drug for improving the learning and memory ability of AD patients, the use for preparing a drug for improving the cognitive impairment of AD patients, the use for preparing a drug for inhibiting the activation of microglia in the brain tissue, the use for preparing a health food for assisting in improving memory function.

[0020] C1-C4 alkyl refers to an alkyl group with 1 to 4 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, etc.

[0021] On the other hand, the present disclosure provides a pharmaceutical composition, which can be used for preventing or treating AD, for improving the learning and memory ability of AD patients, for improving the cognitive impairment of AD patients, for inhibiting the activation of microglia in the brain tissue, or for assisting in improving memory function, and contains a therapeutically effective amount of one or more selected from the compound shown in formula I, its pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph, and an optional pharmaceutically acceptable carrier.

[0022] On the further hand, the present disclosure provides a method for preventing or treating AD, improving the learning and memory ability of AD patients, improving the cognitive impairment of AD patients, inhibiting the activation of microglia in the brain tissue, or improving memory function, including administering to a subject a therapeutically effective amount of one or more selected from the compound shown in formula I, its pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph, or the above-mentioned pharmaceutical composition.

[0023] In an embodiment, the compound shown in formula I prevents or treats AD, improves the learning and memory ability of AD patients, improves the cognitive impairment of AD patients, or assists in improving memory function by inhibiting the activation of microglia and protecting neuron survival.

[0024] In some embodiments, in the drugs or pharmaceutical compositions of the present disclosure, the compounds represented by Formula I of the present disclosure, their pharmaceutically acceptable salts, stereoisomers, racemates, solvates, and polymorphs may be the sole active ingredient for preventing or treating AD.

[0025] In some embodiments, the drugs or pharmaceutical compositions of the present disclosure may further contain other active ingredients for preventing or treating AD. The other active ingredients may be any known drugs for treating AD. The other active ingredients for preventing or treating AD may be drugs for treating one or more symptoms of AD.

[0026] When the subject also has other diseases, the drugs or pharmaceutical compositions of the present disclosure may be administered simultaneously with drugs for treating these diseases, or may be administered with a short time interval or a long time interval between administrations.

[0027] The phrase "therapeutically effective amount" used in the present disclosure refers to the amount of an active substance sufficient to elicit a therapeutic physiological and pharmacological response in a patient. Preferably, the effective amount of the active substance elicits the desired physiological and pharmacological responses without producing side effects.

[0028] In the present disclosure, a subject is defined as any human or non-human animal in need of using the 4-hydroxymandelic acid compounds represented by Formula I of the present disclosure or their pharmaceutically acceptable salts, stereoisomers, racemates, solvates, polymorphs, or any object for which treatment with the 4-hydroxymandelic acid compounds represented by Formula I of the present disclosure or their pharmaceutically acceptable salts, stereoisomers, racemates, solvates, polymorphs may be beneficial, including humans or non-human animals, especially humans. These non-human animals to be treated include all domesticated and wild vertebrates. The non-human animals to be treated include all domesticated or wild vertebrates, including, but not limited to, mice, rats, rabbits, fish, birds, hamsters, dogs, cats, pigs, sheep, horses, cows, and non-human primates. When undergoing treatment, the subject may have a steady-state plasma level of any of the active substances of the present disclosure.

[0029] As used herein, the term "prevent or treat" includes both prophylactic treatment modalities and treatment modalities according to the condition, and refers to inhibiting, delaying, halting, or reversing existing AD symptoms or the recurrence and / or progression of AD in a subject, and / or inhibiting, delaying, halting, or reversing the development of mild cognitive impairment to Alzheimer's disease. Here, mild cognitive impairment is defined as a potentially prodromal stage of dementia associated with Alzheimer's disease, which is based on clinical manifestations and the progression of the patient from mild cognitive impairment to Alzheimer's dementia over time. (Morris et al., Arch. Neurol., 58, 397-405 (2001); Petersen et al., Arch. Neurol., 56, 303-308 (1999)).

[0030] The prevention or treatment of a subject includes administering a therapeutically effective amount of a 4-hydroxymandelic acid compound of formula I as described herein or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof. One of ordinary skill in the art can empirically determine the optimal dose and course of treatment for administering the 4-hydroxymandelic acid compound of formula I as described herein or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof. However, a therapeutically effective amount is an amount that can alleviate or relieve the AD symptoms of a subject, prevent the recurrence and / or progression of AD, and / or prevent or delay the development of mild cognitive impairment to Alzheimer's disease.

