CN103113340B - One class Genistein alkyl amine compound, Preparation Method And The Use - Google Patents

Abstract

The present invention discloses a novel genistein alkylamine compound (I) and its pharmaceutically acceptable salt, its preparation method and its use in the preparation of drugs for treating and/or preventing neurodegenerative related diseases. Including but not limited to vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases ; In the formula: Ar represents any structural unit in (A)~(C) as shown below, n=1-2.

Description

A class of genistein alkylamine compounds, their preparation method and use

technical field

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

Background technique

Vascular dementia (Vascular Dementia, VD) is caused by various types of cerebrovascular diseases (including ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and chronic hypoxic cerebrovascular disease, etc.) It is a clinical syndrome of cognitive dysfunction, and its main clinical manifestations include: decline in cognitive ability, memory, and social life ability, as well as changes in emotion and personality. It is a chronic progressive disease. In China, Japan and other Asian countries, vascular dementia is the first cause of senile dementia; with the continuous advancement of the world's population to aging, cerebrovascular diseases are increasing, and the incidence of vascular dementia is gradually increasing, seriously affecting The quality of work and life of the elderly, and bring heavy economic and spiritual burdens to society and families. Therefore, VD has become an important research hotspot in the fields of geriatrics and psychiatry. Due to the complex pathogenesis of vascular dementia, there is no drug that can block the development of the disease. The current clinical treatment is mainly to improve brain blood circulation and brain metabolism, and strengthen brain nutrition.

In recent years, studies at home and abroad have shown that VD patients are often accompanied by abnormalities in the cholinergic system when they exhibit cognitive impairment. The density of ChAT-positive neurons and fibers in the hippocampal region of VD patients decreased, and the activity of ChAT in different parts of the brain decreased. Cerebral ischemia can lead to an increase in the activity of acetylcholinesterase in the brain; at the same time, some acetylcholinesterase inhibitors such as: HuperzineA and Revastigmine have also been found to protect neuronal damage caused by ischemia, and can promote post-cerebral ischemia. Functional recovery, indicating that acetylcholinesterase inhibitors can be used in the treatment of vascular dementia.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system mainly characterized by progressive cognitive impairment and memory impairment. It has risen to the fourth leading cause of death in developed countries such as Europe and the United States. According to the report of the World Health Organization, 10% of people over the age of 65 in the world have mental retardation, one-half of them develop dementia, and the incidence rate of people over the age of 85 is nearly 50%. At present, the number of AD patients in my country has exceeded 5 million. There is no effective treatment for this disease. With the acceleration of the aging process of my country's population, this number will become even larger. Because the clinical manifestations of AD are decreased memory ability, orientation ability, thinking and judgment ability, reduced daily life ability, and even abnormal mental behavior symptoms, etc., it makes patient care more difficult and brings a heavy burden to the society and family. Therefore, research It is of great significance to develop new drugs for the treatment of senile dementia. From the perspective of market demand, the "Alzheimer's Disease Report" recently completed by the world market research and strategic consulting company predicts that the global sales of Alzheimer's disease treatment drugs will reach 10 billion US dollars by 2015; With the rapid rise of the incidence rate, the market for such drugs is also rapidly expanding.

AD is a disease caused by multiple factors, and its pathogenesis is complex. Its pathogenesis has not yet been fully elucidated. After the death of the patient, anatomical findings revealed amyloid senile plaques (Senile Plaques, SP) and neurofibrillary tangles (Neurofibrillary Tangles, NFT) in the brain. It is the most characteristic histopathological change in AD patients. In recent years, many researchers have devoted themselves to revealing the pathogenesis of AD from the molecular and cellular levels, and put forward a variety of hypotheses, such as: cholinergic neuron damage, amyloid deposition, hyperphosphorylation of tau protein, inflammation, freedom Therefore, new treatment approaches and means developed for these pathogenesis will hopefully relieve and improve the condition of AD patients. At present, there are two main types of clinically effective drugs for the treatment of AD: (1) Based on the cholinergic hypothesis that the lack of neurotransmitter acetate choline leads to cognitive dysfunction, acetylcholinesterase inhibitors are used to increase the level of acetylcholine in the brain of patients. Level, such as: Tacrine, Donepezil, Ravastigmine, Galantamine; (2) Use N -methyl-D-aspartic acid (NMDA) receptor inhibitors to reduce the damage of glutamate to nerve cells, such as: Memantine Hydrochloride. However, these drugs have problems such as single target, many toxic and side effects, and poor long-term curative effect on AD patients.

Therefore, the research and development of anti-neurodegenerative disease therapeutic drugs with new chemical structures, new mechanisms of action, multiple targets, and low side effects not only meets the urgent needs of the aging society, but also has good market prospects.

Contents of the invention

The purpose of the present invention is to disclose a class of genistein alkylamine compounds ( I ) and pharmaceutically acceptable salts thereof.

Another object of the present invention is to disclose the preparation method of the genistein alkylamine compound ( I ) and the pharmaceutically acceptable salt thereof.

Another object of the present invention is to disclose the use of the genistein alkylamine compound ( I ) and its pharmaceutically acceptable salts in the preparation of drugs for the treatment and/or prevention of neurodegenerative related diseases, including but not limited to Vascular dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease, HIV-related dementia, multiple sclerosis, progressive lateral sclerosis, neuropathic pain, glaucoma and other neurodegenerative diseases.

The general chemical structure formula of the genistein alkylamine compound ( I ) provided by the present invention is:

  

In the formula: Ar represents any structural unit in (A) ~ (C) shown below, n=1 or 2;

