CN103113340A - Genistein alkylamine compound, preparation method and use of genistein alkylamine compound - Google Patents

Genistein alkylamine compound, preparation method and use of genistein alkylamine compound Download PDF

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CN103113340A
CN103113340A CN2013100195698A CN201310019569A CN103113340A CN 103113340 A CN103113340 A CN 103113340A CN 2013100195698 A CN2013100195698 A CN 2013100195698A CN 201310019569 A CN201310019569 A CN 201310019569A CN 103113340 A CN103113340 A CN 103113340A
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genistein
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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 a novel genistein alkylamine compound (I), pragmatically acceptable salt of the novel genistein alkylamine compound, a preparation method of the novel genistein alkylamine compound and use for preparing related disease medicaments for treating or/and preventing neurodegeneration of the genistein alkylamine compound. The neurodegenerative diseases comprise but not limited to vascular dementia, Alzheimer disease, Parkinsonism disease, Huntington disease, HIV (human immunodeficiency virus) related Alzheimer disease, multiple sclerosis, progressive amyotrophic lateral sclerosis, neuropathic pain, glaucoma, and the like. In the formula, Ar is expressed as any one of the structural units shown in (A) to (C), and n equals to 1 to 2.

Description

One class Genistein alkyl amine compound, Preparation Method And The Use
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the novel Genistein alkyl amine compound of a class ( i) and pharmacy acceptable salt, its preparation method and treat and/or prevent the purposes in nervus retrogression relative disease medicine in preparation, include but not limited to the nerve degenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, the relevant dementia of HIV, multiple sclerosis, progressive lateral sclerosis disease, neuropathic pain, glaucoma.
Background technology
Vascular dementia (Vascular Dementia, VD) be by the intelligence due to various types of cerebrovascular diseases (comprising ischemic cerebrovascular disease, hemorrhagic cerebrovascular disease, acute and hypoxia-induced cerebrovascular disease etc.) and the clinical syndrome of cognition dysfunction, its main clinical manifestation comprises: going down and the change of emotion, personality of cognitive ability, memory and social-life ability is a kind of chronic progressive disease.In Asian countries's vascular dementia such as Chinese, Japanese, be first reason of senile dementia; Along with the continuous propelling of world population to aging, cerebro-vascular diseases is increasing, and the Onset of Vascular Dementia rate has the trend risen gradually, has a strong impact on the elderly's work and quality of life, and brings heavy economy and mental burden to society and family.Therefore, VD has become an important study hotspot in current geriatrics and psychologic medicine field.Vascular dementia, due to the pathogenesis complexity, there is no the medicine that can block disease progression, and clinical treatment is to improve brain blood circulation and brain metabolism at present, and it is main strengthening brain nutrition.
In recent years, research shows when VD patient shows cerebral damage also often abnormal with cholinergic system both at home and abroad.VD patient's hippocampus ChAT positive neuron and fibre density lower, and in brain, different sites ChAT is active descends, and the ACh concentration in the VD Cerebrospinal Fluid in Patients is starkly lower than normal level, and the degree that reduces of its concentration and dull-witted severity are proportionate; 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 can protect ischemic to cause, and can promote the recovery of nerve injury and brain function after cerebral ischemia to show that acetylcholinesterase depressant can be used for the treatment of vascular dementia.
Alzheimer's disease (Alzheimer ' s disease, AD) be that a kind of to take the infringement of carrying out property cognitive disorder and memory be main central nervous system degenerative disease, its sickness rate is ascendant trend year by year, become the frequently-occurring disease that is only second to cardiovascular diseases and cancer, risen to the 4th of the cause of death in developed countries such as America and Europes.According to World Health Organization's report, global over-65s old man has 10% dysnoesia, and wherein 1/2nd dementia occurs, and more than 85 years old, sickness rate nearly 50%.At present, China AD number of patients surpasses 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 the AD clinical manifestation is that memory capability, orientation property, thinking and judgement go down, and activity of daily living reduces, abnormal mental act symptom etc. even appears, make the patient care difficulty larger, bring heavy burden to society and family, thereby, research and develop novel senile dementia medicine significant.From the market requirement, " senile dementia report " that world market research and strategist company complete recently prediction, will reach 10,000,000,000 dollars to the global marketing volume of senile dementia disease medicine in 2015; In China, along with the rapid rising of senile dementia sickness rate, the market of this class medicine is rapid expansion also.
AD belongs to the disease that many factors causes, the pathogeny complexity, so far also do not illustrate its pathogenesis fully, dissect after death and find brain amyloid senile plaque (Senile Plaques, SP) and neurofibrillary tangles (Neurofibrillary Tangles, NFT) be that the histopathology of the tool feature of patient AD changes.In recent years, many investigators are devoted to disclose from molecule and cell levels the pathogeny of AD, multiple hypothesis has been proposed, as: the deposition of cholinergic neuron damage, amyloid, Protein tau Hyperphosphorylationof, inflammation, free-radical oxidn, metal ion imbalance etc., therefore, the novel therapeutic approach and the means that for these pathogenesis, develop, will be hopeful to alleviate and improve AD patient's the state of an illness.The medicine of effectively treating clinically AD at present mainly contains two classes: (1) causes the cholinergic hypothesis of cognitive function imbalance based on neurotransmitter acetic acid choline deficiency, adopt acetylcholinesterase depressant 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 the damage of glutaminate to neurocyte, as: Memantine Hydrochloride.But these medicines exist, and action target spot is single, toxic side effect is more, to the problem such as AD patient's long-term efficacy is not good enough.
