WO2014111028A1

WO2014111028A1 - Genistein alkylamine compound, preparation method and use thereof

Info

Publication number: WO2014111028A1
Application number: PCT/CN2014/070720
Authority: WO
Inventors: 邓勇; 谭正怀; 强晓明; 袁文; 桑志培; 刘强; 李岩
Original assignee: 四川大学
Priority date: 2013-01-21
Filing date: 2014-01-16
Publication date: 2014-07-24
Also published as: CN103113340B; CN103113340A

Abstract

Disclosed in the present invention are a new genistein alkylamine compound (I) and pharmaceutically acceptable salts thereof, and the preparation method and use thereof in the preparation of drugs for the treatment and/or prevention of diseases related to neurodegeneration, comprising but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV related dementia, multiple sclerosis, progressive amyotrophic lateral sclerosis, neuropathic pain and glaucoma, wherein Ar represents any of the structure units as shown in the following (A)-(C), and n=1-2.

Description

Genistein isoflavone alkylamine compound, preparation method and use thereof

3⁄4b ^ field

The present invention belongs to the field of medicinal chemistry, and relates to a novel class of genistein alkylamine compound (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof and a medicament for treating and/or preventing a neurodegenerative disease Uses, including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive spinal sclerosis, neuropathic pain, glaucoma, etc. Neurodegenerative disease.

Background technique

Vascular Dementia (VD) is a type of cerebrovascular disease (including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and chronic hypoxic cerebrovascular disease, etc.) The main clinical manifestations of clinical syndromes with dysfunction include: cognitive ability, memory and social life decline, as well as emotional and personality changes, is a chronic progressive disease. Vascular dementia in Asian countries such as China and Japan is the first cause of senile dementia. With the gradual advancement of the world population, cerebrovascular diseases are increasing, and the incidence of vascular dementia is gradually increasing, seriously affecting The quality of work and quality of the elderly and the heavy economic and spiritual burden on society and families. Therefore, VD has become an important research hotspot in the field of geriatrics and psychiatry. Vascular dementia is complicated by the pathogenesis, and there are no drugs that can block the development of the disease. At present, clinical treatment is to improve blood circulation and brain metabolism in the brain, and strengthen brain nutrition.

In recent years, studies at home and abroad have shown that patients with VD are often accompanied by abnormalities in the cholinergic system while exhibiting cognitive impairment. ChAT-positive neurons and fiber density in hippocampus of patients with VD were decreased, and ChAT activity in different parts of the brain decreased. The concentration of ACh in cerebrospinal fluid of patients with VD was significantly lower than normal, and the degree of decrease in concentration was positively correlated with the severity of dementia. Cerebral ischemia can lead to an increase in acetylcholinesterase activity in the brain. At the same time, some acetylcholinesterase inhibitors such as HuperzineA and Revastigmine can also protect neuronal damage caused by ischemia and promote nerve damage after cerebral ischemia. Recovery of brain function indicates that acetylcholinesterase inhibitors can be used for the treatment of vascular dementia.

Alzheimer's disease (AD) is a central nervous system degenerative disease characterized by progressive cognitive impairment and memory impairment. Its incidence is increasing year by year, becoming the second only to cardiovascular disease and cancer. The high-risk disease has risen to the fourth place in the developed countries in Europe and the United States. According to the World Health Organization, there are 10% mental retardation in the world's 65-year-olds, and one-half of them have dementia, and the incidence rate is over 50%. At present, there are more than 5 million patients with AD in China. There is no effective treatment for this disease. As China's population ages, the number will be even larger. Because the clinical manifestations of AD are memory ability, orientation ability, loss of thinking and judgment ability, and decreased daily living ability, and even abnormal mental behavior symptoms, it is difficult for patients to care, which imposes a heavy burden on society and families. The development of new treatment drugs for Alzheimer's disease is of great significance. From the perspective of market demand, the world city Field research and strategic consulting firm's recently completed "Alzheimer's Disease Report" predicts that global sales of Alzheimer's treatment drugs will reach $10 billion by 2015; in China, with the rapid increase in the incidence of Alzheimer's disease, this The market for generic drugs is also expanding rapidly.

AD is a disease caused by a variety of factors, the pathogenesis is complex, and its pathogenesis has not yet been fully elucidated. After death, the patient found anatomy of the brain amyloid senile plaque (Senile Plaques, SP) and neurofibrillary Tangles (NFT) It is the most characteristic histopathological change in AD patients. In recent years, many researchers have devoted themselves to revealing the pathogenesis of AD at the molecular and cellular levels, and have proposed various hypotheses such as: cholinergic neuronal damage, amyloid deposition, tau hyperphosphorylation, inflammation, and freedom. Base oxidation, metal ion imbalance, etc. Therefore, new therapeutic approaches and means to develop these pathogenesis will hopefully alleviate and improve the condition of AD patients. At present, there are two main types of drugs effective in the treatment of AD in clinical practice: (1) Cholinergic hypothesis based on neurotransmitter choline acetate deficiency leading to cognitive dysfunction, using acetylcholinesterase inhibitors to improve acetylcholine in the brain of patients Levels such as: Tacrine, DonepeziK Ravastigmine, Galantamine; (2) N-methyl-D-aspartate (NMDA) receptor inhibitors reduce glutamate damage to nerve cells, such as: Memantine Hydrochloride » These drugs have problems such as single target, more toxic side effects, and poor long-term efficacy for AD patients.

Therefore, research and development of anti-neurodegenerative diseases with new chemical structures, novel mechanisms of action, multiple targets, and low toxic side effects are not only in line with the urgent needs of the society's aging process, but also have good market prospects.

Summary of the invention

The object of the present invention is to disclose a class of genistein isolamine alkylamine compound (I) and a pharmaceutically acceptable salt thereof. Another object of the present invention is to disclose a process for producing such a ginkgo isoflavone alkylamine compound (I) and a pharmaceutically acceptable salt thereof.

A further object of the present invention is to disclose the use of the genistein-like alkylamine compound (I) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating and/or preventing a neurodegenerative disease, including but not Limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive spinal cord sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases.

The chemical structure of the genistein is exemplified by the present invention:

Ar O-Linkei^N

, R ₂

(I)

Where: Ar represents any of the structural units shown in (A (C), n = 1 or 2;

(A) (B) (C)

Represents H, d Cu alkyl; R ₂ represents d Cu alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridine 9-yl, 6-chloro-1,2,3,4 -tetrahydroacridine 9-yl, 8-chloro-1,2,3,4-tetrahydroacridine 9-yl, 6,8-dichloro-1,2,3,4-tetrahydroacridine 9- Or N-demethylgalantamine; NR ₂ also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position (^~(:^alkyl substituted piperidinyl, a piperidinyl group substituted with a benzyl group or a substituted benzyl group, a piperazinyl group, a piperazinyl group substituted at the 4-position by a d-C ₁₂ alkyl group, and a 4-position substituted with a benzyl group or a substituted benzyl group Piperazine; R ₃ represents H, C Cu alkyl, CF ₃ , C ac; Linker table (C3⁄4) _m , m Table 1-12;

Wherein, when Ar represents (A) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 3 or 4, NR ₂ does not represent 4-benzylpiperazinyl; when Ar represents (A) structure And R ₃ represents H, Linker is (CH ₂ ) _m , and when m is 3, NR2 does not represent morpholinyl, tetrahydropyrrolyl, 4-methylpiperazinyl; when Ar represents (B) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 2, 3 or 4, and when R _{2 is} different, it represents methyl, ethyl, n-propyl or n-butyl; when Ar represents (B) structural unit And R ₃ represents H, Linker is (CH ₂ ) _m , and when m is 2, 3, 4, 5 or 6, RiNR ₂ does not represent morpholinyl, piperazinyl or 4-methylpiperazinyl; (B) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 2, 3 or 4, R R2 does not represent tetrahydropyrrolyl, piperidinyl; when Ar represents (B) structural unit and R ₃ means

H, Linker is (CH ₂ ) _m , m is 4 or 6, Ι^ΝΙ^ does not represent 4-ethylpiperazinyl; when Ar represents (B) structural unit and R ₃ represents H, Linker is (CH ₂ When _m , m is 3 or 5, RiNRz does not represent 4-benzyl piperazinyl;

, — , — 0-(H ₂ C) _m — < NR ₄ ,^ _^

"-O-Linker-NRilV can also be V", m Table 1-12, Table H, Ci~Ci2 alkyl, benzyl or substituted benzyl;

The above term "substituted benzyl" refers to a benzyl group substituted by a group of 1-4 selected from the group consisting of the following groups: F, Cl, Br,

I, d_ ₄ alkyl, d_ ₄ alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, these substituents may be at any possible position of the benzene ring.

The genistein isolamine alkylamine compound (I) proposed by the present invention can be prepared by the following method:

(1) When Ar represents a structural unit (A), and R ₃ = H, and Linker represents (CH ₂ ) _m :

, ^R 1

HN ₄

Base R ₂ Ri

Ar'- OH + X(CH ₂ ) _m X Ar'-0-(CH ₂ ) _m X *► Ar'— 0_(CH ₂ ) _m — N

R ₂

Wherein: X represents Cl, Br, I; Ar represents a structural unit (A), and R ₃ represents H _; and R ₂ , m have the same definitions as the chemical structural formula (I).

