RU2791317C2 - New composition for treatment or prevention of a neurodegenerative disease and its use - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: group of inventions is described, including a compound represented by formula (I) or a pharmaceutically acceptable salt thereof

(I),

the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of drugs or kits for the prevention, alleviation or treatment of neurodegenerative diseases, depression or seizure, the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of compositions, kits or kits for reducing the suppression of neuroinflammation, the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of compositions, kits or kits for promoting the production of neural progenitor cells, the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of compositions, kits or kits to reduce the production of Aβ, a pharmaceutical composition for preventing, alleviating, or treating Alzheimer's disease; and a method for preventing, alleviating, or treating neurodegenerative diseases, depression caused by a neurodegenerative disease, or an attack of a neurodegenerative disease.

EFFECT: invention expands the arsenal of means for the prevention, alleviation or treatment of neurodegenerative diseases.

4 cl, 10 dwg, 7 ex

Description

BACKGROUND OF THE INVENTION

Field of invention

The present invention relates to the field of pharmaceutical technology. More specifically, the present invention relates to novel compounds for the prevention or treatment of neurodegenerative diseases and their use.

Prior Art

Neurodegenerative diseases are a group of diseases caused by chronic progressive degeneration of tissue in the central nervous system. Such diseases mainly include Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), etc.

Alzheimer's disease (AD), also referred to as presenile dementia, is a chronic and progressive neurodegenerative disease that manifests itself primarily as progressive memory loss, cognitive dysfunction, and loss of the ability to live and care for oneself. With an increasing aging population, the incidence of AD is increasing every year and AD has become the most important public health concern. The main pathological feature of Alzheimer's disease is the formation of amyloid plaques and neurofilament tangles in the patient's brain. Amyloid plaque is a pathological change specific to Alzheimer's disease, which is mainly the result of extracellular accumulation of beta-amyloid (Αβ) protein, which is secreted in abnormally large amounts in cells. Currently, several theories have been proposed in an attempt to explain the development of the pathological process. The "Αβ hypothesis" proposed by Hardy and Selko is a generally accepted theory. The theory is that due to long-term exposure to complex genetic and environmental factors, nerve cells secrete abnormally large amounts of Αβ, which accumulates to form oligomers and amyloid plaques. Αβ (particularly oligomerized Αβ) undergoes a series of cascade reactions (including, for example, free radical reaction, mitochondrial oxidative damage, and inflammatory responses that affect neurons and glial cells directly or indirectly) leading to synaptic dysfunction and neuronal damage, causing activation of microglia and astrocytes. This accelerates the formation of neurofilament tangles, leading to cognitive impairment after prolonged exposure. Recently, through numerous studies, various evidence has been presented in support of the "Αβ hypothesis", showing the critical role of Αβ in the pathogenesis of Alzheimer's disease.

Parkinson's disease is a common neurodegenerative disease, the clinical manifestation of which takes the form of symptoms such as slow reactions, trembling, body immobility and subsequent loss of balance. Studies of the brain tissues of patients with PD have shown that dopaminergic neurons are absent in the substantia nigra of patients. Lewy inclusion bodies are one of the hallmark lesions of degenerative neurons in Parkinson's disease. Studies have shown that Lewy inclusion bodies are formed in the brain cells of many patients with neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and dementia with Lewy bodies (LDB).

In mammalian brains, the proliferation and self-renewal of neural progenitor cells (NPCs) continues throughout life and is an important part of neurogenesis. In the case of aging, long-term stress and neurological diseases such as Alzheimer's disease (AD), the ability to proliferate and self-renewal of neural progenitor cells is reduced, which leads to impaired cognitive function. Providing neurogenesis is considered a potential treatment for aging and neurodegenerative diseases associated with aging. Therefore, a possible solution is cell replacement therapy by transplantation of embryonic neural progenitors or in vitro induced neural progenitors. However, there is still some controversy regarding the newly created complex technology, in particular on the safety and sources of cells. Another approach is to activate intrinsic neural progenitor cells with pharmacological means to achieve the goal of treating neurodegenerative diseases. Pharmacological agents are easy to use and can be directed to specific functions of neural progenitor cells. Therefore, the activation of intrinsic neural progenitor cells is not only a reasonable treatment, but also a useful way of prevention. However, there is still a need for those skilled in the art to provide suitable drugs that can better overcome obstacles in the human body to effectively activate internal neural progenitor cells to achieve effective treatment.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide a novel compound for the prevention or treatment of neurodegenerative diseases and a method of using the same.

According to a first aspect, the present invention provides a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof,

- шестичленное гетероциклическое кольцо, причем X представлено О; R1-R4 каждое по отдельности подбираются из числа водорода, гидроксила, С1-С4 алкила, С2-С4 алкенила, С2-С4 алкинила и галогена, или же две соседние группы R1-R4 связаны друг с другом для образования циклической структуры с основным кольцом; и R1'-R3' каждое по отдельности подбираются из числа водорода, гидроксила, С1-С4 алкила, С2-С4 алкенила, С2-С4 алкинила и галогена, или же две соседние группы R1'-R3' связаны друг с другом для образования циклической структуры с основным кольцом.in which

- six-membered heterocyclic ring, and X is represented by O; R1-R4 are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen, or two adjacent R1-R4 groups are bonded to each other to form a cyclic structure with a basic ring; and R1'-R3' are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen, or two adjacent R1'-R3' groups are bonded to each other to form a cyclic structures with a main ring.

имеется циклическая структура, выбранная из группы, включающей:

и

.In a preferred embodiment, in a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof,

there is a cyclic structure selected from the group consisting of:

And

.

имеется циклическая структура

.In a preferred embodiment, in a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof,

there is a cyclic structure

.

In a preferred embodiment, in a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, R1-R4 are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, or two adjacent R1-R4 groups are linked with each other to form a five-membered ring with a basic ring; and R1'-R3' are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, or two R1'-R3' groups are bonded to each other to form a five-membered ring with a basic ring.

In another preferred embodiment, in a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, the five-membered ring is an oxygen-containing heterocyclic ring and preferably contains two oxygen atoms.