Therefore, the anti-nerve degenerative diseases medicine that research and development have new chemical structure, novel mechanism of action, multiaction target spot, low toxic side effect not only meets the active demand of social senilization's process, and has 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 purpose 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 treat and/or prevent the purposes in nervus retrogression relative disease medicine in preparation, include but not limited to the nerve degenerative diseases such as the relevant dementia of vascular dementia, Alzheimer, parkinsonism, huntington disease, HIV, 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:
Figure 316749DEST_PATH_IMAGE001
In formula: arshown in being expressed as follows (A)~ (C)in arbitrary structural unit, n=1 or 2;
Figure 76895DEST_PATH_IMAGE002
R 1mean H, C 1~ C 12alkyl; R 2mean C 1~ C 12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, 6-are chloro-1,2,3,4-tetrahydro acridine 9-base, 8-are chloro-1,2,3,4-tetrahydro acridine 9-base, 6,8-bis-is chloro-1,2,3,4-tetrahydro acridine 9-base or n-demethylgalanthamine base; R 1nR 2also mean that Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C 1~ C 12the piperidyl that alkyl replaces, 4-position by piperidyl that benzyl or substituted benzyl replaced, piperazinyl, 4-position by C 1~ C 12the piperazinyl that alkyl replaces, 4-position are by piperazinyl that benzyl or substituted benzyl replaced; R 3mean H, C 1~ C 12alkyl, CF 3, C 1~ C 4acyl group; linkermean (CH 2) m, m means 1-12.Wherein, when Ar mean ( a) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 or 4 o'clock, r 1 nR 2 do not mean 4-benzyl diethylenediamine base; When armean ( a) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 o'clock, r 1 nR 2 do not mean morpholinyl, Pyrrolidine base, 4-methylpiperazine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3 or 4 o'clock, R 1and R 2mean methyl, ethyl, n-propyl or normal-butyl when different; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3,4,5 or 6 o'clock, r 1 nR 2 do not mean morpholinyl, piperazinyl, 4-methylpiperazine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3 or 4 o'clock, r 1 nR 2 do not mean Pyrrolidine base, piperidyl; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 4 or 6 o'clock, r 1 nR 2 do not mean 4-ethyl piperazidine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 or 5 o'clock, r 1 nR 2 do not mean 4-benzyl diethylenediamine base; " -O-Linker-NR 1 r 2 " also can be , m means 1-12, R 4mean H, C 1~ C 12alkyl, benzyl or substituted benzyl.
Above-mentioned term " substituted benzyl " refers to and is selected from the benzyl that group replaced of lower group by 1-4 on phenyl ring: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can be at any possible position of phenyl ring.
Genistein alkyl amine compound proposed by the invention ( i) can prepare by the following method:
(1) mean structural unit (A) as Ar, and R 3 =H, Linker means (CH 2 ) m the time:
Figure 480511DEST_PATH_IMAGE004
In formula: X means Cl, Br, I; Ar means structural unit (A), and R 3mean H; R 1, R 2, the definition of m and chemical structure of general formula ( i) identical.
The Genistein of protecting with the methoxy methylene radical ( 1) be starting raw material, under solvent and alkaline condition with the dihalo-alkylate ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 3), the gained intermediate 3with organic amine compound ( 4) in solvent, react, obtain the protection of corresponding methoxy methylene radical Genistein alkyl amine compound ( 5), compound 5remove methoxy methylene radical protecting group under solvent and acidic conditions, obtain corresponding Genistein alkyl amine compound ( i).
Its concrete preparation method is described below:
Described step a)in, react alkali used and be: 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, trimethylamine class or the quaternary ammonium bases of alcohol (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; The 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): the dihalo-alkylate ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 10.0:1.0 ~ 10.0, and preferably molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, the 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, preferably molar feed ratio is 1.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step c)in, the 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 the preferred mass mark is 10%-95%, and temperature of reaction is 0 ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 8 hour.
(2) mean structural unit (B) or (C) or R as Ar 3 do not mean the structural unit (A) of H, Linker means (CH 2 ) m the time:
In formula: X means Cl, Br, I; Ar means structural unit (B) or (C) and R 3the structural unit (A) that does not mean 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, under alkaline condition with the dihalo-alkylate ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 7), the 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, react alkali used and be: 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, trimethylamine class or the quaternary ammonium bases of alcohol (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; The 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): the dihalo-alkylate ( 2): the molar feed ratio of alkali is 1.0:1.0 ~ 15.0:1.0 ~ 15.0, and preferably molar feed ratio is 1.0:1.0 ~ 6.0:1.0 ~ 6.0; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, the 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, preferably molar feed ratio is 1.0:1.0 ~ 6.0; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
(3) when Ar be structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 for
Figure 80437DEST_PATH_IMAGE006
the time:
In formula: X means Cl, Br, I; Ar means structural unit (A), and R 3mean H; M, R 4definition and chemical structure of general formula ( i) identical.
