CN103382203B - Puerarin derivate and synthetic method thereof and application - Google Patents

Puerarin derivate and synthetic method thereof and application Download PDF

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CN103382203B
CN103382203B CN201310354892.0A CN201310354892A CN103382203B CN 103382203 B CN103382203 B CN 103382203B CN 201310354892 A CN201310354892 A CN 201310354892A CN 103382203 B CN103382203 B CN 103382203B
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puerarin
puerarin derivate
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CN103382203A (en
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江培
季宇彬
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Harbin University of Commerce
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Abstract

Puerarin derivate and synthetic method thereof and application, it belongs to cerebrovascular disease field.The present invention is by modifying the selectivity of puerarin raising to vascular dementia therapy target.The logical formula I of puerarin derivate of the present invention represents: , it utilizes chemical synthesis process, and its product is applied to treatment vascular dementia.The present invention improve puerarin fat-soluble and water-soluble while, improve its selectivity to acceptor, osmotic pressure inside and outside balance brain cell, improve the edema because inflammation damnification causes thus give prominence to puerarin self and improve microcirculation, improve the pharmacological action of cholinergic nerve system function, improve the learning memory disorder caused by ischemia-reperfusion damage.

Description

Puerarin derivate and synthetic method thereof and application
Technical field
The present invention relates to a kind of derivative and synthetic method thereof and application.
Background technology
Cerebrovascular disease is Neurology Department common disease the most, also be the common factors of disabling of being grown up, in addition the problem of an aging population, dementia incidence increases gradually, increase the weight of the burden of family social especially, it is the most remarkable with ischemia-reperfusion damage to be wherein that the sickness rate of the vascular dementia (VD) that major cause causes increases, and vascular dementia has become the second largest dementia disease after alzheimer's disease.According to foreign data, VD is the dementia uniquely can prevented and treated up to now, as early treatment can have reversibility.Therefore exploring correlative factor and the pathogenesis of VD morbidity, to seeking the effective measure of early diagnosis, early prevention, early treatment, having become the important topic of medical basic research and clinical study.
For the pathogenesis of vascular dementia, in the market multidigit some improve brain microcirculation medicine, as Cyclelate (Cycandelate), naftidrofuryl (Naftidrofuryl), vinpocetin (Vinpocetine) etc.; Anticholinesterase, as lycoremine (Galantamine), E2020 (Donepezil), kappa Xi Ting (Rivastigmine) etc.; Neuroprotective Agents, as nimodipine (Nimodipine), memantine (Memantine) etc.
Also do not treat the specifics of vascular dementia at present in the world, this is relevant with VD pathogenesis complexity, little for the new drug that VD is clinical in recent years, possess simultaneously and improve brain microcirculation and cholinergic nerve system function, antagonism effect such as ischemical reperfusion injury and the little medicine of toxic side effect are are urgently researched and developed.
Major part medicine curative effect be produced by the interaction between drug molecule and biological receptor molecules, therefore, drug molecule size, shape, space structure and solubility property thereof on drug effect impact very large.So except design novel form, its sterie configuration can be changed by structural modification, improve its original pharmacologically active or make its pharmacological action have targeting by introducing active function groups.
Puerarin is a kind of isoflavones carbon glycosides, has and improves cardiovascular and cerebrovascular circulation, anti-oxidant, extensive pharmacological action such as antitumor grade, and due to certainly as natural product, have the advantage that toxic side effect is little, the medicinal application of Chang Zuowei cardiovascular treatment is in clinical.But due to the isoflavones structure of puerarin, make it water-soluble and fat-soluble all poor, in water, solubleness is only 1.1 × 10 -2mol/L, fat water coefficient P is 0.38.
For obtaining having the puerarin of better fat-soluble and water-soluble, higher pharmacologically active, investigators have done a large amount of research work.
On puerarin molecular structure 7,4 ' hydroxyl is the active group of puerarin, and wherein 7 is hydroxyl because of by 8 sugared steric influences, active weak compared with 4 hydroxyls.For improving the shortcoming of puerarin poorly water-soluble; Zhang Shouguo; The synthesis of pur and derivatives and Preliminary activation are studied [D]. Academy of Military Medicine, PLA's master thesis, 2005,5; Take puerarin as raw material, through the reaction of 1,3-dibromopropane, then react with a series of amine, prepared the puerarin class novel derivative of 12 4' position hydroxyl alkylamino radicals, alkyl replacement.
