CN101104612A - Flavonol beta-secretase inhibitor in ginkgo leaf standard extract, extracting method and use thereof - Google Patents
Flavonol beta-secretase inhibitor in ginkgo leaf standard extract, extracting method and use thereof Download PDFInfo
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- CN101104612A CN101104612A CNA2006100288264A CN200610028826A CN101104612A CN 101104612 A CN101104612 A CN 101104612A CN A2006100288264 A CNA2006100288264 A CN A2006100288264A CN 200610028826 A CN200610028826 A CN 200610028826A CN 101104612 A CN101104612 A CN 101104612A
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Abstract
The present invention discloses a novel flavonol beta-secretory enzyme inhibitor with a structure shown in the following general formula, wherein, R1, R2, R3 are respectively and independently H, -OH or -OCH3. The invention also discloses drugs which take the beta-secretory enzyme inhibitor as active ingredients; the drugs can be used for the treatment of senile dementia.
Description
Technical field
The present invention relates to a kind of biotechnological formulation, be specifically related to the Flavonol beta-secretase inhibitor in a kind of ginkgo leaf standard extract.This beta-secretase inhibitor can be used for treating senile dementia (Alzherimer ' s Disease, AD).
Background technology
China faces the severe challenge of aging population at present, the whole nation in 2000 more than 60 years old population be about 2.7 hundred million, expect the middle of this century and will reach 4.1 hundred million.And epidemiological study finds that the sickness rate of the crowd person in middle and old age dementia above 65 years old is exponential form and increases; Country's " 95 " tackling of key scientific and technical problems problem " senile dementia and Parkinson's disease epidemiological study " shows: at present, the over-65s old man's of Beijing senium morbidity is 7.3%, wherein the morbidity every the age bracket senile dementia in 5 years increases about one times, as 70 years old morbidity was 5.3%, when being 11%, 80 years old in 75 years old up to 22%; Enter the Shanghai of aging society already, the number of patients of senile dementia also day by day increases.In the U.S., alzheimer's disease (AD) causes 100 000 people's death every year at least, is the 4th major causes of death that is only second to heart trouble, cancer, apoplexy.It also is the common cause that causes the elderly dementia.This illness is a feature with gradual cognitive ability forfeiture and personality change.Common sympton has the recent memory obstacle, usually with language, visual space and attention problem.After making a definite diagnosis AD, about 8 years of mean survival time, death is sent out due to the disease between often being.The same with other degenerative disorders, senile dementia is except the infringement to patient health, its treatment all can produce huge social and economic impact with nursing to patient, family and even entire society, single with regard to the U.S., the associated cost of annual flower on curing senile dementia estimated up to 1,000 hundred million dollars of (Milligan C.E., Nat.Med., 2000,6:385).And along with the increase of aging population degree, this trend also can obviously increase.
Senile dementia can be divided into three kinds of cerebrovascular property (VD), Alzheimer's disease (AD) and mixed types (BD).Wherein AD is a kind of systemic disease of complexity, and is also more about its achievement in research.Alzheimer's disease (AD) is commonly called as senile dementia, is able-bodied a kind of neural system degenerative disorders (Vassar, R. etc., Science, 1999,286:735-741 of current social serious harm the elderly; Wouter, B. etc., Protein Expression and Purification, 2002,26:139-148.).The europathology feature of AD be cortex have the disappearance of axon cell widely, a large amount of senile plaque and neurofibrillary tangles accumulation (Vassar, R. etc., J.Biol.Chem., 2000,275:37712-37717.).The cortex atrophy occurring on big brain morphology, with neurofibrillary tangles and senile plaque, the onset of hiding, the course of disease are carries out sexual development, cause at last dementia (Yan, R. etc., Nature., 1999,402:533-537.).Hypophrenia with slow appearance is a main clinical characteristics, comprises going down and personality change in various degree of functions such as memory, thinking, understanding, judgement, calculating, but do not have the disturbance of consciousness (Sinha, S. etc., Nature, 1999,402:537-540.).
