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

One class Genistein alkyl amine compound, Preparation Method And The Use Download PDF

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CN103113340B
CN103113340B CN201310019569.8A CN201310019569A CN103113340B CN 103113340 B CN103113340 B CN 103113340B CN 201310019569 A CN201310019569 A CN 201310019569A CN 103113340 B CN103113340 B CN 103113340B
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acid
genistein
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amine compound
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邓勇
强晓明
谭正怀
袁文
桑志培
刘强
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Sichuan University
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Abstract

The invention discloses the novel Genistein alkyl amine compound (I) of a class and pharmacy acceptable salt thereof, its preparation method and preparing the purposes treated and/or prevented in nervus retrogression relative disease medicine, including but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma; in formula: Ar is expressed as follows arbitrary structural unit in shown (A) ~ (C), n=1-2

Description

One class Genistein alkyl amine compound, Preparation Method And The Use
Technical field
The invention belongs to medicinal chemistry art, relate to the novel Genistein alkyl amine compound of a class ( i) and pharmacy acceptable salt, its preparation method and preparing the purposes that treats and/or prevents in nervus retrogression relative disease medicine, include but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
Background technology
Vascular dementia (Vascular Dementia, VD) be the clinical syndrome of intelligence caused by various types of cerebrovascular disease (comprising ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and hypoxia-induced cerebrovascular disease etc.) and cognition dysfunction, its main clinical manifestation comprises: cognitive ability, memory and social-life ability go down and emotion, personality change, be a kind of chronic progressive disease.In first reason that Asian countries's vascular dementia such as Chinese, Japanese is senile dementia; Along with world population is to the continuous propelling of aging, cerebro-vascular diseases is increasing, and Onset of Vascular Dementia rate has the trend risen gradually, has a strong impact on work and the quality of life of the elderly, and brings heavy economy and mental burden to society and family.Therefore, VD to have become in current geriatrics and psychologic medicine field an important study hotspot.Vascular dementia is complicated due to pathogenesis, there is no the medicine that can block disease progression, and current clinical treatment is to improve brain blood circulation and brain metabolism, and it is main for strengthening brain nutrition.
In recent years, research both at home and abroad shows while VD patients cerebral damage also frequent abnormal with cholinergic system.VD patient's hippocampus ChAT positive neuron and fibre density lower, different sites ChAT activity decrease in brain, and the ACh concentration in VD Cerebrospinal Fluid in Patients is starkly lower than normal level, and the degree that its concentration reduces is proportionate with dull-witted severity; And cerebral ischemia can cause acetylcholine esterase active in brain to rise; Simultaneously; also find that some acetylcholinesterase depressant are as HuperzineA and Revastigmine; the neuronal damage that ischemic causes can be protected, and the recovery of nerve injury and brain function after cerebral ischemia can be promoted, show that acetylcholinesterase depressant can be used for the treatment of vascular dementia.
Alzheimer's disease (Alzheimer ' s disease, AD) be a kind of central nervous system degenerative disease damaged based on Progressive symmetric erythrokeratodermia cognitive disorder and memory, its sickness rate is in ascendant trend year by year, become the frequently-occurring disease being only second to cardiovascular diseases and cancer, rise to the 4th of the cause of death in developed countries such as America and Europes.According to WHO Report, global over-65s old man has 10% dysnoesia, and wherein 1/2nd dementia occur, more than 85 years old sickness rate nearly 50%.At present, China AD number of patients is more than 5,000,000, and this disease there is no effective treatment means at present, and along with the quickening of China's aging population process, this numeral will be more huge.Because AD clinical manifestation is that memory capability, orientation property, thinking and judgement go down, and activity of daily living reduces, even there is abnormal Behavioral and psychological symptom etc., make patient care difficulty larger, bring heavy burden to society and family, thus, novel senile dementia medicine is researched and developed significant.From the market requirement, " senile dementia report " prediction that world market research and strategist company complete recently, the global marketing volume to senile dementia medicine in 2015 will reach 10,000,000,000 dollars; In China, along with the rapid rising of senile dementia sickness rate, the market also rapid expansion of this kind of medicine.
AD belongs to the disease that many factors causes, pathogeny is complicated, so far also its pathogenesis is not illustrated completely, dissect after death and find cerebral amyloid sample senile plaque (Senile Plaques, SP) and neurofibrillary tangles (Neurofibrillary Tangles, NFT) be the histopathologic change of patient's AD most feature.In recent years, many investigators are devoted to from molecule and cell levels to disclose the pathogeny of AD, propose multiple hypothesis, as: the deposition, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidn, metal ion imbalance etc. of cholinergic neuron damage, amyloid, therefore, the novel therapeutic approach developed for these pathogenesis and means, will be hopeful the state of an illness alleviating and improve AD patient.The medicine of effectively treating AD at present clinically mainly contains two classes: the cholinergic hypothesis that (1) causes cognitive function to be lacked of proper care based on neurotransmitter acetic acid choline deficiency, acetylcholinesterase depressant is adopted to improve second phthalein choline levels in patient's brain, as: Tacrine, Donepezil, Ravastigmine, Galantamine; (2) adopt n-methyl-D-asparagic acid (NMDA) acceptor inhibitor reduces glutaminate to the damage of neurocyte, as: Memantine Hydrochloride.But these medicines exist, and action target spot is single, toxic side effect is more, to the problem such as the long-term efficacy of AD patient is not good enough.
Therefore, research and development have novel chemical structure, novel mechanism of action, multiaction target spot, low toxic side effect anti-neurodegenerative disease therapeutic agent not only meet the active demand of social senilization's process, and there are good market outlook.
Summary of the invention
The object of the invention be to disclose a class Genistein alkyl amine compound ( i) and pharmacy acceptable salt.
Another object of the present invention be to disclose such Genistein alkyl amine compound ( i) and the preparation method of pharmacy acceptable salt.