In another preferred embodiment, the compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof contains:

In another preferred embodiment, the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is provided in the preparation of medicaments or kits for the prevention, amelioration or treatment of neurodegenerative diseases, depression or seizure.

In another preferred embodiment, neurodegenerative diseases include:

neurodegenerative diseases characterized by neuroinflammation in the brain;

neurodegenerative diseases characterized by a significant increase in the production of Αβ;

neurodegenerative diseases characterized by a significant decrease in learning ability and memory impairment; or

neurodegenerative diseases characterized by a significant decrease in the number of neural progenitor cells.

In another preferred embodiment, neuroinflammation in the brain is characterized by a significant increase in manifestations of allergic inflammatory factors such as IL-6 and IL-1β.

In another preferred embodiment, neurodegenerative diseases include: Alzheimer's disease, Parkinson's disease, and Lewy body dementia (LBD).

According to another aspect of the present invention, the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is provided in the preparation of compositions, kits or kits for suppressing neuroinflammation.

According to another aspect of the present invention, the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is provided in the preparation of compositions, kits or kits to promote the production of neural progenitor cells.

According to another aspect of the present invention, the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is provided in the preparation of compositions, kits or kits for reducing Αβ production.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound represented by formula (I) or an isomer, solvate, precursor, or a pharmaceutically acceptable salt thereof; as well as a pharmaceutically acceptable carrier.

In a preferred embodiment, a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition in an effective amount. Preferably, the effective amount is 0.01-50% by weight, such as 0.01-5%, 0.03-3%, 0.05-1%, 20-30% and 40-50%, but not limited to these values, and more preferably 0.03-30%, and most preferably 0.05-10%.

According to another aspect of the present invention, dosage forms of the pharmaceutical composition provided include: granulate, powder, tablets, pills, capsules, sustained release preparations, controlled release preparations, injections, infusion solutions or suspensions.

According to another aspect of the present invention, there is provided a kit comprising a compound represented by formula (I) or an isomer, solvate, precursor, or a pharmaceutically acceptable salt thereof; as well as a pharmaceutical composition.

According to another aspect of the present invention, there is provided a method for preventing, alleviating, or treating neurodegenerative diseases, depression, or an attack, comprising administering an effective amount of a compound represented by formula (I) or an isomer, solvate, precursor, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

According to another aspect of the present invention, there is provided a method for preparing a compound represented by formula II, comprising the step of reacting a diramnopyranosyl glycoside with tetrabutylammonium fluoride to obtain a compound represented by formula (II).

According to another preferred embodiment, diramnopyranosyl glycoside is prepared by reacting diramnopyranosyl thioglycoside with (4-O-tert-butyldimethylsilyl)-ferulic acid.

According to another preferred embodiment, diramnopyranosyl thioglycoside is prepared by reacting rhamnopyranosyl thioglycoside with 2,3,4-O-triacetylramnosyl-1-O-trichloroacetimidate.

According to another aspect of the present invention, there is provided a method for preparing a compound represented by formula (III) or (IV), comprising the step of:

(конкретно, удаления изопропилиденовой защитной группы вицинального диола) для получения соединения, представленного формулой (III) или (IV).connection recovery

(specifically, removing the isopropylidene protecting group of the vicinal diol) to obtain a compound represented by formula (III) or (IV).

получают за счет этапа конденсации соединения

с соединением

.In one preferred embodiment, the connection

obtained by the condensation step of the compound

with connection

.

where Ρ is represented by Η or a protecting group, and the protecting group is preferably selected from the group consisting of: AII, Boc, TBS, Ac, Βn, PMB and Cbz; and this protecting group can be reduced to H.

получают за счет этапов проведения реакции присоединения соединений

и

и защиты вицинального диола изопропилиденовой группой.In another preferred embodiment, the connection

obtained through the steps of the addition reaction of compounds

And

and protecting the vicinal diol with an isopropylidene group.

Other aspects of the present invention will become apparent to a person skilled in the art from the description in this document.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the improvement in Morris water maze test score in a mouse model of Alzheimer's disease by PL402.

Figure 2 shows the suppression of neuroinflammation due to PL402.

Figure 3 shows the reduction in the production of Αβ due to PL402.

Figure 4 shows the effect of PL404 on the learning ability and memory of animals.

Figure 5 shows the effect of PL404 on the proliferation of human neural progenitor cells.

Figure 6 shows the effect of PL405 on the proliferation of human neural progenitor cells.

Figure 7 presents a qualitative analysis of compound 5.

Figure 8 presents a qualitative analysis of PL402.

Figure 9 presents a qualitative analysis of PL404.

Figure 10 presents a qualitative analysis of PL405.

DETAILED DESCRIPTION

After extensive research, the inventors found that the compound of formula (I) can significantly alleviate the symptoms of neurodegenerative diseases. Under both in vitro and in vivo experiments, the compound of formula (I) can effectively promote the proliferation of neural progenitor cells, which is not only a prophylactic, but can also serve as a treatment approach to promote the regeneration of nerve cells to counteract cognitive impairment associated with aging and neurodegenerative diseases.

Terms

As used herein, the term "alkyl" refers to a linear or branched group of saturated aliphatic hydrocarbons with 1-4 carbon atoms, and preferably with 1-2 carbon atoms. For example, alkyl includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

As used herein, the term "alkenyl" includes a linear or branched hydrocarbon group with at least one carbon-carbon double bond and 2-4 carbon atoms, and preferably 2-3 carbon atoms.

As used herein, the term "alkynyl" includes a linear or branched hydrocarbon group with at least one carbon-carbon triple bond and 2-4 carbon atoms, and preferably 2-3 carbon atoms.

As used herein, the term "halogen" refers to F, Cl, Br, or I.

The term "isomer" includes geometric isomers, enantiomers, and diastereomers, such as cis-trans isomers and conformational isomers.

, применяемое в настоящем документе, хорошо известно специалистам в этой области техники, и оно обозначает гетероциклическое кольцо с атомом X В предпочтительном варианте реализации настоящего изобретения

- шестичленное гетероциклическое кольцо.Designation

as used herein is well known to those skilled in the art and denotes a heterocyclic ring with an X atom. In a preferred embodiment of the present invention

- six-membered heterocyclic ring.