[0031] The therapeutically effective amount can be administered in a single dose or multiple doses throughout the course of treatment. The 4-hydroxymandelic acid compound of formula I as described herein or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof can be administered by any means familiar to those skilled in the art. For example, the 4-hydroxymandelic acid compound of formula I as described herein or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof can be administered orally, intravenously, intraperitoneally (IP), in vivo, intra-articularly, intramuscularly, subcutaneously, mucosally, rectally, vaginally, or by inhalation.

[0032] The drug or pharmaceutical composition herein may comprise a pharmaceutically acceptable carrier.

[0033] The term "carrier" as used herein includes acceptable diluents, excipients, adjuvants, media, solubilizing aids, viscosity regulators, preservatives, and other known agents for providing advantageous properties in the final drug or pharmaceutical composition administered to a subject.

[0034] More specifically, the carriers that can be included in the pharmaceutical or pharmaceutical composition of the present disclosure include: acidifying agents or alkalizing agents for obtaining the desired or predetermined pH value; antimicrobial agents (including antibacterial agents, antifungal agents, and antiprotozoal agents); antioxidants for protecting the components of the pharmaceutical composition from destruction or degradation; buffers for maintaining the desired pH value; chelating agents for maintaining the ionic strength; dispersants and suspending agents; emulsifying agents; excipients; preservatives; stabilizers; sugars; fillers; diluents; solvents; sweeteners; odorants; flavoring agents; lubricants, and surfactants. Examples of these various types of carriers are known to those skilled in the art.

[0035] According to the desired route of administration, the pharmaceutical or pharmaceutical composition of the present disclosure can be prepared into any suitable dosage form. For example, the pharmaceutical or pharmaceutical composition of the present disclosure can be an oral dosage form, such as syrup, tablets, capsules (hard capsules, soft capsules), powders, tinctures, oral liquids, dripping pills, or lozenges, etc.; dosage forms suitable for inhalation administration, such as dry powders, solutions, dispersions, aerosols, etc.; injection dosage forms, such as dosage forms for parenteral injection, intradermal injection, subcutaneous injection, intramuscular injection, or intravenous injection. The pharmaceutical or pharmaceutical composition of the present disclosure can be a controlled-release preparation or an immediate-release preparation.

[0036] The pharmaceutical preparation can be prepared by any known method in the pharmaceutical field. Generally, the active compound can be uniformly and finely mixed with a liquid carrier or a solid carrier or both, and then, if necessary, the product is formed or packaged into the desired preparation.

[0037] In some embodiments, the drug is administered orally. The pharmaceutical or pharmaceutical composition of the present disclosure is a preparation suitable for oral administration. The oral preparation can exist in the form of discrete units containing a predetermined amount of the active compound, such as capsules, cachets, or tablets. The preparation can be a powder or granule; a solution or suspension in water or a non-aqueous liquid; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or a bolus or paste.

[0038] The oral drug or pharmaceutical composition of the present disclosure generally includes an inert diluent, an edible carrier, excipients, binders, disintegrants, lubricants, glidants, flavoring agents, etc. The binder can include, for example, microcrystalline cellulose, tragacanth gum, or gelatin. The excipient can include, for example, starch or lactose. The disintegrant can include, for example, alginic acid or corn starch. The lubricant can include, for example, magnesium stearate. The glidant can include, for example, colloidal silica. The flavoring agent can include, for example, mint, methyl salicylate, or citrus flavors.

[0039] When the oral composition is in the form of a syrup, the preparation generally consists of a suspension or solution of the compound or salt in a liquid carrier. Examples of liquid carriers are: ethanol, peanut oil, olive oil, glycerol, or water.

[0040] When the composition is in the form of tablets, any pharmaceutical carrier conventionally used for preparing solid dosage forms can be used, including: magnesium stearate, gypsum powder, talc powder, gelatin, gum arabic, stearic acid, starch, lactose, and sucrose. The tablets can be prepared by compressing or molding, optionally together with one or more auxiliary ingredients.

[0041] When the composition is in the form of capsules, any conventional encapsulation method is suitable, such as hard or soft gelatin capsule shells.

[0042] In controlled release formulations, biodegradable and / or biocompatible polymers can be used, such as povidone, copovidone, hydroxypropylcellulose, ethylene-vinyl acetate copolymer, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polyacrylic acid.