At present, all treatments of senile dementia are according to its nosetiology hypothesis and take, and still do not have special efficacy, can end or reverse the therapy of progression of disease, so be symptomatic treatment.The treatment means of mainly taking in the world at present is as follows:
1. replenish the cholinergic neuron insufficiency of function
2. nerve growth factor (NGF) toughener is protected basal forebrain choline neurone
3. oestrogenic hormon
4. amyloid beta enzyme inhibitors
5. anti-inflammatory drug
6. neuropeptide systemic effect medicine
7. antioxidant
8. improve cerebral circulation and brain metabolism
9. calcium ion antagonist
10. act on agonist with excitatory amino acid receptor
The AD medicine continues to bring out since the nineties in 20th century, the medicine that commercially available some are used for the treatment of AD can only be alleviated some symptoms of AD mostly, temporarily improve patient's AD memory and attention (Kahana, J. etc., Trends Cell Biol., 2001,11:192.), as use some second Pseudocholinesterase (acetylcholinesterase, AchE) inhibitor such as selagine (Huperzine A), can reverse study, the memory impairment of choline function damage animal, and minority senile dementia patient's symptom is had some improvement.Yet because the mechanism of senile dementia morbidity is extremely complicated, these medicines that use can not fundamentally improve morbid state at present, so recent research focuses mostly on and seeking the target spot of new gene as new drug research from molecular biological angle.Wherein Secretases (secretase) is exactly recent focus (Selkoe, D.J., Science, 1997, a 275:630-1 aspect senile dementia research; Hardy, J., Proc.Natl.Acad.Sci.U.S.A., 1997,94:2095-7; Schenk, D. etc., Nature, 1999,400:173-177; Morgan, D., etc., Nature, 2000,408:982-985.).Therefore, up to the present, the clinical treatment of AD remains a global problem of demanding urgently breaking through.
Nearest scientific payoffs shows that the patient who suffers from AD causes that dull-witted reason is because the death of the neuronal cell that causes because of high-caliber " old plate " and " nerve fiber disorder " in the human brain zone." the unusual generation and the deposition of amyloid-beta (A β) " thinks to cause neuronal damage and the one of the main reasons of losing.Result of study shows that the deposition of A β in the brain is the pathogenetic key point of AD.
A β is formed by β and gamma-secretase catalytic hydrolysis by starch precursor protein APP (Amyloid precursor protein).A β contains 39-42 amino-acid residue, and according to the length of amino-acid residue, A β can be divided into A β
40With A β
42Result of study shows A β
42Generation be the early stage the most key factor of AD morbidity.Early stage in the AD morbidity, A β
42Excessive generation meeting directly cause stacked on its pathology, and excessive A β
42Be difficult to be eliminated, thus under the effect of some agglomerative factors A β
42Can deposit.The relation of A β and dementia as shown in Figure 1.
The precursor protein APP of A β is the macromole that contains about 700 amino-acid residues, it moves to cell surface by Secretory Pathway and shifts to endosome again, in shifting to the process of cell surface, two different proteolytic enzyme, alpha-secretase enzyme and beta-secretase cut the different sites of APP respectively to play catalytic hydrolysis effect (Fiona, G.L. wait J.Biol.Chem., 2002,277:4687-4693.).The catalytic hydrolysis of APP can carry out along two main paties: alpha-secretase enzymatic pathway and beta-secretase approach.In the alpha-secretase enzymatic pathway, the alpha-secretase enzyme becomes the APP fragment α-APPs and the C83 peptide of solubility with the APP catalytic hydrolysis, and the latter is metabolised to p3 under the effect of gamma-secretase
40And p3
42(William, D. etc., Mol Pharmacol, 2001,59:619-626.).In the beta-secretase approach, beta-secretase becomes the APP fragment β-APPs and the C99 peptide of solubility with the APP catalytic hydrolysis, and the latter then is metabolised to A β under the effect of gamma-secretase
40With A β
42(Vinod S. etc., ProteinExpression and Purification, 2004,34:190-196.), as shown in Figure 2.This shows that the inhibitor of beta-secretase can suppress the generation of β-APPs and C99; Inhibitors of gamma-secretase can suppress the generation of p3 and A β, suppresses the activity of β and gamma-secretase fully and can all control the generation of A β to reach the purpose of treatment AD.