в рамках настоящего документа хорошо известно специалистам в этой области техники, и оно значит, что происходит замещение дополнительными группами R1-R4 в одной или нескольких точках на кольце, которые могут быть замещены. Также в разных точках замещения группы могут разниться.Designation

within the scope of this document is well known to those skilled in the art and means that there is substitution with additional R1-R4 groups at one or more points on the ring that may be substituted. Also, at different substitution points, the groups may differ.

в рамках настоящего документа хорошо известно специалистам в этой области техники, и оно значит, что происходит замещение дополнительными группами R'-R3' в одной или нескольких точках на кольце, которые могут быть замещены. Также в разных точках замещения группы могут разниться.Designation

within the scope of this document is well known to those skilled in the art and means that there is substitution with additional R'-R3' groups at one or more points on the ring that may be substituted. Also, at different substitution points, the groups may differ.

"P" herein is represented by Η or a protecting group, and the protecting group is preferably selected from the group consisting of: AII, Boc, TBS, Ac, Bn, PMB, and Cbz; and this protecting group can be reduced to H.

Also, in different compounds, the protecting groups may be the same or different. Even in the case of the same series of reactions, the group P at different points in different or similar compounds may also differ.

The term "solvate" as used herein refers to a compound containing a solvent molecule, for example, the solvent may be a hydrate.

The term "comprising/comprising" in the present invention means that various ingredients can be used in the mixture or compound of the present invention. Thus, the terms "mainly consisting of" and "consisting of" are included within the scope of the term "comprising/comprising".

According to the present invention, a "pharmaceutically acceptable" ingredient is a substance suitable for use in humans and/or animals without excessive undesirable side effects such as toxicity, irritation and allergic reactions, i.e. one that has a reasonable balance of effect and risk.

According to the present invention, a "pharmaceutically acceptable carrier" is a solvent, suspending agent, or excipient, pharmaceutically or nutritionally acceptable, which is used to deliver a compound of formula (I) of the present invention, or an isomer, solvate, precursor, or a pharmaceutically acceptable salt thereof, to animals, and of people. The carrier may be liquid or solid.

Compound

The present invention provides a compound represented by the structural formula (I):

, а также R4 и группой

; также она может находиться между R2' и R3', R1' и

, R2' и

, а также R3' и группой

. Например, соединение может представлять собой:It should be understood that the point X in formula (I) is a schematic point and is not limited to the sides R1 or R1' shown in the figure. It can also be located between R1 and R3, R3 and R4, R2 and the group

, as well as R4 and the group

; it can also be between R2' and R3', R1' and

, R2' and

, as well as R3' and the group

. For example, a connection might be:

или

or

,

,

- шестичленное гетероциклическое кольцо, причем X представлено О; R1-R4 каждое по отдельности подбираются из числа водорода, гидроксила, С1-С4 алкила, С2-С4 алкенила, С2-С4 алкинила и галогена, или же две соседние группы R1-R4 связаны друг с другом для образования циклической структуры с основным кольцом; и R1'-R3' каждое по отдельности подбираются из числа водорода, гидроксила, С1-С4 алкила, С2-С4 алкенила, С2-С4 алкинила и галогена, или же две соседние группы R1'-R3' связаны друг с другом для образования циклической структуры с основным кольцом.in which

- six-membered heterocyclic ring, and X is represented by O; R1-R4 are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen, or two adjacent R1-R4 groups are bonded to each other to form a cyclic structure with a basic ring; and R1'-R3' are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen, or two adjacent R1'-R3' groups are bonded to each other to form a cyclic structures with a main ring.

In a preferred embodiment of the present invention, R1-R4 are each individually selected from hydrogen, hydroxyl and C1-C2 alkyl, or two adjacent R1-R4 groups are bonded to each other to form a five-membered ring with a main ring; and R1'-R3' are each individually selected from hydrogen, hydroxyl and C1-C2 alkyl, or two adjacent R1'-R3' groups are bonded to each other to form a five-membered ring with a main ring.

The present invention also includes an isomer, solvate, precursor or pharmaceutically acceptable salt of the compound of formula (I) as long as they also have functions similar or substantially similar to those of the compound of formula (I). A "pharmaceutically acceptable salt" refers to a salt formed by the reaction of a compound with an inorganic, organic acid, alkali or alkaline earth metal. These salts include, but are not limited to, (1) salts with inorganic acids such as hydrochloric, sulfuric, nitric, and phosphoric acids; (2) salts with organic acids such as acetic, oxalic, succinic, tartaric, methanesulfonic, maleic acids or arginine. Other salts include salts with alkali or alkaline earth metals (such as sodium, potassium, calcium, or magnesium) in the form of esters, carbamates, or other standard "predrugs". The compound has one or more non-symmetrical centers. Thus, these compounds may exist as racemic mixtures, individual enantiomers, individual diastereomers, mixtures of diastereomers, cis or trans isomers.

"Compound precursor" refers to a compound precursor that is converted to a compound of structural formula (I) or a salt or solution thereof through metabolic or chemical reactions in a patient after administration by an appropriate route.

In a preferred embodiment of the present invention, the five-membered ring is a heterocyclic ring containing an oxygen atom; preferably, the five-membered ring contains two oxygen atoms.

In a preferred embodiment of the present invention, the compound includes compounds of formulas (II)-(IV), among which the compound of formula (II) is most preferred.

, также обозначаемая как PL402;

, also referred to as PL402;

, также обозначаемая как PL404;

, also referred to as PL404;

, также обозначаемая как PL405.

, also referred to as PL405.

According to one embodiment of the present invention, a compound of Formula II comprises:

step 1: mixing 2,3,4-O-triacetylramnosyl-1-O-trichloroacetimidate and rhamnopyranosyl thioglycoside, and carrying out the reaction to obtain the final product as diramnopyranosyl thioglycoside with the structure represented by formula (V);

step 2: mixing the final product in the form of diramnopyranosyl-thioglycoside with the structure represented by formula (V), and

(4-O-tert-butyldimethylsilyl)-ferulic acid, as well as carrying out the reaction to obtain the final product in the form of diramnopyranosyl glycoside with the structure represented by formula VI;

step 3: mixing the final product diramnopyranosyl glycoside with the structure represented by formula VI and tetrabutylammonium fluoride, and carrying out the reaction to obtain a product without tert-butyldimethylsilyl (TBS) with the structure represented by formula VII; And

step 4: hydrolysis of the final product without tert-butyldimethylsilyl (TBS) to obtain a compound of formula P.