R ₁ represents H, C ₁ ~C ₁₂ alkyl; R ₂ represents C ₁ ~C ₁₂ alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridinyl 9-yl, 6-chloro -1,2,3,4-tetrahydroacridinium-9-yl, 8-chloro-1,2,3,4-tetrahydroacridinium-9-yl, 6,8-dichloro-1,2,3, 4-tetrahydroacridinyl 9-yl, or N -demethylgalantamine; R ₁ NR ₂ also represents tetrahydropyrrolyl, morpholinyl, piperidinyl, 4-position is C ₁ ~C ₁₂ Piperidinyl substituted by alkyl, piperidinyl substituted by benzyl or substituted benzyl at 4-position, piperazinyl, piperazinyl substituted by C ₁ ~C ₁₂ alkyl at 4-position, 4- Piperazinyl substituted by benzyl or substituted benzyl; R ₃ represents H, C ₁ ~C ₁₂ alkyl, CF ₃ , C ₁ ~C ₄ acyl; Linker represents (CH ₂ ) _m , m represents 1- 12. Wherein, when Ar represents ( A ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 3 or 4, R ₁ NR ₂ does not represent 4-benzylpiperazinyl; when Ar represents ( A ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 3, R ₁ NR ₂ does not represent morpholinyl, tetrahydropyrrolyl, 4-methylpiperazinyl; when Ar represents ( B ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , when m is 2, 3 or 4, R ₁ and R ₂ do not represent methyl, ethyl, n-propyl, or n-butyl at the same time; when Ar represents ( B ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , when m is 2, 3, 4, 5 or 6, R ₁ NR ₂ 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, R ₁ NR ₂ does not represent tetrahydropyrrolyl, piperidine group; when Ar represents ( B ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , m is 4 or 6, R ₁ NR ₂ does not represent 4-ethylpiperazinyl; when Ar represents ( B ) structural unit and R ₃ represents H, Linker is (CH ₂ ) _m , when m is 3 or 5, R ₁ NR ₂ does not represent 4-benzylpiperazinyl; " -O-Linker-NR ₁ R ₂ " also Can be , m represents 1-12, R ₄ represents H, C ₁ ~ C ₁₂ alkyl, benzyl or substituted benzyl.

The above-mentioned term "substituted benzyl" refers to a benzyl group substituted by 1-4 groups selected from the following group on the benzene ring: F, Cl, Br, I, C _1-4 alkyl, C _1-4 Alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, these substituents can be in any possible position of the benzene ring.

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

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

In the formula: X represents Cl, Br, I; Ar represents the structural unit (A), and R ₃ represents H; the definitions of R ₁ , R ₂ , and m are the same as those in the general chemical structure formula ( I ).

Starting from genistein ( 1 ) protected by methoxymethylene group, it reacts with dihaloalkyl compound ( 2 ) under solvent and alkaline conditions to generate the corresponding aryloxyalkyl halide compound ( 3 ) , the obtained intermediate 3 reacts with the organic amine compound ( 4 ) in a solvent to obtain the corresponding genistein alkylamine compound ( 5 ) protected by the methoxymethylene group, and the compound 5 is removed under solvent and acidic conditions Methoxymethylene protecting group, the corresponding genistein alkylamine compound ( I ).

Its specific preparation method is described as follows:

In the step a) , the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, _C1 Alkali metal salts of _-8 alcohols, organic tertiary amines or quaternary ammonium bases (such as: triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylene diamine, tetrabutylammonium hydroxide), the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformaldehyde Amides, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, acetone, acetonitrile , tetrahydrofuran or toluene; compound ( 1 ): dihaloalkyl compound ( 2 ): the molar feeding ratio of alkali is 1.0: 1.0~10.0: 1.0~10.0, preferably the molar feeding ratio is 1.0: 1.0~5.0: 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 to 24 hours.

In the step b) , the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketone, benzene, toluene, acetonitrile , C _1-8 alcohol, or C _5-8 alkane, the preferred solvent is: N,N -dimethylformamide, acetone, acetonitrile, tetrahydrofuran, ethanol or toluene; intermediate ( 3 ): organic amine compound ( 4 ) molar feeding ratio is 1.0:1.0~10.0, the preferred molar feeding ratio is 1.0:1.0~5.0; the reaction temperature is room temperature~150°C, the preferred reaction temperature is room temperature~120°C; the reaction time is 1~72 hours, the preferred reaction The time is 2 to 24 hours.

In the step c) , the solvent used for the reaction is: water, C _1-6 fatty alcohol, N,N -dimethylformamide, tetrahydrofuran, C _3-8 fatty ketone, acetonitrile, 1,4-dioxane , or dimethyl sulfoxide, the preferred 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, C _{1- 6} fatty acid, C _1-6 alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably acid: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid Acetic acid; the mass fraction of the acid in the reaction system is 0.1%-100%, the preferred mass fraction is 10%-95%, the reaction temperature is 0~150°C, the preferred reaction temperature is room temperature~120°C; the reaction time is 30 minutes~ 24 hours, the preferred reaction time is 1 to 8 hours.

(2) When Ar represents the structural unit (B), or (C), or R ₃ The structural unit (A) that does not represent H, Linker represents (CH ₂ ) _m hour:

In the formula: X represents Cl, Br, I; Ar represents the structural unit (B) or (C), and R ₃ does not represent the structural unit (A) of H; the definition of R ₁ , R ₂ , R ₃ , m, n It is the same as the general chemical structure formula ( I ).

Using the corresponding genistein compound ( 6 ) as the starting material, it reacts with the dihaloalkyl compound ( 2 ) under alkaline conditions to generate the corresponding aryloxyalkyl halide compound ( 7 ), and the obtained compound 7 is compatible with The organic amine compound ( 4 ) reacts to obtain the corresponding genistein alkylamine compound ( I ).

Its specific preparation method is described as follows:

In the step a) , the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, _C1 Alkali metal salts of _-8 alcohols, organic tertiary amines or quaternary ammonium bases (such as: triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylene diamine, tetrabutylammonium hydroxide), the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformaldehyde Amides, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, acetone, acetonitrile , tetrahydrofuran or toluene; compound ( 6 ): dihaloalkyl compound ( 2 ): the molar feeding ratio of alkali is 1.0: 1.0~15.0: 1.0~15.0, preferably the molar feeding ratio is 1.0: 1.0~6.0: 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 to 24 hours.

In the step b) , the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketone, benzene, toluene, acetonitrile , C _1-8 alcohol, or C _5-8 alkane, the preferred solvent is: N,N -dimethylformamide, acetone, acetonitrile, tetrahydrofuran, ethanol or toluene; compound ( 7 ): organic amine compound ( 4 ) The molar feeding ratio is 1.0:1.0~15.0, the preferred molar feeding ratio is 1.0:1.0~6.0; the reaction temperature is room temperature~150°C, the preferred reaction temperature is room temperature~120°C; the reaction time is 1~72 hours, the preferred reaction time 2 to 24 hours.

(3) When Ar is the structural unit (A) and R ₃ =H, -O-Linker-NR ₁ R ₂ is hour:

In the formula: X represents Cl, Br, I; Ar represents the structural unit (A), and R ₃ represents H; the definitions of m and R ₄ are the same as those in the general chemical structure formula ( I ).