Using methoxymethylene-protected genistein (1) as a starting material, reacting with a dihaloalkyl compound (2) under solvent and basic conditions to form the corresponding aryloxyalkyl halide compound (3) , the obtained intermediate 3 and the organic amine compound (4) are reacted in a solvent to obtain a corresponding methoxymethylene-protected genistein isolamine alkylamine compound (5), and the compound 5 is removed under solvent and acidic conditions. The methoxymethylene protecting group gives the corresponding ginseng isoflavone alkylamine compound (1).

The specific preparation method is described as follows:

In the step a), the base used in the reaction is: an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal hydrogencarbonate, an alkaline earth metal hydrogencarbonate, d- an alkali metal salt of ₈ alcohol, an organic tertiary amines or quaternary ammonium hydroxides (such as: triethylamine, tributylamine, trioctylamine, pyridine, N- methylmorpholine, N- methylpiperidine, triethylene two Amine, tetrabutylammonium hydroxide), preferably a base: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, two methyl sulfoxide, dichloromethane, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ - ₈ alkane, preferably solvents: NN- dimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene; Compound (1): dihaloalkyl compound (2): The molar ratio of the base is 1.0: 1.0-10.0: 1.0-10.0, preferably the molar charge ratio is 1.0: 1.0-5.0: 1.0-5.0; the reaction temperature is room temperature~ 150 ° C, preferably the reaction temperature is room temperature ~ 120 ° _C; reaction Room is 1~Ί1 hours, the reaction time is preferably 2 to 24 hours.

Said step b), the solvent used in the reaction: ether, tetrahydrofuran, NN- dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, d - _8-ol, or a C ₅ - ₈ alkane, preferably solvents: NN- dimethylformamide, acetone, acetonitrile, tetrahydrofuran, ethanol or toluene; intermediate (3): moles of an organic amine compound (4) the feed ratio The ratio is 1.0: 1.0-10.0, preferably the molar ratio is 1.0: 1.0-5.0; the reaction temperature is room temperature to 150 ° C, preferably the reaction temperature is room temperature to 120 ° C; the reaction time is 1 to 72 hours, and the preferred reaction time is 2 ~24 hours.

Said step c), the solvent used in the reaction: water, d_ ₆ alcohols, NN- dimethylformamide, tetrahydrofuran, C ₃ _ ₈ aliphatic ketone, acetonitrile, 1,4-dioxane, or dimethyl The sulfoxide, preferably the solvent is: water, methanol, ethanol, 1,4-dioxane, or acetone; the acid used is: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, d- ₆ fatty acid, d- ₆ alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably the acid is: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid; acid in the reaction system The mass fraction is from 0.1% to 100%, preferably the mass fraction is from 10% to 95%, the reaction temperature is from 0 to 150 ° C, and the preferred reaction temperature is from room temperature to 120 ° C; the reaction time is from 30 minutes to 24 hours, preferably. The reaction time is 1 to 8 hours.

(2) When Ar represents structural unit (B), or (C), or structural unit (A) in which R ₃ does not represent H, and Linker represents (CH ₂ ) _m : HN ₄

Base R ₂ i

Arf OH I + X(CH ₂ ) _m X Ar - 十-00__((CCHH ₂₂ )) _mm XX| AArr 十- 0_(CH ₂ ) _m — N,

Nb R ₂

6 2 7 (I)

Where: X represents Cl, Br, I; Ar represents structural unit (B) or (C), and R ₃ does not represent H structural unit (A); , R ₂ , R ₃ , m, n definition and chemistry The structural formula (I) is the same.

Starting with the corresponding genistein is used as a starting material, and reacting with the dihaloalkyl compound (2) under basic conditions to form the corresponding aryloxyalkyl halide compound (7), and the resulting compound 7 is The organic amine compound (4) is reacted to obtain the corresponding genistein isolamine alkylamine compound (1).

The specific preparation method is described as follows:

Said step a), the base used for the reaction: alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alcohol ₈ Alkali metal salt, organic tertiary amine or quaternary ammonium base (eg: triethylamine, tributylamine, trioctylamine, pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, Tetrabutylammonium hydroxide), preferably the base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ _ ₈ alkane, preferably solvents: NN- dimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene; compound ( 6): dihaloalkyl compound (2): the molar ratio of the base is 1.0: 1.0-15.0: 1.0-15.0, preferably the molar ratio is 1.0: 1.0-6.0: 1.0-6.0; the reaction temperature is room temperature ~ 150 ° C, preferably the reaction temperature is room temperature to 120 ° C _{; the} reaction time is 1 to Ί 1 hour, preferably the reaction time is 2 to 24 hours.

Said step b), the solvent used in the reaction: ether, tetrahydrofuran, NN- dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, d - _8-ol, or a C ₅ - ₈ alkane, preferably solvents: NN- dimethylformamide, acetone, acetonitrile, tetrahydrofuran, ethanol or toluene; compound (7): moles of an organic amine compound (4) the feed ratio 1.0: 1.0-15.0, preferably the molar charge ratio is 1.0: 1.0-6.0; the reaction temperature is room temperature to 150 ° C, preferably the reaction temperature is room temperature to 120 ° C; the reaction time is 1 to 72 hours, and the preferred reaction time is 2~ 24 hours.

(3) When Ar table

Wherein: X represents Cl, Br, I; Ar represents a structural unit (A), and R ₃ represents H _; m, R4 have the same definitions as the chemical structural formula (I). Using methoxymethylene-protected genistein (1) as a starting material, it is reacted with 1-substituted-4-haloalkylpiperazine (8) under solvent and basic conditions to obtain the corresponding methoxy group. Methyl-protected genistein alkylamine compound (9), compound 9 The methoxymethylene protecting group is removed under solvent and acidic conditions to give the corresponding genistein alkylamine compound (1).

The specific preparation method is described as follows:

Said step a), the base used for the reaction: alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alcohol ₈ Alkali metal salt, organic tertiary amine or quaternary ammonium base (eg: triethylamine, tributylamine, trioctylamine, pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, Tetrabutylammonium hydroxide), preferably the base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl Sulfoxide, dichloromethane, chloroform, C ₃ _-8 fatty ketone, benzene, toluene, acetonitrile or C ₅ _-8 alkane, preferred solvents are: NN-dimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene; methoxy Methylene-protected genistein (1): 1-substituted-4-haloalkylpiperazine (8): The molar molar ratio of the base is 1.0: 1.0-10.0: 1.0-10.0, preferably the molar charge ratio is 1.0 : 1.0-5.0: 1.0-5.0; The reaction temperature is room temperature ~ 150 °C, preferably the reaction temperature Room temperature ~ 120 ° C; the reaction time is 1 to 72 hours, the reaction time is preferably 2 to 24 hours.

Said step b), the reaction solvent used was: water, d- ₆ alcohols, NN- dimethylformamide, tetrahydrofuran, C ₃ - ₈ aliphatic ketone, acetonitrile, 1,4-dioxane, or di- The methyl sulfoxide, preferably the solvent is: water, methanol, ethanol, 1,4-dioxane, or acetone; the acid used is: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, d- ₆ fatty acid, d — ₆ alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably the acid is: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid; The mass fraction in the system is from 0.1% to 100%, preferably the mass fraction is from 10% to 95%, the reaction temperature is from 0 to 150 ° C, and the preferred reaction temperature is from room temperature to 120 ° C; the reaction time is from 30 minutes to 24 hours. Preferably, the reaction time is from 1 to 8 hours.

B), or (C), or R ₃ does not represent structural unit (H) of H, -O-Linker-Ni^Rz

Wherein: X represents Cl, Br, I; Ar represents a structural unit (B;), or (C;), or R ₃ does not represent H structural unit (A); , m, n definition and chemical structure formula (I) Same.

Corresponding genistein is used as a starting material to react with 1-substituted-4-haloalkylpiperazine (8) under basic conditions to obtain the corresponding genistein alkylamine compound. (1).

The specific preparation method is as follows: The alkali used for the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, organic uncle Amine or quaternary ammonium base (Such as: triethylamine, tributylamine, trioctylamine, pyridine, N- methylmorpholine, N- methylpiperidine, triethylenediamine, tetrabutyl ammonium hydroxide) or alkali metal salt of an alcohol d_ ₈ Preferably, the base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine, or sodium methoxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide, two methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ - ₈ alkane, preferably solvents: NN- dimethylformamide, acetone, acetonitrile, tetrahydrofuran or toluene; isoflavones genistein (6): 1-substituted-4-haloalkylpiperazine (8): The molar ratio of the base is 1.0: 1.0-20.0: 1.0-20.0, preferably the molar charge ratio is 1.0: 1.0-8.0: 1.0-8.0; Reaction temperature is room temperature ~ 150

°C, the reaction temperature is preferably room temperature to 120 ° C; the reaction time is 1 to 72 hours, and the preferred reaction time is 2 to 24 hours.

The starting material of the present invention - methoxymethylene protected genistein (1), 1-substituted-4-haloalkyl piperazine (8) can be obtained by techniques common in the art, including but not limited to The methods disclosed in the following documents: 1. Qiang Xiaoming et al. Organic Chemistry DOI: 10.6023/cjoc201210042; 2. Rodriguez-Franco, MI et. al. Bioorganic Medicinal Chemistry 2005, 13, 6795-6802; 3. Bolea, R. et. al. J. Med. Chem. 2011, 54, 8251-8270.