In one embodiment of the present invention, the reaction in step 1) comprises adding 2,3,4-O-triacetylramnosyl-1-O-trichloroacetimidate dropwise to rhamnopyranosyl-thioglycoside at -78°C.

In one embodiment of the present invention, the reaction in step 2) comprises adding diramnopyranosyl-thioglycoside dropwise to (4-O-tert-butyldimethylsilyl)-ferulic acid at -78°C.

According to one embodiment of the present invention, mixing in step 3) comprises adding tetrabutylammonium fluoride dropwise to the final diramnopyranosyl glycoside product at room temperature.

According to one embodiment of the present invention, a method for preparing a compound of formula III or IV comprises the following steps:

и

для получения продукта присоединения;stage 1: carrying out the addition reaction of compounds

And

to obtain an addition product;

step 2: protection of the vicinal diol in the adduct obtained in step 1) with an isopropylidene group to obtain a reaction product stable at a particular point;

для получения продукта конденсации; иstep 3: condensation of the reaction product according to step 2) with

to obtain a condensation product; And

step 4: reduction of the condensation product, and specifically removal of the isopropylidene group protecting the vicinal diol, to obtain a compound represented by formula (III) or (IV).

Upon familiarization with the structure of the compound of the present invention, it will be clear to those skilled in the art that this compound can be produced in a variety of ways well known in the prior art, using well known raw materials, for example, through chemical synthesis or extraction from organisms (such as animals or plants) which are fully included in the present invention.

This synthesized compound can be further purified by column chromatography, HPLC, and other methods.

Application

The inventors have found that the compound of formula (I) of the present invention can significantly alleviate the symptoms of neurodegenerative diseases and is also effective in case of depression or seizure. The compound of the present invention can suppress neuroinflammation, reduce the production of Αβ, and promote the production of neural progenitor cells. Experimental results have shown that the compound of the present invention significantly improves the learning ability and memory of animals. The increase in neural progenitor cells will further contribute to the increase in neurons. In general, the whole process is known as neurogenesis. Based on the principle of action of the compound of the present invention, it is possible to increase the number of neural progenitor cells, so this method is also effective in Huntington's disease and amyotrophic lateral sclerosis. Based on the principle of action of the compound of the present invention, this method is also effective in case of depression and attack. In the pathogenesis of depression or an attack, there is also neuroinflammation in the brain, which in turn leads to a reduction in the number of neural progenitor cells and changes in neuronal function. The compound of formula (I) according to the present invention can increase the number of neural progenitor cells, making it effective also in case of depression and seizure.

Based on the new observations of the inventors, the present invention proposes the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, in the preparation of drugs or kits for the prevention, alleviation or treatment of neurodegenerative diseases, depression or seizure.

The present invention also provides the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits for suppressing neuroinflammation.

The present invention also provides the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits to promote the production of neural progenitor cells.

The present invention also provides the use of a compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits for reducing Αβ production.

pharmaceutical composition

The present invention also provides a pharmaceutical composition comprising: (a) an effective amount of a compound of formula (I) or an isomer, solvate, precursor, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient.

In the pharmaceutical composition of the present invention, the compound represented by formula (I) or an isomer, solvate, precursor or pharmaceutically acceptable salt thereof is present in an effective amount. For example, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.001-50% by weight. Preferably, the pharmaceutical composition is 0.01-20% by weight of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention can be in various dosage forms, as long as the dosage form can enable the active ingredient to effectively reach the desired sites in the mammalian body. For example, the following dosage forms are available for selection: granulate, powder, tablets, pills, capsules, sustained release preparations, controlled release preparations, injections, infusion solutions or suspensions. According to the types of diseases to be treated with the compound of the present invention, those skilled in the art can use a dosage form that is convenient for administration.

For ease of preparation and storage, it is preferable that the pharmaceutical composition has a solid structure, in particular for tablets and solid or liquid-filled capsules. For ease of administration, it is preferred that the pharmaceutical composition is an oral medicament. The compound of the present invention or its pharmaceutical composition may also be stored in a sterilized device suitable for injection and infusion solution.

An effective dose of the compound of formula (I) as an ingredient may differ depending on the mode of administration and the severity of the disease being treated. However, in general, when the compound of the present invention is administered at a dose of about 0.01-100 mg/kg of body weight per day, satisfactory results can be achieved. Preferably, the compound of the present invention is administered in 1-3 divided doses per day or in a sustained absorption dosage form. This dosing regimen may be varied to provide an optimal therapeutic response. For example, in view of the imperative requirements of the therapeutic status, several divided doses may be given daily, or the dose may be proportionally reduced.

Below will be a further description of the present invention with reference to specific examples. It should be understood that these embodiments are provided for the sole purpose of demonstrating the present invention and are not intended to limit the scope of the present invention. Experimental methods that are not shown in the following examples are usually carried out in accordance with standard conditions, for example, the conditions described in ed. J. Sambrook "Molecular cloning: A Laboratory manuals", 3rd Edition, Science Press, 2002 ("Molecular cloning: instructions for laboratory work", 3rd edition, Science Press, 2002), or in accordance with the conditions, offered by the manufacturer.

Statistical data analysis

In the following examples, all experimental data are expressed as mean ± standard error. Student's t-test was used to compare between different treatment groups. One-way analysis of variance was used to examine outcomes across multiple groups, as well as retrospective analysis by Fisher's protected least significant difference or Bonferroni test; or two-way analysis of variance was used, and the Tukey method was used as a retrospective analysis. When P<0.05, there is a significant difference between groups.