Beta-secretase in people's brain cell is that an I type is striden diaphragm area albumen, and it contains 1 N-terminal propetide, 2 activation site and 3 intramolecular disulfide linkage (Anja that are made up of asparagicacid residue, C. etc., J.Biol.Chem., 2002,277:5637-5643.).Beta-secretase and beta-secretase the-the 2nd, unique known symphysis aspartate protease at present.Beta-secretase albumen by signal peptide, precursor, maturing enzyme, stride the film district and cytoplasmic region constitute (Regina, F. etc., J.Biol.Chem., 2003,278:5531-5538.).Up to now, understand that not as beta-secretase this gives gamma-secretase is that medicinal design and the screening operation that target spot carried out brings many unfavorable factors about the structure and the characteristic of gamma-secretase.Over the past two years, some beta-secretase inhibitors that with the beta-secretase are target spot were by design was synthetic in succession, and the achievement that this institute obtains provides very important theory clue for the exploitation of the newtype drug of treatment AD.Yet although these compounds are inhibitor of beta-secretase, its complex structure, molecule are huge, have limited the further exploration of their pharmaceutical use.
As previously mentioned, because the vital role that A β is risen in the senile dementia pathogenic process, so by the inhibition to beta-secretase (BACE) and gamma-secretase, the generation that reduces or partly reduce A β should stop the further deterioration of the senile dementia state of an illness.This viewpoint is confirmed by newest research results, the Ribert Vassar research group of the Donald Price research group of Johns Hopkins University and medical college of Northwest University successfully obtains the beta-secretase knock out mice respectively, no matter be that this mouse or the neurocyte that derives from this mouse all can not produce A β (Luo, Y., Deng, Nature Neurosci., 4:231-232; Cai, H., etc., NatureNeurosci., 4:233-234.).And this mouse is healthy, fecundity is arranged, and from anatomy, histology, hematology and clinical chemistry angle analysis, also all is normal.Therefore, beta-secretase has clearly become a novel targets of treatment senile dementia, the not only effective but also safety to its inhibition.At present, its specific inhibitor is being sought by external many big drugmakers and research institution.
Up to the present the beta-secretase inhibitor of bibliographical information only is confined to some and contains 7-8 amino acid whose peptide class, peptide compounds and some heterogeneous ring compound (Takede Chemical Industries Ltds, PCT/JP01/04144), for example based on the inhibitor OM99-1 (1) of beta-secretase to the transition state design of APP hydrolysis, OM99-2 (2) and 3 (Ghosh, A.K., Deng, J.Am.Chem.Soc., 2000,122:3522.) (as shown in the formula expression), these provide opportunity for we seek the non-peptide class of new small molecules organic compound from herbal medicine as beta-secretase inhibitor undoubtedly.
Semen Ginkgo extrac starts from 1986 to the clinical study report of early and middle portion AD and MID (vascular dementia), existing so far many pieces of summaries.Ernst has summed up the clinical position of GBE in the past in 1998 in detail, uses EGb761 for 7 in 9 researchs, uses LI1370 for 2; There is 1 year observing time, 24 weeks, 12 weeks, 6 weeks, do not wait in 4 weeks; Dosage 120-240mg every day does not wait.Add up substantially, 2/3 experiment is taken medicine to organize and is significantly improved than control group.Think that most of testing data supports GBE that dull-witted patient is postponed clinical symptom and worsen or improve syndrome certain effect is arranged.