In order to strengthen the pharmacologically active of puerarin, Wang Jing etc.; The structure of modification of puerarin and pharmacology activity research [D]. China Medicine University's master thesis, 2003,5; Synthesized 17 derivatives, carried out preliminary pharmacological tests research to synthesized compound, carried out oil and water zonation research to synthesized compound, result shows simultaneously, and the solubleness, oil and water zonation etc. of derivative all improve.
As can be seen here, puerarin is strong as a kind of pharmacologically active, and drug effect is clear and definite, and clinical application has the medicine of development prospect widely, carries out modification transformation to improve its water-soluble grease dissolubility, strengthen its pharmacologically active to become the focus of investigators to its structure.
Summary of the invention
Improving water-soluble and fat-soluble by modifying puerarin, strengthen its pharmacologically active, but its selectivity is not high, give prominence to it to the pharmacological action of specified disease, and indefinite to the screening of its pharmacologically active.
Although the technical problem to be solved in the present invention is prior art, to improve puerarin by modification water-soluble and fat-soluble but not high to its pharmacological action target spot selectivity; And provide puerarin derivate and synthetic method thereof and application.
For solving the problem, the following logical formula I of puerarin derivate of the present invention represents:
(I), wherein R 1for hydrogen, cyano group, sub-cyano group, ethyl acetate base or acetamido, R 2for hydrogen, cyano group, sub-cyano group, ethyl acetate base or acetamido, R 1, R 2be asynchronously hydrogen.
When puerarin derivate following structural formula (II) or structure formula III represent:
(III), its synthetic method is carried out in the steps below:
Be dissolved in by 36mmol puerarin in the dehydrated alcohol of 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 60 ~ 90min, add 216mmol chloromethyl cyanide, stirring at room temperature 10 ~ 12h, filter (removing solid insoluble), revolve and be steamed into oily, grind with solvent orange 2 A, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, then use elutriant that methylene dichloride (DCM) and methyl alcohol (MeOH) volume ratio are 40:1 to 15:1 to carry out silica gel column chromatography to be separated and to obtain structure formula II puerarin derivate, carry out silica gel column chromatography with methylene dichloride (DCM) and the elutriant of methyl alcohol (MeOH) volume ratio 15:1 to 10:1 to be separated and to obtain structure formula III puerarin derivate.
When puerarin derivate following structural formula (IV) or structural formula (V) represent:
(V), its synthetic method is carried out in the steps below:
Be dissolved in by 36mmol puerarin in the dehydrated alcohol of 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 30 ~ 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter (removing solid insoluble), revolve and be steamed into oily, grind with solvent orange 2 A, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, then use elutriant that methylene dichloride (DCM) and methyl alcohol (MeOH) volume ratio are 40:1 to 15:1 to carry out silica gel column chromatography to be separated and to obtain structural formula (V) puerarin derivate, carry out silica gel column chromatography with the elutriant that methylene dichloride (DCM) and methyl alcohol (MeOH) volume ratio are 15:1 ~ 10:1 to be separated and to obtain structure formula IV puerarin derivate.
When puerarin derivate following structural formula (VI) represents:
(VI), its synthetic method is carried out in the steps below:
The synthetic method of puerarin derivate is carried out in the steps below:
In step one, dehydrated alcohol 36mmol puerarin being dissolved in 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 30 ~ 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter, revolve and be steamed into oily, with solvent orange 2 A grinding, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 40:1 ~ 15:1 and be separated and obtain structural formula (V) puerarin derivate;
It is in the ammonia methanol solution of 7mol/L that step 2, structural formula (V) puerarin derivate 15mmol step one obtained add 100mL concentration, stirring at room temperature 10 ~ 12h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structure formula VI puerarin derivate, light yellow solid.
When puerarin derivate following structural formula (VI) or structural formula (VII) represent:
(VII), its synthetic method is carried out in the steps below: the synthetic method of puerarin derivate is carried out in the steps below:
In step one, dehydrated alcohol 36mmol puerarin being dissolved in 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 30 ~ 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter, revolve and be steamed into oily, with solvent orange 2 A grinding, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 15:1 ~ 10:1 and be separated and obtain structure formula IV puerarin derivate;
It is in the ammonia methanol solution of 7mol/L that step 2, structure formula IV puerarin derivate 15mmol step one obtained add 100mL concentration, stirring at room temperature 10 ~ 12h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structural formula (VII) puerarin derivate, light yellow solid.