Example 1 Synthesis of compound PL402

1. Preparation of Compound 3

(250 мг) и CH₂Cl₂ (12 мл) добавлялись в сухую реакционную колбу и помешивались в течение 10 минут при комнатной температуре. После охлаждения до -78°С, были добавлены раствор фильтрата триметилсилила (TMSOTf) (0,036 мл, 0,2 ммоль) в CH₂Cl₂ и раствор соединения 1 (521 мг, 1,2 ммоль) (Journal of the American Chemical Society, 2000, том 122, №41, c. 9939-9953) в CH₂Cl₂ (2 мл). По прошествии 30 мин для прекращения реакции добавлялся Et₃N в объеме 0,1 мл. Реакционный раствор был отфильтрован, упарен и очищен посредством колоночной хроматографии (петролейный эфир:этилацетат = 3:1) для получения соединения 3 (468 г, 0,9 ммоль, выход 90%).According to the method described in J. Chem. Soc, Perkin Trans. 1, 2000, 1445-1453, compound 2 (248 mg, 1.0 mmol) (Organic and Biomolecular Chemistry, 2014, vol. 12, no. 7, p. 1114-1123), dry molecular sieve

(250 mg) and CH ₂ Cl ₂ (12 ml) were added to a dry reaction flask and stirred for 10 minutes at room temperature. After cooling to -78°C, a solution of trimethylsilyl filtrate (TMSOTf) (0.036 ml, 0.2 mmol) in CH ₂ Cl ₂ and a solution of compound 1 (521 mg, 1.2 mmol) were added (Journal of the American Chemical Society , 2000, Vol. 122, No. 41, pp. 9939-9953) in CH ₂ Cl ₂ (2 ml). After 30 minutes, Et ₃ N was added in a volume of 0.1 ml to terminate the reaction. The reaction solution was filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 3 (468 g, 0.9 mmol, 90% yield).

1H NMR (300 MHz; CDCl ₃ ) 5.51 (s, 1 H), 5.33 (d, 1 H, J=1.7 Hz), 5.30 (dd, 1 H, J=1.9 Hz, 3.3), 5.22 (dd, 1 H, J ₁ =3.3 Hz, J ₂ =10.1 Hz), 5.08 (t, 1 H, J=10.0 Hz), 4.21-4.13 (m, 2 H), 4.06 (m, 1 H), 3.89 (m, 1 H), 3.56 (dd, 1 H, h=7.1 Hz, J2=9.9 Hz), 2.61 (m, 2 N), 2.15 (s, 1 N), 2.05 (s, 1 N), 1.98 (s, 1 N), 1, 53 (s, 1 H), 1.32 (s, 1 H), 1.34-1.21 (m, 9 H); MS IER m/z 521 (M+1) ⁺ .

2. Preparation of Compound 5

, 308 мг, 1,0 ммоль) и молекулярное сито

смешивались в сухом CH₂Cl₂ (20 мл), помешивались при комнатной температуре в течение 30 мин, затем охлаждались до -78°С, и дополнительно помешивались в течение 30 мин. N-йодсукцинимид (NIS) (225 мг, 1,0 ммоль) и TMSOTf (0,018 мл, 0,1 ммоль) были добавлены поочередно. Наконец, соединение 3 (312 мг, 0,6 ммоль), растворенное в сухом CH₂Cl₂ (DCM, 20 мл), добавлялось по каплям в реакционную смесь, помешивалось при -78°С в течение 20 мин с медленным возвратом к комнатной температуре и помешивалось снова. По прошествии 2 часов, насыщенные растворы Na₂S₂O₃ и NaHCO₃ добавлялись для гашения реакции, отфильтровывались, извлекались с помощью этилацетата, промывались насыщенным раствором хлорида натрия, высушивались посредством безводного Na₂SO₄, отфильтровывались, упаривались и очищались посредством колоночной хроматографии (петролейный эфир:этилацетат = 3:1) для получения соединения 5 в виде белого твердого вещества (368 мг, 0,48 ммоль, выход 80%).Compound 4 (

, 308 mg, 1.0 mmol) and molecular sieve

were mixed in dry CH ₂ Cl ₂ (20 ml), stirred at room temperature for 30 minutes, then cooled to -78°C, and further stirred for 30 minutes. N-iodosuccinimide (NIS) (225 mg, 1.0 mmol) and TMSOTf (0.018 ml, 0.1 mmol) were added in turn. Finally, compound 3 (312 mg, 0.6 mmol) dissolved in dry CH ₂ Cl ₂ (DCM, 20 ml) was added dropwise to the reaction mixture, stirred at -78°C for 20 min with slow return to room temperature. temperature and stir again. After 2 hours, saturated solutions of Na ₂ S ₂ O ₃ and NaHCO ₃ were added to quench the reaction, filtered, taken up with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous Na ₂ SO ₄ , filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate=3:1) to give compound 5 as a white solid (368 mg, 0.48 mmol, 80% yield).

1H NMR (400 MHz, CDCl ₃ ) 7.52 (d, 1 H, J=12 Hz), 6.09-6.88 (m, 2 H), 6.69 (d, 1 H, J=8 Hz), 6.24 (s, 1 H), 6.14 (d, 1 H, J=8 Hz), 5.20-5.15 (m, 2 H), 5.03 (d, 1 H , J=8 Hz), 4.93-4.90 (m, 1 H), 4.14 (dd, 1 H, J ₁ =4 Hz, J ₂ =8 Hz), 3.99 (d, 1 H, J=4 Hz), 3.37-3.69 (m, 2 H), 3.68 (s, 3 H), 3.43 (dd, 1 H, J ₁ =4 Hz, J ₂ = 8 Hz), 1.98 (s, 3 H), 1.89 (s, 3 H), 1.81 (s, 3 H), 1.38 (s, 3 H), 1.15 (s, 3 H), 1.11-1.05 (m, 6 H), 0.82 (s, 9 H), 0 (s, 6 H); MS IER m/z 767 (M+1) ⁺ .

Qualitative analysis of compound 5 is presented in Fig.7.

3. Preparation of compound PL402

Compound 5 (306 mg, 0.4 mmol) was dissolved in tetrahydrofuran (8 ml) and acetic acid (16 μl, 1.12 mmol), and a solution of tetrabutylammonium fluoride 1 Μ (TBAF) in tetrahydrofuran (THF) (0.54 ml, 0.54 mmol) was added with magnetic stirring at room temperature. After reaction at room temperature for 3.5 h, the reaction solution was diluted with ethyl acetate (30 ml), distilled and washed with water, saturated NaHCO ₃ solution and brine, and then dried over anhydrous Na ₂ SO ₄ . By filtration and drying in a rotary drum, a crude mixture (253 mg) was obtained, which was directly used in the next step.