The Genistein of protecting with the methoxy methylene radical ( 1) be starting raw material, under solvent and alkaline condition with 1-replacement-4-alkylhalide group piperazine ( 8) reaction, obtain the protection of corresponding methoxy methylene radical Genistein alkyl amine compound ( 9), compound 9remove methoxy methylene radical protecting group under solvent and acidic conditions, obtain corresponding Genistein alkyl amine compound ( i).
Its concrete preparation method is described below:
Described step a)in, react alkali used and be: 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, trimethylamine class or the quaternary ammonium bases of alcohol (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; The 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; The Genistein of methoxy methylene radical protection ( 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 preferably molar feed ratio is 1.0:1.0 ~ 5.0:1.0 ~ 5.0; Temperature of reaction is room temperature ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and the preferred reaction time is 2 ~ 24 hours.
Described step b)in, the 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 the preferred mass mark is 10%-95%, and temperature of reaction is 0 ~ 150 ℃, and preferable reaction temperature is room temperature ~ 120 ℃; Reaction times is 30 minutes ~ 24 hours, and the preferred reaction time is 1 ~ 8 hour.
(4) mean structural unit (B) or (C) or R as Ar 3 the structural unit (A) that does not mean H ,-O-Linker-NR 1 r 2 mean
Figure 447144DEST_PATH_IMAGE006
the time:
Figure 970529DEST_PATH_IMAGE008
In formula: X means Cl, Br, I; Ar means structural unit (B) or (C) or R 3the structural unit (A) that does not mean 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, under alkaline condition with 1-replacement-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; The 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; The 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 preferably molar feed ratio is 1.0:1.0 ~ 8.0:1.0 ~ 8.0; Temperature of reaction is room temperature ~ 150 ℃, is preferably room temperature ~ 120 ℃; Reaction times is 1 ~ 72 hour, and preferably the time is 2 ~ 24 hours.
The Genistein of starting raw material of the present invention---methoxy methylene radical protection ( 1), 1-replacement-4-alkylhalide group piperazine ( 8) the common technology in available this area makes, including, but not limited to disclosed method 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 the Genistein alkyl amine compound of above-mentioned four kinds of method gained ( i) containing amino in molecule, this amino is alkalescence, can make acceptable salt on its pharmacology by pharmaceutically conventional salifying method with any suitable acid, and 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, all higher than 98.5%, carried out following bioactivity screening to these compounds.
(1) acetylcholinesterase and butyrylcholine esterase suppress active
In 96 orifice plates, add successively 1.0 mmol/L acetylthiocholine iodides or sulfur iodide for BuCh (all purchased from Sigma company) 30 μ L, 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 is made the homogenate medium) or butyrylcholine esterase (rat blood serum 25% supernatant liquor, the pH7.4 phosphoric acid buffer is made the homogenate medium) solution, after finishing and mixing, hatch 15min for 37 ℃, to add in each hole 0.2% 5, 5 '-dithio-bis-(2-nitrobenzoic acid) (DTNB, purchased from Sigma company) solution 30 μ L colour developings, measure the optical density(OD) (OD value) in each hole, 405nm place by microplate reader, with the blank well that does not add testing sample, compare, the inhibiting rate (enzyme inhibition rate (%)=(1-sample sets OD value/blank group OD value) * 100%) of computerized compound to enzyme, select five to six concentration of compound, measure its enzyme inhibition rate, and, with the inhibiting rate linear regression of negative logarithm and the enzyme of this compound volumetric molar concentration, the volumetric molar concentration while trying to achieve 50% inhibiting rate is the IC of this compound 50.Measurement result shows, in the embodiment of the present invention, disclosed compound all has remarkable restraining effect to acetylcholinesterase, its IC 50for 0.1nM ~ 5.0 μ M, wherein, the IC of disclosed compound 2-B4-14 in the embodiment of the present invention 2 50be 2.5 μ M, and the IC of isonomic all the other compounds (2-B4-1 to 2-B4-13,2-B4-15 to 2-B4-21) 50all be less than 2.5 μ M, and positive control medicine---the IC that Rivastigmine suppresses acetylcholinesterase 50be 6.3 μ M; Measurement result also shows, in the embodiment of the present invention, disclosed compound is much higher than the inhibition activity to butyrylcholine esterase to the inhibition activity of acetylcholinesterase, 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 inducing
DMEM nutrient solution containing 10% calf serum for the PC12 cell, with 1 * 10 5individual/mL density is inoculated on 96 well culture plates, and the inoculation volume is 100 μ L/ holes, puts into subsequently containing 5% CO 237 ℃ of constant incubators in cultivate.Cultivate after 24 hours, (final concentration is 10 to add the compound of respective concentration in the administration group -5mol/L, 10 -6mol/L) 10 μ L/ holes, preincubate 2 hours (control group and damage group add respectively 10 μ L/ hole PBS, make its volume keep equating).After the PC12 cell is hatched 2 hours, add respectively 100 μ M H in administration group and damage group 2o 2damage agent 10 μ L/ holes (control group adds 10 μ L/ hole PBS), after 30 minutes, the RPMI-1640 nutrient solution that the nutrient solution of each group is all changed into without calf serum continues to put into constant incubator cultivation 24 hours, and the nutrient solution volume is still 100 μ L/ holes.Continue to cultivate after 24 hours, add 5mg/mL MTT 100 μ L/holes in each group, carry out viable cell dyeing.After 3 hours, add 100% DMSO stop buffer 100 μ L/ holes in each group, fully dissolve and mix.Measure the OD value of each group under the wavelength of 490 nm, test result repeats 3 times, uses Duncan ' s test method statistic, and each organizes numeric representation is mean ± S.E.M., take control group as 100%, and administration group and damage class value mean with the per-cent of control group.Measurement result shows, in the embodiment of the present invention, disclosed compound all has significant provide protection to the PC12 cell injury of hydrogen peroxide-induced, and 10 -5anti-oxidant activity under mol/L concentration all is better than Genistein.