The chemical ingredients of Ginkgo Leaf has been studied more clearlyly, and certified chemical ingredients has kind more than 200.Its main component is flavonoid glycoside and lactone.The content of this two constituents has also become the quality index composition of ginkgo leaf standard extract.Folium Ginkgo extract is by the have some improvement symptom of senile dementia of clinical and pharmacological evaluation proof tool, also there is research to relate to relevant (Colciaghi F. etc. with the activity of secretion inhibitor enzyme, Neurobiology of disease, 2004,16:454-460), but do not see which kind of composition is the inhibitor of beta-secretase.According to the metabolism research of flavonoid glycoside compound, absorbed composition mainly is flavonols composition and and carboxylic-acid degraded composition.So we to standard extract carry out acid hydrolysis, column chromatography has extracted 4 main flavonols compositions: Quercetin, kaempferol, Isorhamnetol and 5 '-hydroxyl Quercetin; The direct column chromatography of standard extract has prepared Ginkgolide A, B, C and bilobalide.Then 8 compounds that obtain have been carried out external beta-secretase and suppressed active testing, found that ginkgolic flavone glycoside alcohol constituents is strong beta-secretase inhibitor, and then finished the present invention.
Summary of the invention
The object of the invention provides a kind of ginkgo leaf standard extract acid hydrolysis products flavonols compound that can be used as beta-secretase inhibitor.
Another object of the present invention provides the extracting method of this beta-secretase inhibitor.
A further object of the present invention provides this beta-secretase inhibitor and is used for the treatment of application in the senile dementia disease drug in preparation.
A further object of the present invention provides a kind of medicine that comprises this beta-secretase inhibitor as active substance.
The invention has the advantages that the flavonols compound that the present invention extracts is the beta-secretase inhibitor of a class brand new, compare that they are the hydrolysates that derive from natural product with present known beta-secretase inhibitor.In the screening process, the contriver finds that ginkgolic flavone glycoside alcohols chemical combination shows the activity that suppresses beta-secretase preferably.
Flavone alcohol aglycon beta-secretase inhibitor of the present invention has following structure:
R wherein
1, R
2And R
3Respectively be independently H ,-OH or-OCH
3
The compound that the present invention obtains is four compounds with following formula.They are followed successively by Quercetin through the spectral data analytical proof, Isorhamnetol, and kaempferol, 5-hydroxyl Quercetin:
Wherein, Quercetin: R
1=OH, R
2=H;
Isorhamnetol: R
1=OCH
3, R
2=H;
Kaempferol: R
1=R
2=H; With
5 '-hydroxyl Quercetin: R
1=R
2=OH.
The extracting method of compound of the present invention is as follows:
The standard ethanol extraction of Ginkgo Leaf is dissolved with amount of methanol earlier, add 2% H then
2SO4 aqueous solution reflux 1 hour, after the cooling, concentrating under reduced pressure obtains not having alcohol mixture, uses chloroform and water dispenser then, obtains the chloroform phase.After chloroform concentrates mutually,, obtain Quercetin, Isorhamnetol, kaempferol and 5 ' hydroxyl Quercetin with 1: 1 chloroform-methanol wash-out with going up the dextran chromatography column behind the minimum of chloroform dissolve with methanol.Though ginkgolic flavone glycoside glycosides kind is a lot, their aglycon is essentially these 4 kinds.After acid hydrolysis, column chromatography is very easy to obtain them.
Beta-secretase inhibitor compound of the present invention can be used for preparing the medicine of treatment senile dementia illness.
Said medicine can also comprise other auxiliary agents as vehicle etc. except comprising the beta-secretase inhibitor of the present invention as active substance, the selection of auxiliary agent is common practise for ability in the technician.
Description of drawings
Fig. 1 represents the unusual generation of amyloid-beta (A β) and the relation of deposition and senile dementia;
Fig. 2 is the hydrolysis approach synoptic diagram of APP;
Fig. 3 surveys the principle schematic of living for beta-secretase.
Embodiment
The present invention is further elaborated below in conjunction with concrete embodiment, but do not limit the present invention.
1H-NMR measures with Varian Mercury AMX300 type instrument; MS measures with VG ZAB-HS or VG-7070 type instrument, is EI source (70ev) except that indicating; The purifying of product all uses the column chromatography of silica gel (200-300mesh) except that explanation; Employed silica gel comprises 200-300 order and GF
254Be Haiyang Chemical Plant, Qingdao or the production of the rich silica gel company of Yantai edge.