Still a further object of the present invention be to disclose such Genistein alkyl amine compound ( i) and pharmacy acceptable salt preparing the purposes that treats and/or prevents in nervus retrogression relative disease medicine, include but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
Genistein alkyl amine compound provided by the present invention ( i) chemical structure of general formula be:
In formula: arbe expressed as follows shown (A)~ (C)in arbitrary structural unit, n=1 or 2;
R 1represent H, C 1~ C 12alkyl; R 2represent C 1~ C 12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 6-, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 8-, 6,8-bis-chloro-1,2,3,4-tetrahydro acridine 9-bases or n-demethylgalanthamine base; R 1nR 2also represent that Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C 1~ C 12the piperidyl that alkyl replaces, 4-position by benzyl or substituted benzyl replace piperidyl, piperazinyl, 4-position is by C 1~ C 12the piperazinyl that alkyl replaces, 4-position by benzyl or substituted benzyl the piperazinyl that replaces; R 3represent H, C 1~ C 12alkyl, CF 3, C 1~ C 4acyl group; linkerrepresent (CH 2) m, m represents 1-12.Wherein, when Ar represent ( a) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 3 or 4, r 1 nR 2 do not represent 4-benzyl diethylenediamine base; When arrepresent ( a) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 3, r 1 nR 2 do not represent morpholinyl, Pyrrolidine base, 4-methylpiperazine base; When arrepresent ( b) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 2,3 or 4, R 1and R 2asynchronously represent methyl, ethyl, n-propyl or normal-butyl; When arrepresent ( b) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 2,3,4,5 or 6, r 1 nR 2 do not represent morpholinyl, piperazinyl, 4-methylpiperazine base; When arrepresent ( b) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 2,3 or 4, r 1 nR 2 do not represent Pyrrolidine base, piperidyl; When arrepresent ( b) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 4 or 6, r 1 nR 2 do not represent 4-ethyl piperazidine base; When arrepresent ( b) structural unit and R 3represent H, linkerfor (CH 2) m, when m is 3 or 5, r 1 nR 2 do not represent 4-benzyl diethylenediamine base; " -O-Linker-NR 1 r 2 " also can be , m represents 1-12, R 4represent H, C 1~ C 12alkyl, benzyl or substituted benzyl.
Above-mentioned term " substituted benzyl " refer to by phenyl ring by 1-4 to be selected from the group of lower group the benzyl that replaces: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can at any possible position of phenyl ring.
Genistein alkyl amine compound proposed by the invention ( i) prepare by following methods:
(1) when Ar represents structural unit (A), and R 3 =H, Linker represent (CH 2 ) m time:
In formula: X represents Cl, Br, I; Ar represents structural unit (A), and R 3represent H; R 1, R 2, the definition of m and chemical structure of general formula ( i) identical.
With methoxy methylene radical protection Genistein ( 1) be starting raw material, under solvent and alkaline condition with Dihaloalkyl compound ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 3), gained intermediate 3with organic amine compound ( 4) react in a solvent, obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 5), compound 5under solvent and acidic conditions, remove methoxy methylene radical protecting group, obtain corresponding Genistein alkyl amine compound ( i).
Its concrete preparation method is described below:
Described step a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine, TBAH), preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF) or toluene; Compound ( 1): Dihaloalkyl compound ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, and preferred molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile, C 1-8alcohol or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF), ethanol or toluene; Intermediate ( 3): organic amine compound ( 4) molar feed ratio be 1.0:1.0 ~ 10.0, preferred molar feed ratio is 1.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step c)in, reaction solvent for use is: water, C 1-6fatty alcohol, n,N-dimethyl formamide, tetrahydrofuran (THF), C 3-8aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO), preferred solvent is: water, methyl alcohol, ethanol, Isosorbide-5-Nitrae-dioxane or acetone; Acid used is: hydrogenchloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C 1-6lipid acid, C 1-6alkylsulphonic acid, Phenylsulfonic acid, tosic acid or trifluoroacetic acid, preferred acid is: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic, tosic acid or trifluoroacetic acid; The massfraction of acid in reaction system is 0.1%-100%, and preferred mass mark is 10%-95%, and temperature of reaction is 0 ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 8 hour.
(2) when Ar represents structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H, Linker represents (CH 2 ) m time:
In formula: X represents Cl, Br, I; Ar represents structural unit (B) or (C), and R 3do not represent the structural unit (A) of H; R 1, R 2, R 3, the definition of m, n and chemical structure of general formula ( i) identical.
With corresponding Genistein compounds ( 6) be starting raw material, in the basic conditions with Dihaloalkyl compound ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 7), gained compound 7with organic amine compound ( 4) reaction, obtain corresponding Genistein alkyl amine compound ( i).
Its concrete preparation method is described below:
Described step a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine, TBAH), preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF) or toluene; Compound ( 6): Dihaloalkyl compound ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 15.0:1.0 ~ 15.0, and preferred molar feed ratio is 1.0:1.0 ~ 6.0:1.0 ~ 6.0; Temperature of reaction is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile, C 1-8alcohol or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF), ethanol or toluene; Compound ( 7): organic amine compound ( 4) molar feed ratio be 1.0:1.0 ~ 15.0, preferred molar feed ratio is 1.0:1.0 ~ 6.0; Temperature of reaction is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
(3) when Ar is structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 for time:
In formula: X represents Cl, Br, I; Ar represents structural unit (A), and R 3represent H; M, R 4definition and chemical structure of general formula ( i) identical.
With methoxy methylene radical protection Genistein ( 1) be starting raw material, replace with 1-under solvent and alkaline condition-4-alkylhalide group piperazine ( 8) reaction, obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 9), compound 9under solvent and acidic conditions, remove methoxy methylene radical protecting group, obtain corresponding Genistein alkyl amine compound ( i).
Its concrete preparation method is described below:
Described step a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine, TBAH), preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF) or toluene; Methoxy methylene radical protection Genistein ( 1): 1-replacement-4-alkylhalide group piperazine ( 8): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, and preferred molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, reaction solvent for use is: water, C 1-6fatty alcohol, n,N-dimethyl formamide, tetrahydrofuran (THF), C 3-8aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO), preferred solvent is: water, methyl alcohol, ethanol, Isosorbide-5-Nitrae-dioxane or acetone; Acid used is: hydrogenchloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C 1-6lipid acid, C 1-6alkylsulphonic acid, Phenylsulfonic acid, tosic acid or trifluoroacetic acid, preferred acid is: hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, methanesulfonic, tosic acid or trifluoroacetic acid; The massfraction of acid in reaction system is 0.1%-100%, and preferred mass mark is 10%-95%, and temperature of reaction is 0 ~ 150 DEG C, and preferable reaction temperature is room temperature ~ 120 DEG C; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 8 hour.
(4) when Ar represents structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H ,-O-Linker-NR 1 r 2 represent time:
In formula: X represents Cl, Br, I; Ar represents structural unit (B) or (C) or R 3do not represent the structural unit (A) of H; R 4, the definition of m, n and chemical structure of general formula ( i) identical.