[0043] In some embodiments, the drug is administered parenterally, intradermally, or subcutaneously. The drugs or pharmaceutical compositions of the present disclosure are preparations for parenteral, intradermal, or subcutaneous administration, which may include: sterile diluents such as water, saline solutions, non-volatile oils, polyethylene glycols, glycerol, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; agents for adjusting osmotic pressure such as sodium chloride or glucose; agents for adjusting the pH value including acids such as hydrochloric acid and bases such as sodium hydroxide. The preparation can be encapsulated in ampoules, disposable syringes, or multi-dose bottles made of glass or plastic.

[0044] The drugs or pharmaceutical compositions of the present disclosure suitable for injectable applications include sterile aqueous solutions or dispersions and sterile powders for immediate preparation of sterile injectable solutions or dispersions. In addition to the active ingredient, the drugs or pharmaceutical compositions of the present disclosure may contain carriers, surfactants, antibacterial agents, antifungal agents, isotonic agents, agents for delaying absorption, etc. The carrier can be a solvent or a dispersion medium, such as water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.) and their suitable mixtures, especially physiological saline, bacteriostatic water, or phosphate buffered saline. Antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. Isotonic agents such as sugars, such as the polyols mannitol and sorbitol, or sodium chloride. Agents for delaying absorption such as aluminum monostearate and gelatin.

[0045] The drug or pharmaceutical composition of the present disclosure may be in unit dosage forms, such as tablets, capsules or metered aerosol doses, so that a single dose can be administered to a subject.

[0046] The drug or pharmaceutical composition of the present disclosure can be administered in a single manner or in a combination of multiple manners. When administered in combination in different dosage forms, they can be administered simultaneously, or can be administered at a very close time interval or a very long time interval, for example, one dosage form is administered in the morning and the other dosage form is administered in the evening.

[0047] The exact amount of the drug or pharmaceutical composition of the present disclosure required to obtain a therapeutic effect will vary with the subject, depending on the species, age, weight and general condition of the subject, the severity of the medical condition being treated, the specific active agent used, its mode of administration, etc. The dosage range for administering the drug or pharmaceutical composition of the present disclosure is large enough to produce a therapeutic effect. The dosage can be adjusted to avoid or mitigate the occurrence of adverse side effects, such as unwanted cross-reactions, allergic reactions, etc. The dosage can vary with the age, condition, sex of the patient and the degree of the disease, the route of administration or whether other drugs are included in the treatment regimen. In the event of any contrary indications, the dosage can be adjusted by an individual physician. The dosage can be changed and can be administered in one or more doses per day, for one or several days. For a given type of drug product, guidelines for a suitable dosage can be found in the literature.

[0048] For example, the administration of the drug or pharmaceutical composition of the present disclosure can be once a month, once every two weeks, once a week, once every three days, 1 to 6 times a day, etc., but is not limited thereto. In one embodiment, the drug or pharmaceutical composition of the present disclosure is administered once a day.

[0049] In the compound structure represented by Formula I, there are chiral molecules, so there are stereoisomers. These stereoisomers generally also have partial activities of the active ingredient of the 4-hydroxymandelic acid compounds represented by Formula I. Therefore, the compounds represented by Formula I of the present disclosure also include these stereoisomers. "Stereoisomers" refer to compounds that have the same molecular formula and their atoms are bonded together in the same order but the configuration of their atoms in space is different. Stereoisomers include enantiomers (also called optical isomers, which are mirror images and have equal but opposite optical rotation rates) and diastereomers (stereoisomers without mirror images). The compounds represented by Formula I described in the present disclosure can be in the form of individual enantiomers, diastereomers, atropisomers or geometric isomers, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers.

[0050] In some embodiments, the compound represented by Formula I is 4-hydroxymandelic acid (also known as p-hydroxymandelic acid or 2-hydroxy-2-(4-hydroxyphenyl)acetic acid), which can be (R)-4-hydroxymandelic acid, (S)-4-hydroxymandelic acid, or DL-4-hydroxymandelic acid.

[0051] The structure of 4-hydroxymandelic acid is shown below: 。

[0052] In some embodiments, 4-hydroxymandelic acid is (R)-4-hydroxymandelic acid as shown below: 。

[0053] In some embodiments, 4-hydroxymandelic acid is (S)-4-hydroxymandelic acid as shown below: 。

[0054] In some embodiments, 4-hydroxymandelic acid is in racemic form, i.e., DL-4-hydroxymandelic acid.