Starting from genistein ( 1 ) protected by methoxymethylene, reacting with 1-substituted-4-haloalkylpiperazine ( 8 ) under solvent and alkaline conditions to obtain the corresponding methoxymethylene Methyl-protected genistein alkylamine compound ( 9 ), compound 9 removes the methoxymethylene protecting group under solvent and acidic conditions to obtain the corresponding genistein alkylamine compound ( I ).

Its specific preparation method is described as follows:

In the step a) , the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, _C1 Alkali metal salts of _-8 alcohols, organic tertiary amines or quaternary ammonium bases (such as: triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylene diamine, tetrabutylammonium hydroxide), the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformaldehyde Amides, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, acetone, acetonitrile , tetrahydrofuran or toluene; genistein protected by methoxymethylene ( 1 ): 1-substituted-4-haloalkylpiperazine ( 8 ): the molar ratio of base is 1.0:1.0~10.0:1.0~10.0 , the preferred molar feed 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; the reaction time is 1~72 hours, preferably the reaction time is 2~24 hours.

In the step b) , the solvent used for the reaction is: water, C _1-6 fatty alcohol, N,N -dimethylformamide, tetrahydrofuran, C _3-8 fatty ketone, acetonitrile, 1,4-dioxane , or dimethyl sulfoxide, the preferred 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, C _{1- 6} fatty acid, C _1-6 alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid, preferably acid: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid Acetic acid; the mass fraction of the acid in the reaction system is 0.1%-100%, the preferred mass fraction is 10%-95%, the reaction temperature is 0~150°C, the preferred reaction temperature is room temperature~120°C; the reaction time is 30 minutes~ 24 hours, the preferred reaction time is 1 to 8 hours.

(4) When Ar represents the structural unit (B), or (C), or R ₃ does not represent the structural unit (A) of H, -O-Linker-NR ₁ R ₂ represents hour:

In the formula: X represents Cl, Br, I; Ar represents the structural unit (B), or (C), or R ₃ does not represent the structural unit (A) of H; the definition of R ₄ , m, n and the general chemical structure formula ( I ) same.

Using the corresponding genistein compound ( 6 ) as the starting material, react with 1-substituted-4-haloalkylpiperazine ( 8 ) under alkaline conditions to obtain the corresponding genistein alkylamine compound ( I ).

The specific preparation method is described as follows: the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, organic tertiary amine Class or quaternary ammonium bases (such as: triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide), or C The alkali metal salt of _1-8 alcohol, the preferred base is: potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, pyridine, or sodium methoxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethyl Formamide, dimethylsulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes, preferred solvents are: N,N -dimethylformamide, acetone, Acetonitrile, tetrahydrofuran or toluene; genistein compound ( 6 ): 1-substituted-4-haloalkylpiperazine ( 8 ): molar feed ratio of base is 1.0:1.0~20.0:1.0~20.0, preferably molar feed The ratio is 1.0:1.0~8.0:1.0~8.0; the reaction temperature is room temperature~150°C, preferably room temperature~120°C; the reaction time is 1~72 hours, preferably 2~24 hours.

The starting materials of the present invention—methoxymethylene-protected genistein ( 1 ), 1-substituted-4-haloalkylpiperazine ( 8 ) can be prepared by common techniques in the art, including but not limited to 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 genistein alkylamine compound ( I ) obtained according to the above four methods contains an amino group in its molecule, which is basic and can be prepared with any suitable acid by a pharmaceutically conventional salt-forming method. Acceptable salts, the acid is: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C _1-6 fatty carboxylic acid (such as: formic acid, acetic acid, propionic acid, etc.), oxalic acid, benzoic acid, salicylic acid , maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, C _1-6 alkylsulfonic acid (such as: methylsulfonic acid, ethylsulfonic acid, etc.), camphorsulfonic acid, benzenesulfonic acid or p-toluene sulfonic acid.

The purity of the genistein alkylamine compounds ( I ) and their pharmaceutically acceptable salts disclosed by the present invention are determined by HPLC, which shows that the purity is higher than 98.5%, and these compounds have been screened for their biological activity as follows .

(1) Acetylcholinesterase and butyrylcholinesterase inhibitory activity

Add 30 μL of 1.0 mmol/L thioacetylcholine iodide or thiobutyrylcholine iodide (both purchased from Sigma), 40 μL of PBS buffer solution with pH 7.4, and 20 μL of the compound solution to be tested (DMSO content less than 1%) and 10 μL acetylcholinesterase (5% homogenate supernatant of rat cerebral cortex, pH 7.4 phosphate buffer as homogenate medium) or butyrylcholinesterase (25% supernatant of rat serum Solution, pH7.4 phosphate buffer as homogenization medium) solution, after adding and mixing, incubate at 37°C for 15min, add 0.2% 5,5'-dithio-bis(2-nitrobenzene Formic acid) (DTNB, purchased from Sigma Company) solution 30 μL for color development, measured the optical density (OD value) of each well at 405 nm with a microplate reader, compared with the blank well without the sample to be tested, and calculated the inhibition rate of the compound on the enzyme (Enzyme inhibition rate (%)=(1-sample group OD value/blank group OD value)×100%); Select five to six concentrations of the compound, measure its enzyme inhibition rate, and use the negative comparison of the molar concentration of the compound The linear regression between the number and the inhibition rate of the enzyme, the molar concentration at which the 50% inhibition rate is obtained is the IC ₅₀ of the compound. The measurement results show that the compounds disclosed in the examples of the present invention all have significant inhibitory effect on acetylcholinesterase, and its _IC50 is 0.1nM~5.0μM, wherein, the compound 2-B4-14 disclosed in the example 2 of the present invention The IC ₅₀ is 2.5 μM, while the IC ₅₀ of the remaining compounds in the same series (2-B4-1 to 2-B4-13, 2-B4-15 to 2-B4-21) are all less than 2.5 μM, while the positive control drug— —Rivastigmine is 6.3 μ M to the _IC50 of acetylcholinesterase inhibition; Determination result also shows, the inhibitory activity of the compound disclosed in the embodiment of the present invention is much higher than the inhibitory activity to butyrylcholinesterase to butyrylcholinesterase, illustrates The compound disclosed in the invention has certain selective inhibitory effect on acetylcholinesterase.