The ginkrose isoflavone alkylamine compound (I) obtained by the above four methods contains an amino group in the molecule, and the amino group is basic, and can be obtained by a pharmaceutically conventional salt formation method with any suitable acid. Acceptable salts are: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, ₆ fatty carboxylic acids (eg: formic acid, acetic acid, propionic acid, etc.), oxalic acid, benzoic acid, salicylic acid, malay Acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, d- ₆ alkylsulfonic acid (eg methanesulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, benzenesulfonic acid or p-toluene acid.

The pharmaceutical composition disclosed herein comprises a therapeutically effective amount of one or more genistein alkylamine compounds (I) or a pharmaceutically acceptable salt thereof, which may further comprise one or more A pharmaceutically acceptable carrier or excipient. By "therapeutically effective amount" is meant an amount of a drug or agent that elicits a biological or pharmaceutical response of a tissue, system or animal to which a researcher or physician is directed; said "composition" means by passing more than one substance or group A mixture of products; a "pharmaceutically acceptable carrier" means a pharmaceutically acceptable substance, composition or carrier, such as: a liquid or solid filler, diluent, excipient, solvent or capsule. Substances, which carry or transport a chemical. The pharmaceutical composition provided by the present invention preferably has a genistein alkylamine compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in an amount by 10% to 99.5% by weight, the remainder being It accounts for less than 90% of the total weight.

The geranium isoflavone alkylamine compound (I) and the pharmaceutically acceptable salt thereof disclosed by the present invention have a purity determined by HPLC, indicating that the purity thereof is higher than 98.5%, and the following biological activity screening is performed on these compounds. .

(1) Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity

Add 1.0 mmol/L thioacetylcholine iodide or thiobutyric acid acetylcholine (both purchased from Sigma) to a 96-well plate. 30 μί, ρΗ7.4 PBS buffer 40 μί, test compound solution 20 (DMSO content less than 1%) and 10 acetylcholinesterase (rat cortex 5% homogenate supernatant, pH 7.4 phosphate buffer for homogenization medium) or butyrylcholinesterase (rat serum 25%) The supernatant, pH 7.4 phosphate buffer as a homogenization medium) solution, after mixing, 37 ° C After incubating for 15 min, 0.2% of 5,5'-dithio-bis(2-nitrobenzoic acid) (DTNB, purchased from Sigma) solution was added to each well to develop color, and each was measured at 405 nm by a microplate reader. The optical density (OD value) of the hole is calculated by comparing the inhibition rate of the compound with the enzyme (%) = (1 - sample group OD value / blank group OD value;) xl00 %) _; select five to six concentrations of the compound, determine the enzyme inhibition rate, and linearly regress the negative logarithm of the molar concentration of the compound with the inhibition rate of the enzyme, and obtain the molar concentration at the 50% inhibition rate. IC _5Q . The results of the assay indicate that all of the compounds disclosed in the examples of the present invention have a significant inhibitory effect on AChE, IC ₅ . 0.1 Μ Μ - 5.0 μΜ, wherein the compound 5-B4-14 disclosed in Example 2 of the present invention has an IC _5Q of 2.5 μΜ, and the remaining compounds of the same series (BP : 2-B4-1 to 2-B4- The IC ₅ Q of 13,2-B4-15 to 2-B4-21) was less than 1.0 μΜ; and the IC _{5 of the} positive control drug Rivastigmine inhibited AChE. For 6.3 μΜ, genistein inhibits IC ₂ inhibition of AChE. It is larger than ΙΟΟμΜ; the measurement results also show that the inhibitory activity of the compound disclosed in the examples of the present invention on AChE is much higher than that of BuChE, indicating that the compound disclosed in the present invention has a certain selective inhibitory effect on AChE.

(2) Screening of protective effects of compounds on H ₂ 0 ₂ induced PC12 cell injury

PC12 cells were seeded in a DMEM medium containing 10% calf serum at a density of l x lO ⁵ / mL on a 96-well culture plate, inoculated in a volume of 100 μΙ 7 wells, and then placed in a constant temperature of 37 ° C containing 5% CO ₂ . Cultivate in the box. After 24 hours of incubation, the concentration of the administration group of the corresponding compound was added (final concentration of ^{^{10- 5 mol / L, 10- 6}} mol / L) 10μΙ7? Ί, pre-incubated for 2 hours (the control group in the lesion were added 10μΙ7 hole PBS, keep their volume equal). After incubating PC12 cells for 2 hours, ΙΟΟμΜ Η ₂ 0 ₂ damaging agent 10 μΙ 7 ί was added to the drug-administered group and the injured group (control group plus 1 (^L/?L PBS), and after 30 minutes, the cultures of each group were added. The medium was replaced with RPMI 1640 medium without calf serum and cultured for 24 hours in a constant temperature incubator. The volume of the culture medium was still 100 μΙ7?ί. After 24 hours of incubation, 5 mg/mL ΜΤΤ 100 μΙ 7 wells were added to each group. After living for 3 hours, add 100% DMSO stop solution 100 μΙ 7 wells to each group, fully dissolve and mix. Determine the OD value of each group at 490 nm, repeat the test results 3 times, using Duncan's test According to the method statistics, the values of each group are expressed as mean ± SEM, which is 100% in the control group, and the values of the administration group and the injury group are expressed as a percentage of the control group. The results of the measurement indicate that all the compounds disclosed in the examples of the present invention are H ₂ 0 . protective effects of _2-induced PC12 cells significantly, and the antioxidant activity at a concentration of 10- ⁵ mol / L are stronger than genistein.

(3) Effects of compounds on memory impairment in mice induced by scopolamine

SPF-grade ICR male mice, 25-30 g, were randomly divided into: normal group, model group, high-dose and low-dose groups (5.0, 2.5 mg/kg), and 10 animals in each group. The test drug was administered by one-time intragastric administration. The blank group and the model group were given 0.5% CMC-Na in the vehicle, and the dosage volume was 0.1 ml/10 g _. 45 min after the drug, the normal group was intraperitoneally injected with normal saline, and the other groups of animals were given. Scopolamine (5 mg/kg) was injected at a dose of 0.1 ml/10 g _. After 30 min of modeling, the mice were placed in a non-electrically stimulated Y-maze for behavioral testing. During the test, the mice were placed at the end of one arm, let them walk freely in the labyrinth for 8 min, record the number of times they entered each arm and the number of alternations, and calculate the alternation rate according to the following formula: Alternation rate %= [alternate times/(total entry) The number of times-2;)]><100, the results are expressed as mean±standard deviation, and the difference between groups is analyzed by one-way analysis of variance. The results of the assay showed that under the experimental conditions, all the compounds disclosed in the examples of the present invention had a dose-dependent improvement effect on scopolamine-induced memory impairment in mice, and were statistically different from the model group (p<0.01). , and the activity was significantly higher than Rivastigmine (p<0.01) at the same molar concentration.

(4) Effect of compounds on memory reproduction disorder in ethanol f3⁄4 mice

SPF grade ICR male mice, 25-30g, were randomly divided into: normal group, model group, high dose and low dose group (5.0,

2.5 mg/kg), rivastigmine group (3 mg/kg), 10 animals per group. The test drug was administered intragastrically every day. The blank group and the model group were given 0.5% CMC-Na in the vehicle, and the administration volume was 0.1 ml/10 g, and the administration was continued for 32 days. During the daily administration period of 1 to 24 days, the drug was administered daily. 30 min, the model group and each administration group were intragastrically administered with 0.1 ml/10 g ethanol (15% w/v) for 24 consecutive days, and the ethanol was withdrawn to the ethanol washing period, and the drug continued to be administered; Animals are subjected to the platform test, and training or test experiments are carried out 45 minutes after the medicine. During the training, the mice are placed in the platform, placed on the platform, and energized. When the animals jump off the stage, the feet are simultaneously contacted with the copper grid. Electric shock, regarded as an error response, the normal avoidance response of the mice after electric shock was to escape to the platform, record the incubation period of the mouse to escape to the platform, and record the number of electric shocks within 5 minutes, as the academic achievement. After 24 hours, the test was performed to record the time when the mouse first jumped off the shock (latency period) and the number of times of electric shock (the number of errors) within 5 minutes, which was used as an evaluation index of the memory reproduction function. The test results were expressed as mean ± standard deviation, and the differences between groups were analyzed by one-way ANOVA. The results of the assay showed that under the experimental conditions, the compounds disclosed in the present invention significantly improved the memory dysfunction of mice induced by ethanol, and were statistically different from the model group (p < 0.01).