(3) impact of compound on Scopolamine induced mice memory acquisition disturbance
SPF level ICR male mice, 25-30g is divided at random: normal group, model group, be subject to reagent high and low dose group (5.0,2.5mg/kg), every group of 10 animals.Disposable gavage gives tested medicine, and blank group and model group give solvent 0.5% CMC-Na, and the administration volume is 0.1ml/10g; 45 min after medicine, normal group mouse peritoneal injecting normal saline, all the other each treated animals are all injected Scopolamine (5mg/kg), and the administration volume is 0.1ml/10g; After modeling 30 min, mouse is put into to non-electricity irritation Y labyrinth and carry out the study of behaviour test.During test, mouse is put in to an arm end, be allowed to condition in labyrinth and freely walk 8min, record its number of times that enters each arm and alternate frequency, calculate alternately rate according to following formula: replace rate %=[alternate frequency/(always entering number of times-2)] * 100, result means with mean ± standard deviation, group difference employing one-way analysis of variance.Measurement result shows, under this experiment condition, compound disclosed in this invention causes to Scopolamine the improvement effect that the acquired dysmnesia of mouse have dose-dependently, with model group, significant difference (p<0.01) is more all arranged.
(4) impact of compound on ethanol induced mice memory represents obstacle
SPF level ICR male mice, 25-30g is divided at random: normal group, model group, be subject to reagent high and low dose group (5.0,2.5mg/kg), rivastigmine group (3mg/kg), every group of 10 animals.Every day, gavage gave tested medicine, and blank group and model group give solvent 0.5%CMC-Na, and the administration volume is 0.1ml/10g, successive administration 32 days; In administration during 1 ~ 24 day, 30 min after the every day medicine, model group and each administration group gavage 0.1ml/10g ethanol (15% w/v), give 24 days continuously, removes ethanol and enter ethanol and clean the phase, and medicine continues to give; Within 31,32 days, carry out the experiment of animal diving tower in administration; after medicine, 45min is trained or test experiments; during training, allow mouse be placed in the diving tower instrument, put down gently on platform, energising; the biped of take when platform jumps off when animal contacts the copper grid as electric shock simultaneously; be considered as wrong reaction, the normal avoiding reaction after mouse is shocked by electricity is for escaping to platform, records mouse and escapes to the latent period on platform; and record the electric shock number of times in 5min, using this as school grade.Tested after 24 hours, record mouse and jump off for the first time the number of times (errors number) shocked by electricity in time (latent period) of being shocked by electricity and 5 min thereof, usingd this evaluation index as the memory represents function.Test result means with mean ± standard deviation, group difference employing 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, with model group, significant difference (p<0.01) is more all arranged.
(5) neuroprotective of compound to vascular dementia rats
(a) animal model, grouping and administration
Rats by intraperitoneal injection 3.5% chloral hydrate anesthesia (350 mg/kg), separate bilateral carotid, ligation, not ligation of sham-operation normal group 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: the equal latent period of SR=(operation group average latency-normal group average latency)/normal group animal.With the SR<handicapped model success of 0.2 screening neurobehavioral animal, be divided at random normal group, model group, medicine high dose group (45 mg/kg) and low dose group (15 mg/kg), 12 every group; Postoperative the 13rd day starts to gavage administration, and normal group and model group give the equal-volume solvent; After successive administration 3 weeks, 7 days labyrinth test experiments of row water are to estimate the impact of medicine on vascular dementia rats neurobehavioral function.After study of behaviour is completed, 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 is fixed 24 hours, paraffin embedding, make the approximately crown section of brain of 5 μ m of thickness, for the europathology histological examination.Experimental data all means with mean ± standard deviation, and experimental result adopts SPSS16 software to carry out statistical study, relatively adopts one-way analysis of variance LSD method between group, take P<0.05 as significant difference.