With corresponding Genistein compounds ( 6) be starting raw material, replace with 1-in the basic conditions-4-alkylhalide group piperazine ( 8) reaction, obtain corresponding Genistein alkyl amine compound ( i).
Concrete preparation method is described below: reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, trimethylamine class or quaternary ammonium bases (as: triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine, TBAH) or C 1-8an alkali metal salt of alcohol, preferred bases is: potassium hydroxide, sodium hydroxide, salt of wormwood, triethylamine, pyridine or sodium methylate; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane, preferred solvent is: n,N-dimethyl formamide, acetone, acetonitrile, tetrahydrofuran (THF) or toluene; Genistein compounds ( 6): 1-replacement-4-alkylhalide group piperazine ( 8): the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0, and preferred molar feed ratio is 1.0:1.0 ~ 8.0:1.0 ~ 8.0; Temperature of reaction is room temperature ~ 150 DEG C, is preferably room temperature ~ 120 DEG C; Reaction times is 1 ~ 72 hour, and the preferred time is 2 ~ 24 hours.
Starting raw material of the present invention---methoxy methylene radical protection Genistein ( 1), 1-replace-4-alkylhalide group piperazine ( 8) the common technology in available this area obtains, including, but not limited to method disclosed in Publication about Document: 1, Qiang Xiaoming etc. organic chemistrydOI:10.6023/cjoc201210042; 2, Rodriguez-Franco, M.I. et. al.Bioorganic Medicinal Chemistry 2005, 13,6795-6802; 3, Bolea, R. et. al.J. Med. Chem. 2011, 54,8251-8270.
According to above-mentioned four kinds of method gained Genistein alkyl amine compound ( i) in molecule containing amino, this amino is in alkalescence, and can obtain acceptable salt on its pharmacology with any suitable acid by the salifying method of pharmaceutically routine, described acid is: hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, C 1-6aliphatic carboxylic acid (as: formic acid, acetic acid, propionic acid etc.), oxalic acid, phenylformic acid, Whitfield's ointment, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, C 1-6alkylsulphonic acid (as: methylsulphonic acid, ethylsulfonic acid etc.), camphorsulfonic acid, Phenylsulfonic acid or tosic acid.
Genistein alkyl amine compound disclosed in this invention ( i) and pharmacy acceptable salt measure its purity through HPLC, show that its purity is all higher than 98.5%, following bioactivity screening carried out to these compounds.
(1) acetylcholinesterase and butyrylcholine esterase inhibit activities
1.0 mmol/L acetylthiocholine iodides or sulfur iodide is added successively for BuCh (equal available from Sigma) 30 μ L in 96 orifice plates, the PBS damping fluid 40 μ L of pH7.4, testing compound solution 20 μ L (DMSO content is less than 1%) and 10 μ L acetylcholinesterases (rat brain cortex 5% homogenate supernatant liquor, the phosphoric acid buffer of pH7.4 makes homogenate medium) or butyrylcholine esterase (rat blood serum 25% supernatant liquor, pH7.4 phosphoric acid buffer makes homogenate medium) solution, after finishing mixing, hatch 15min for 37 DEG C, 0.2% 5 are added in each hole, 5 '-dithio-bis-(2-nitrobenzoic acid) (DTNB, available from Sigma) solution 30 μ L develops the color, the optical density(OD) (OD value) in each hole, 405nm place is measured by microplate reader, compare with the blank well not adding testing sample, computerized compound is to the inhibiting rate (enzyme inhibition rate (%)=(1-sample sets OD value/blank group OD value) × 100%) of enzyme, select five to six concentration of compound, measure its enzyme inhibition rate, and with the inhibiting rate linear regression of the negative logarithm of this compound volumetric molar concentration and enzyme, volumetric molar concentration when trying to achieve 50% inhibiting rate is the IC of this compound 50.Measurement result shows, compound disclosed in the embodiment of the present invention all has remarkable restraining effect to acetylcholinesterase, its IC 50for 0.1nM ~ 5.0 μM, wherein, the IC of disclosed compound 2-B4-14 in the embodiment of the present invention 2 50be 2.5 μMs, and the IC of all the other compounds isonomic (2-B4-1 to 2-B4-13,2-B4-15 to 2-B4-21) 50all be less than 2.5 μMs, and positive control medicine---Rivastigmine is to the IC of acetylcholine ester enzyme level 50it is 6.3 μMs; Measurement result also shows, the inhibit activities of compound to acetylcholinesterase disclosed in the embodiment of the present invention is much higher than the inhibit activities to butyrylcholine esterase, illustrates that compound disclosed in this invention has certain selective inhibitory to acetylcholinesterase.
(2) compound is to H 2 o 2 the provide protection screening of the PC12 cell injury of induction
The DMEM nutrient solution of PC12 cell containing 10% calf serum, with 1 × 10 5individual/mL density is inoculated on 96 well culture plates, and inoculation volume is 100 μ L/ holes, puts into subsequently containing 5% CO 237 DEG C of constant incubators in cultivate.Cultivate after 24 hours, (final concentration is 10 to add the compound of respective concentration in administration group -5mol/L, 10 -6mol/L) 10 μ L/ holes, 2 hours (control group and damage group add 10 μ L/ hole PBS respectively, make its volume keep equal) of preincubate.PC12 cell incubation, after 2 hours, adds 100 μMs of H respectively in administration group and damage group 2o 2damage agent 10 μ L/ hole (control group adds 10 μ L/ hole PBS), after 30 minutes, the RPMI-1640 nutrient solution all changed into by the nutrient solution of each group without calf serum continues to put into constant incubator cultivation 24 hours, and nutrient solution volume is still 100 μ L/ holes.Continue cultivation after 24 hours, add 5mg/mL MTT 100 μ L/hole in each group, carry out viable cell dyeing.After 3 hours, add 100% DMSO stop buffer 100 μ L/ hole in each group, fully dissolve mixing.Under the wavelength of 490 nm, measure the OD value of each group, test result repeats 3 times, and with Duncan ' s test method statistic, the numeric representation of each group is mean ± S.E.M., and with control group for 100%, administration group and damage class value represent with the per-cent of control group.Measurement result shows, in the embodiment of the present invention, the PC12 cell injury of disclosed compound to hydrogen peroxide-induced all has significant provide protection, and 10 -5anti-oxidant activity under mol/L concentration is all better than Genistein.