The application of above-mentioned puerarin derivate treatment vascular dementia.
The present invention is 7 of puerarin, functional group is introduced in 4 ' position, effectively can suppress the crucial enzyme in Onset of Vascular Dementia process, improve puerarin fat-soluble and while, improve its selectivity to acceptor, osmotic pressure inside and outside balance brain cell, improve the edema because inflammation damnification causes thus outstanding puerarin self improves microcirculation, improve the pharmacological action of cholinergic nerve system function, improve the learning memory disorder caused by ischemia-reperfusion damage.The present invention had both retained the superiority of original natural drug at the derivative of puerarin, turn improved its selectivity to vascular dementia therapy target, had certain prospect in medicine and commercial value.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of structure formula II puerarin derivate; Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of structure formula III puerarin derivate; Fig. 3 is Jumping test result figure; Fig. 4 is biochemical test (SOD) result figure; Fig. 5 is the hydrogen nuclear magnetic resonance spectrogram of structural formula (V) puerarin derivate; Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of structure formula IV puerarin derivate; Fig. 7 is the cellular form figure under the biomicroscope of control group; Fig. 8 is the cellular form figure under the biomicroscope of L-glutamic acid; Fig. 9 is the cellular form figure under the biomicroscope of structure formula VI puerarin derivate; Figure 10 is the cellular form figure under the biomicroscope of puerarin injection.
Wherein in Fig. 3, P1-25, P1-100 are respectively the 25mg/kg of structure formula II puerarin derivate, 100mg/kg; P2-25, P2-100 are respectively the 25mg/kg of structure formula III puerarin derivate, 100mg/kg; Puerarin 100mg/kg; #p<0.05 is compared with sham-operation; * p<0.05 is compared with model group; N=10.In Fig. 4, P1-25, P1-100 are respectively the 25mg/kg of structure formula II puerarin derivate, 100mg/kg; p2-100 is respectively the 25mg/kg of structure formula III puerarin derivate, 100mg/kg; Puerarin 100mg/kg.
Embodiment
Embodiment one: in present embodiment, the following logical formula I of puerarin derivate represents:
(I), wherein R 1for hydrogen, cyano group, sub-cyano group, ethyl acetate base or acetamido, R 2for hydrogen, cyano group, sub-cyano group, ethyl acetate base or acetamido, R 1, R 2be asynchronously hydrogen.
Puerarin derivate described in present embodiment is mainly made by chemical synthesis process such as addition reactions.
Puerarin derivate treatment vascular dementia application described in present embodiment.
Embodiment two: present embodiment puerarin derivate following structural formula (II) represents:
(II), its synthetic method is carried out in the steps below:
Be dissolved in the dehydrated alcohol of 200mL by 36mmol puerarin, room temperature adds 216.3mmolK 2cO 3stir 80min, add 216mmol chloromethyl cyanide, stirring at room temperature 10h, filter (removing solid insoluble), revolve and be steamed into oily, with anhydrous diethyl ether grinding, topple over and fall anhydrous diethyl ether, be spin-dried for, dissolve with anhydrous methanol, then carry out silica gel column chromatography with the elutriant being 40:1 ~ 15:1 by methylene dichloride and methyl alcohol volume ratio and be separated and obtain structure formula II puerarin derivate.
Puerarin derivate treatment vascular dementia application described in present embodiment.
The hydrogen nuclear magnetic resonance spectrogram of structure formula II puerarin derivate is shown in Fig. 1, M+H495.1H-NMR (300MHz, DMSO) δ: 8.56 (1H, d, J=5.4Hz), 8.18 (1H, dd, J=9.0Hz, J=2.7Hz) 7.62 (1H, m), 7.37 (1H, m), 7.15 (2H, dd, J=9.0Hz, J=2.1Hz), 5.38 (1H, s), 5.28 (1H, s), 5.23 (2H, s), 5.06 (1H, d, J=39Hz), 4.76-5.02 (3H, m), 4.45 (1H, m), 4.08 (1H, m), 3.74 (1H, m), 3.43 (1H, m), 3.24-3.28 (3H, m). containing methanol solvate peak in sample, 3.16, 4.01.
Embodiment three: present embodiment puerarin derivate following structural formula (III) represents:
(III), its synthetic method is carried out in the steps below:
36mmol puerarin is dissolved in the dry DMF of 200mL, room temperature adds 216.3mmolNaOH, stirs 60min, adds 216mmol chloromethyl cyanide, stirring at room temperature 10h, filter (removing solid insoluble), revolve and be steamed into oily, grind with anhydrous propanone, topple over and fall solvent anhydrous propanone, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with methylene dichloride and the elutriant of methyl alcohol volume ratio 15:1 ~ 10:1 and be separated and obtain structure formula III puerarin derivate.