(2) Compound pair H ₂ o ₂ Screening for the protective effect of induced PC12 cell injury

PC12 cells were inoculated on 96-well culture plates at a density of 1×10 ⁵ cells/mL in DMEM medium containing 10% calf serum, and the inoculation volume was 100 μL/well, and then placed in a 37°C thermostat containing 5% CO ₂ Cultured in an incubator. After 24 hours of culture, 10 μL/well of the corresponding concentration of compound (final concentration: 10 ^-5 mol/L, 10 ^-6 mol/L) was added to the administration group, and pre-incubated for 2 hours (10 μL/well was added to the control group and the injury group respectively). well PBS so that the volume remains equal). After PC12 cells were incubated for 2 hours, 10 μL/well of 100 μM H ₂ O ₂ injury agent was added to the administration group and the injury group respectively (10 μL/well PBS was added to the control group), and after 30 minutes, the culture medium of each group was replaced with The RPMI-1640 culture solution without calf serum was continued to be cultured in a constant temperature incubator for 24 hours, and the volume of the culture solution was still 100 μL/well. After continuing to culture for 24 hours, 5 mg/mL MTT 100 μL/well was added to each group for live cell staining. After 3 hours, 100 μL/well of 100% DMSO stop solution was added to each group, fully dissolved and mixed. The OD value of each group was measured at a wavelength of 490 nm. The test results were repeated 3 times, and the Duncan's test method was used for statistics. Expressed as a percentage of the control group. The measurement results show that the compounds disclosed in the examples of the present invention have significant protective effects on PC12 cell damage induced by hydrogen peroxide, and the antioxidant activity at a concentration of 10 ^-5 mol/L is stronger than that of genistein.

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

SPF grade ICR male mice, 25-30g, were randomly divided into: normal group, model group, high and low dose groups of the test drug (5.0, 2.5mg/kg), 10 animals in each group. The test drug was administered intragastrically at one time, and the blank group and the model group were administered 0.5% CMC-Na as a solvent, and the administration volume was 0.1ml/10g; 45 minutes after the administration, the mice in the normal group were intraperitoneally injected with normal saline, and the animals in the other groups were injected with normal saline intraperitoneally. All were injected with scopolamine (5mg/kg), and the administration volume was 0.1ml/10g. After 30 minutes of modeling, the mice were put into the non-electrically stimulated Y maze for behavioral tests. During the test, put the mouse at the end of one arm, let it walk freely in the maze for 8 minutes, record the number of times it enters each arm and the number of alternations, and calculate the alternation rate according to the following formula: alternation rate%=[alteration times/(total number of entries -2)] × 100, and the results were expressed as mean ± standard deviation, and the differences between groups were analyzed by one-way analysis of variance. The measurement results show that under the experimental conditions, the compound disclosed in the present invention has a dose-dependent improvement effect on scopolamine-induced acquired memory impairment in mice, and there is a statistical difference compared with the model group (p<0.01).

(4) The effect of the compound on the impairment of memory reproduction in mice induced by ethanol

SPF grade ICR male mice, 25-30g, were randomly divided into: normal group, model group, test drug high and low dose groups (5.0, 2.5mg/kg), rivastigmine group (3mg/kg), each group 10 animals. The test drug was given by intragastric administration every day, and the blank group and the model group were given the vehicle 0.5% CMC-Na, and the administration volume was 0.1ml/10g, and the administration was continued for 32 days; For 30 minutes, the model group and each administration group were given 0.1ml/10g ethanol (15% w/v) by intragastric administration for 24 consecutive days. The animal platform experiment was carried out every day, and the training or test experiment was carried out 45 minutes after the drug. During the training, the mice were placed in the platform device, lightly placed on the platform, and energized. When the animal jumped off the platform, the two feet touched the copper grid simultaneously Electric shock is regarded as a wrong response. The normal avoidance reaction of mice after receiving electric shock is to escape to the platform. The latency period for mice to escape to the platform is recorded, and the number of electric shocks within 5 minutes is recorded as the academic performance. After 24 hours, the test was carried out, and the time when the mice first jumped to receive the electric shock (latency period) and the number of electric shocks received within 5 minutes (the number of errors) were recorded as the evaluation index of memory reproduction function. The test results were expressed as mean ± standard deviation, and the differences among groups were analyzed by one-way analysis of variance. The results show that under the experimental conditions, the compounds disclosed in the present invention can significantly improve the dysfunction of memory reproduction in mice induced by ethanol, and there are statistical differences compared with the model group (p<0.01).

(5) The neuroprotective effect of the compound on rats with vascular dementia

(a) Animal modeling, grouping and administration

Rats were anesthetized by intraperitoneal injection of 3.5% chloral hydrate (350 mg/kg), the bilateral common carotid arteries were separated and ligated, and the bilateral common carotid arteries were not ligated in the sham-operated normal group. The hidden platform screening experiment of the 5-day water maze test was performed 7 days after the operation, and the incubation period of the animals on the fifth day was used as the screening index: SR=(average latency of the operation group-average latency of the normal group)/average latency of the animals in the normal group. Successful model animals with neurobehavioral dysfunction were screened with SR<0.2, and randomly divided into normal group, model group, high-dose drug group (45 mg/kg) and low-dose group (15 mg/kg), 12 in each group; On the 13th day afterward, the drug was administered by gavage, and the normal group and the model group were given equal volumes of vehicle; after 3 weeks of continuous administration, a water maze test was performed for 7 days to evaluate the effect of the drug on the neurobehavioral function of rats with vascular dementia. After the behavioral test was completed and the animals were anesthetized, the heart was perfused with PBS (pH 7.4) and 4% paraformaldehyde solution sequentially, and the brain was quickly removed from the craniotomy, fixed in 10% neutral formaldehyde for 24 hours, embedded in paraffin, and made Coronal sections of the brain with a thickness of about 5 μm were used for neuropathological examination. The experimental data are expressed as mean ± standard deviation. The experimental results are statistically analyzed by SPSS16 software. The comparison between groups is performed by the one-way analysis of variance LSD method, and P<0.05 is considered a significant difference.