[0055] In some embodiments, the compound represented by Formula I or its pharmaceutically acceptable salts, stereoisomers, racemates can absorb solvents (such as water) to form solvates (such as hydrates). Therefore, these solvates are also included within the scope of the present disclosure. For example, 4-hydroxymandelic acid can be in solvate form, such as 4-hydroxymandelic acid monohydrate (CASRN: 184901-84-6) In some embodiments, the compound represented by Formula I or its pharmaceutically acceptable salts, stereoisomers, racemates can form polymorphs with solvents (such as water). Therefore, these polymorphs are also included within the scope of the present disclosure. In certain embodiments, these polymorphs may provide additional benefits, such as higher solubility, faster dissolution rate, higher bioavailability, lower toxicity and side effects, etc.

[0056] There are also some prodrugs of 4-hydroxymandelic acid that can be converted into the active form of 4-hydroxymandelic acid in vivo through hydrolysis or enzymatic hydrolysis, etc. For example, the prodrug may be an ester compound that is hydrolyzed or enzymatically hydrolyzed in vivo to be converted into the active form of 4-hydroxymandelic acid. Therefore, the compounds represented by Formula I of the present disclosure also include these prodrugs, especially ester compounds, such as ethyl 4-hydroxymandelate.

[0057] Said pharmaceutically acceptable salts may confer improved pharmacokinetic properties to the active compound compared to the free form of the active compound. Said pharmaceutically acceptable salts may also confer desired pharmacokinetic properties that the active compound did not have before, and may even positively affect the pharmacodynamic effect of the active compound with respect to its therapeutic activity in vivo.

[0058] Said pharmaceutically acceptable salts can be formed by treating the free acid form of the active compound with a sufficient amount of a pharmaceutically acceptable organic or inorganic base. Examples of inorganic base salts include, without limitation: alkali metal salts such as potassium salts, sodium salts; alkaline earth metal salts such as calcium salts, magnesium salts; transition metal salts such as iron salts, ferrous salts, zinc salts; and ammonium salts. Examples of organic base salts include, without limitation: salts with primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, etc., such as alkylamines such as ethylenediamine, triethylamine, trimethylamine, tripropylamine, isopropylamine, diethylamine, N,N'-dibenzylethylenediamine, etc.; hydroxyalkylamines such as ethanolamine, tromethamine, choline, 2-diethylaminoethanol, 2-dimethylaminoethanol, etc.; amino acids such as arginine, histidine, lysine, etc.; glucosamines such as glucosamine, reduced glucosamine (methyl reduced glucosamine), etc.; cyclic amines such as caffeine, morpholine, piperazine, piperidine, purine, theobromine, etc.

[0059] The 4-hydroxymandelic acid compounds represented by Formula I of the present disclosure also cover isotopically labeled compounds. The isotopically labeled compounds are the same as the 4-hydroxymandelic acid compounds represented by Formula I of the present disclosure, except that one or more atoms are replaced by atoms with an atomic mass or mass number different from one of the atomic masses or mass numbers commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, and oxygen, respectively, such as: 2 hydrogen (deuterium), 3 hydrogen (tritium), 11 carbon, 13 carbon, 14 carbon, 15 oxygen, 17 oxygen and 18 oxygen.

[0060] Certain isotopically labeled compounds (such as those labeled with 3 H and 14 C) are used in compound and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because they are easy to prepare and detect. Moreover, heavier isotopes such as deuterium (i.e., 2H) Performing substitutions can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and may thus be preferred in certain cases. Positron-emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F are used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting non-isotopically labeled reagents with isotopically labeled reagents.

[0061] The present disclosure has been described in detail above, but the above embodiments are merely illustrative in nature and are not intended to limit the invention. In addition, the present disclosure is not limited by any theory described in the foregoing prior art or the summary of the invention or the following examples.

[0062] Examples The following examples will further illustrate the present invention in conjunction with the accompanying drawings.

[0063] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods.

[0064] Unless otherwise specified, the materials, reagents, etc. used in the following examples are all commercially available.

[0065] Main experimental materials and sources Animals SPF-grade c57 mice, male, 4 months old, purchased from Spf (Beijing) Biotechnology Co., Ltd.

[0066] SPF-grade APP / PS1 / Tau triple transgenic mice, male, 4 months old, purchased from Jiangsu Jicui Yakang Biotechnology Co., Ltd.