(5) Neurological effects of compounds on vascular dementia rats

(a) Animal modeling, ω administration

The rats were intraperitoneally injected with 3.5% chloral hydrate (350 mg/kg), the common carotid arteries were separated and ligated, and the bilateral common carotid arteries were not ligated in the normal sham operation group. The occult platform screening experiment of the 5-day water maze test was performed 7 days after surgery, and the incubation period of the fifth day of the animal was used as a screening index: SR = (average latency of the surgery group - average latency of the normal group;) / average latency of the normal group of animals. The successful animals with neurological dysfunction were screened by SR<0.2, and were randomly divided into normal group, model group, high-dose group (45 mg/kg) and low-dose group (15 mg/kg), with 12 rats in each group. The drug was administered on the 13th day afterwards, and the normal group and the model group were given an equal volume of vehicle; after 3 weeks of continuous administration, a 7-day labyrinth test was performed to evaluate the effect of the drug on the neurobehavioral function of rats with vascular dementia. After the behavioral test, the animals were anesthetized, and then rapidly perfused through the heart with PBS (pH 7.4) and 4% paraformaldehyde solution. The brain was quickly craniotomy, 10% neutral formaldehyde was fixed for 24 hours, embedded in paraffin, and made. Coronal sections of the brain with a thickness of about 5 μm for neuropathological histological examination. The experimental data were expressed as mean ± standard deviation. The experimental results were statistically analyzed by SPSS16 software. The comparison between groups was performed by one-way analysis of variance LSD method, and PO.05 was considered as significant difference. (b) Determination of neurobehavioral function

The Morris water maze test method was used to evaluate the effects of drugs on spatial learning and memory in rats with vascular dementia. The water maze is a round white stainless steel pool with a diameter of 120cm and a height of 60cm. The pool is divided into 4 quadrants. A platform is placed in the center of the quadrant. The platform is equidistant from the center of the circle and the wall. The platform is white and round, 10cm in diameter and high. 20cm, the platform is located 2cm below the water surface, the temperature of the pool water is kept at 25±2°C, and the appropriate amount of food additive white pigment is added into the water to make the pool water opaque milky white. Animals cannot reach the platform through vision to detect the animal's sensitivity to spatial position. . There is a camera directly above the pool. The camera is connected to the computer and records the activity of the animals in the pool. After the administration, the water maze test was carried out continuously for 7 days. On the first day 1-2, the occult platform experiment was performed to record the time when the rats found the platform (latency period); the third day was to explore the platform experiment (ie, remove the platform), and the rats entered the water point. The position was unchanged, and the residence time and number of crossings of the rat in the quadrant of the original platform position were recorded. On the 4th to 6th days, the new platform experiment (ie, the position of the platform was changed), the position of the water entry point of the rat was unchanged, and the time when the rat found the platform was recorded. (latency period); Day 7 is the visible platform experiment, the position of the water entry point of the rats is unchanged, and the time (latency period) at which the rats find the platform is recorded. The Morris water maze is an experiment that relies on the memory function of the hippocampus and is mainly used for the evaluation of cognitive dysfunction caused by cerebral ischemic injury. Cognitive function generally consists of three stages: acquisition, consolidation, and memory. In our experiments, the hidden platform test was used to obtain the function, the new platform experiment was used to test the consolidation function, and the platform experiment was used to detect the memory function.

The results showed that compared with the model group, the latency of the hidden platform and the new platform was significantly shortened in the drug-treated group, while in the exploration platform experiment, the residence time and the number of crossings of the animal in the original platform quadrant were significantly prolonged. The experimental results confirmed that the drug treatment of the disclosed compounds can significantly improve the cognitive dysfunction of vascular dementia caused by long-term hypoperfusion of the brain in a dose-dependent manner. In addition, the results of the platform test showed that there was no significant difference in the latency of the platform between the groups, thus eliminating the impact of surgery on animal vision and exercise capacity, further confirming the therapeutic effect of the drug on vascular dementia.

(c) Detection of neuronal damage

The expression of neuron nuclear antigen (NeuN) in the cerebral cortex and hippocampus of VD animals was detected by immunohistochemistry, and the effects of drugs on neuronal damage in VD animals were evaluated. Coronary paraffin sections of each animal brain, dewaxing xylene, 3% of 3⁄40 ₂ inactivated endogenous peroxidase, add 5% BSA blocking solution, incubate for 1 hour at 37 °C, add separately NeuN polyclonal antibody (1:200, Beijing Boaosen Biotechnology Co., Ltd.;), incubated at 37 ° C for 2 hours and then placed in a refrigerator at 4 ° C overnight. Biotinylated goat anti-mouse secondary antibody was added, incubated at 37 ° C for 1 hour, and then added to SABC, incubated at 37 ° C for 1 hour, DAB coloration, hematoxylin counterstaining. Conventional dehydration, xylene transparent, neutral gum seal. Under the 400x optical microscope, the number of positive cells in the three non-overlapping regions of the cortex and hippocampus was observed and recorded blindly. The average value of each slice was calculated, 100% in the control group, and the number of positive cells in the model group and the drug-administered group. Expressed as a percentage of the control group.

The results showed that the number of NeuN immunopositive neurons in the cortex and hippocampus of the model group was significantly lower than that of the normal group (PO.01). Compared with the model group, the drug dose-dependently increased the number of neurons ( PO.05 or P<0.01). The experimental results show that all the compounds disclosed in the present invention can inhibit the brain neuron cells of vascular dementia rats. Injury, which is consistent with the results of drugs that improve cognitive function in vascular dementia rats in the Morris water maze test.

(d) Detection of glial cell activation

Coronary paraffin sections of each animal brain, dewaxing xylene, 3% of 3⁄40 ₂ inactivated endogenous peroxidase, add 5% BSA blocking solution, incubate in 37 ° C incubator for 1 hour, then add separately OX-42 polyclonal antibody (1:200, Millipore, USA) or GFAP polyclonal antibody (1:100, Wuhan Boster Bioengineering Co., Ltd.), incubated at 37 ° C for 2 hours and then placed in a refrigerator at 4 ° C overnight . Biotinylated goat anti-mouse secondary antibody was added, incubated at 37 ° C for 1 hour, then added to SABC, incubated at 37 ° C for 1 hour, DAB coloration, hematoxylin counterstaining, conventional dehydration, xylene transparent, neutral gum seal Immunohistochemical staining with Axiovert 40 CFL micrograph: Under a 400x optical microscope, each slice was taken at three locations in the cerebral cortex at a fixed location, and the immunoreactive cells were analyzed using Image Pro-plus 5.0 software. Cumulative optical density values (IOD), the average of the IOD of each slice was calculated, and the results of each group were expressed as mean ± standard deviation.

The results showed that the expression levels of OX-42 and GFAP in the cortex of the model group were significantly increased compared with the normal group (PO.01). Compared with the model group, the drug could decrease the expression of OX-42 and GFAP in a dose-dependent manner. There was a statistically significant difference in the high dose group (P < 0.01). The experimental results show that all the compounds disclosed in the present invention can inhibit the activation of microglia and astrocytes in vascular dementia rats, and prevent and treat vascular dementia by inhibiting neuroinflammatory reaction. Specific lung

The invention is further described by the following examples, however, the scope of the invention is not limited to the embodiments described below. A person skilled in the art will appreciate that various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention.

Example 1 When Ar represents structural unit (A) and R ₃ = H, and Linker represents (CH ₂ ) _m , the preparation of genus flavonoid compound (I)

7-methoxymethylene-protected genistein (1) 2.0 mmo 30 ml acetonitrile, 8.0 mmol anhydrous potassium carbonate and dibromoalkyl compound (2) 7.0 mmol were added to the reaction flask. ~9.0 hours (the progress of the reaction is followed by TLC); after the reaction is completed, the filter cake is washed with a small amount of acetonitrile, and the solvent is evaporated under reduced pressure to remove the solvent and excess dibromoalkyl compound, and the residue is purified by column chromatography. Liquid: dichloromethane) to give an aryloxyalkyl bromide compound (3) in a yield of 75% to 93%. The above aryloxyalkyl bromide compound (3) is dissolved in 40 ml of ethanol in total, 6.0 mmol of the organic amine compound (4) is added, and the reaction is stirred under reflux for 6.0 to 16.0 hours (the progress of the reaction is followed by TLC); The solvent was evaporated under reduced pressure. EtOAc EtOAc m. The residue was purified by column chromatography (eluent: chloroform), corresponding methoxymethylene-protected genistein-saltamines (5), yield 80%-96% _; In a mixed solution of 15% aqueous hydrochloric acid and 20 ml of ethanol, the reaction was stirred at room temperature for 3.0 to 8.0 hours (the progress of the reaction was followed by TLC). After the reaction was completed, the solvent was evaporated under reduced pressure and 50 ml of dichloromethane was added to the residue. Dissolved with 20 ml of 5% sodium bicarbonate The organic layer was dried over anhydrous sodium sulfate and filtered. v), the corresponding genistein isolamine alkylamine compound (1), the yield is 90%-98%, and its chemical structure is confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS. Target structure prepared by the above general method

Note: In the table and when sharing a cell, it means the substituent " Ν ".

Example 2 When Ar represents structural unit (B), or (C), or structural unit (A) in which R ₃ does not represent H, and Linker represents (CH ₂ ) _m , preparation of genus flavonoid compound (I) General law

5.0 mmol of the corresponding genistein (6), 10.0 mmol of potassium carbonate and 60 ml of N,N-dimethylformamide were added to the reaction flask, and the reaction was stirred at room temperature for 30 minutes, and then 10.0 mmol of dibromoalkyl compound was added. (2), stir the reaction at 50~60 °C for 5-18 hours (the progress of the reaction is followed by TLC); after the reaction is completed, filter it with hot water, distill off the solvent under reduced pressure, and add 150 ml of dichloromethane to the residue, and then use After washing with 50 ml of 10% aqueous sodium carbonate and 50 ml of EtOAc. 1 v / v), the corresponding aryloxyalkyl bromide compound (7).

According to the difference of the starting material compound (6) used, the corresponding 7-position, 4'-position, or 7,4'-disubstituted aryloxyalkyl bromide compound (7) can be obtained; When the genistein compound (6) is a structural unit (B) in which R ₃ does not represent H, a 7-substituted aryloxyalkyl bromide compound (7) is obtained in a yield of 78% to 95% _; When the genistein compound (6) is a structural unit (A) which does not represent H, the 4'-substituted aryloxyalkyl bromide compound (7) is obtained, and the yield is 66%-87% _; The flavonoids (6) are genistein (representing the structural unit of H (A) or (when Bp, the 7-substituted aryloxyalkyl bromide compound (7) and 7, 4'- The disubstituted aryloxyalkyl bromide compound (7) has a yield of 35% to 58% and 20% to 35%, respectively.