(b) Measurement of neurobehavioral function

The Morris water maze test was used to evaluate the effects of drugs on the spatial learning and memory abilities of 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 four quadrants. A platform is placed in the center of quadrant 1. The platform is equidistant from the center of the circle and the pool wall. The platform is white and circular, with a diameter of 10cm and a height of 20cm, the platform is located 2cm below the water surface, the temperature of the pool water is kept at 25±2°C, and an appropriate amount of food additive white pigment is added to the water to make the pool water opaque milky white, so that animals cannot reach the platform through vision, so as to detect animals’ sensitivity to spatial positions. There is a camera directly above the pool, and the camera is connected to a computer to record the animal activities in the pool through the computer. After administration, the water maze test was carried out continuously for 7 days, and the 1st-2nd day was the concealed platform experiment, and the time (latency period) for the rats to find the platform was recorded; The position remains the same, record the stay time and crossing times of the rats in the quadrant of the original platform position; the 4th to 6th day is a new platform experiment (that is, the platform position is changed), the position of the rat’s water entry point remains unchanged, and the time when the rat finds the platform is recorded (latency period); the seventh day was the visible platform experiment, the position of the water entry point of the rats remained unchanged, and the time for the rats to find the platform (latency period) was recorded. The Morris water maze is an experiment that depends on the memory function of the hippocampus, and is mainly used for the evaluation of cognitive dysfunction caused by cerebral ischemic injury. Cognitive function consists of three phases: acquisition, consolidation, and memory. In our experiment, the hidden platform experiment detects the acquisition function, the new platform experiment detects the learning consolidation function, and the exploration platform experiment detects the memory function.

The measurement results showed that compared with the model group, the latency period of the rats in the drug treatment group on the hidden platform and the new platform was significantly shortened, while in the exploration platform experiment, the animals stayed in the quadrant of the original platform and the times of crossing were significantly prolonged. The experimental results prove that the drug treatment of the compound disclosed in the present invention can significantly improve the cognitive dysfunction of vascular dementia caused by long-term cerebral hypoperfusion in a dose-dependent manner. In addition, the results of the visible platform experiment showed that there was no significant difference in the platform latency between the groups, thereby excluding the impact of the operation on the animal's vision and motor ability, and further confirming the therapeutic effect of the drug on vascular dementia.

(c) Detection of neuronal damage

The expression level of neuronal nuclear antigen (NeuN) in the cerebral cortex and hippocampus of VD animals was detected by immunohistochemical method, and the effect of drugs on neuronal damage in the brain of VD animals was evaluated. Take coronal paraffin sections of the brains of each animal, dewax them with xylene, inactivate endogenous peroxidases with 3% H ₂ O ₂ , add 5% BSA blocking solution dropwise, and incubate in an incubator at 37°C for 1 hour. Add NeuN polyclonal antibody (1:200, Beijing Boaosen Biotechnology Co., Ltd.), incubate at 37°C for 2 hours, then transfer to 4°C refrigerator overnight. Add biotinylated goat anti-mouse secondary antibody, incubate at 37°C for 1 hour, then add SABC, incubate at 37°C for 1 hour, develop color with DAB, and counterstain with hematoxylin. Routine dehydration, xylene transparency, and neutral gum mounting. Under a 400X optical microscope, blindly observe and record the number of positive cells in three non-overlapping regions of the cortex and hippocampus, and calculate the average value of each slice, taking the control group as 100%, the number of positive cells in the model group and the administration group Expressed as a percentage of the control group.

The measurement results showed that compared with the normal group, the number of NeuN immunopositive neurons in the cortex and hippocampus of the model group was significantly reduced (P<0.01); compared with the model group, the drug could increase the number of neurons in a dose-dependent manner (P <0.05 or P<0.01). Experimental results show that the compound disclosed in the present invention can inhibit the injury of neuron cells in the brain of rats with vascular dementia, which is consistent with the result that the drug can improve the cognitive function of rats with vascular dementia in the Morris water maze test.

(d) Detection of glial cell activation

Take coronal paraffin sections of the brains of each animal, dewax them with xylene, inactivate endogenous peroxidases with 3% H ₂ O ₂ , add 5% BSA blocking solution dropwise, and incubate in an incubator at 37°C for 1 hour. Add OX-42 polyclonal antibody (1:200, Millipore Company, USA) or GFAP polyclonal antibody (1:100, Wuhan Boster Bioengineering Co., Ltd.), incubate at 37°C for 2 hours and transfer to 4°C refrigerator overnight. Add biotinylated goat anti-mouse secondary antibody, incubate at 37°C for 1 hour, then add SABC, incubate at 37°C for 1 hour, develop color with DAB, counterstain with hematoxylin, routinely dehydrate, clear with xylene, seal with neutral gum; Histochemical staining was collected with an Axiovert 40 CFL microscope: under a 400x optical microscope, three different areas were selected for each section at a fixed position in the cerebral cortex, and the accumulated light of the positive cells in the immune response was analyzed using Image Pro-plus5.0 software Density value (IOD), the average value of IOD of each slice was calculated, and the results of each group were expressed as mean ± standard deviation. The results showed that, compared with the normal group, the expression levels of OX-42 and GFAP in the cortex of the model group were significantly increased (P<0.01); compared with the model group, the drug could reduce the expression of OX-42 and GFAP in a dose-dependent manner, among which There was a significant statistical difference in the high-dose group (P<0.01). Experimental results show that the compound disclosed in the present invention can inhibit the activation of microglial cells and astrocytes in rats with vascular dementia, and exert preventive and therapeutic effects on vascular dementia by inhibiting neuroinflammation.

Detailed ways

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

Example 1 When Ar represents a structural unit (A) and R ₃ =H, Linker means (CH ₂ ) _m General method for the preparation of genistein alkylamine compound (I)