Puerarin derivate treatment vascular dementia application described in present embodiment.
The hydrogen nuclear magnetic resonance spectrogram of structure formula III puerarin derivate is shown in Fig. 2, M+H457.1H-NMR (300MHz, DMSO) δ: 9.56 (1H, d, J=4.2Hz), 8.46 (1H, d, J=7.5Hz), 8.16 (1H, dd, J=9.0Hz, J=2.4Hz) 7.41 (2H, dd, J=8.7Hz, J=3.3Hz), 7.32-7.37 (1H, m), 6.81 (2H, dd, J=8.4Hz, J=1.8Hz), 5.37 (1H, s), 5.27 (1H, s), 4.75-5.06 (4H, m), 4.04 (1H, m), 3.74 (1H, m), 3.42 (1H, m), 3.14-3.24 (3H, m). containing ethyl acetate solvent peak in sample, 4.00 (~ 0.56, 2H, q), 2.00 (0.88, 3H, s), 1.17 (0.89, 3H, t)
Embodiment two and three, by introducing cyano group in puerarin derivate, while stablizing original Structures of Natural Products, improves microcirculation and K +channel blocking effect, by regulating intraor extracellular osmotic pressure to improve the edema caused by ischemic brain injury, thus improves learning and memory function to antibody Monoclonal.
The lipid of structure formula II puerarin derivate is 0.41, and the lipid of fusing point 170.5 DEG C of structure formula III puerarin derivates is 0.52, fusing point 140.8 DEG C
The fat-soluble puerarin that is better than of structure formula III puerarin derivate more easily passes through hemato encephalic barrier.AutoDock4.2 is passed through in selectivity experiment, the medicine target acetylcholinesterase (AchE) for the treatment of VD, its periphery negatively charged ion (PAS) point is relevant to VD pathogenic process, at puerarin 7,4 ' upper introducing can suppress AchE active as part with the group of PAS effect, evaluate through the marking of SYBYL/CScore consistence and semiempirical free energy evaluation function XSCORE, described in embodiment two and three, puerarin derivate has therapeutic action to vascular dementia.
Experimentation on animals to vascular dementia therapeutic action:
Adopt mouse bilateral ligation re-perfusion model, by Behaviors survey and biochemical test, investigate compound to the change of (cortex, hippocampus) SOD vigor in the learning and memory improvement result of ischemia-reperfusion damage model mice and brain, thus evaluate the therapeutic action of new compound antagonism ischemical reperfusion injury.
Experiment in vivo has investigated the improvement result of puerarin derivate to repeated cerebral ischemia-reperfusion memory dysfunction using puerarin as positive control.The impact of puerarin derivate on learning memory disorder caused by mouse repeated cerebral ischemia-reperfusion has been investigated by Behaviors survey methods such as Y labyrinth, water maze, diving towers; SOD vigor in mouse cortex is detected with biochemistry method.Data statistic analysis adopts SPSS15.0, and carry out one-way analysis of variance to all data, P<0.05 is for having significant difference.Wherein Jumping test structure formula III puerarin derivate 100mg/kg significantly increases (p<0.05, n=10) latent period, and errors number according to dosage dependency reduces.(as Fig. 3) chemical result is pointed out; Structure formula III puerarin derivate 100mg/kg effectively can increase SOD vigor (as Fig. 4).
Embodiment four: in present embodiment, puerarin derivate following structural formula (IV) represents:
(IV), its synthetic method is carried out in the steps below:
Be dissolved in the anhydrous methanol of 200mL by 36mmol puerarin, room temperature adds 216.3mmolK 2cO 3stir 30min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter (removing solid insoluble), revolve and be steamed into oily, with solvent orange 2 A grinding, described solvent orange 2 A is anhydrous diethyl ether, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, then carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 15:1 ~ 10:1 and be separated and obtain structure formula IV puerarin derivate.
Puerarin derivate treatment vascular dementia application described in present embodiment.