To the reaction flask containing the product (235 mg, 0.36 mmol) from the previous step was added a solution of trifluoroacetic acid (TFA) dissolved in CH ₂ Cl ₂ (2:25, 5 ml), the reaction mixture was stirred at room temperature for 1 hour, then the stirring was stopped. Aqueous NaOH solution (5 ml, 1 M) was added to an ice bath to quench the reaction, taken up with CH ₂ Cl ₂ and then dried over anhydrous Na ₂ SO ₄ . By filtration and drying in a rotary drum, a crude mixture (165 mg) was obtained, which was directly used in the next step.

The product from the previous step (165 mg, 0.27 mmol) was dissolved in a mixed solution (8 ml) of anhydrous CH ₃ OH and anhydrous CH ₂ Cl ₂ (1:1), and the catalytic concentration of sodium methoxide (0.2 eq.) was added to bring the pH to 9-10. The reaction mixture was stirred at 40°C for 5 hours, and an acidic cationic resin was added to neutralize the reaction mixture. By filtration and evaporation a white solid was obtained. The product was dissolved in water (1 ml) and purified by silica gel reverse phase chromatography to give compound PL402 (78 mg, 0.16 mmol, three steps yield: 40%).

1H NMR (400 MHz; MeOD) 7.683 (d, 1 H, J=15.6 Hz), 7.229 (d, 1 H, J=1.6 Hz), 7.114 (dd, 1 H, 1=1.6 Hz, J ₂ =8 Hz), 6.829 (d, 1 Η, J=8.8 Hz), 6.407 (d, 1 Η, J=15.6 Hz), 6.403 (d, 1 Η, J=1, 6 Hz), 5.231 (d, 1 Η, J=1.6 Hz), 3.994 (q, 1 Η, J=2 Hz), 3.896 (s, 3 Η), 3.880 (s, 1 Η), 3.845- 3.831 (m, 1 Η), 3.777-3.700 (m, 2 Η), 3.650-3.621 (m, 2 Η), 3.431-3.408 (m, 1 Η), 1.319 (d, 3 Η, J=6 Hz) , 1268 (d, 3 Η, J=6.4 Hz); MS IER m/z 487 (M+1) ⁺ .

Qualitative analysis of PL402 is presented in Fig.8.

Example 2 Synthesis of Compounds PL404 and PL405

1. Preparation of Compound 7

(20 г) и CH2Cl2 (1,5 л) добавлялись в сухую реакционную колбу, помешивались при комнатной температуре в течение 20 мин и охлаждались до -78°С. Были добавлены раствор фильтрата триметилсилила (TMSOTf) (0,18 мл, 1 ммоль) в CH2Cl2 и соединение 1 (25,6 г, 60 ммоль) (Journal of the American Chemical Society, 2000, том 122, №41, с. 9939-9953) в CH2Cl2 (2,5 л). По прошествии 30 мин для прекращения реакции добавлялся Et3N в объеме 0,5 мл. Реакционный раствор был отфильтрован, упарен и очищен посредством колоночной хроматографии (петролейный эфир:этилацетат = от 10:1 к 3:1) для получения соединения 7 (21,9 г, 42,4 ммоль, выход 85%). МС ИЭР м/з 517 (М+1)⁺.Compound 6 (12.2 g, 5 mmol) (Chemistry - A European Journal, 21(29), 10416-10430; 2015), dry molecular sieve

(20 g) and CH2Cl2 (1.5 L) were added to a dry reaction flask, stirred at room temperature for 20 min and cooled to -78°C. A solution of trimethylsilyl filtrate (TMSOTf) (0.18 ml, 1 mmol) in CH2Cl2 and compound 1 (25.6 g, 60 mmol) were added (Journal of the American Chemical Society, 2000, vol. 122, no. 41, p. 9939 -9953) in CH2Cl2 (2.5 L). After 30 min, Et3N was added in a volume of 0.5 ml to terminate the reaction. The reaction solution was filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain compound 7 (21.9 g, 42.4 mmol, 85% yield). MS IER m/z 517 (M+1) ⁺ .

2. Preparation of Compound 8

Compound 7 (21.9 g, 42.4 mmol) was dissolved in a mixed solution (2 L) of anhydrous CH3OH and anhydrous CH2Cl2 (1:1) and a catalytic concentration of sodium methoxide (0.2 eq) was added to adjust the pH until 9-10. The reaction mixture was stirred at 40°C for 4 hours, and an acidic cationic resin was added to neutralize the reaction mixture. The reaction solution was filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 8 (11.6 g, 29.7 mmol, 70% yield). MS IER m/z 391 (M+1) ⁺ .

3. Preparation of compound 9

To a 1 L three-necked flask were added the compound (11.6 g, 29.7 mmol), acetone (120 mL), p-toluenesulfonic acid (116 mg, 1% w/w) and then 2,2-dimethoxypropane (9. 3 g, 89.4 mmol). The reaction solution was reacted at 15-20° C. for 1 hour until TLC indicated that the reaction was complete. Triethylamine (24 ml) was added to the reaction solution, then it was evaporated, dried and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain compound 9 (8.9 g, 20.7 mmol, 70% yield.

MS IER m/z 431 (M+1) ⁺ .

4. Preparation of Compound 10

Compound 9 (8.9 g, 20.7 mmol), dichloromethane (500 ml) and compound 4 (9.6 g, 30.2 mmol) were added to a 1 L three-necked flask. Diisopropylethylamine (10.7 g, 82.9 mmol), 1-ethyl-3-3-dimethylaminopropylcarbodiimide (7.9 g, 41.1 mmol),

4-dimethylaminopyridine (0.3 g, 2.5 mmol) and diisopropylethylamine (6.7 g, 51.9 mmol). The reaction solution was stirred at 15-20°C for 18 hours, then the organic phase was washed with saturated sodium chloride solution (50 ml), evaporated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2: 1) to obtain compound 10 (10 g, 13.9 mmol, 70% yield).

MS IER m/z 721 (M+1) ⁺ .