Add 2.0 mmol of genistein ( 1 ) protected by 7-methoxymethylene group, 30 ml of acetonitrile, 8.0 mmol of anhydrous potassium carbonate and 7.0 mmol of dibromoalkyl compound ( 2 ) into the reaction flask, heat up and reflux to stir the reaction 3.0 to 9.0 hours (reaction progress tracked by TLC); after the reaction, filter while hot, wash the filter cake with a small amount of acetonitrile, distill off the solvent and excess dibromoalkyl compound from the filtrate under reduced pressure, and purify the residue by column chromatography (washing Dehydration: dichloromethane) to obtain the aryloxyalkyl bromide compound ( 3 ), with a yield of 75%-93%. Dissolve the above-mentioned aryloxyalkyl bromide compound ( 3 ) in 40 ml of ethanol, add 6.0 mmol of organic amine compound ( 4 ), heat and reflux and stir for 6.0-16.0 hours (track the reaction process with TLC); after the reaction, The solvent was evaporated under reduced pressure, 50 ml of dichloromethane was added to the residue, washed with 30 ml of 10% aqueous sodium carbonate solution and 30 ml of deionized water successively, the organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (eluent: chloroform), and the corresponding genistein alkylamine compound ( 5 ) protected by methoxymethylene group had a yield of 80%-96%; the obtained compound 5 was added to 10 ml of 15% hydrochloric acid aqueous solution and 20 ml of ethanol, stirred and reacted at room temperature for 3.0 to 8.0 hours (the reaction process was tracked by TLC), after the reaction was completed, the solvent was evaporated under reduced pressure, and 50 ml of dichloromethane was added to the residue, followed by Wash with 20 ml of 5% aqueous sodium bicarbonate solution and 20 ml of deionized water, dry the organic layer over anhydrous sodium sulfate and filter, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: petroleum ether-acetic acid Ethyl ester=30:1 v/v), the corresponding genistein alkylamine compound ( I ) was obtained with a yield of 90%-98%, and its chemical structure was confirmed by ¹ H-NMR, ¹³ C-NMR and Confirmed by ESI-MS. The structure of the target object prepared by the above-mentioned general method is as follows:

 

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Example 2 When Ar represents a structural unit (B), or (C), or R ₃ does not represent a structural unit (A) of H, and Linker represents (CH ₂ ) _m , genistein alkylamine compound (I) general method of preparation

Add 5.0 mmol of the corresponding genistein compound ( 6 ), 10.0 mmol of potassium carbonate and 60 ml of N , N -dimethylformamide into the reaction flask, stir at room temperature for 30 minutes, then add 10.0 mmol of dibromoalkyl compound ( 2 ) Stir and react at 50~60°C for 5-18 hours (the reaction progress is tracked by TLC); after the reaction is completed, filter while it is hot, evaporate the filtrate to remove the solvent under reduced pressure, add 150 ml of dichloromethane to the residue, and use 50 ml of 10% sodium carbonate aqueous solution and 50 ml of deionized water, the organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: chloroform/methanol=30:1 v/v), to obtain the corresponding aryloxyalkyl bromide compound ( 7 ).

According to the difference of the starting material compound ( 6 ), the corresponding 7-position, 4'-position, or 7,4'-position disubstituted aryloxyalkyl bromide compound ( 7 ) can be obtained; wherein, when the starting material When the genistein compound ( 6 ) is the structural unit ( B ) whose R ₃ does not represent H, the 7-substituted aryloxyalkyl bromide compound ( 7 ) is obtained with a yield of 78%-95%; when the starting When the genistein compound ( 6 ) is the structural unit ( A ) whose R ₃ does not represent H, the aryloxyalkyl bromide compound ( 7 ) substituted at the 4'-position is obtained with a yield of 66%-87%; When the starting material genistein compound ( 6 ) is genistein (R ₃ represents the structural unit ( A ) or ( B ) of H), the 7-substituted aryloxyalkyl bromide compound ( 7 ) can be obtained at the same time and 7,4'-disubstituted aryloxyalkyl bromide compounds ( 7 ), the yields were 35%-58% and 20%-35%, respectively.

Dissolve 1.0 mmol of the corresponding 7-position, 4'-position, or 7,4'-position disubstituted aryloxyalkyl bromide ( 7 ) prepared above in 15 ml of ethanol, and add 3.0 mmol of organic amine compounds ( 4 ), heat up and reflux and stir for 6.0 to 16.0 hours (the reaction process is tracked by TLC); after the reaction, the solvent is evaporated under reduced pressure, 50 ml of dichloromethane is added to the residue, and 15 ml of 5% sodium carbonate aqueous solution and Wash with 15 ml of deionized water, dry the organic layer over anhydrous sodium sulfate and filter, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (eluent: dichloromethane-acetone=30:1 v/v), The corresponding genistein alkylamine compound ( I ) was obtained with a yield of 80%-96.5%, and its chemical structure was confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS. The structure of the target object prepared by the above-mentioned general method is as follows:

Ar said

 

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Example 3 When Ar represents the structural unit (A) and R ₃ =H, -O-Linker-NR ₁ R ₂ represents General method for the preparation of genistein alkylamine compound (I)

Add 2.0 mmol of 7-methoxymethylene-protected genistein ( 1 ), 50 ml of acetonitrile, 3.0 mmol of anhydrous potassium carbonate and 2.5 mmol of 1-substituted-4-chloroalkylpiperazine ( 8 ), reflux and stir the reaction for 5.0 to 18.0 hours (the reaction process is tracked by TLC); after the reaction is completed, filter while it is hot, wash the filter cake with a small amount of acetonitrile, evaporate the filtrate to remove the solvent under reduced pressure, and the residue is purified by column chromatography (eluent: Chloroform) to obtain the corresponding genistein alkylamines ( 9 ) protected by methoxymethylene, with a yield of 78.0%-95.0%. The resulting compound 9 was added to a mixed solution of 10 ml of 15% aqueous hydrochloric acid and 20 ml of ethanol, stirred at room temperature for 3.0 to 7.0 hours (the reaction progress was tracked by TLC), after the reaction was completed, the solvent was evaporated under reduced pressure, and 50 ml of dichloromethane, washed successively with 20 ml of 5% aqueous sodium bicarbonate and 20 ml of deionized water, the organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (elution solution: petroleum ether-ethyl acetate=30:1 v/v), the corresponding genistein alkylamine compound ( I ) was obtained with a yield of 85%-95%, and its chemical structure was verified by ¹ H-NMR , ¹³ C-NMR and ESI-MS confirmation. The structure of the target object prepared by the above-mentioned general method is as follows:

 

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Example 4 When Ar represents the structural unit (B), or (C), or R ₃ does not represent the structural unit (A) of H, -O-Linker-NR ₁ R ₂ represents General method for the preparation of genistein alkylamine compound (I)

Add 5.0 mmol of the corresponding genistein compound ( 6 ), 10.0 mmol of potassium carbonate and 60 ml of N , N -dimethylformamide into the reaction flask, stir at room temperature for 30 minutes, then add 1-substituted-4-chloro Alkylpiperazine ( 8 ) 10.0 mmol, stirred and reacted at 50~60°C for 5-15 hours (the reaction progress was tracked by TLC); after the reaction was completed, filtered while hot, the filtrate was evaporated to remove the solvent under reduced pressure, and 150 ml di Chloromethane was washed successively with 50 ml of 10% sodium carbonate aqueous solution and 50 ml of deionized water, the organic layer was dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (eluent: chloroform /methanol=30:1 v/v), to get the corresponding genistein alkylamine compound ( I ).