The extraction of 1: four kind of beta-secretase inhibitor compound of embodiment
With Ginkgo Leaf 2.0kg, behind 5L alcohol immersion 72h, filter out filtrate.Filter residue adds 5L ethanol and refluxes 3 times down at 64 ℃～65 ℃, and each 45min has wherein refluxed at every turn, is cooled to room temperature, filters filtrate, and the ethanol that filter residue adds equal volume continues reflux (it is more complete in order to extract doing like this).Merge all extracting solutions and standing over night.Decant, suction filtration, filtrate is condensed into Vandyke brown thick paste (500mL), be dispersed in the 2 L water, with sherwood oil (volume ratio=1: 1) extraction 4 times, extraction liquid dry paste.The paste dissolve with ethanol of 200mL 95%, suction filtration is removed insolubles, gets reddish-brown filtrate, and refrigeration is spent the night.Suction filtration is removed insolubles once more, with the filtrate decompression evaporate to dryness.Medicinal extract dissolves with amount of methanol, adds 2% H then
2SO
4Aqueous solution reflux 1 hour, after the cooling, concentrating under reduced pressure obtains not having alcohol mixture, uses chloroform and water dispenser then, obtains the chloroform phase.Chloroform with separating with the dextran chromatography column behind the minimum of chloroform dissolve with methanol, obtains four kinds of compounds with 1: 1 chloroform-methanol wash-out after concentrating mutually, and they are followed successively by Quercetin through the spectral data analytical proof, Isorhamnetol, kaempferol, 5 '-hydroxyl Quercetin.
Their spectral data is as follows:
Quercetin: yellow crystal, C
15H
10O
7Mp 313-314 °; UV (EtOH) λ
Max(log ε): 258 (4.32), 375 (4.32) nm;
1H NMR (CDCl
3, 300MHz) (δ): 6.19 (1H, d, J=1.8Hz, 6-H), 6.37 (1H, s, 8-H), 7.52 (1H, d, J=2.1Hz, 2 '-H), 6.89 (1H, d, J=8.4Hz, 5 '-H), 7.48 (1H, dd, J=8.4,1.6Hz, 6 '-H);
13C NMR (CDCl
3, 75.0MHz) δ: 146.9 (C-2), 135.8 (C-3), 175.9 (C-4), 156.2 (C-5), 98.3 (C-6), 164.0 (C-7), 93.5 (C-8), 160.8 (C-9), 103.1 (C-10), 122.1 (C-1), 115.2 (C-2), 145.1 (C-3), 147.7 (C-4), 115.7 (C-5), 120.1 (C-6).
Kaempferol: yellow needle, C
15H
10O
6Mp 276-278 °; UV (EtOH) λ
Max: 265,365nm;
1H NMR (CDCl
3, 300 MHz) (δ) 6.17 (1H, d, J=1.8Hz, 6-H), 6.36 (1H, d, J=1.5Hz, 8-H), 7.92 (2H, d, J=8.7Hz, 2 '-H, 6 '-H), 6.89 (2H, d, J=9.0Hz, 3 '-H, 5 '-H);
13C NMR (CDCl
3, 75.0MHz) δ: 146.1 (C-2), 135.5 (C-3), 175.7 (C-4), 156.0 (C-5), 98.2 (C-6), 163.8 (C-7), 93.4 (C-8), 160.5 (C-9), 102.9 (C-10), 121.6 (C-1), 129.3 (C-2), 115.3 (C-3), 159.0 (C-4), 115.3 (C-5), 129.3 (C-6).