The corresponding 7-position, 4'-position or 7,4'-position disubstituted aryloxyalkyl bromide compound (7) 1.0 mmol prepared above was dissolved in 15 ml of ethanol, and 3.0 mmol of organic amine compound was added. (4), heating and refluxing, stirring reaction, 6.0~16.0 hours (reverse) The reaction was followed by TLC); after the reaction was completed, the solvent was evaporated under reduced pressure, and 50 ml of dichloromethane was added to the residue, which was washed successively with 15 ml of 5% aqueous sodium carbonate and 15 ml of deionized water. The sodium was dried and filtered, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1), the yield was 80%-96.5%, and its chemical structure was confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS. The structure of the target prepared by the above general method is as follows:

-A8-4 A 8 -CH2CH3 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 560.3-B2-1 B 2 -CH ₃ -CH ₂ Ph H 1 418.2-B2-2 B 2 -CH ₃ -CH ₂ Ph(2'-OCH ₃ ) H 1 448.2-B2-3 B 2 -CH ₃ -CH ₂ Ph(2'-OCr ₃ ) H 1 502.1-B2-4 B 2 -CH ₃ -CH ₂ Ph(2 '-CH ₃ ) H 1 432.2-B2-5 B 2 -CH ₃ -CH ₂ Ph(2'-Cr ₃ ) H 1 486.1-B2-6 B 2 -CH ₃ -CH ₂ Ph(2'-Cl) H 1 452.2-B2-7 B 2 -CH2CH3 -CH ₂ Ph H 1 432.1-B2-8 B 2 -CH2CH3 -CH ₂ Ph(2'-OCH ₃ ) H 1 462.2-B2-9 B 2 -CH2CH3 -CH ₂ Ph(2'-OCr ₃ ) H 1 516.2-B2-10 B 2 -CH2CH3 -CH ₂ Ph(2'-CH ₃ ) H 1 446.1-B2-11 B 2 -CH2CH3 -CH ₂ Ph(2'- Cr ₃ ) H 1 500.2-B2-12 B 2 -CH2CH3 -CH ₂ Ph(2'-Cl) H 1 466.2-B2-13 B 2 -CH ₃ -CH2CH3 H 1 356.1-B2-14 B 2 HH 1 495.2 -B2-15 B 2 HH 1 529.2

-B2-16 B 2 H 1 570.1 -B2-17 B 2 — ^N-CH ₂ PH 1 473.2-B2-18 B 2 — ^N-CH ₂ P (2'-OCH ₃ ) H 1 503.0-B2 -19 B 2 — ^>— CH ₂ CH ₃ H 1 410.1-B2-20 B 2 —N( ~ ^)— CH ₂ PH 1 472.2-B3-1 B 3 —CH ₃ —CH ₂ Ph H 1 432.1- B3-2 B 3 -CH ₃ -CH ₂ Ph(2'-OCH ₃ ) H 1 462.2-B3-3 B 3 -CH ₃ -CH ₂ Ph(2'-OCr ₃ ) H 1 516.1-B3-4 B 3 -CH ₃ -CH ₂ Ph(2'-CH ₃ ) H 1 446.2-B3-5 B 3 -CH ₃ -CH ₂ Ph(2'-Cr ₃ ) H 1 500.2-B3-6 B 3 -CH ₃ -CH ₂ Ph(2'-Cl) H 1 466.4-B3-7 B 3 -CH2CH3 -CH ₂ Ph H 1 446.1-B3-8 B 3 -CH2CH3 -CH ₂ Ph(2'-OCH ₃ ) H 1 476.2 -B3-9 B 3 -CH2CH3 -CH ₂ Ph(2'-OCr ₃ ) H 1 530.2-B3-10 B 3 -CH2CH3 -CH ₂ Ph(2'-CH ₃ ) H 1 460.1-B3-11 B 3 -CH2CH3 -CH ₂ Ph(2'-Cr ₃ ) H 1 514.2-B3-12 B 3 -CH2CH3 -CH ₂ Ph(2'-Cl) H 1 480.1-B3-15 B 3 -CH ₃ -CH2CH3 H 1 370.2-B3-16 B 3 HH 1 509.2 -B3-17 B 3 HH 1 543.2 -B3-18 B 3 H 1 584.2

Note: When the table is shared with a cell, it means the substituent "Ν". Example 3 When Ar represents structural unit (A) and R ₃ = H, -0-Linker-NRiR ₂

Preparation method of gold finch yellow lanthanide compound (I)

Add 7-methoxymethylene protected genistein (1) 2.0 mmo 50 ml acetonitrile, 3.0 mmol anhydrous potassium carbonate and 2.5 mmol 1-substituted-4-chloroalkyl piperazine (8) in the reaction flask. The mixture was stirred under reflux and refluxed for 5.0 to 18.0 hours (the progress of the reaction was followed by TLC). After the reaction was completed, the mixture was filtered while hot, and the cake was washed with a small amount of acetonitrile. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography. Chloroform) gave the corresponding methoxymethylene-protected genistein alkylamine compound (9) in a yield of 78.0%-95.0%. The obtained compound 9 was added to a mixed solution of 10 ml of a 15% aqueous hydrochloric acid solution and 20 ml of ethanol, and the reaction was stirred at room temperature for 3.0 to 7.0 hours (the progress of the reaction was followed by TLC). After the reaction was completed, the solvent was evaporated under reduced pressure and 50 The methylene chloride was washed with 20 ml of 5% aqueous sodium hydrogencarbonate and 20 ml of EtOAc. Liquid: petroleum ether - ethyl acetate = 30:1 v / v), corresponding corresponding genistein alkylamine compound (1), yield 85%-95%, its chemical structure by ¹ H-NMR , ¹³ C-NMR and ESI-MS confirmed. The structure of the target prepared by the above general method is as follows:

Compound ESI-MS Compound ESI-MS m R ₄ m

^3⁄4 bow. (+Q) m/z bow. R ₄ (+Q) m/z

3-1-1 1 -CH ₂ Ph 458.2 3-3-3 3 -CH ₂ Ph(4'-OCH ₃ ) 516.2

3-1-2 1 -CH ₂ Ph(2'-OCH ₃ ) 488.1 3-3-4 3 -CH ₂ Ph(3'-OCH ₃ ) 516.3

3-1-3 1 -CH ₂ Ph(4'-OCH ₃ ) 488.2 3-3-5 3 -CH ₂ Ph(2'-OCr ₃ ) 570.2

3-1-4 1 -CH ₂ Ph(3'-OCH ₃ ) 488.2 3-3-6 3 -CH ₂ Ph(3'-OCr ₃ ) 570.2

3-1-5 1 -CH ₂ Ph(2'-OCr ₃ ) 542.2 3-3-7 3 -CH ₂ Ph(2'-CH ₃ ) 500.1

3-1-6 1 -CH ₂ Ph(3'-OCr ₃ ) 542.4 3-3-8 3 -CH ₂ Ph(4'-CH ₃ ) 500.0

3-1-7 1 -CH ₂ Ph(2'-CH ₃ ) 472.0 3-3-9 3 -CH ₂ Ph(2'-Cr ₃ ) 554.2

3-1-8 1 -CH ₂ Ph(4'-CH ₃ ) 472.2 3-3-10 3 -CH ₂ Ph(3'-Cr ₃ ) 554.2

3-1-9 1 -CH ₂ Ph(2'-Cr ₃ ) 526.2 3-3-11 3 -CH ₃ 410.3

3-1-10 1 -CH ₂ Ph(3'-Cr ₃ ) 526.2 3-3-12 3 -CH2CH3 424.2

3-1-11 1 -CH ₃ 382.3 3-4-1 4 -CH ₂ Ph 500.2

3-1-12 1 -CH2CH3 396.1 3-4-2 4 -CH ₂ Ph(2'-OCH ₃ ) 530.3

3-2-1 2 -CH ₂ Ph 472.2 3-4-3 4 -CH ₂ Ph(4'-OCH ₃ ) 530.2

3-2-2 2 -CH ₂ Ph(2'-OCH ₃ ) 502.0 3-4-4 4 -CH ₂ Ph(3'-OCH ₃ ) 530.3

3-2-3 2 -CH ₂ Ph(4'-OCH ₃ ) 502.2 3-4-5 4 -CH ₂ Ph(2'-OCr ₃ ) 584.3

3-2-4 2 -CH ₂ Ph(3'-OCH ₃ ) 502.1 3-4-6 4 -CH ₂ Ph(3'-OCr ₃ ) 584.2

3-2-5 2 -CH ₂ Ph(2'-OCr ₃ ) 556.2 3-4-7 4 -CH ₂ Ph(2'-CH ₃ ) 514.2

3-2-6 2 -CH ₂ Ph(3'-OCr ₃ ) 556.2 3-4-8 4 -CH ₂ Ph(4'-CH ₃ ) 514.1

3-2-7 2 -CH ₂ Ph(2'-CH ₃ ) 486.1 3-4-9 4 -CH ₂ Ph(2'-Cr ₃ ) 568.2

3-2-8 2 -CH ₂ Ph(4'-CH ₃ ) 486.0 3-4-10 4 -CH ₂ Ph(3'-Cr ₃ ) 568.3

3-2-9 2 -CH ₂ Ph(2'-Cr ₃ ) 540.2 3-4-11 4 -CH ₃ 424.2

3-2-10 2 -CH ₂ Ph(3'-Cr ₃ ) 540.1 3-4-12 4 -CH2CH3 438.2

3-2-11 2 -CH ₃ 396.2 3-5-1 5 -CH ₂ Ph 514.0

3-2-12 2 -CH2CH3 410.0 3-5-2 5 -CH ₂ Ph(2'-OCH ₃ ) 544.1

3-3-1 3 -CH ₂ Ph 486.2 3-6-1 6 -CH ₂ Ph 528.2

3-3-2 3 -CH ₂ Ph(2'-OCH ₃ ) 516.2 3-6-2 6 -CH ₂ Ph(2'-OCH ₃ ) 558.3 Example 4 When Ar represents a structural unit (B), or (C , or R ₃ does not represent H structural unit (A), -0-Linker-NRiR ₂ represents - ^{Q R4} , the preparation of the genus flavonoids (I)