According to the difference of the starting material compound ( 6 ), the corresponding 7-position, 4'-position, or 7,4'-position disubstituted genistein alkylamine compound ( I ) can be obtained; wherein, When the starting material genistein compound ( 6 ) is a structural unit ( B ) in which R ₃ does not represent H, the 7-substituted genistein alkylamine compound ( I ) is obtained with a yield of 70%- 92%; when the starting material genistein compound ( 6 ) is a structural unit ( A ) in which R ₃ does not represent H, the genistein alkylamine compound ( I ) substituted at the 4'-position is obtained, and the yield The rate is 78%-96%; when the starting material genistein compound ( 6 ) is genistein (that is: R ₃ represents the structural unit ( A ) or ( B ) of H), the 7-position Substituted genisteine alkylamines ( I ), yield 30%-58% and 7,4'-disubstituted genisteine alkylamines ( I ), yield 23%- 38%. Its chemical structure was confirmed by ¹ H-NMR, ¹³ C-NMR and ESI-MS. The structure of the target object prepared by the above-mentioned general method is as follows:

Ar said

 

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Example 5

General method for the preparation of aryloxyalkylamine compound (I) and acid salt formation

Add 2.0 mmol of genistein alkylamine compound ( I ) and 50 ml of ethanol into the reaction flask according to the above-mentioned examples 1-4, stir evenly, add 6.0 mmol of the corresponding acid, heat up and reflux and stir for 20 minutes, After the reaction, cool to room temperature, evaporate the solvent under reduced pressure, recrystallize the residue with acetone, and filter the precipitated solid to obtain the salt of genistein alkylamine compound ( I ), whose chemical structure has been verified by ¹ H NMR and Confirmed by ESI-MS.

Claims (9)