Isorhamnetol: yellow-green colour crystallization, C
16H
12O
7305 ° of Mp;
1H NMR (CDCl
3, 300MHz) (δ): 6.18 (1H, d, J=1.8Hz, 6-H), 6.39 (1H, d, J=1.7Hz, 8-H), 7.53 (1H, d, J=2.0Hz, 2 '-H), 6.87 (1H, d, J=8.7Hz, 5 '-H), 7.51 (1H, dd, J=8.6,1.8Hz, 6 '-H), 3.76 (3H, s, OCH
3);
13C NMR (CDCl
3, 75.0MHz) δ: 146.7 (C-2), 136.1 (C-3), 175.5 (C-4), 156.0 (C-5), 98.5 (C-6), 163.8 (C-7), 93.8 (C-8), 161.1 (C-9), 102.8 (C-10), 121.8 (C-1), 115.5 (C-2), 151.3 (C-3), 147.3 (C-4), 116.1 (C-5), 118.7 (C-6), OCH
3(56,1).
5 '-hydroxyl Quercetin: glassy yellow needle, C
15H
10O
8Mp 357-360 °; UV (EtOH) λ
Max: 255,375nm;
1H NMR (CDCl
3, 300MHz) (δ): 6.19 (1H, d, J=2.0Hz, 6-H), 6.37 (1H, d, J=1.8Hz, 8-H), 7.12 (2H, s, 2 '-H, 6 '-H);
13C NMR (CDCl
3, 75.0MHz) δ: 147.1 (C-2), 136.1 (C-3), 176.0 (C-4), 161.0 (C-5), 98.5 (C-6), 164.2 (C-7), 93.5 (C-8), 156.4 (C-9), 103.3 (C-10), 121.2 (C-1), 107.5 (C-2), 146.0 (C-3), 136.1 (C-4), 146.0 (C-5), 136.1 (C-6).
Embodiment 2: beta-secretase suppresses active testing
1, the clone of beta-secretase
Express the amino acid whose cDNA sequence of beta-secretase 1-454 by PCR (polymerase chain reaction technique) amplification, then extension increasing sequence is cloned on the insect cell expression carrier pFastBac-1, added that at the C-terminal of extension increasing sequence 6*His-tag is convenient to being further purified of beta-secretase afterwards, the pFastBac1 of reorganization has been transformed in the competence DH10Bac E.coli cell.Identify positive colony by blue hickie, PCR further proves conclusively, and obtains recombinant baculovirus DNA, and gene sequencing is finally confirmed the exactness of cloning.
2, the expression and purification of beta-secretase
To the TN expressed in insect cells, 27 ℃ of constant temperature culture are collected substratum and are obtained recombinant virus after 72 hours with recombinant baculovirus DNA transfection.Recombinant virus is mixed (MOI=5) infect the TN insect cell with liposome, 27 ℃ of constant temperature culture 72 hours are collected supernatant.Then the supernatant of collecting is carried out dialysis in PBS (pH8.0) solution, dialyse 6 times, changed liquid once in per 6 hours.Supernatant after the dialysis is crossed the Ni-NTA column chromatography, collects elutriant, through SDS-PAGE electrophoresis detection and Western Blot detect conclusive evidence errorless after, great expression, behind the purifying and concentrate (Ultra-15), measure protein concentration after, be stored in 4 ℃, wait until to survey and live.
3, the survey of beta-secretase is lived and the sieve medicine
Test philosophy: as shown in Figure 3, surveying the false bottom thing is Rhodamine-EVNLDAEFK-Quencher, and when not having optical excitation, whole substrate is in a kind of fluorescence resonance energy equilibrium state.Add after the beta-secretase, substrate is by enzymic hydrolysis, and under the optical excitation of 535nm, fluorophor is launched fluorescence at the 585nm place, detects by TECAN (GENios) machine.