(b) neurobehavioral functional examination
Adopt Morris water maze testing method to estimate the impact of medicine on 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, at quadrant 1 center, places a platform, and platform and the center of circle and pool wall are equidistant, platform is that white is circular, diameter 10cm, high 20cm, platform is positioned at underwater 2cm, pond water temperature remains on 25 ± 2 ℃, adds appropriate foodstuff additive antholeucin in water, makes Chi Shui be opaque oyster white, animal can not arrive platform by vision, in order to detect the acuteness of animal to locus.A camera is arranged directly over pond, and camera is connected with computer, by animal activity situation in the computer record pond.After administration, water maze laboratory carries out 7 days continuously, within 1-2 days, is the concealment platform experiments, records rat and finds the time of platform (latent period); Within the 3rd day, in order to explore platform experiments (removing platform), rat place of entry invariant position, record the residence time and the traversing times of rat at place, original platform position quadrant; Within 4-6 days, be new platform experiments (being that position of platform changes), rat place of entry invariant position, record rat and find the time of platform (latent period); The 7th day is visible platform experiments, and rat place of entry invariant position records rat and finds the time of platform (latent period).The Morris water maze is a kind of experiment that relies on the 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, the 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, with model group, compares, and the medication therapy groups rat obviously shortened in the latent period of concealment platform and new platform, and, in exploring platform experiments, animal obviously extends at the residence time and the traversing times of original platform quadrant.Experimental result has confirmed that the pharmacological agent energy dose-dependently ground of compound disclosed in this invention obviously improves the cognition dysfunction by the brain vascular dementia that low perfusion causes for a long time.In addition, the visible platform experiments result shows platform no significant difference in latent period between each group, thereby gets rid of the impact of operation on animal vision and motor capacity, has further confirmed the result for the treatment of of medicine to vascular dementia.
(c) detection of neuronal damage
Detect neuronal kernel antigen (NeuN) expression level of VD animal brain cortex and hippocampus by ImmunohistochemistryMethods Methods, estimate the impact of medicine on VD animal brain neuronal damage.Get every crown paraffin section of animal brain, dimethylbenzene dewaxing, 3% H 2o 2after deactivating endogenous peroxydase, drip the 5%BSA confining liquid, after 37 ℃ of incubators are hatched 1 hour, add respectively NeuN polyclonal antibody (1:200, Beijing Bo Aosen Bioisystech Co., Ltd), hatch after 2 hours dislocation in 4 ℃ of refrigerator overnight for 37 ℃.Add biotinylation goat-anti mouse two anti-, 37 ℃ hatch 1 hour, then, after adding SABC, 37 ℃ to hatch 1 hour, DAB colour developing, Hematorylin are redyed.Routine is dewatered, dimethylbenzene is transparent, the neutral gum mounting.Under 400 times of opticmicroscopes, cortex and 3 nonoverlapping regional positive cell numbers of hippocampus are observed and recorded to blind method, calculates every section mean value, take control group as 100%, and the positive cell number of model group and administration group means with the per-cent of control group.
Measurement result shows, with the cortex of normal group comparison model group and the immune positive neuronal cell quantity of NeuN of hippocampus, significantly reduces (P<0.01); With model group, compare, but the medicine dose-dependently increases neuronal cell quantity (P<0.05 or P<0.01).Experimental result shows, compound disclosed in this invention can suppress the damage of vascular dementia rats cerebral neuron cell, and the result that can improve Morris water maze laboratory medium vessels dementia rats cognitive function with medicine conforms to.
(d) detection that spongiocyte activates
Get every crown paraffin section of animal brain, dimethylbenzene dewaxing, 3% H 2o 2after deactivating endogenous peroxydase, drip the 5%BSA confining liquid, after 37 ℃ of incubators are hatched 1 hour, add respectively OX-42 polyclonal antibody (1:200, Millipore company, USA) or GFAP polyclonal antibody (1:100, Wuhan Boster Biological Technology Co., Ltd.), hatch after 2 hours dislocation in 4 ℃ of refrigerator overnight for 37 ℃.Add biotinylation goat-anti mouse two anti-, 37 ℃ hatch 1 hour, then, after adding SABC, 37 ℃ to hatch 1 hour, DAB colour developing, Hematorylin are redyed, conventional dehydration, dimethylbenzene are transparent, the neutral gum mounting; Immunohistochemical staining is adopted figure with Axiovert 40 CFL microscopes: under 400 times of opticmicroscopes, every section is chosen 3 different zones and is adopted figure in the pallium fixed position, accumulation optical density value (IOD) with Image Pro-plus5.0 software analysis immune response positive cell, calculate every section IOD mean value, every group of result means with mean ± standard deviation.Measurement result shows, with normal group, compares, and the OX-42 of model group cortex and the expression level of GFAP all significantly increase (P<0.01); With model group, compare, but the medicine dose-dependently reduces OX-42 and GFAP expresses, 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, by suppressing Neuroinflammation, vascular dementia brought into play to prevention and treatment.
Embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.
embodiment 1 works as Ar and means structural unit (A) and R 3 =H, Linker means (CH 2 ) m the time Genistein alkyl amine compound (I) the logical method of preparation
In reaction flask, add 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 is followed the tracks of with TLC); After reaction finishes, filtered while hot, a small amount of acetonitrile washing leaching cake, filtrate decompression is steamed and is desolventized and excessive dibromo alkylate, resistates through column chromatography purification (elutriant: methylene dichloride), obtain the 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 is followed the tracks of with TLC); After reaction finishes; remove solvent under reduced pressure; add 50 ml methylene dichloride in resistates; use successively 30 ml 10% aqueous sodium carbonates and 30 ml deionized water wash; 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 the gained compound 5add in the mixing solutions of 10 ml 15% aqueous hydrochloric acids and 20 ml ethanol, 3.0～8.0 hours (reaction process is followed the tracks of with TLC) of stirring at room reaction, after reaction finishes, remove solvent under reduced pressure, add 50 ml methylene dichloride in resistates, use successively 20 ml 5% sodium bicarbonate aqueous solutions and 20 ml deionized water wash, 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 conclusive evidence.Adopt the standby target compound structure obtained of above-mentioned logical legal system as follows:
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(continuous page)
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(continuous page)
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(continuous page)
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。
embodiment 2 means structural unit (B) or (C) or R as Ar 3 do not mean the structural unit (A) of H, Linker means (CH 2 ) m the time Genistein alkyl amine compound (I) the logical method of preparation
In reaction flask, add 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 reaction after 30 minutes, add 10.0 mmol dibromo alkylates ( 2), 50 ~ 60 ℃ stirring reaction 5-18 hour (reaction process is followed the tracks of with TLC); After reaction finishes, filtered while hot, filtrate decompression is steamed and is desolventized, add 150 ml methylene dichloride in resistates, use successively 50 ml 10% aqueous sodium carbonates and 50 ml deionized water wash, 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, can obtain corresponding 7-position, 4 '-position or 7,4 '-disubstituted aryloxyalkyl group bromine compounds in position ( 7); Wherein, when starting raw material Genistein compounds ( 6) be R 3do not mean H structural unit ( b) time, obtain the aryloxyalkyl group bromine compounds that the 7-position replaces ( 7), yield 78%-95%; When starting raw material Genistein compounds ( 6) be R 3do not mean H structural unit ( a) time, obtain 4 '-aryloxyalkyl group bromine compounds that position replaces ( 7), yield 66%-87%; When starting raw material Genistein compounds ( 6) be Genistein (R 3the structural unit of expression H ( a) or ( b)) time, can obtain simultaneously the aryloxyalkyl group bromine compounds that the 7-position replaces ( 7) and the disubstituted aryloxyalkyl group bromine compounds in 7,4 '-position ( 7), yield is respectively 35%-58% and 20%-35%.
By the above-mentioned corresponding 7-position, 4 ' prepared-position or 7,4 '-disubstituted aryloxyalkyl group bromine compounds in 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 is followed the tracks of with TLC); After reaction finishes, remove solvent under reduced pressure, add 50 ml methylene dichloride in resistates, use successively 15 ml 5% aqueous sodium carbonates and 15 ml deionized water wash, organic layer filters after anhydrous sodium sulfate drying, remove solvent under reduced pressure, resistates through column chromatography purification (elutriant: methylene dichloride-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 conclusive evidence.Adopt the standby target compound structure obtained of above-mentioned logical legal system as follows:
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ar means
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(continuous page)
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(continuous page)
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(continuous page)
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(continuous page)
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(continuous page)
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ar means
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(continuous page)
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。
embodiment 3 works as Ar and means structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 mean
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the time Genistein alkyl amine compound (I) the logical method of preparation
In reaction flask, add 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 alkylpiperazines ( 8), 5.0～18.0 hours (reaction process is followed the tracks of with TLC) of return stirring reaction; After reaction finishes, filtered while hot, a small amount of acetonitrile washing leaching cake, filtrate decompression is steamed and is desolventized, resistates through column chromatography purification (elutriant: chloroform), obtain corresponding methoxy methylene radical protection Genistein alkyl amine compound ( 9), yield 78.0%-95.0%.By the gained compound 9add in the mixing solutions of 10 ml 15% aqueous hydrochloric acids and 20 ml ethanol, 3.0～7.0 hours (reaction process is followed the tracks of with TLC) of stirring at room reaction, after reaction finishes, remove solvent under reduced pressure, add 50 ml methylene dichloride in resistates, use successively 20 ml 5% sodium bicarbonate aqueous solutions and 20 ml deionized water wash, 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 conclusive evidence.Adopt the standby target compound structure obtained of above-mentioned logical legal system as follows:
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(continuous page)
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。
embodiment 4 means structural unit (B) or (C) or R as Ar 3 the structural unit (A) that does not mean H ,-O-Linker-NR 1 r 2 mean
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the time Genistein alkyl amine compound (I) the logical method of preparation
In reaction flask, add 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 reaction after 30 minutes, add 1-replacement-4-chlorine alkylpiperazine ( 8) 10.0 mmol, 50 ~ 60 ℃ stirring reaction 5-15 hour (reaction process is followed the tracks of with TLC); After reaction finishes, filtered while hot, filtrate decompression is steamed and is desolventized, add 150 ml methylene dichloride in resistates, use successively 50 ml 10% aqueous sodium carbonates and 50 ml deionized water wash, 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, can obtain the disubstituted Genistein alkyl amine compound in corresponding 7-position, 4 '-position or 7,4 '-position ( i); Wherein, when starting raw material Genistein compounds ( 6) be R 3do not mean H structural unit ( b) time, obtain the Genistein alkyl amine compound that the 7-position replaces ( i), yield 70%-92%; When starting raw material Genistein compounds ( 6) be R 3do not mean H structural unit ( a) time, obtain 4 '-Genistein alkyl amine compound that position replaces ( i), yield 78%-96%; When starting raw material Genistein compounds ( 6) be Genistein (that is: R 3the structural unit of expression H ( a) or ( b)) time, can obtain simultaneously the Genistein alkyl amine compound that the 7-position replaces ( i), yield 30%-58% and 7, the disubstituted Genistein alkyl amine compound in 4 '-position ( i), yield 23%-38%.The equal warp of its chemical structure 1h-NMR, 13c-NMR and ESI-MS conclusive evidence.Adopt the standby target compound structure obtained of above-mentioned logical legal system as follows:
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ar means
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(continuous page)
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；
ar means
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。
embodiment 5
aryloxyalkyl group aminated compounds (I) and the logical method of sour salify preparation
In reaction flask, add Genistein alkyl amine compound according to above-described embodiment 1-4 gained ( i) 2.0 mmol and ethanol 50 ml, add 6.0 mmol acid accordingly after stirring, temperature rising reflux stirring reaction 20 minutes, reaction is cooled to room temperature after finishing, and removes solvent under reduced pressure, the resistates acetone recrystallization, the solid that filtration is separated out, obtain Genistein alkyl amine compound ( i) salt, its chemical structure warp 1h NMR and ESI-MS conclusive evidence.

Claims (10)

1. class Genistein alkyl amine compound or its pharmacy acceptable salt, the chemical structure of general formula that it is characterized in that this compounds as ( i) shown in:
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In formula: arshown in being expressed as follows (A)~ (C)in arbitrary structural unit, n=1 or 2;
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；
R 1mean H, C 1~ C 12alkyl; R 2mean C 1~ C 12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, 6-are chloro-1,2,3,4-tetrahydro acridine 9-base, 8-are chloro-1,2,3,4-tetrahydro acridine 9-base, 6,8-bis-is chloro-1,2,3,4-tetrahydro acridine 9-base or n-demethylgalanthamine base; R 1nR 2also mean that Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C 1~ C 12the piperidyl that alkyl replaces, 4-position by piperidyl that benzyl or substituted benzyl replaced, piperazinyl, 4-position by C 1~ C 12the piperazinyl that alkyl replaces, 4-position are by piperazinyl that benzyl or substituted benzyl replaced; R 3mean H, C 1~ C 12alkyl, CF 3, C 1~ C 4acyl group; linkermean (CH 2) m; " -O-Linker-NR 1 r 2 " also mean
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; M means 1-12; R 4mean H, C 1~ C 12alkyl, benzyl or substituted benzyl;
Wherein, when Ar mean ( a) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 or 4 o'clock, r 1 nR 2 do not mean 4-benzyl diethylenediamine base; When armean ( a) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 o'clock, r 1 nR 2 do not mean morpholinyl, Pyrrolidine base, 4-methylpiperazine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3 or 4 o'clock, R 1and R 2mean methyl, ethyl, n-propyl or normal-butyl when different; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3,4,5 or 6 o'clock, r 1 nR 2 do not mean morpholinyl, piperazinyl, 4-methylpiperazine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 2,3 or 4 o'clock, r 1 nR 2 do not mean Pyrrolidine base, piperidyl; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 4 or 6 o'clock, r 1 nR 2 do not mean 4-ethyl piperazidine base; When armean ( b) structural unit and R 3mean H, linkerfor (CH 2) m, m is 3 or 5 o'clock, r 1 nR 2 do not mean 4-benzyl diethylenediamine base;
Above-mentioned term " substituted benzyl " refers to and is selected from the benzyl that group replaced of lower group by 1-4 on phenyl ring: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can be at any possible position of phenyl ring.
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 formed salt of alkylsulphonic acid, camphorsulfonic acid, Phenylsulfonic acid or tosic acid.