5.0 mmol of the corresponding genistein (6), 10.0 mmol of potassium carbonate and 60 ml of N,N-dimethylformamide were added to the reaction flask, and the reaction was stirred at room temperature for 30 minutes, then 1-substituted-4-chloro was added. Alkyl piperazine (8) 10.0 mmol, 50-60 ° C Stirring reaction for 5-15 hours (the progress of the reaction is followed by TLC); after the reaction is completed, it is filtered while hot, the filtrate is evaporated under reduced pressure, and the residue is 150 ml. Dichloromethane, washed with 50 ml of 10% aqueous sodium carbonate and 50 ml of EtOAc EtOAc. Chloroform/methanol = 30:1 v/v), corresponding ginsyl isoflavone alkylamine compound (1).

Depending on the difference of the starting material compound (6) used, the corresponding 7-position, 4'-position, or 7,4'-position disubstituted genipa isoflavone alkylamine compound (I) can be obtained; When the starting material genistein compound (6) is a structural unit (B) which does not represent H, a 7-substituted ginkrose isoflavone alkylamine compound (1) is obtained, and the yield is 70%-92%. _; genistein when the starting material compound (6) is not a structural unit represented by H (a), the resulting 4'-substituted isoflavone genistein Ketoalkylamine compound (1), yield 78%-96% _; when the starting material genistein compound (6) is genistein (ie: R ₃ represents H structural unit (A) or ( At the time of Bp, a 7-substituted genipa isoflavone alkylamine compound (1) can be obtained at a yield of 30% to 58% and a 7,4'-position disubstituted genipa isoflavone alkylamine compound (1), the yield was 23% - 38%. The structure was confirmed by ^-NMFL ¹³ C-NMR and ESI-MS. The structure of the target obtained by the above general method is as follows:

Ar

Compound ESI-MS

Ar m R4 ₃ n

(+Q) m/z

4-A1-1 A 1 -CH ₂ Ph CH ₃ 1 472.2

4-A1-2 A 1 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 502.2

4-A1-3 A 1 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 502.3

4-A1-4 A 1 -CH ₂ Ph(3'-OCH ₃ ) CH ₃ 1 502.1

4-A1-5 A 1 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 556.2

4-A1-6 A 1 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 556.1

4-A1-7 A 1 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 486.2

4-A1-8 A 1 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 486.3

4-A1-9 A 1 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 540.2

4-A1-10 A 1 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 540.2

4-A1-11 A 1 -CH ₃ CH ₃ 1 396.3

4-A1-12 A 1 -CH2CH3 CH ₃ 1 410.2

4-A1-13 A 1 -CH ₂ Ph CH3CO 1 500.0

4-A1-14 A 1 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 530.2

4-A1-15 A 1 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 530.1

4-A1-16 A 1 -CH ₂ Ph(3'-OCH ₃ ) CH3CO 1 530.2

4-A2-1 A 2 -CH ₂ Ph CH ₃ 1 486.1

4-A2-2 A 2 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 516.2

4-A2-3 A 2 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 516.2

4-A2-4 A 2 -CH ₂ Ph(3'-OCH ₃ ) CH ₃ 1 516.3

4-A2-5 A 2 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 570.2

4-A2-6 A 2 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 570.2

4-A2-7 A 2 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 500.2

4-A2-8 A 2 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 500.1

4-A2-9 A 2 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 554.2

4-A2-10 A 2 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 554.3

4-A2-11 A 2 -CH ₃ CH ₃ 1 410.2

4-A2-12 A 2 -CH2CH3 CH ₃ 1 424.0

4-A2-13 A 2 -CH ₂ Ph CH3CO 1 514.2

4-A2-14 A 2 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 544.3

4-A2-15 A 2 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 544.2

4-A2-16 A 2 -CH ₂ Ph(3'-OCH ₃ ) CH3CO 1 544.1

4-A2-17 A 2 -CH ₃ CH3CO 1 438.2

4-A2-18 A 2 -CH2CH3 CH3CO 1 452.3

4-A3-1 A 3 -CH ₂ Ph CH ₃ 1 500.2

4-A3-2 A 3 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 530.3 -A3-3 A 3 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 530.2-A3-4 A 3 -CH ₂ Ph(3'-OCH ₃ ) 530.2-A3-5 A 3 -CH ₂ Ph( 2'-OCr ₃ ) CH ₃ 1 584.2-A3-6 A 3 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 584.0-A3-7 A 3 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 514.2-A3-8 A 3 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 514.1-A3-9 A 3 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 568.2-A3-10 A 3 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 568.1-A3-11 A 3 -CH ₃ CH ₃ 1 424.2-A3-12 A 3 -CH2CH3 CH ₃ 1 438.3-A3-13 A 3 -CH ₂ Ph CH3CO 1 528.2-A3-14 A 3 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 558.1-A3-15 A 3 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 558.2-A3-16 A 3 - CH ₂ Ph(3'-OCH ₃ ) CH3CO 1 558.3-A3-17 A 3 -CH ₃ CH3CO 1 452.3-A3-18 A 3 -CH2CH3 CH3CO 1 466.2-A4-1 A 4 -CH ₂ Ph CH ₃ 1 514.0 -A4-2 A 4 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 544.2-A4-3 A 4 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 544.3-A4-4 A 4 -CH ₂ Ph(3'-OCH ₃ ) CH ₃ 1 544.2-A4-5 A 4 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 598.2-A4-6 A 4 -CH ₂ Ph(3'-OCr ₃ CH ₃ 1 598.1-A4-7 A 4 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 528.2-A4-8 A 4 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 528.1-A4- 9 A 4 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 582.3-A4-10 A 4 -CH ₂ Ph(3'- Cr ₃ ) CH ₃ 1 582.2-A4-11 A 4 -CH ₃ CH ₃ 1 438.2-A4-12 A 4 -CH2CH3 CH ₃ 1 452.1-A4-13 A 4 -CH ₂ Ph CH3CO 1 542.2-A4-14 A 4 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 572.1-A4-15 A 4 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 572.2-A4-16 A 4 -CH ₂ Ph(3'-OCH ₃ ) CH3CO 1 572.0-A4-17 A 4 -CH ₃ CH3CO 1 466.2-A4-18 A 4 -CH2CH3 CH3CO 1 480.2-A5-1 A 5 -CH ₂ Ph CH ₃ 1 528.3-A5-2 A 5 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 558.2-A6-1 A 6 -CH ₂ Ph CH ₃ 1 542.1-A6-2 A 6 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 572.2-B1 -1 B 1 -CH ₂ Ph CH ₃ 1 472.4-B1-2 B 1 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 502.1-B1-3 B 1 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 502.2-B1-4 B 1 -CH ₂ Ph(3'-OCH ₃ ) CH ₃ 1 502.0-B1-5 B 1 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 556.2-B1-6 B 1 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 556.2-B1-7 B 1 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 486.2-B1-8 B 1 -CH ₂ Ph(4 '-CH ₃ ) CH ₃ 1 486.1-B1-9 B 1 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 540.3-B1-10 B 1 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 540.0-B1-11 B 1 -CH ₃ CH ₃ 1 396.1-B1-12 B 1 -CH2CH3 CH ₃ 1 410.2-B1-13 B 1 -CH ₂ Ph CH3CO 1 500.2 -B1-14 B 1 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 530.1-B1-15 B 1 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 530.3-B1-16 B 1 -CH ₂ Ph (3'-OCH ₃ ) CH3CO 1 530.0-B2-1 B 2 -CH ₂ Ph CH ₃ 1 486.2-B2-2 B 2 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 516.1-B2-3 B 2 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 516.2-B2-4 B 2 -CH ₂ Ph(3'-OCH ₃ ) CH ₃ 1 516.3-B2-5 B 2 -CH ₂ Ph(2' -OCr ₃ ) CH ₃ 1 570.2-B2-6 B 2 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 570.1-B2-7 B 2 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 500.2 -B2-8 B 2 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 500.2-B2-9 B 2 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 554.1-B2-10 B 2 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 554.2-B2-11 B 2 -CH ₃ CH ₃ 1 410.2-B2-12 B 2 -CH2CH3 CH ₃ 1 424.2-B2-13 B 2 -CH ₂ Ph CH3CO 1 514.1-B2-14 B 2 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 544.2-B2-15 B 2 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 544.0-B2-16 B 2 -CH ₂ Ph(3'-OCH ₃ ) CH3CO 1 544.2-B2-17 B 2 -CH ₃ CH3CO 1 438.1-B2-18 B 2 -CH2CH3 CH3CO 1 452.0-B3-1 B 3 -CH ₂ Ph CH ₃ 1 500.2-B3 -2 B 3 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 530.1-B3-3 B 3 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 530.2-B3-4 B 3 -CH ₂ Ph (3'-OCH ₃ ) 530.3-B3-5 B 3 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 584.2-B3-6 B 3 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 584.1-B3-7 B 3 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 514.2-B3 -8 B 3 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 514.4-B3-9 B 3 -CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 568.2-B3-10 B 3 -CH ₂ Ph (3'-Cr ₃ ) CH ₃ 1 568.0-B3-11 B 3 -CH ₃ CH ₃ 1 424.2-B3-12 B 3 -CH2CH3 CH ₃ 1 438.1-B3-13 B 3 -CH ₂ Ph CH3CO 1 528.3- B3-14 B 3 -CH ₂ Ph(2'-OCH ₃ ) CH3CO 1 558.2-B3-15 B 3 -CH ₂ Ph(4'-OCH ₃ ) CH3CO 1 558.1-B3-16 B 3 -CH ₂ Ph( 3'-OCH ₃ ) CH3CO 1 558.2-B3-17 B 3 -CH ₃ CH3CO 1 452.0-B3-18 B 3 -CH2CH3 CH3CO 1 466.1-B4-1 B 4 -CH ₂ Ph CH ₃ 1 514.2-B4-2 B 4 -CH ₂ Ph(2'-OCH ₃ ) CH ₃ 1 544.1-B4-3 B 4 -CH ₂ Ph(4'-OCH ₃ ) CH ₃ 1 544.1-B4-4 B 4 -CH ₂ Ph(3 '-OCH ₃ ) CH ₃ 1 544.4-B4-5 B 4 -CH ₂ Ph(2'-OCr ₃ ) CH ₃ 1 598.2-B4-6 B 4 -CH ₂ Ph(3'-OCr ₃ ) CH ₃ 1 598.2-B4-7 B 4 -CH ₂ Ph(2'-CH ₃ ) CH ₃ 1 528.2-B4-8 B 4 -CH ₂ Ph(4'-CH ₃ ) CH ₃ 1 528.2-B4-9 B 4 - CH ₂ Ph(2'-Cr ₃ ) CH ₃ 1 582.0-B4-10 B 4 -CH ₂ Ph(3'-Cr ₃ ) CH ₃ 1 582.2-B4-11 B 4 -CH ₃ CH ₃ 1 438.3-B4 -12 B 4 -CH2CH3 CH ₃ 1 452.2