1. A class of genistein alkylamine compounds or pharmaceutically acceptable salts thereof, characterized in that the general chemical structure of the compounds is as shown in ( I ): In the formula: Ar represents any structural unit in (A) ~ (C) shown below, n=1 or 2; ; R ₁ represents H, C ₁ ~C ₁₂ alkyl; R ₂ represents benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridinyl, 6-chloro-1,2,3,4 -Tetrahydroacridinium-9-yl, 8-chloro-1,2,3,4-tetrahydroacridinium-9-yl, 6,8-dichloro-1,2,3,4-tetrahydroacridinium-9- or N -demethyl galantamine; R ₃ represents H, C ₁ ~C ₁₂ alkyl, CF ₃ , C ₁ ~C ₄ acyl; Linker represents (CH ₂ ) _m ; " -O-Linker -NR ₁ R ₂ ” also means ; m represents 1-12; R ₄ represents H, C ₁ ~ C ₁₂ alkyl, benzyl or substituted benzyl; the above-mentioned term "substituted benzyl" means that the benzene ring is replaced by 1-4 Benzyl substituted by the group: F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, these substitutions The group can be in any possible position of the benzene ring. 2. The genistein alkylamine compound ( I ) or its pharmaceutically acceptable salt as claimed in claim 1, characterized in that the pharmaceutically acceptable salt is such genistein Base amine compounds with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C _1-6 fatty carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, A salt formed of C _1-6 alkylsulfonic acid, camphorsulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid. 3. The preparation method of the genistein alkylamine compound ( I ) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2, characterized in that the preparation method of the compound is represented by Ar The structural unit and Linker or -O-Linker-NR ₁ R ₂ represent different substituents, and there are the following four methods: Method 1: When Ar represents the structural unit (A) and R ₃ =H, Linker means (CH ₂ ) _m hour: In the formula: X represents Cl, Br, I; Ar represents the structural unit (A) and R ₃ represents H; the definitions of R ₁ , R ₂ , and m are the same as those in the general chemical structure formula ( I ); Starting from genistein ( 1 ) protected by methoxymethylene group, it reacts with dihaloalkyl compound ( 2 ) under solvent and alkaline conditions to generate the corresponding aryloxyalkyl halide compound ( 3 ) , the obtained intermediate 3 reacts with the organic amine compound ( 4 ) in a solvent to obtain the corresponding genistein alkylamine compound ( 5 ) protected by the methoxymethylene group, and the compound 5 is removed under solvent and acidic conditions Methoxymethylene protecting group to obtain the corresponding genistein alkylamine compound ( I ); Method 2: When Ar represents the structural unit (B), or (C), or R ₃ The structural unit (A) that does not represent H, Linker represents (CH ₂ ) _m hour: In the formula: X represents Cl, Br, I; Ar represents the structural unit (B) or (C), and R ₃ does not represent the structural unit (A) of H; the definition of R ₁ , R ₂ , R ₃ , m, n Same as the general chemical structure formula ( I ); Using the corresponding genistein compound ( 6 ) as the starting material, it reacts with the dihaloalkyl compound ( 2 ) under alkaline conditions to generate the corresponding aryloxyalkyl halide compound ( 7 ), and the obtained compound 7 is compatible with The organic amine compound ( 4 ) reacts to obtain the corresponding genistein alkylamine compound ( I ); Method 3: When Ar represents the structural unit (A) and R ₃ =H, -O-Linker-NR ₁ R ₂ represents hour: In the formula: X represents Cl, Br, I; Ar represents the structural unit ( _A ) and _R3 represents H; the definitions of m and R4 are the same as those of the general chemical structure formula ( I ); Starting from genistein ( 1 ) protected by methoxymethylene, reacting with 1-substituted-4-haloalkylpiperazine ( 8 ) under solvent and alkaline conditions to obtain the corresponding methoxymethylene Methyl-protected genistein alkylamine compound ( 9 ), compound 9 removes the methoxymethylene protecting group under solvent and acidic conditions to obtain the corresponding genistein alkylamine compound ( I ); Method 4: When Ar represents the structural unit (B), or (C), or R ₃ does not represent the structural unit (A) of H, -O-Linker-NR ₁ R ₂ represents hour: In the formula: X represents Cl, Br, I; Ar represents the structural unit (B), or (C), or R ₃ does not represent the structural unit (A) of H; the definition of R ₄ , m, n and the general chemical structure formula ( I ) the same; Using the corresponding genistein compound ( 6 ) as the starting material, react with 1-substituted-4-haloalkylpiperazine ( 8 ) under alkaline conditions to obtain the corresponding genistein alkylamine compound ( I ); The molecule of the genistein alkylamine compound ( I ) obtained by the above four methods contains an amino group, which is basic and can be prepared with any suitable acid by a pharmaceutically conventional salt-forming method. acceptable salt. 4. as claimed in claim 3, the preparation method of genistein alkylamine compound or its pharmaceutically acceptable salt is characterized in that in the step a) of method one, the alkali used in the reaction is: alkali metal hydroxide , alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal salts of C _1-8 alcohols, triethylamine, tributylamine, tri Octylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, di Methyl sulfoxide, methylene chloride, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; compound ( 1 ): dihaloalkyl compound ( 2 ): the molar feed ratio of base is 1.0: 1.0~10.0: 1.0~10.0; the reaction temperature is room temperature~150℃; the reaction time is 1~72 hours; In step b) of Method 1, the solvents used in the reaction are: diethyl ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, Acetonitrile, C _1-8 alcohol, or C _5-8 alkane; the molar ratio of intermediate ( 3 ): organic amine compound ( 4 ) is 1.0:1.0~10.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours; In step c) of method 1, the solvent used for the reaction is: water, C _1-6 fatty alcohol, N,N -dimethylformamide, tetrahydrofuran, C _3-8 fatty ketone, acetonitrile, 1,4-dioxane ring, or dimethylsulfoxide; the acids used are: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C _1-6 fatty acid, C _1-6 alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Or trifluoroacetic acid; the mass fraction of the acid in the reaction system is 0.1%-95%, the reaction temperature is 0-150°C; the reaction time is 30 minutes-24 hours. 5. as claimed in claim 3, the preparation method of genistein alkylamine compound or its pharmaceutically acceptable salt is characterized in that in the step a) of method two, the alkali used in the reaction is: alkali metal hydroxide , alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal salts of C _1-8 alcohols, triethylamine, tributylamine, tri Octylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, di Methyl sulfoxide, methylene chloride, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; compound ( 6 ): dihaloalkyl compound ( 2 ): the molar feed ratio of base is 1.0: 1.0~15.0: 1.0~15.0; the reaction temperature is room temperature~150℃; the reaction time is 1~72 hours; In step b) of Method 2, the solvents used in the reaction are: diethyl ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, Acetonitrile, C _1-8 alcohol, or C _5-8 alkane; the molar ratio of compound ( 7 ):organic amine compound ( 4 ) is 1.0:1.0~15.0; the reaction temperature is room temperature~150°C; the reaction time is 1 ~72 hours. 6. the preparation method of genistein alkylamine compound or its pharmaceutically acceptable salt as claimed in claim 3, it is characterized in that in the step a) of method three, the alkali used for reaction is: alkali metal hydroxide , alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, alkali metal salts of C _1-8 alcohols, triethylamine, tributylamine, tri Octylamine, pyridine, N -methylmorpholine, N -methylpiperidine, triethylenediamine, or tetrabutylammonium hydroxide; the solvent used for the reaction is: ether, tetrahydrofuran, N,N -dimethylformamide, di Methyl sulfoxide, dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; genistein ( 1 ) protected by methoxymethylene: 1-substituted-4 -Haloalkylpiperazine ( 8 ): The molar ratio of base to feed is 1.0:1.0~10.0:1.0~10.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours; In step b) of Method 3, the solvent used for the reaction is: water, C _1-6 fatty alcohol, N,N -dimethylformamide, tetrahydrofuran, C _3-8 fatty ketone, acetonitrile, 1,4-dioxane ring, or dimethylsulfoxide; the acids used are: hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, benzoic acid, C _1-6 fatty acid, C _1-6 alkylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Or trifluoroacetic acid; the mass fraction of the acid in the reaction system is 0.1%-95%; the reaction temperature is 0-150°C; the reaction time is 30 minutes-24 hours. 7. as claimed in claim 3, the preparation method of genistein alkylamine compound or its pharmaceutically acceptable salt is characterized in that in the method four, the alkali used in the reaction is: alkali metal hydroxide, alkaline earth metal hydrogen Oxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates, alkaline earth metal bicarbonates, triethylamine, tributylamine, trioctylamine, pyridine, N -methylmorpholine, N- Methylpiperidine, triethylenediamine, tetrabutylammonium hydroxide, or alkali metal salts of C _1-8 alcohols; the solvents used for the reaction are: ether, tetrahydrofuran, N,N -dimethylformamide, dimethyl sulfoxide , dichloromethane, chloroform, C _3-8 aliphatic ketones, benzene, toluene, acetonitrile or C _5-8 alkanes; genistein compounds ( 6 ): 1-substituted-4-haloalkylpiperazines ( 8 ) : The molar feeding ratio of alkali is 1.0:1.0~20.0:1.0~20.0; the reaction temperature is room temperature~150°C; the reaction time is 1~72 hours. 8. Use of the genistein alkylamine compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 in the preparation of medicines for treating and/or preventing neurodegenerative related diseases, such The neurodegenerative related disease is: 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 represented by general chemical structure formula ( II ) or ( III ): In the formula: R ₁ represents H, C ₁ ~C ₁₂ alkyl; R ₂ represents benzyl, substituted benzyl, 1,2,3,4-tetrahydroacridinyl, 6-chloro-1,2, 3,4-tetrahydroacridin-9-yl, 8-chloro-1,2,3,4-tetrahydroacridin-9-yl, 6,8-dichloro-1,2,3,4-tetrahydroacridine Pyridine 9-yl, or N -demethyl galantamine; m represents _{1-12; R represents H, C 1 ~} C ₁₂ alkyl, benzyl or substituted benzyl; the above-mentioned "substituted benzyl" is Refers to benzyl substituted by 1-4 groups selected from the following group on the benzene ring: F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethyl , trifluoromethoxy, nitro, cyano, these substituents can be in any possible position of the benzene ring. 10. Use of any compound as claimed in claim 9 in the preparation of genistein alkylamine compounds or pharmaceutically acceptable salts thereof as claimed in any one of claims 1-2.