(3) compound is on the impact of Scopolamine induced mice memory acquisition disturbance
SPF level ICR male mice, 25-30g, is divided at random: normal group, model group, by reagent high and low dose group (5.0,2.5mg/kg), often organize 10 animals.Disposable gavage gives test medicine, and blank group and model group give solvent 0.5% CMC-Na, and administration volume is 0.1ml/10g; 45 min after medicine, normal group mouse peritoneal injecting normal saline, all the other each treated animals all inject Scopolamine (5mg/kg), and administration volume is 0.1ml/10g; After modeling 30 min, mouse is put into non-electricity irritation Y labyrinth and carry out Behavior test.Mouse is put in an arm end during test, be allowed to condition in labyrinth and freely walk 8min, record its number of times entering each arm and alternate frequency, rate is replaced: alternately rate %=[alternate frequency/(always entering number of times-2)] × 100 according to following formulae discovery, result represents with mean ± standard deviation, and group difference adopts one-way analysis of variance.Measurement result shows, under this experiment condition, compound disclosed in this invention causes to Scopolamine the improvement result that the acquired dysmnesia of mouse have dose-dependently, more all has significant difference (p<0.01) with model group.
(4) compound is on the impact of ethanol induced mice reproducibility dysmnesia
SPF level ICR male mice, 25-30g, is divided at random: normal group, model group, by reagent high and low dose group (5.0,2.5mg/kg), rivastigmine group (3mg/kg), often organize 10 animals.Every day, gavage gave test medicine, and blank group and model group give solvent 0.5%CMC-Na, and administration volume is 0.1ml/10g, successive administration 32 days; In administration during 1 ~ 24 day, 30 min after every day medicine, model group and each administration group gavage 0.1ml/10g ethanol (15% w/v), give 24 days continuously, and remove ethanol and enter ethanol and clean the phase, medicine continues to give; Within 31,32 days, animal Jumping test is carried out in administration; after medicine, 45min carries out training or test experiments; allow mouse be placed in diving tower instrument during training, put down gently on platform, energising; contact copper grid for getting an electric shock with biped when animal jumps off from platform simultaneously; be considered as wrong reaction, mouse shocked by electricity after normal avoiding reaction for escape on platform, record mouse escape to the latent period on platform; and the electric shock number of times recorded in 5min, in this, as school grade.Test after 24 hours, record mouse first time jumps off the time (latent period) and the interior number of times (errors number) shocked by electricity of 5 min thereof of being shocked by electricity, in this, as the evaluation index of memory represents function.Test result represents with mean ± standard deviation, and group difference adopts one-way analysis of variance.Result shows, under this experiment condition, compound disclosed in this invention is significantly improved the equal tool of ethanol induced mice memory represents dysfunction, more all has significant difference (p<0.01) with model group.
(5) neuroprotective of compound on vascular dementia rats
(a) animal model, grouping and administration
Rats by intraperitoneal injection 3.5% chloral hydrate anesthesia (350 mg/kg), is separated bilateral carotid, ligation, sham-operation normal group not ligation bilateral common carotid arteries.The concealment Platform Screening experiment of postoperative 7 days row water maze test in 5 days, using animal latent period of the 5th day as screening index: SR=(operation group average latency-normal group average latency) equal latent period of/normal group animal.Screen neurobehavioral handicapped model success animal with SR<0.2, be divided into normal group, model group, medicine high dose group (45 mg/kg) and low dose group (15 mg/kg) at random, often organize 12; Postoperative 13rd day starts to gavage administration, and normal group and model group give equal-volume solvent; Successive administration is after 3 weeks, and row water 7 days labyrinth test experiments are to evaluate the impact of medicine on vascular dementia rats neurobehavioral function.After Behavior test, after Animal Anesthesia, sequentially use PBS(pH 7.4) and 4% paraformaldehyde solution through the quick perfusion of heart, open rapidly cranium and get brain, 10% neutral formalin fixes 24 hours, paraffin embedding, make the brain coronal section of thickness about 5 μm, for europathology histological examination.Experimental data all represents with mean ± standard deviation, and experimental result adopts SPSS16 software to carry out statistical study, and comparing between group and adopt one-way analysis of variance LSD method, take P<0.05 as significant difference.
(b) neurobehavioral functional examination
Morris water maze testing method is adopted to evaluate medicine to the impact of vascular dementia rats Spatial learning and memory ability.Water maze is a circular white stainless steel pond, diameter 120cm, high 60cm, pond is divided into 4 quadrants, places a platform at quadrant 1 center, platform and the center of circle and pool wall equidistant, platform is that white is circular, diameter 10cm, high 20cm, platform is positioned at underwater 2cm, pond water temperature remains on 25 ± 2 DEG C, adds appropriate foodstuff additive antholeucin in water, makes Chi Shui be opaque oyster white, animal does not arrive platform, to detect the acuteness of animal to locus by vision.Have a camera directly over pond, camera is connected with computer, by animal activity situation in computer record pond.After administration, water maze laboratory carries out 7 days continuously, and 1-2 days is concealment platform experiments, and record rat finds the time (latent period) of platform; Within 3rd day, in order to explore platform experiments (namely removing platform), rat place of entry invariant position, record rat is at residence time of place, original platform position quadrant and traversing times; Within 4-6 days, be new platform experiments (namely position of platform changes), rat place of entry invariant position, record rat finds the time (latent period) of platform; 7th day is visible platform experiments, rat place of entry invariant position, and record rat finds the time (latent period) of platform.Morris water maze is a kind of experiment relying on hippocampus memory function, is mainly used in the evaluation of cerebral ischemic injury Cognitive Impairment.Cognitive function comprises three phases: obtain, consolidate and memory.In our experiment, concealment platform experiments detects and obtains function, and new platform experiments detects study and consolidates function, explores platform experiments and detects memory function.