Compound ESI-MS

Ar m ₄ n

(+Q) m/z

4-Cl-l C 1 -CH ₂ Ph 2 645.3

4-C1-2 C 1 -CH ₂ Ph(2'-OCH ₃ ) 2 705.4

4-C1-3 C 1 -CH ₂ Ph(4'-OCH ₃ ) 2 705.2

4-C1-4 C 1 -CH ₂ Ph(3'-OCH ₃ ) 2 705.3

4-C1-5 C 1 -CH ₂ Ph(2'-OCr ₃ ) 2 813.1

4-C1-6 C 1 -CH ₂ Ph(3'-OCr ₃ ) 2 813.2

4-C1-7 C 1 -CH ₂ Ph(2'-CH ₃ ) 2 673.4

4-C1-8 C 1 -CH ₂ Ph(4'-CH ₃ ) 2 673.2

4-C1-9 C 1 -CH ₂ Ph(2'-Cr ₃ ) 2 781.2

4-C1-10 C 1 -CH ₂ Ph(3'-Cr ₃ ) 2 781.3

4-C1-11 C 1 -CH ₃ 2 493.2

4-C1-12 C 1 -CH2CH3 2 521.3

4-C2-1 C 2 -CH ₂ Ph 2 673.2

4-C2-2 C 2 -CH ₂ Ph(2'-OCH ₃ ) 2 733.1

4-C2-3 C 2 -CH ₂ Ph(4'-OCH ₃ ) 2 733.2

4-C2-4 C 2 -CH ₂ Ph(3'-OCH ₃ ) 2 733.2

4-C2-5 C 2 -CH ₂ Ph(2'-OCr ₃ ) 2 841.0

4-C2-6 C 2 -CH ₂ Ph(3'-OCr ₃ ) 2 841.1

4-C2-7 C 2 -CH ₂ Ph(2'-CH ₃ ) 2 701.3

4-C2-8 C 2 -CH ₂ Ph(4'-CH ₃ ) 2 701.0

4-C2-9 C 2 -CH ₂ Ph(2'-Cr ₃ ) 2 809.3

4-C2-10 C 2 -CH ₂ Ph(3'-Cr ₃ ) 2 809.2

4-C2-11 C 2 -CH ₃ 2 521.1

4-C2-12 C 2 -CH2CH3 2 549.2

4-C3-1 c 3 -CH ₂ Ph 2 701.2

4-C3-2 c 3 -CH ₂ Ph(2'-OCH ₃ ) 2 761.2

4-C3-3 c 3 -CH ₂ Ph(4'-OCH ₃ ) 2 761.0

4-C3-4 c 3 -CH ₂ Ph(3'-OCH ₃ ) 2 761.3

4-C3-5 c 3 -CH ₂ Ph(2'-OCr ₃ ) 2 869.2

4-C3-6 c 3 -CH ₂ Ph(3'-OCr ₃ ) 2 869.4

4-C3-7 c 3 -CH ₂ Ph(2'-CH ₃ ) 2 729.1

4-C3-8 c 3 -CH ₂ Ph(4'-CH ₃ ) 2 729.2

4-C3-9 c 3 -CH ₂ Ph(2'-Cr ₃ ) 2 837.4

4-C3-10 c 3 -CH ₂ Ph(3'-Cr ₃ ) 2 837.2 4-C3-11 C 3 -CH ₃ 2 549.3

4-C3-12 C 3 -CH2CH3 2 577.3

4-C4-1 C 4 -CH ₂ Ph 2 729.1

4-C4-2 C 4 -CH ₂ Ph(2'-OCH ₃ ) 2 789.0

4-C4-3 C 4 -CH ₂ Ph(4'-OCH ₃ ) 2 789.2

4-C4-4 C 4 -CH ₂ Ph(3'-OCH ₃ ) 2 789.2

4-C4-5 C 4 -CH ₂ Ph(2'-OCr ₃ ) 2 897.2

4-C4-6 C 4 -CH ₂ Ph(3'-OCr ₃ ) 2 897.1

4-C4-7 C 4 -CH ₂ Ph(2'-CH ₃ ) 2 757.2

4-C4-8 C 4 -CH ₂ Ph(4'-CH ₃ ) 2 757.3

4-C4-9 C 4 -CH ₂ Ph(2'-Cr ₃ ) 2 865.2

4-C4-10 C 4 -CH ₂ Ph(3'-Cr ₃ ) 2 865.2

4-C4-11 C 4 -CH ₃ 2 577.1

4-C4-12 C 4 -CH2CH3 2 605.2 Example 5

Preparation method of Wei alkylamine compound (I) and acid salt formation

To the reaction flask, 2.0 mmol of the genistein alkylamine compound (I) and 50 ml of ethanol obtained according to the above Examples 1-4 were added, and after stirring, 6.0 mmol of the corresponding acid was added, and the reaction was stirred under reflux for 20 minutes. After the completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was crystallised from acetone, and the precipitated solid was filtered to give the salt of the genistein alkylamine compound (I). The chemical structure was subjected to ¹ H NMR and Confirmed by ESI-MS.

Claims

A ginkgo isoflavone alkylamine compound or a pharmaceutically acceptable salt thereof, characterized in that the chemical structure of the compound is as shown in (I):

Where: Ar represents any of the structural units (A) to (C) shown below, n = 1 or 2;

Represents H, CH: ₁₂ alkyl; R ₂ represents CH: ₁₂ alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridine 9-yl, 6-chloro-1,2,3 , 4-tetrahydroacridine 9-yl, 8-chloro-1,2,3,4-tetrahydroacridine 9-yl, or 6,8-dichloro-1,2,3,4-tetrahydroindole Acridine 9-yl; NR ₂ also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position by (^~0 ₁₂ alkyl substituted piperidinyl, 4-position by benzyl or substituted benzyl Substituted piperidinyl, piperazinyl, piperazinyl substituted at the 4-position with (^~0 ₁₂ alkyl, piperazinyl substituted at the 4-position with benzyl or substituted benzyl, N-demethyl Kigalanalamine; R ₃ represents H, CC ₁₂ alkyl, CF ₃ , d~C ₄ acyl; Linker

\

Ν — R ₄

Represents (CH ₂ ) _m ; "-O-Linker-NRiRz" also denotes " , '' ^m Vj'; m denotes 1-12 ; represents H, d-C ₁₂ alkyl, benzyl or substituted benzyl;

Wherein, when Ar represents (A) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 3 or 4, NR ₂ does not represent 4-benzylpiperazinyl; when Ar represents (A) structure And R ₃ represents H, Linker is (CH ₂ ) _m , and when m is 3, NR2 does not represent morpholinyl, tetrahydropyrrolyl, 4-methylpiperazinyl; when Ar represents (B) structural unit and R ₃ represents H, when Linker is (CH ₂ ) _m , when it is different from R _{2 ,} it represents d~C ₁₂ alkyl; when Ar represents (B) structural unit and R ₃ represents