Embodiment five: in present embodiment, puerarin derivate following structural formula (V) represents:
(V), its synthetic method is carried out in the steps below:
36mmol puerarin is dissolved in the dehydrated alcohol of 200mL, room temperature adds 216.3mmolNaOH, stirs 30 ~ 90min, adds 216mmol ethyl bromoacetate, stirring at room temperature 4h, filter (removing solid insoluble), revolve and be steamed into oily, grind with anhydrous diethyl ether, topple over and fall anhydrous diethyl ether, be spin-dried for, dissolve with anhydrous methanol, then carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 40:1 ~ 15:1 and be separated and obtain structural formula (V) puerarin derivate.
Puerarin derivate treatment vascular dementia application described in present embodiment.
Embodiment six: the following structural formula (VI) of the puerarin derivate in present embodiment represents:
(VI), its synthetic method is carried out in the steps below:
The synthetic method of puerarin derivate is carried out in the steps below:
Step one, be dissolved in the dehydrated alcohol of 200mL by 36mmol puerarin, room temperature adds 216.3mmolK 2cO 3stir 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 4h, filter (removing solid insoluble), revolve and be steamed into oily, with anhydrous diethyl ether grinding, topple over and fall solvent anhydrous diethyl ether, be spin-dried for, dissolving with anhydrous methanol, is that 40:1 ~ 15:1 carries out silica gel column chromatography and is separated and obtains structural formula (V) puerarin derivate by methylene dichloride (DCM) and methyl alcohol (MeOH) volume ratio;
It is in the ammonia methanol solution of 7mol/L that step 2, structural formula (V) puerarin derivate 15mmol step one obtained add 100mL concentration, stirring at room temperature 10h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structure formula VI puerarin derivate, light yellow solid.
Puerarin derivate treatment vascular dementia application described in present embodiment.
Embodiment seven: the puerarin derivate in present embodiment following structural formula (VI) or structural formula (VII) represent:
(VII), its synthetic method is carried out in the steps below: the synthetic method of puerarin derivate is carried out in the steps below:
Step one, be dissolved in the dehydrated alcohol of 200mL by 36mmol puerarin, room temperature adds 216.3mmolK 2cO 3stir 40min, add 216mmol ethyl bromoacetate, stirring at room temperature 3h, filter (removing solid insoluble), revolve and be steamed into oily, with anhydrous diethyl ether grinding, topple over and fall anhydrous diethyl ether, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 15:1 ~ 10:1 and be separated and obtain structural formula (V) puerarin derivate;
It is in the ammonia methanol solution of 7mol/L that step 2, structural formula (V) puerarin derivate 15mmol step one obtained add 100mL concentration, stirred overnight at room temperature 12h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structural formula (VII) puerarin derivate, light yellow solid.
Puerarin derivate treatment vascular dementia application described in present embodiment.
The puerarin derivate of embodiment four to seven introduces ethyl acetate base and kharophen respectively, with isoflavones Structure composing ketenes formula cyclooxygenase (COX-2) inhibitor structure of original natural product, kharophen also has the effect of activation cholinergic nerve system function, more contributes to the treatment of vascular dementia.
The lipid of structure formula IV puerarin derivate is 0.27, fusing point 140.5 DEG C; The lipid of structural formula (V) puerarin derivate is 0.31, fusing point 139.8 DEG C; The lipid of structure formula VI puerarin derivate is 0.49, fusing point 184.1 DEG C; The lipid of structural formula (VII) puerarin derivate is 0.43, fusing point 181.3 DEG C; Wherein structural formula (V) and structure formula VI puerarin derivate have more lipotropy, easily through hemato encephalic barrier; Structure formula IV puerarin derivate is water-soluble is better than puerarin.AutoDock4.2 is passed through in selectivity experiment, according to the medicine target COX-2 (COX-2) of to treat VD according to research reports, COX 120 of passage side have a polarity comparatively large, arginine (Arg) residue of hydrogen bonded can be set up with drug molecule; At 523 of passage opposite side, COX-1 has different leucin residue (Ile), COX-2's is then the valine residue (Val) that molecule is larger, therefore one can be formed on the side of COX-2 and the side pocket of covalent bonds can be formed with drug molecule, and the Arg of 513 is better, therefore easier with the effect in COX-2 site than Histidine (His) snappiness of 513 of COX-1 bottom COX-2 side pocket.Computer is utilized to carry out virtual screening to cox 2 inhibitor, filter out candidate compound on a molecular scale, evaluate through the marking of SYBYL/CScore consistence and semiempirical free energy evaluation function XSCORE, described in embodiment four, five, six and seven, puerarin derivate contributes to the treatment of vascular dementia.