Measurement result shows, compares with model group, and medication therapy groups rat obviously shortens at concealment platform and latent period of new platform, and in exploration platform experiments, and animal obviously extended in residence time of original platform quadrant and traversing times.Experimental result confirms that the pharmacological agent of compound disclosed in this invention dose-dependently obviously can improve the cognition dysfunction of the vascular dementia caused by the long-term Low perfusion of brain.In addition, visible platform experiments result shows platform no significant difference in latent period between each group, thus gets rid of the impact of performing the operation on animal vision and motor capacity, further demonstrate that the result for the treatment of of medicine to vascular dementia.
the detection of (c) neuronal damage
Detected neuronal nuclear antigen (NeuN) expression level of VD animal brain cortex and hippocampus by ImmunohistochemistryMethods Methods, evaluate medicine to the impact of VD animal brain neuronal damage.Get every animal brain coronal paraffin slides, dimethylbenzene dewaxes, the H of 3% 2o 2after deactivating endogenous peroxydase, drip 5%BSA confining liquid, after 37 DEG C of incubators hatch 1 hour, add NeuN polyclonal antibody (1:200, Beijing Bo Aosen Bioisystech Co., Ltd) respectively, to hatch after 2 hours dislocation in 4 DEG C of refrigerator overnight for 37 DEG C.Add biotinylation sheep anti-Mouse two anti-, 37 DEG C hatch 1 hour, then add SABC, 37 DEG C hatch 1 hour after, DAB colour developing, Hematorylin are redyed.Routine is dewatered, dimethylbenzene is transparent, neutral gum mounting.Under 400 times of opticmicroscopes, blind is observed and is recorded cortex and the nonoverlapping region positive cell count of hippocampus 3, and calculate and often open section mean value, with control group for 100%, the positive cell number of model group and administration group represents with the per-cent of control group.
Measurement result shows, significantly reduces (P<0.01) with the neuronal cell quantity of the cortex of normal group comparison model group and the NeuN immuno positive of hippocampus; Compared with model group, medicine can increase neuronal cell quantity (P<0.05 or P<0.01) by dose-dependently.Experimental result shows, compound disclosed in this invention can suppress the damage of vascular dementia rats cerebral neuron cell, and the result can improving Morris water maze laboratory medium vessels dementia rats cognitive function with medicine conforms to.
the detection of (d) microglia activation
Get every animal brain coronal paraffin slides, dimethylbenzene dewaxes, the H of 3% 2o 2after deactivating endogenous peroxydase, drip 5%BSA confining liquid, after 37 DEG C of incubators hatch 1 hour, add OX-42 polyclonal antibody (1:200 respectively, Millipore company, USA) or GFAP polyclonal antibody (1:100, Wuhan Boster Biological Technology Co., Ltd.), dislocation is hatched after 2 hours in 4 DEG C of refrigerator overnight for 37 DEG C.Add biotinylation sheep anti-Mouse two anti-, 37 DEG C hatch 1 hour, then add SABC, 37 DEG C hatch 1 hour after, DAB colour developing, Hematorylin are redyed, and conventional dehydration, dimethylbenzene are transparent, neutral gum mounting; Figure adopted by immunohistochemical staining Axiovert 40 CFL microscope: under 400 times of opticmicroscopes, often opening section to choose 3 different zones in pallium fixed position and adopt figure, by the accumulation optical density value (IOD) of Image Pro-plus5.0 software analysis immune response positive cell, calculate and often open section IOD mean value, often organize result and represent with mean ± standard deviation.Measurement result shows, compares with normal group, and the expression level of OX-42 and the GFAP of model group cortex all significantly increases (P<0.01); Compared with model group, medicine can reduce OX-42 and GFAP expression by dose-dependently, and wherein high dose group has remarkable significant difference (P<0.01).Experimental result shows, compound disclosed in this invention can suppress the activation of vascular dementia rats microglia and astroglia cell, plays prevention and treatment by suppressing Neuroinflammation to vascular dementia.
Embodiment
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.
embodiment 1 is worked as Ar and is represented structural unit (A) and R 3 =H, Linker represent (CH 2 ) m time Genistein alkyl amine compound (I) preparation lead to method
Add in reaction flask 7-methoxy methylene radical protection Genistein ( 1) 2.0 mmol, 30 ml acetonitriles, 8.0 mmol Anhydrous potassium carbonates and dibromo alkylate ( 2) 7.0 mmol, temperature rising reflux stirring reaction 3.0 ~ 9.0 hours (reaction process TLC follows the tracks of); Reaction terminate after, filtered while hot, a small amount of acetonitrile wash filter cake, filtrate decompression steam desolventize and excessive dibromo alkylate, resistates through column chromatography purification (elutriant: methylene dichloride), obtain aryloxyalkyl group bromine compounds ( 3), yield 75%-93%.By above-mentioned aryloxyalkyl group bromine compounds ( 3) full dose is dissolved in 40 ml ethanol, add 6.0 mmol organic amine compounds ( 4), temperature rising reflux stirring reaction 6.0 ~ 16.0 hours (reaction process TLC follows the tracks of); After reaction terminates; remove solvent under reduced pressure; 50 ml methylene dichloride are added in resistates; use 30 ml 10% aqueous sodium carbonates and 30 ml deionized water wash successively; organic layer filters after anhydrous sodium sulfate drying; remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: chloroform), the Genistein alkyl amine compound of corresponding methoxy methylene radical protection ( 5), yield 80%-96%; By gained compound 5add in the mixing solutions of 10 ml 15% aqueous hydrochloric acids and 20 ml ethanol, stirring at room temperature reaction 3.0 ~ 8.0 hours (reaction process TLC follows the tracks of), after reaction terminates, remove solvent under reduced pressure, 50 ml methylene dichloride are added in resistates, use 20 ml 5% sodium bicarbonate aqueous solutions and 20 ml deionized water wash successively, organic layer filters after anhydrous sodium sulfate drying, remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: petroleum ether-ethyl acetate=30:1 v/v), obtain corresponding Genistein alkyl amine compound ( i), yield 90%-98%, the equal warp of its chemical structure 1h-NMR, 13c-NMR and ESI-MS confirms.The target compound structure adopting above-mentioned logical method to prepare is as follows:
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embodiment 2 is worked as Ar and is represented structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H, Linker represents (CH 2 ) m time Genistein alkyl amine compound (I) preparation lead to method
Add in reaction flask the corresponding Genistein compounds of 5.0 mmol ( 6), 10.0 mmol salt of wormwood and 60 ml n, n-dimethyl formamide, stirring at room temperature add after reacting 30 minutes 10.0 mmol dibromo alkylates ( 2), 50 ~ 60 DEG C stirring reaction 5-18 hour (reaction process TLC follows the tracks of); After reaction terminates, filtered while hot, filtrate decompression is steamed and is desolventized, 150 ml methylene dichloride are added in resistates, use 50 ml 10% aqueous sodium carbonates and 50 ml deionized water wash successively, organic layer filters after anhydrous sodium sulfate drying, removes solvent under reduced pressure, resistates through column chromatography purification (elutriant: chloroform/methanol=30:1 v/v), obtain corresponding aryloxyalkyl group bromine compounds ( 7).