H, Linker is (CH ₂ ) _m , m is 2, 3, 4, 5 or 6, RiNRz does not represent morpholinyl, piperazinyl, 4-methylpiperazinyl; when Ar represents (B) structural unit And R ₃ represents H, Linker is (CH ₂ ) _m , m is 2, 3 or 4, RjNRz ^ represents tetrahydropyrrolyl, piperidinyl; when Ar represents (B) structural unit and R ₃ represents H, Linker When (CH ₂ ) _m , m is 4 or 6, R R2 does not represent 4-ethylpiperazinyl; when Ar represents (B) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is At 3 or 5, NR2 does not represent 4-benzyl piperazinyl;

The genistein alkylamine compound (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is characterized in that The pharmaceutically acceptable salt is such a genistein alkylamine compound with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, d- ₆ fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid. a salt formed from maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, d- ₆ alkylsulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

The method for producing a genistein-type alkylamine compound (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein the method for producing the compound is represented by Ar The structural unit and Linker or -0-Linker-NRiR ₂ indicate the difference in substituents. There are four methods:

One: When Ar represents structural unit (A) and R ₃ =H, and Linker represents (CH ₂ ) _m :

Wherein: X represents Cl, Br, I; Ar represents a structural unit (A) and R ₃ represents H; and R ₂ , m have the same definitions as the chemical structural formula (I);

Using methoxymethylene-protected genistein (1) as a starting material, reacting with a dihaloalkyl compound (2) under solvent and basic conditions to form the corresponding aryloxyalkyl halide compound (3) , the obtained intermediate 3 and the organic amine compound (4) are reacted in a solvent to obtain a corresponding methoxymethylene-protected genistein isolamine alkylamine compound (5), and the compound 5 is removed under solvent and acidic conditions. a methoxymethylene protecting group, corresponding to the genus genistein alkylamine compound (I);

She also denotes that structural unit (B), or (C), or structural unit (A) where R ₃ does not represent H, and Linker represents (CH ₂ ) _m : alkali

Ar OH X(CH ₂ ) _m X Ar

R ₂

6 22 7 (I)

Where: X represents Cl, Br, I; Ar represents structural unit (B) or (C), and R ₃ does not represent H structural unit (A); , R ₂ , R ₃ , m, n definition and chemistry The structural formula (I) is the same;

The corresponding aryloxyalkyl halide compound (7) is reacted under basic conditions with a corresponding genistein is used as a starting material to form a corresponding aryloxyalkyl halide compound (7). The organic amine compound (4) is reacted to obtain the corresponding genistein isolamine alkylamine compound (I);

3⁄43⁄4H: When Ar represents structural unit (A) and R ₃ =H, -O-Linker-NRiRz

Deprotection group

Wherein: X represents Cl, Br, I; Ar represents a structural unit (A) and R ₃ represents H _; m, has the same definition as the chemical structure formula (I);

Using methoxymethylene-protected genistein (1) as a starting material, it is reacted with 1-substituted-4-haloalkylpiperazine (8) under solvent and basic conditions to obtain the corresponding methoxy group. Methyl-protected genistein isolamine alkylamine compound (9), compound 9 is removed under solvent and acidic conditions to obtain the corresponding genistein isoflavone alkylamine compound (I);

(B), or (C), or R ₃ does not represent structural unit (H) of H, -O-Linker-NRiRz

Wherein: X represents Cl, Br, I; Ar represents a structural unit (B;), or (C;), or R ₃ does not represent H structural unit (A); , m, n definition and chemical structure formula (I) the same;

Corresponding genistein is used as a starting material to react with 1-substituted-4-haloalkylpiperazine (8) under basic conditions to obtain the corresponding genistein alkylamine compound. (I);

The genistein is found to contain an amino group in the molecule, and the amino group is basic, and can be prepared by any pharmaceutically acceptable salt formation method with any suitable acid. Acceptable salt.

The method for producing a genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the step a) of the first method, the base used in the reaction is: an alkali metal hydroxide , alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, alkali metal salt of ₈ alcohol, triethylamine, tributylamine, trioctylamine, Pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ - ₈ alkanes; compound (1): dihalo alkyl compound (2): base molar feed ratio of 1.0: 1.0 to 10.0 : 1.0-10.0; The reaction temperature is room temperature to 150 ° C; the reaction time is 1 to 72 hours;

In the step b) of the first method, the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C ₃ _-8 aliphatic ketone, benzene, toluene, acetonitrile, d_ ₈ alcohol, or a C ₅ _ ₈ alkanes; intermediate (3): moles of an organic amine compound (4) the feed ratio of 1.0: 1.0 to 10.0; the reaction temperature is room temperature ~ 150 ° C; the reaction time is 1 to 72 small Time;

The method of step C), the reaction solvent used was: water, d_ ₆ alcohols, NN- dimethylformamide, tetrahydrofuran, C ₃ _ ₈ aliphatic ketone, acetonitrile, 1,4-dioxane, or di- Methyl sulfoxide; the acid used is: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, d- ₆ fatty acid, d- ₆ alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid; The mass fraction in the reaction system is from 0.1% to 100%, the reaction temperature is from 0 to 150 ° C _{, and the} reaction time is from 30 minutes to 24 hours.

The method for producing a genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the step a) of the second method, the base used in the reaction is: an alkali metal hydroxide , alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, alkali metal salt of d- ₈ alcohol, triethylamine, tributylamine, trioctylamine , pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide , chloride, chloroform, C ₃ _ ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ - ₈ alkanes; compound (6): dihalo alkyl compound (2): base molar feed ratio of 1.0: 1.0 15.0: 1.0-15.0; reaction temperature is room temperature to 150 ° C; reaction time is 1 to 72 hours;

Method II Step b), the solvent used in the reaction: ether, tetrahydrofuran, NN- dimethylformamide, dimethylsulfoxide, methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, d- ₈ alcohols, or a C ₅ - ₈ alkanes; compound (7): moles of an organic amine compound (4) the feed ratio of 1.0: 1.0 to 15.0; the reaction temperature is room temperature ~ 150 ° C; the reaction time is 1 to 72 hour.

The method for producing a genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the step a) of the third method, the alkali used for the reaction is: an alkali metal hydroxide , alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, alkali metal salt of ₈ alcohol, triethylamine, tributylamine, trioctylamine, Pyridine, N-methylmorpholine, N-methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, dimethyl sulfoxide, methylene chloride, chloroform, C ₃ - ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ _ ₈ alkanes; methoxymethylene protected genistein (1): l-substituted-4 haloalkyl l Oxazine

(8): The molar ratio of the base is 1.0: 1.0-10.0: 1.0-10.0; the reaction temperature is room temperature to 150 ° C; the reaction time is 1 to 72 hours;

Three steps of the method b), the solvent used in the reaction: water, d- ₆ alcohols, NN- dimethylformamide, tetrahydrofuran, C ₃ - ₈ aliphatic ketone, acetonitrile, 1,4-dioxane, or Dimethyl sulfoxide; the acid used is: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, d- ₆ fatty acid, d- ₆ alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid; The mass fraction of the acid in the reaction system is 0.1%-100% _{; the} reaction temperature is 0-150 ° C _{; and the} reaction time is 30 minutes to 24 hours.

The method for producing a genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein in the fourth method, the base used for the reaction is: an alkali metal hydroxide or an alkaline earth metal hydrogen Oxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal hydrogencarbonate, alkaline earth metal hydrogencarbonate, triethylamine, tributylamine, trioctylamine, pyridine, N-A An alkali metal salt of morpholine, N-methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide, or (^ _-8 alcohol; the solvent used for the reaction is: diethyl ether, tetrahydrofuran, NN-dimethylformamide, two methyl sulfoxide, dichloromethane, chloroform, C ₃ _ ₈ aliphatic ketone, benzene, toluene, acetonitrile, or a C ₅ - ₈ alkanes; genistein compound (6): l-substituted-4 haloalkyl l The molar ratio of the base (8): base is 1.0: 1.0-20.0: 1.0-20.0; the reaction temperature is room temperature to 150 ° C; and the reaction time is 1 to 72 hours.

The use of the genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 for the preparation of a medicament for treating and/or preventing a neurodegenerative disease, such Neurodegenerative diseases are: vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, or glaucoma.

9. A class of compounds characterized in that it is a compound of the formula (II) or (III) having a chemical structure:

Wherein: H, CH: ₁₂ alkyl; R ₂ represents CH: ₁₂ alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridine 9-yl, 6-chloro-1, 2,3,4-tetrahydroacridine 9-yl, 8-chloro-1,2,3,4-tetrahydroacridine 9-yl, 6,8-dichloro-1,2,3,4-tetra Hydrogen acridine 9-yl or N-demethylgalanthryl; NR ₂ also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, piperidine substituted at the 4-position by C^Cu alkyl a piperidinyl group having a 4-position substituted with a benzyl group or a substituted benzyl group, a piperazinyl group, a piperazinyl group substituted at the 4-position by a C Cu alkyl group, and a 4-position substituted with a benzyl group or a substituted benzyl group. Piperazine; m represents 1-12; represents H, C-C ₁₂ alkyl, benzyl or substituted benzyl; the above "substituted benzyl" means that one to four of the benzene rings are selected from the group consisting of groups substituted benzyl group: F, Cl, Br, I , d_ 4 alkyl, d_ ₄ alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, phenyl which may be substituted Any possible position of the ring.

10. Use of any of the compounds according to claim 9 for the preparation of the genistein alkylamine compound of any of claims 1-2, or a pharmaceutically acceptable salt thereof.