The experiment of following Pharmacological Activity Screening is the laboratory experiment to vascular dementia done for above 4 kinds of compounds, adopt mtt assay, investigate new compound causes the PC12 cells survival rate of damage impact on L-glutamic acid, the effect of its anti-nerve cell apoptosis of preliminary assessment.
External activity the selection result is pointed out, ischemical reperfusion injury in application glutamate induction apoptosis mode analogue body, adopt mtt assay, take puerarin injection as positive control, investigate puerarin derivate structure formula IV puerarin derivate, structural formula (V) puerarin derivate, structure formula VI puerarin derivate, structural formula (VII) puerarin derivate is 10 μm of ol/L at dosage, on the impact of the PC12 cells survival rate of L-glutamic acid 170mmol/L induced damage during 40 μm of ol/L and 100 μm of ol/L, data analysis adopts SPSS15.0, all data are checked through one-way analysis of variance and Student ' st, P<0.05 is for having significance.Experimental result as Fig. 7,8, shown in 9 and 10, compared with model group (Fig. 7), puerarin derivate structure formula VI puerarin derivate cells survival rate is 71.4% (P<0.05), and higher than puerarin injection group 68.7%, Microscopic observation cellular form, structure formula VI puerarin derivate group significantly can reduce the cell shrinkage that Glu-induced Injury causes, cellular form is intact adherent, projection is longer, is mutually crossed as netted.

Claims (7)

1. puerarin derivate, is characterized in that puerarin derivate following structural formula (II) or structure formula III represent:
2. puerarin derivate, is characterized in that puerarin derivate following structural formula (VI) represents:
3. puerarin derivate, is characterized in that puerarin derivate following structural formula (VII) represents:
4. the synthetic method of puerarin derivate according to claim 1, is characterized in that the synthetic method of puerarin derivate is carried out in the steps below:
Be dissolved in by 36mmol puerarin in the dehydrated alcohol of 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 60 ~ 90min, add 216mmol chloromethyl cyanide, stirring at room temperature 10 ~ 12h, filter, revolve and be steamed into oily, grind with solvent orange 2 A, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, then carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 40:1 ~ 15:1 to be separated and to obtain structure formula II puerarin derivate, carry out silica gel column chromatography with methylene dichloride and the elutriant of methyl alcohol volume ratio 15:1 ~ 10:1 and be separated and obtain structure formula III puerarin derivate.
5. the synthetic method of puerarin derivate according to claim 2, is characterized in that the synthetic method of puerarin derivate is carried out in the steps below:
In step one, dehydrated alcohol 36mmol puerarin being dissolved in 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 30 ~ 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter, revolve and be steamed into oily, with solvent orange 2 A grinding, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 40:1 ~ 15:1 and be separated and obtain structural formula (V) puerarin derivate;
It is in the ammonia methanol solution of 7mol/L that step 2, structural formula (V) puerarin derivate 15mmol step one obtained add 100mL concentration, stirring at room temperature 10 ~ 12h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structure formula VI puerarin derivate;
Wherein, the concrete structure of structural formula (V) puerarin derivate is as follows:
6. the synthetic method of puerarin derivate according to claim 3, is characterized in that the synthetic method of puerarin derivate is carried out in the steps below:
In step one, dehydrated alcohol 36mmol puerarin being dissolved in 200mL, anhydrous methanol or dry DMF, room temperature adds 216.3mmolK 2cO 3or NaOH, stir 30 ~ 90min, add 216mmol ethyl bromoacetate, stirring at room temperature 3 ~ 4h, filter, revolve and be steamed into oily, with solvent orange 2 A grinding, described solvent orange 2 A is anhydrous diethyl ether or acetone, topple over and fall solvent orange 2 A, be spin-dried for, dissolve with anhydrous methanol, carry out silica gel column chromatography with the elutriant that methylene dichloride and methyl alcohol volume ratio are 15:1 ~ 10:1 and be separated and obtain structure formula IV puerarin derivate;
It is in the ammonia methanol solution of 7mol/L that step 2, structure formula IV puerarin derivate 15mmol step one obtained add 100mL concentration, stirring at room temperature 10 ~ 12h, a large amount of solid is separated out in solution, filter, wash with ethanol, obtain structural formula (VII) puerarin derivate;
Wherein, the concrete structure of structure formula IV puerarin derivate is as follows:
7. the application of puerarin derivate in preparation treatment vascular dementia medicine as described in claim 1,2 or 3.
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