According to starting material compound used ( 6) difference, corresponding 7-position, 4 '-position or 7 can be obtained, the disubstituted aryloxyalkyl group bromine compounds in 4 '-position ( 7); Wherein, when starting raw material Genistein compounds ( 6) be R 3do not represent H structural unit ( b) time, obtain 7-position replace aryloxyalkyl group bromine compounds ( 7), yield 78%-95%; When starting raw material Genistein compounds ( 6) be R 3do not represent H structural unit ( a) time, obtain 4 '-position replace aryloxyalkyl group bromine compounds ( 7), yield 66%-87%; When starting raw material Genistein compounds ( 6) be Genistein (R 3represent H structural unit ( a) or ( b)) time, can obtain simultaneously 7-position replace aryloxyalkyl group bromine compounds ( 7) and 7, the disubstituted aryloxyalkyl group bromine compounds in 4 '-position ( 7), yield is respectively 35%-58% and 20%-35%.
The corresponding 7-position prepared above-mentioned, 4 '-position or 7, the disubstituted aryloxyalkyl group bromine compounds in 4 '-position ( 7) 1.0 mmol are dissolved in 15 ml ethanol, add 3.0 mmol organic amine compounds ( 4), temperature rising reflux stirring reaction 6.0 ~ 16.0 hours (reaction process TLC follows the tracks of); After reaction terminates, remove solvent under reduced pressure, 50 ml methylene dichloride are added in resistates, use 15 ml 5% aqueous sodium carbonates and 15 ml deionized water wash successively, organic layer filters after anhydrous sodium sulfate drying, remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: dichloromethane-acetone=30:1 v/v), obtain corresponding Genistein alkyl amine compound ( i), yield 80%-96.5%, the equal warp of its chemical structure 1h-NMR, 13c-NMR and ESI-MS confirms.The target compound structure adopting above-mentioned logical method to prepare is as follows:
ar represents
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embodiment 3 is worked as Ar and is represented structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 represent time Genistein alkyl amine compound (I) preparation lead to method
Add in reaction flask 7-methoxy methylene radical protection Genistein ( 1) 2.0 mmol, 50 ml acetonitriles, 3.0 mmol Anhydrous potassium carbonates and 2.5 mmol 1-replacement-4-chlorine alkylpiperazine ( 8), return stirring reaction 5.0 ~ 18.0 hours (reaction process TLC follows the tracks of); Reaction terminate after, filtered while hot, a small amount of acetonitrile wash filter cake, filtrate decompression steam desolventize, resistates through column chromatography purification (elutriant: chloroform), obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 9), yield 78.0%-95.0%.By gained compound 9add in the mixing solutions of 10 ml 15% aqueous hydrochloric acids and 20 ml ethanol, stirring at room temperature reaction 3.0 ~ 7.0 hours (reaction process TLC follows the tracks of), after reaction terminates, remove solvent under reduced pressure, 50 ml methylene dichloride are added in resistates, use 20 ml 5% sodium bicarbonate aqueous solutions and 20 ml deionized water wash successively, organic layer filters after anhydrous sodium sulfate drying, remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: petroleum ether-ethyl acetate=30:1 v/v), obtain corresponding Genistein alkyl amine compound ( i), yield 85%-95%, the equal warp of its chemical structure 1h-NMR, 13c-NMR and ESI-MS confirms.The target compound structure adopting above-mentioned logical method to prepare is as follows:
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embodiment 4 is worked as Ar and is represented structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H ,-O-Linker-NR 1 r 2 represent time Genistein alkyl amine compound (I) preparation lead to method
Add in reaction flask the corresponding Genistein compounds of 5.0 mmol ( 6), 10.0 mmol salt of wormwood and 60 ml n, n-dimethyl formamide, stirring at room temperature add after reacting 30 minutes 1-replace-4-chlorine alkylpiperazine ( 8) 10.0 mmol, 50 ~ 60 DEG C stirring reaction 5-15 hour (reaction process TLC follows the tracks of); After reaction terminates, filtered while hot, filtrate decompression is steamed and is desolventized, 150 ml methylene dichloride are added in resistates, use 50 ml 10% aqueous sodium carbonates and 50 ml deionized water wash successively, organic layer filters after anhydrous sodium sulfate drying, removes solvent under reduced pressure, resistates through column chromatography purification (elutriant: chloroform/methanol=30:1 v/v), obtain corresponding Genistein alkyl amine compound ( i).
According to starting material compound used ( 6) difference, corresponding 7-position, 4 '-position or 7 can be obtained, 4 '-position disubstituted Genistein alkyl amine compound ( i); Wherein, when starting raw material Genistein compounds ( 6) be R 3do not represent H structural unit ( b) time, obtain 7-position replace Genistein alkyl amine compound ( i), yield 70%-92%; When starting raw material Genistein compounds ( 6) be R 3do not represent H structural unit ( a) time, obtain 4 '-position replace Genistein alkyl amine compound ( i), yield 78%-96%; When starting raw material Genistein compounds ( 6) be Genistein (that is: R 3represent H structural unit ( a) or ( b)) time, can obtain simultaneously 7-position replace Genistein alkyl amine compound ( i), yield 30%-58% and 7,4 '-position disubstituted Genistein alkyl amine compound ( i), yield 23%-38%.The equal warp of its chemical structure 1h-NMR, 13c-NMR and ESI-MS confirms.The target compound structure adopting above-mentioned logical method to prepare is as follows:
ar represents
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embodiment 5
logical method prepared by aryloxyalkyl group aminated compounds (I) and sour salify
Add in reaction flask according to above-described embodiment 1-4 gained Genistein alkyl amine compound ( i) 2.0 mmol and ethanol 50 ml, it is sour accordingly to add 6.0 mmol after stirring, temperature rising reflux stirring reaction 20 minutes, be cooled to room temperature after reaction terminates, remove solvent under reduced pressure, resistates acetone recrystallization, filter separate out solid, obtain Genistein alkyl amine compound ( i) salt, its chemical structure warp 1h NMR and ESI-MS confirms.