[0067] Main experimental drugs and reagents 4-Hydroxymandelic acid (4-HMA), purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd., CAS: 184901-84-6. Method for preparing the drug: Prepared into a concentration of 10 mg / mL with sodium chloride injection.

[0068] Sodium chloride injection, purchased from Shijiazhuang No. 4 Pharmaceutical Co., Ltd.

[0069] Paraformaldehyde, purchased from Beijing Yili Fine Chemical Co., Ltd.

[0070] Avertin, purchased from Meilun Biotech Co., Ltd.

[0071] Sucrose, xylene, absolute ethanol, purchased from Sinopharm Chemical Reagent Co., Ltd.

[0072] The DAPI anti-fluorescence quenching mounting medium was purchased from Prime Science Co., Ltd.

[0073] The IBA1 antibody and NeuN antibody were purchased from Abcam (Shanghai) Trading Co., Ltd.

[0074] Main instruments The water maze, model XR-XM101, was purchased from Shanghai Xinruan Information Technology Co., Ltd.

[0075] The cryostat, model CM1950, was purchased from Leica Microsystems (Shanghai) Trading Co., Ltd.

[0076] The upright fluorescence microscope, model Ni-U, was purchased from Nikon Precision Instruments (Shanghai) Co., Ltd.

[0077] Experimental methods C57 mice were used as the control group (Ctrl). The APP / PS1 / Tau triple transgenic mice were randomly divided into a model group (AD) and a 4-HMA drug treatment group (AD-4HMA, with a dosing dose of 120 mg / kg), with 5 mice in each group. After the mice were acclimated to the environment, gavage administration was started once a day for 2 consecutive months. The control group and the model group were given an equal volume of normal saline solution.

[0078] After 2 consecutive months of dosing, the Morris water maze experiment was conducted to evaluate the cognitive function of the mice in each group. The water maze device consisted of a circular water tank (height 50 cm, diameter 120 cm). Before the experiment, a hidden escape platform was placed at a fixed position in the third quadrant. First, the mice were trained in the water maze for 5 days (d). The activity trajectories of the mice were tracked and recorded through the Morris software visual tracking system installed at the center position directly above the pool, and the time and swimming distance for the mice to reach the platform were calculated as the escape latency. The escape latency in this experiment was set to 60 s. During the positioning navigation process, the mice learned to find the hidden platform at a fixed position, and the formation of spatial cognition could indirectly reflect the learning ability of the mice. 6 days after the Morris water maze test, the hidden platform in the water was removed, and a 1-day spatial exploration experiment was conducted on the mice. The mice were placed facing the pool wall at the water entry point farthest from the original platform, and their swimming trajectories, activity time in the target quadrant, and the number of times they crossed the platform within 60 s were recorded to evaluate the memory ability of the mice.

[0079] After the behavioral experiments of each group of mice were completed, the mice were anesthetized with avertin. After the mice were deeply anesthetized, perfusion fixation of the brain was performed using 4% paraformaldehyde. The brain tissue samples were placed in 4% paraformaldehyde and fixed at 4 °C for 48 h, and then successively transferred to 15%-20%-30% sucrose solutions for gradient precipitation dehydration. After dehydration, the samples were embedded and coronally sectioned using a cryostat. The brain tissue sections were subjected to immunofluorescence staining, incubated with IBA1 antibody, and the activation of microglia in the cortex and hippocampus of each group of mice was detected and calculated by observing under a fluorescence microscope. Three mice were selected from each group, and for each mouse, three fields of view of the cortex and hippocampus were respectively selected within a 20-fold magnification range for fluorescence intensity statistics. The average fluorescence intensity of all fields of view of the three mice in each group was used as the fluorescence intensity result of that group.

[0080] Experimental results The test results of the spatial exploration experiment are as Figure 1 shown. Among them, A shows the statistical chart of the comparison of the escape latency duration of each group of mice during the training period, B shows the statistical chart of the comparison of the escape latency duration of each group of mice on the 5th day of training, C shows the schematic diagram of the movement trajectories of each group of mice during the spatial exploration experiment, D shows the statistical chart of the number of times each group of mice passed through the target platform during the spatial exploration experiment, E shows the statistical chart of the percentage of time each group of mice spent in the target quadrant during the spatial exploration experiment, and F shows the statistical chart of the swimming speed of each group of mice during the spatial exploration experiment. "*" indicates p < 0.05 compared with the AD model group, "**" indicates p < 0.01 compared with the AD model group, "#" indicates p < 0.05 compared with the control group, "##" indicates p < 0.01 compared with the control group, and "" indicates p < 0.001 compared with the control group.