5. Preparation of compound 11

THF (100 ml), compound 10 (10 g, 13.9 mmol) and TABF compound (25 ml, 1 mol/l solution in THF) were added to a 500 ml three-necked flask. The reaction mixture was prepared at 10-20° C. until TLC indicated that the reaction was complete. The reaction solution was added to water (200 ml) and extracted with ethyl acetate (200 ml * 3). The organic phases were combined, washed with saturated brine (200 ml * 6), dried over anhydrous sodium sulfate, filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain compound 11 (4 .2 g, 6.9 mmol, 50% yield.

MS IER m/z 607 (M+1) ⁺ .

6. Preparation of Compound 12

Compound 11 (4.2 g, 6.9 mmol), acetic acid (100 ml), water (5 ml), NaOAc (37.5 g, 276 mmol) and PdCl2 (2, 0 g, 11.3 mmol). The reaction solution was stirred at 15-20°C for 40 hours. It was filtered, evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain compound 12 (2.35 g, 4 .2 mmol, 60% yield.

MS IER m/z 567 (M+1) ⁺ .

7. Preparation of PL404 and PL405

Compound 12 (2.35 g, 4.2 mmol), dichloromethane (28 ml) and TFA (2.4 g, 21 mmol) were added to a 500 ml three-necked flask. The reaction solution was stirred at 15-20°C for 20 minutes, cooled to 0-5°C, adjusted to pH 8-9 with sodium bicarbonate solution, and separated. The organic phase was evaporated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to give compounds PL404 (273 mg, 0.52 mmol) and PL405 (200 mg, 0.41 mmol).

PL404:

1H NMR (400 MHz; CDCl3) 7.689 (d, 1 H, J=15.6 Hz), 7.081 (dd, 1 H, J1=1.6 Hz, J2=8 Hz), 7.034 (s, 1 H) , 6.936 (d, 1 H, J=13.6 Hz), 6.339 (d, 1 H, J=16 Hz), 5.372 (d, 0.7 H, J=6 Hz), 5.086 (s, 1 H ), 4.99 (d, 0.3 N, J=6 Hz), 4.86-4.80 (m, 1 N), 4.768 (d, 0.7 N, J=6 Hz), 4.695 ( d, 0.3 N, J=6 Hz), 4.609 (d, 0.7 N, J=6 Hz), 4.524 (d, 0.3 N, J=6 Hz), 4.028-4.008 (m, 2 H), 3.981-3.896 (m, 6 H), 1.446-1.223 (m, 12 H); MS IER m/z 527 (M+1) ⁺ .

Qualitative analysis of PL404 is presented in Fig.9.

PL405:

1H NMR (400 MHz; MeOD) 7.67 (dd, 1 H, J1=4 Hz, J2=8 Hz), 7.21 (s, 1 H, J=1.6 Hz), 7.09 (dd , 1 H, J1=1.6 Hz, J2=8 Hz), 6.81 (d, 1 H, J=8 Hz), 6.43 (dd, 1 H, J1=4 Hz, J2=12 Hz ), 5.26 (d, 1 H, J=4 Hz), 5.05 (t, 1 H, J=8 Hz), 5.00 (s, 0.5 H), 4.72 (s, 0.5 N), 4.04-4.00 (m, 1 N), 3.95-3.93 (m, 1 N), 3.89 (s, 3 N), 3.88-3, 85 (m, 2 N), 3.77-3.75 (m, 1 N), 3.55-3.50 (m, 0.5 N), 3.48-3.45 (m, 1 N ), 3.34-3.31 (m, 0.5 H), 1.33 (d, 1 H, J=4 Hz), 1.30 (d, 2 H, J=4 Hz), 1, 27 (d, 3 H, J=4 Hz); MS IER m/z 487 (M+1) ⁺ .

Qualitative analysis of PL405 is presented in Fig.10.

Example 3 Improved Learning and Memory in Alzheimer's Model Mice with PL402

1. Morris water maze test

Twenty transgenic male APP/PS1 mice (AD model mice) aged 5-6 months were selected and divided into reference and polysaccharide groups according to the random number table method. PL402 was administered daily intragastrically (50 mg/kg), and 10 non-transgenic mice were used for the negative control group (no injection). After 90 days of consecutive administration, a Morris water maze test was performed to determine the effect of PL402 on learning ability and cognition in APP/PS1 mice.

In this experiment, the standard procedure for conducting the Morris water maze test was used, which includes tests for orientation to the ground and spatial orientation. The duration of the experiment was 7 days in total, and the spatial orientation test was activated on days 4 and 7.

According to the results presented in Figure 1, it can be seen that during the orientation test, all three groups of animals showed an accelerated escape latency after 3 days of accommodation, indicating that each mouse was able to successfully complete the exploration task. The rescue latency is taken as a defining indicator.

The results showed that mice in the negative control group reacted faster and took less time to find the platform after entering the water. As the preparation time increased, the latency to reach the platform decreased. In contrast, the response of mice in the reference group was slow. After entering the water, they walked in circles along the wall of the vessel and did not show any attempts to save themselves. After being forcibly guided to the platform, they jumped back into the water. After repeated attempts, they finally found the platform, but the time spent searching for it was quite long. The ability of mice in the PL402 group to find the platform improved significantly as the number of trials increased. All mice in these three groups had a certain spatial memory. The latency to reach the platform in the reference group was longer than in the control group, indicating that the learning and memory ability of mice in the reference group was reduced, and these mice better modeled the manifestations of learning and memory impairments in AD. Compared to the reference group, the latency of mice in the PL402 group showed a statistically significant improvement, proving that the learning and memory abilities of the AD model mice improved significantly after PL402 administration.

2. Treatment with 5-bromo-2-deoxyuridine (BrdU)

When conducting an experiment with the introduction of the drug, each mouse with a model of AD at the age of 5-6 months was intragastrically injected with 100 μl of PL402 at a dosage of 50 mg/kg of body weight. A control group was established and the mice were injected once a day with 100 µl of water intragastrically. The administration continued for 90 days, and from day 60, intraperitoneal injection of 5-bromo-2-deoxyuridine (BrdU) was performed once a day at a dosage of 50 mg/kg of body weight for a total of 7 days. After 90 days of administration, the mice were euthanized and then subjected to paraformaldehyde (PFA) perfusion, after which their entire brains were removed for further experiments.