As Genistein alkyl amine compound as described in claim 1-2 any one ( i) or the preparation method of its pharmacy acceptable salt, it is characterized in that structural unit that the preparation method of described compound means according to Ar and Linker or-O-Linker-NR 1r 2mean substituent difference, following four kinds of methods arranged:
method one: when Ar means structural unit (A) and R 3 =H, Linker means (CH 2 ) m the time:
Figure 726738DEST_PATH_IMAGE004
In formula: X means Cl, Br, I; Ar means structural unit (A) and R 3mean H; R 1, R 2, the definition of m and chemical structure of general formula ( i) identical;
The Genistein of protecting with the methoxy methylene radical ( 1) be starting raw material, under solvent and alkaline condition with the dihalo-alkylate ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 3), the gained intermediate 3with organic amine compound ( 4) in solvent, react, obtain the protection of corresponding methoxy methylene radical Genistein alkyl amine compound ( 5), compound 5remove methoxy methylene radical protecting group under solvent and acidic conditions, obtain corresponding Genistein alkyl amine compound ( i);
method two: when Ar means structural unit (B) or (C) or R 3 do not mean the structural unit (A) of H, Linker means (CH 2 ) m the time:
Figure 481067DEST_PATH_IMAGE005
In formula: X means Cl, Br, I; Ar means structural unit (B) or (C) and R 3the structural unit (A) that does not mean 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, under alkaline condition with the dihalo-alkylate ( 2) reaction, generate corresponding aryloxyalkyl group halogen compound ( 7), the gained compound 7with organic amine compound ( 4) reaction, obtain corresponding Genistein alkyl amine compound ( i);
method three: when Ar means structural unit (A) and R 3 =H ,-O-Linker-NR 1 r 2 mean
Figure 686921DEST_PATH_IMAGE006
the time:
Figure 803781DEST_PATH_IMAGE007
In formula: X means Cl, Br, I; Ar means structural unit (A) and R 3mean H; M, R 4definition and chemical structure of general formula ( i) identical;
The Genistein of protecting with the methoxy methylene radical ( 1) be starting raw material, under solvent and alkaline condition with 1-replacement-4-alkylhalide group piperazine ( 8) reaction, obtain the protection of corresponding methoxy methylene radical Genistein alkyl amine compound ( 9), compound 9remove methoxy methylene radical protecting group under solvent and acidic conditions, obtain corresponding Genistein alkyl amine compound ( i);
method four: when Ar means structural unit (B) or (C) or R 3 the structural unit (A) that does not mean H ,-O-Linker-NR 1 r 2 mean
Figure 233626DEST_PATH_IMAGE006
the time:
Figure 944093DEST_PATH_IMAGE008
In formula: X means Cl, Br, I; Ar means structural unit (B) or (C) or R 3the structural unit (A) that does not mean 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, under alkaline condition with 1-replacement-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) containing amino in molecule, this amino is alkalescence, can make acceptable salt on its pharmacology by pharmaceutically conventional salifying method with any suitable acid.
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, react alkali used and be: 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, triethylamine, Tributylamine, trioctylamine, pyridine of alcohol, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; The 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): the dihalo-alkylate ( 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 ℃; Reaction times is 1 ~ 72 hour;
The step of method one b)in, the 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 ℃; Reaction times is 1 ~ 72 hour;
The step of method one c)in, the 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%-100%, and temperature of reaction is 0 ~ 150 ℃; 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, react alkali used and be: 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, triethylamine, Tributylamine, trioctylamine, pyridine of alcohol, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; The 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): the dihalo-alkylate ( 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 ℃; Reaction times is 1 ~ 72 hour;
The step of method two b)in, the 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 ℃; 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, react alkali used and be: 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, triethylamine, Tributylamine, trioctylamine, pyridine of alcohol, n-methylmorpholine, n-methyl piperidine, triethylene diamine or TBAH; The 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; The Genistein of methoxy methylene radical protection ( 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 ℃; Reaction times is 1 ~ 72 hour;
The step of method three b)in, the 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%-100%; Temperature of reaction is 0 ~ 150 ℃; 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, react alkali used and be: 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; The 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; The 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 ℃; Reaction times is 1 ~ 72 hour.
8. treat and/or prevent the purposes in nervus retrogression relative disease medicine as claim 1-2 any one described Genistein alkyl amine compound or its pharmacy acceptable salt in preparation, this class nervus retrogression relative disease is: vascular dementia, Alzheimer's disease, parkinsonism, huntington disease, the relevant dementia of HIV, 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:
Figure 219216DEST_PATH_IMAGE009
In formula: R 1mean H, C 1~ C 12alkyl; R 2mean C 1~ C 12alkyl, benzyl, substituted benzyl, 1,2,3,4-tetrahydro acridine 9-base, 6-are chloro-1,2,3,4-tetrahydro acridine 9-base, 8-are chloro-1,2,3,4-tetrahydro acridine 9-base, 6,8-bis-is chloro-1,2,3,4-tetrahydro acridine 9-base or n-demethylgalanthamine base; R 1nR 2also mean that Pyrrolidine base, morpholinyl, piperidyl, 4-position are by C 1~ C 12the piperidyl that alkyl replaces, 4-position by piperidyl that benzyl or substituted benzyl replaced, piperazinyl, 4-position by C 1~ C 12the piperazinyl that alkyl replaces, 4-position are by piperazinyl that benzyl or substituted benzyl replaced; M means 1-12; R 4mean H, C 1~ C 12alkyl, benzyl or substituted benzyl; Above-mentioned " substituted benzyl " refers to and is selected from the benzyl that group replaced of lower group by 1-4 on phenyl ring: F, Cl, Br, I, C 1-4alkyl, C 1-4alkoxyl group, trifluoromethyl, trifluoromethoxy, nitro, cyano group, these substituting groups can be at any possible position of phenyl ring.
10. any compound application as claim 1-2 any one described Genistein alkyl amine compound or its pharmacy acceptable salt in preparation as claimed in claim 9.
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