Sieve medicine standard: to the percent inhibition of enzymic activity, suppress activity and be higher than at 80% o'clock when the concentration of detection compound is 100 μ m, further do a series of concentration gradients, obtain under the corresponding concentration percent inhibition, thereby calculate the IC of each compound to enzyme
50
Main component suppresses the beta-secretase activity data in the Semen Ginkgo extrac
Beta-secretase is a kind of enzyme that plays extremely important effect in senile dementia.In recent years to the also awfully hot door of its research.The inhibitor that designs at this enzyme is a lot, but great majority are the bigger polypeptide compounds of molecular weight, and the report of micromolecular inhibitor is less relatively.Though polypeptide compounds has shown good active in the screening of enzyme, because its molecular weight is bigger, complex structure, the cost of preparation is very high, and oral administration biaavailability is relatively poor, up to now, goes back the listing of none compound.Though the inhibitor of this flavonols that we find is not by force special on the activity of enzyme, and is simple in structure owing to it, is easy to preparation, for better this type small molecular inhibitor of further exploitation activity provides a good lead compound.The a lot of bibliographical informations of Chinese medicine ginkgo have the anti-senile dementia activity, but mechanism is not very clear and definite for a long time, and the beta-secretase of this flavonoid alcohol compound suppresses active being found to be and illustrates its mechanism a thinking is provided.
Claims (6)
1. a class has the Flavonol beta-secretase inhibitor of the structure that following general formula represents:
R wherein
1, R
2And R
3Respectively be independently H ,-OH or-OCH
3
2. Flavonol beta-secretase inhibitor as claimed in claim 1, it can be following compound:
1) Quercetin
2) Isorhamnetol
3) kaempferol
4) 5 '-hydroxyl Quercetin
3. method of extracting the described Flavonol beta-secretase inhibitor of claim 1 is characterized in that:
Standard ethanol extraction dissolve with methanol with Ginkgo Leaf adds H then
2SO
4Aqueous solution reflux, after the cooling, concentrating under reduced pressure obtains not having alcohol mixture, uses chloroform and water dispenser then, obtains the chloroform phase.After chloroform concentrates mutually,, obtain end product with 1: 1 chloroform-methanol wash-out with separating with the dextran chromatography column again after the chloroform methanol dissolving.
4. Flavonol beta-secretase inhibitor as claimed in claim 1 or 2 is used in preparation treatment medicine for senile dementia.
5. application as claimed in claim 4 is wherein treated medicine for senile dementia and is comprised Flavonol beta-secretase inhibitor and auxiliary agent as active substance.
6. a pharmaceutical composition that is used for the treatment of senile dementia is characterized in that this pharmaceutical composition comprises as the Flavonol beta-secretase inhibitor described in the claim 1 or 2 of active substance.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130196976A1 (en) * | 2010-11-17 | 2013-08-01 | Phloronol, Inc. | Compositions for reducing beta-amyloid-induced neurotoxicity comprising beta-secretase inhibitor |
| CN105061378A (en) * | 2015-08-27 | 2015-11-18 | 北京师范大学 | Compound for promoting Abelta gathering and preparation method and application thereof |
| CN105412074A (en) * | 2015-12-24 | 2016-03-23 | 厦门大学 | Application of quercetin in preparation of medicine for preventing and treating diseases related to ApoE protein level |
| CN109134695A (en) * | 2018-08-08 | 2019-01-04 | 劲牌生物医药有限公司 | A kind of alcohol-soluble beta glucan extract and preparation method thereof, application and health liquor |
-
2006
- 2006-07-11 CN CNA2006100288264A patent/CN101104612A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130196976A1 (en) * | 2010-11-17 | 2013-08-01 | Phloronol, Inc. | Compositions for reducing beta-amyloid-induced neurotoxicity comprising beta-secretase inhibitor |
| CN105061378A (en) * | 2015-08-27 | 2015-11-18 | 北京师范大学 | Compound for promoting Abelta gathering and preparation method and application thereof |
| CN105061378B (en) * | 2015-08-27 | 2017-05-24 | 北京师范大学 | Compound for promoting Abelta gathering and preparation method and application thereof |
| CN105412074A (en) * | 2015-12-24 | 2016-03-23 | 厦门大学 | Application of quercetin in preparation of medicine for preventing and treating diseases related to ApoE protein level |
| CN109134695A (en) * | 2018-08-08 | 2019-01-04 | 劲牌生物医药有限公司 | A kind of alcohol-soluble beta glucan extract and preparation method thereof, application and health liquor |
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