Example 4 Suppression of Neuroinflammation by PL402

Neuroinflammation of the brain in AD is one of the causes of cognitive decline. Microglia are key cells that carry neuroinflammation. The inventors conducted a study on the effectiveness of PL402 in suppressing neuroinflammation by detecting the manifestation of allergic inflammatory factors in mouse BV-2 cells.

BV-2 Cell Growth and Stimulation: BV-2 cells were grown in DMEM, seeded in a 24-well plate, and grown for 24 hours. Compound PL402 (0, 10, 30, 100 or 300 μM) and LPS (300 ng/ml) were then added and then incubated for 24 h. RNA was extracted with Trizol, and manifestations of allergic inflammation factors were established by means of qPCR.

The results show that treatment with PL402 can significantly suppress the manifestations of the allergic inflammatory factors IL-6 and IL-1β, as shown in Fig.2.

Example 5 Decrease in Αβ production by PL402

Αβ is the main pathogenic protein in AD. The authors investigated whether compound PL402 had an effect on suppressing Αβ production by determining the level of Αβ in SK-N-SH neuroblastoma cells (which can secrete Αβ).

Growth of SK-N-SH cells and determination of Αβ: SK-N-SH cells were grown in DMEM, seeded in a 24-well plate and grown for 24 hours. Compound PL402 (0, 10, 30, 100 or 300 μM) was then added and then incubated for 24 hours. The supernatant was collected and the total Αβ protein level was determined by ELISA test.

The results show that treatment with PL402 can significantly suppress the production of Αβ, as shown in Fig.3. The suppression effect is strongest at a concentration of PL402 equal to 100 μM.

Example 6 Effect of PL404 on Learning and Memory in Animals

To determine the effect of PL404 on the ability of animals to learn and remember, the selection of animals and the performance of the Morris water maze test described in example 3 were performed.

The results are shown in Fig.4. The latency of mice in the PL402 treated group was significantly different from that of the reference group, and this difference is statistically significant.

Thus, the learning and memory abilities of mice with the AD model improved significantly after administration of PL404.

Example 7 Effect of PL404 on Proliferation of Human Neural Progenitor Cells

The inventors conducted studies on the effect of PL404 on promoting proliferation by determining the incorporation of EdU in a human neural progenitor cell (differentiation by induced pluripotent stem cells). The dosage of PL404 was 0, 1.3, 10, 30 or 100 μM.

The results are shown in Fig.5. The results show that treatment with PL404 can significantly promote the proliferation of human neural progenitor cells. Compared to the control group not treated with PL404, the level of proliferation of human neural progenitor cells increased by 30%.

Example 8 Effect of PL405 on Proliferation of Human Neural Progenitor Cells

A method similar to that of Example 7 was used, except that the PL404 compound was replaced by the PL405 compound, and by determining the incorporation of EdU in a human neural progenitor cell, a study was made of the effect of the PL405 compound on promoting proliferation.

The results are shown in Fig.6. The results show that treatment with PL405 can significantly promote the proliferation of human neural progenitor cells. Compared to the control group, treatment with PL405 increased the proliferation rate of human neural progenitor cells by approximately 60%.

All documents referred to in accordance with the present invention, in this application, are contrasted by reference as if each document were given in the form of a opposed reference. In addition, it should also be understood that after reading the description of the present invention by a person skilled in the art, various changes or modifications can be made to it, and these equivalents will also fall within the scope defined by the appended claims of the present application.

Claims (27)

1. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

, characterized in that in

there is a cyclic structure selected from the group consisting of

R1-R4 are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen, or two adjacent R1-R4 groups are linked together to form a five-membered ring with a basic ring, the five-membered ring is a heterocyclic ring containing two oxygen atoms; while in

there is a cyclic structure

R1'-R3' are each individually selected from hydrogen, hydroxyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen. 2. The compound according to claim 1 represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that R1-R4 are each individually selected from hydrogen, hydroxyl and C1-C2 alkyl, or two adjacent R1-R4 groups are bonded to each other to form a five-membered ring with a main ring, the five-membered ring is a heterocyclic ring containing two oxygen atoms; And R1'-R3' are each individually selected from hydrogen, hydroxyl and C1-C2 alkyl. 3. The compound according to claim 1 represented by formula (I) or a pharmaceutically acceptable salt thereof, characterized in that it includes

4. The use of a compound according to any one of paragraphs. 1-3 represented by formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of drugs or kits for the prevention, alleviation or treatment of neurodegenerative diseases, depression or seizure. 5. Use according to claim 4, characterized in that neurodegenerative diseases are neurodegenerative diseases characterized by significant neuroinflammation in the brain; or neurodegenerative diseases characterized by a significant increase in Aβ production; or neurodegenerative diseases characterized by a significant decrease in learning ability and memory impairment; or neurodegenerative diseases characterized by a significant decrease in the number of neural progenitor cells. 6. Use according to claim 5, wherein the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Lewy body dementia, Huntington's disease and amyotropic lateral sclerosis. 7. The use of a compound according to any one of paragraphs. 1-3 represented by formula (I) or a pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits for reducing the suppression of neuroinflammation. 8. The use of a compound represented by formula (I) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits to promote the production of neural progenitor cells. 9. The use of a compound represented by formula (I) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, in the preparation of compositions, kits or kits to reduce the production of Aβ. 10. Pharmaceutical composition for the prevention, alleviation or treatment of Alzheimer's disease, comprising: a compound represented by formula (I) according to any one of paragraphs. 1-3 or its pharmaceutically acceptable salt; And a pharmaceutically acceptable carrier. 11. Pharmaceutical composition according to claim 10, characterized in that the dosage forms of the pharmaceutical composition include: granulate, powder, tablets, pills, capsules, sustained release preparations, controlled release preparations, injections, infusion solutions or suspensions. 12. A method for preventing, alleviating, or treating neurodegenerative diseases, depression caused by a neurodegenerative disease, or an attack of a neurodegenerative disease, comprising administering an effective amount of a compound represented by formula (I) according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Images