Claims (9)

1. class Genistein alkyl amine compound or its pharmacy acceptable salt, it is characterized in that the chemical structure of general formula of this compounds as ( i) shown in:
In formula: arbe expressed as follows shown (A)~ (C)in arbitrary structural unit, n=1 or 2;
；
R 1represent H, C 1~ C 12alkyl; R 2represent benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 6-, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 8-, 6,8-bis-chloro-1,2,3,4-tetrahydro acridine 9-bases or n-demethylgalanthamine base; R 3represent H, C 1~ C 12alkyl, CF 3, C 1~ C 4acyl group; linkerrepresent (CH 2) m; " -O-Linker-NR 1 r 2 " also represent ; M represents 1-12; R 4represent H, C 1~ C 12alkyl, benzyl or substituted benzyl; Above-mentioned term " substituted benzyl " refer to by phenyl ring by 1-4 to be selected from the group of lower group the benzyl that replaces: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can at any possible position of phenyl ring.
2. Genistein alkyl amine compound as claimed in claim 1 ( i) or its pharmacy acceptable salt, it is characterized in that described pharmacy acceptable salt class Genistein alkyl amine compound and hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, C for this reason 1-6aliphatic carboxylic acid, oxalic acid, phenylformic acid, Whitfield's ointment, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid, C 1-6the salt that alkylsulphonic acid, camphorsulfonic acid, Phenylsulfonic acid or tosic acid are formed.
3. as described in any one of claim 1-2 Genistein alkyl amine compound ( i) or the preparation method of its pharmacy acceptable salt, it is characterized in that the structural unit that the preparation method of described compound represents according to Ar and Linker or-O-Linker-NR 1r 2represent substituent difference, have following four kinds of methods:
method one: when Ar represents structural unit (A) and R 3 =H, Linker represent (CH 2 ) m time:
In formula: X represents Cl, Br, I; Ar represents structural unit (A) and R 3represent H; R 1, R 2, the definition of m and chemical structure of general formula ( i) identical;
With methoxy methylene radical protection Genistein ( 1) be starting raw material, under solvent and alkaline condition with Dihaloalkyl compound ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 3), gained intermediate 3with organic amine compound ( 4) react in a solvent, obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 5), compound 5under solvent and acidic conditions, remove methoxy methylene radical protecting group, obtain corresponding Genistein alkyl amine compound ( i);
method two: when Ar represents structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H, Linker represents (CH 2 ) m time:
In formula: X represents Cl, Br, I; Ar represents structural unit (B) or (C), and R 3do not represent the structural unit (A) of H; R 1, R 2, R 3, the definition of m, n and chemical structure of general formula ( i) identical;
With corresponding Genistein compounds ( 6) be starting raw material, in the basic conditions with Dihaloalkyl compound ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 7), gained compound 7with organic amine compound ( 4) reaction, obtain corresponding Genistein alkyl amine compound ( i);
method three: when Ar represents structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 represent time:
In formula: X represents Cl, Br, I; Ar represents structural unit (A) and R 3represent H; M, R 4definition and chemical structure of general formula ( i) identical;
With methoxy methylene radical protection Genistein ( 1) be starting raw material, replace with 1-under solvent and alkaline condition-4-alkylhalide group piperazine ( 8) reaction, obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 9), compound 9under solvent and acidic conditions, remove methoxy methylene radical protecting group, obtain corresponding Genistein alkyl amine compound ( i);
method four: when Ar represents structural unit (B) or (C) or R 3 do not represent the structural unit (A) of H ,-O-Linker-NR 1 r 2 represent time:
In formula: X represents Cl, Br, I; Ar represents structural unit (B) or (C) or R 3do not represent the structural unit (A) of H; R 4, the definition of m, n and chemical structure of general formula ( i) identical;
With corresponding Genistein compounds ( 6) be starting raw material, replace with 1-in the basic conditions-4-alkylhalide group piperazine ( 8) reaction, obtain corresponding Genistein alkyl amine compound ( i);
Utilize above-mentioned four kinds of method gained Genistein alkyl amine compound ( i) in molecule containing amino, this amino, in alkalescence, can obtain acceptable salt on its pharmacology with any suitable acid by the salifying method of pharmaceutically routine.
4. the preparation method of Genistein alkyl amine compound or its pharmacy acceptable salt as claimed in claim 3, is characterized in that the step of method one a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane; Compound ( 1): Dihaloalkyl compound ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour;
The step of method one b)in, reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile, C 1-8alcohol or C 5-8alkane; Intermediate ( 3): organic amine compound ( 4) molar feed ratio be 1.0:1.0 ~ 10.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour;
The step of method one c)in, reaction solvent for use is: water, C 1-6fatty alcohol, n,N-dimethyl formamide, tetrahydrofuran (THF), C 3-8aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO); Acid used is: hydrogenchloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C 1-6lipid acid, C 1-6alkylsulphonic acid, Phenylsulfonic acid, tosic acid or trifluoroacetic acid; The massfraction of acid in reaction system is 0.1%-95%, and temperature of reaction is 0 ~ 150 DEG C; Reaction times is 30 minutes ~ 24 hours.
5. the preparation method of Genistein alkyl amine compound or its pharmacy acceptable salt as claimed in claim 3, is characterized in that the step of method two a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane; Compound ( 6): Dihaloalkyl compound ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 15.0:1.0 ~ 15.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour;
The step of method two b)in, reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile, C 1-8alcohol or C 5-8alkane; Compound ( 7): organic amine compound ( 4) molar feed ratio be 1.0:1.0 ~ 15.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour.
6. the preparation method of Genistein alkyl amine compound or its pharmacy acceptable salt as claimed in claim 3, is characterized in that the step of method three a)in, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, C 1-8an alkali metal salt of alcohol, triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane; Methoxy methylene radical protection Genistein ( 1): 1-replacement-4-alkylhalide group piperazine ( 8): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour;
The step of method three b)in, reaction solvent for use is: water, C 1-6fatty alcohol, n,N-dimethyl formamide, tetrahydrofuran (THF), C 3-8aliphatic ketone, acetonitrile, Isosorbide-5-Nitrae-dioxane or dimethyl sulfoxide (DMSO); Acid used is: hydrogenchloride, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phenylformic acid, C 1-6lipid acid, C 1-6alkylsulphonic acid, Phenylsulfonic acid, tosic acid or trifluoroacetic acid; The massfraction of acid in reaction system is 0.1%-95%; Temperature of reaction is 0 ~ 150 DEG C; Reaction times is 30 minutes ~ 24 hours.