[0081] As Figure 1 shown in A of, on the 1st day of the place navigation experiment test, the time for each group of mice to find the underwater hidden platform was not significantly different, and they were in the exploration stage. Compared with the control group (Ctrl), the escape latency of the mice in the AD model group (AD) showed a significant increase starting from the 4th day of training, indicating that the spatial cognitive ability of the mice in the AD model group was significantly decreased, reflecting a significant decrease in learning ability (#p < 0.05); while administration of 4-HMA significantly reduced the escape latency of AD mice and alleviated the decrease in the spatial cognitive ability of AD mice, indicating a reduction in the decrease in the learning ability of AD mice (**p < 0.01).

[0082] As Figure 1 shown in D-E of, compared with the control group, the number of times the mice in the AD model group (AD) passed through the platform was significantly reduced ( Figure 1 in D of), and the swimming time in the target quadrant was significantly shortened ( Figure 1Group E), indicating a significant decline in the memory function of the model group mice, while the 4-HMA drug intervention significantly increased the swimming time of the AD model mice in the target quadrant ( Figure 1 Group E) and the number of platform crossings ( Figure 1 Group D). The relevant performance can also be verified from the movement tracking trajectory of the mice ( Figure 1 Group C). The above results indicate that 4-HMA drug treatment can significantly improve the memory function of AD mice and relieve the cognitive dysfunction of AD mice.

[0083] Figure 2 Show the activation of microglia in the cortex and hippocampus of mice in each group. Among them, A shows the fluorescence micrographs of the activation of microglia in the cortex and hippocampus of mice in each group, B shows the statistical results of the fluorescence intensity of microglia activation in the hippocampus of mice in each group, and C shows the statistical results of the fluorescence intensity of microglia activation in the cortex of mice in each group. "* *" indicates p < 0.01 compared with the AD model group, "##" indicates p < 0.01 compared with the control group, and "" indicates p < 0.001 compared with the control group.

[0084] As Figure 2 shown in Figure A, compared with the control group, there was an obvious aggregation reaction of Iba1 in the hippocampus and cortex of the brain tissue of the AD model group mice, indicating an obvious inflammatory reaction in the brains of the AD model group mice; the 4-HMA drug intervention significantly improved the aggregation of Iba1 in the mouse brain tissue, and their relative quantities were significantly reduced ( + Figure B and C), proving that 4-HMA can inhibit the inflammatory reaction in the mouse brain. + Figure B and C), proving that 4-HMA can inhibit the inflammatory reaction in the mouse brain. Figure 2 Figure B and C), proving that 4-HMA can inhibit the inflammatory reaction in the mouse brain.

[0085] The above results indicate that 4-HMA intervention can significantly reduce the activation of microglia in the brain tissue of APP / PS1 / Tau triple transgenic mice, significantly improve the spatial cognitive memory ability (i.e., learning and memory ability) of mice, and improve cognitive impairment.

[0086] The above embodiments are only preferred embodiments of the present invention and cannot be considered as limiting the scope of implementation of the present invention. All equivalent changes and improvements made in accordance with the scope of the present invention application shall still fall within the scope covered by the present invention patent.

Claims

1. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof for the preparation of a medicament for preventing or treating Alzheimer's disease (AD): （I） Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

2. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof for the preparation of a medicament for improving the learning and memory ability of AD patients: （I） Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

3. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof for the preparation of a medicament for improving the cognitive impairment of AD patients: （I） Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

4. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof for the preparation of a medicament for inhibiting the activation of microglia in the brain tissue: （I） Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

5. The use according to claim 4, wherein The microglia are Iba1 + cells.

6. Use of the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof for the preparation of a health food for assisting in improving memory function: （I） Wherein, R is selected from hydrogen, C1-C4 alkyl, phenyl, benzyl.

7. The use according to any one of claims 1 - 4 and 6, characterized in that, The compound of formula I is 4-hydroxymandelic acid.

8. The use according to claim 7, characterized in that, The compound of formula I is (R)-4-hydroxymandelic acid or (S)-4-hydroxymandelic acid.

9. The use according to any one of claims 1-4, characterized in that, The medicament comprises the compound of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, solvate, polymorph thereof as the sole active ingredient.

10. The use according to any one of claims 1 to 4, characterized in that, The medicament is administered orally.

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