7. the preparation method of Genistein alkyl amine compound or its pharmacy acceptable salt as claimed in claim 3, it is characterized in that in method four, reacting alkali used is: alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate, alkali metal bicarbonates, triethylamine, Tributylamine, trioctylamine, pyridine, n-methylmorpholine, n-methyl piperidine, triethylene diamine, TBAH or C 1-8an alkali metal salt of alcohol; Reaction solvent for use is: ether, tetrahydrofuran (THF), n,N-dimethyl formamide, dimethyl sulfoxide (DMSO), methylene dichloride, chloroform, C 3-8aliphatic ketone, benzene, toluene, acetonitrile or C 5-8alkane; Genistein compounds ( 6): 1-replacement-4-alkylhalide group piperazine ( 8): the molar feed ratio of alkali is 1.0:1.0 ~ 20.0:1.0 ~ 20.0; Temperature of reaction is room temperature ~ 150 DEG C; Reaction times is 1 ~ 72 hour.
8. the Genistein alkyl amine compound as described in any one of claim 1-2 or its pharmacy acceptable salt are preparing the purposes treated and/or prevented in nervus retrogression relative disease medicine, and this kind of nervus retrogression relative disease is: vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain or glaucoma.
9. a compounds, it is characterized in that it be have chemical structure of general formula ( iI) or ( iII) shown in compound:
In formula: R 1represent H, C 1~ C 12alkyl; R 2represent benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 6-, chloro-1,2,3, the 4-tetrahydro acridine 9-base of 8-, 6,8-bis-chloro-1,2,3,4-tetrahydro acridine 9-bases or n-demethylgalanthamine base; M represents 1-12; R 4represent H, C 1~ C 12alkyl, benzyl or substituted benzyl; Above-mentioned " substituted benzyl " refer to by phenyl ring by 1-4 to be selected from the group of lower group the benzyl that replaces: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can at any possible position of phenyl ring.
10. any compound is in the Genistein alkyl amine compound of preparation as described in any one of claim 1-2 or the application of its pharmacy acceptable salt as claimed in claim 9.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103113340B (en) * 2013-01-21 2015-08-19 四川大学 One class Genistein alkyl amine compound, Preparation Method And The Use
CA2936506C (en) * 2014-01-13 2021-02-23 Douglas E. Brenneman Novel functionalized 1,3-benzene diols and their method of use for the treatment of hepatic encephalopathy
CN106924246A (en) * 2015-12-31 2017-07-07 中国医学科学院药物研究所 Isoflavonoid prevents or treats the purposes of nerve degenerative diseases
CN106632191B (en) * 2016-09-30 2018-10-30 四川大学 Homoisoflavone Mannich alkaloid compound, preparation method and use
CN108236610A (en) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 Purposes of the siskin isoflavonoid derivative in multiple target point improves learning memory disorder
CN109666013B (en) * 2017-10-16 2021-07-20 中国医学科学院药物研究所 Bipiperidine substituted isoflavone compound and use thereof
CN108299367B (en) * 2018-01-26 2022-04-12 南阳师范学院 Celery aglycone carbamate compound, preparation method and application thereof
CN109651321B (en) * 2019-01-31 2020-06-26 南阳师范学院 apigenin-O-alkylamine compound, preparation method and application
CN110305087B (en) * 2019-07-10 2021-05-04 南阳师范学院 5, 6-dimethoxy indenone compound and preparation method and application thereof
CN115160279B (en) * 2022-07-27 2023-11-24 中国药科大学 Benzopyrone compounds, pharmaceutical compositions and uses
CN116444474A (en) * 2023-04-24 2023-07-18 中国科学院长春应用化学研究所 Amino alkoxy modified flavone compound, pharmaceutical composition and application

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE666541A (en) * 1964-07-08
WO2001017985A1 (en) * 1999-09-03 2001-03-15 Indena S.P.A. Novel derivatives of flavones, xanthones and coumarins
CN101012213A (en) * 2006-12-22 2007-08-08 南京大学 Derivative of genistein and its preparing method and use
CN102127046A (en) * 2010-12-06 2011-07-20 南京大学 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone, preparation method and application of 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone
CN102161648A (en) * 2011-02-18 2011-08-24 中国药科大学 Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102161647A (en) * 2011-03-07 2011-08-24 中国药科大学 Preparation method and applications of isoflavone type multidrug resistance reversal agent of cancer cell
CN103113340B (en) * 2013-01-21 2015-08-19 四川大学 One class Genistein alkyl amine compound, Preparation Method And The Use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE666541A (en) * 1964-07-08
WO2001017985A1 (en) * 1999-09-03 2001-03-15 Indena S.P.A. Novel derivatives of flavones, xanthones and coumarins
CN101012213A (en) * 2006-12-22 2007-08-08 南京大学 Derivative of genistein and its preparing method and use
CN102127046A (en) * 2010-12-06 2011-07-20 南京大学 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone, preparation method and application of 4', 5-dyhydroxyl-7-(4-(N, N-diethylamino group) butoxy) isoflavone
CN102161648A (en) * 2011-02-18 2011-08-24 中国药科大学 Preparation method and applications of isoflavone type compounds with selective estrogen receptor modulating activity

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
A novel 7-O-modified genistein derivative with acetylcholinesterase inhibitory effect, estrogenic activity and neuroprotective effect;Shi,Da-Hua 等;《Archives of Pharmacal Research》;20120930;第35卷(第9期);第1645-1654页 *
Some Derivatives of natural isoflavones;Ferrari,Giorgio 等;《Journal of Medicinal Chemistry》;19661231;第9卷;第980页表1 *
Synthesis and antimicrobial activities of 7-O-modified genistein derivatives;Zhang,Li-Na 等;《European Journal of Medicinal Chemistry》;20080731;第43卷(第7期);都1543-1551页 *
植物雌激素对血管性痴呆大鼠学习记忆及海马神经肽Y的干预效应;高晓兰 等;《中国临床康复》;20060215;第10卷(第6期);第51页摘要 *
金雀异黄素衍生物的合成及潜在的雌激素受体调节活性;芦金荣 等;《中国药科大学学报》;20111225;第42卷(第6期);第497页图1 *
金雀异黄素衍生物的合成及潜在的雌激素受体调节活性;芦金荣 等;《中国药科大学学报》;20111225;第42卷(第6期);第497页图1，第499页实施例6a、7a和8a的合成，第496页和第498页化合物3a和化合物4a合成实施例 *
雌激素对阿尔茨海默病去势雌性SD大鼠学习记忆能力的影响;商秀丽 等;《解剖科学进展》;20100520;第16卷(第3期);第199页左栏3讨论第2段 *

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