CN103961358B - Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant - Google Patents
Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention provides the application in preparation treatment or prevention of neurodegenerative diseases medicine of a kind of protopanoxadiol derivative and Protopanaxatriol's derivant.Showing through the pharmacological results, said derivative is at PC12 cell, the H of N2a cell2O2Compared to 20(S)-aglycone protopanaxadiol on damage model, 20 (S)-Protopanaxatriols show higher anti-oxidation protection effect.At two kinds of vascular dementia models: folder closes rats with bilateral common carotid artery cooperation sodium nitroprusside-induced hypotension method and replicates Rat VD model model and bilateral hippocampus injection A β repeatedly1-42Replicate alzheimer disease animal model and can improve rat space exploration and capacity of orientation.
Description
Technical field
The present invention relates to a kind of panoxadiol's compounds, specifically, relate to a kind of 20 (S)-protopanoxadiol derivatives and 20 (S)-Protopanaxatriol derivants new application in pharmacy.Belong to field of medicaments.
Background technology
Neurodegenerative diseases (Degenerativediseasesofthecentralnervoussystem, ND) is one group of chronic progressive external nervous system disease based on primary neuronal degeneration.Such disease mainly include Alzheimer (Alzheimer ' sdisease, AD) (be commonly called as alzheimer disease), parkinson disease (Parkinson ' sdisease, PD), Huntington chorea (Huntingtondisease), dissimilar spinocerebellar ataxia (spinalcerebellarataxias), amyotrophic lateral sclerosis (amyotrophiclateralsclerosis) and spinal muscular atrophy disease (spinalmuscularatrophy) etc..
Research finds, ND is caused by multiple different reasons, is not provided that sufficient nutrition including neuron or neurogliocyte, axonal transport function is impaired, glutamate receptor activity is too high, reactive oxygen species is too high, metabolic pathway is impaired, mitochondrion energy produces to reduce, the protein of folding mistake is formed increases or the incorrect caused specific proteins of the course of processing of degrade insufficient, inflammatory process, viral infection, nucleus or Mitochondrial DNA Mutation and RNA or protein or the factor such as lipid part merit loss of energy or increase.Although the cause of disease and the diseased region that bring out these diseases are not quite similar, but they have a common feature, namely all there is the major injury of neurocyte and cause accelerating dead feature.
At present mechanism and the treatment of neurodegenerative diseases is had been carried out substantial amounts of research; but there is no effectively ripe method and medicine so far to prevent and treat this disease, exploitation has the medicine of neuro-protective function and the treatment of neurodegenerative diseases is significant.
20 (S)-protopanoxadiols are one of important aglycons of glycol group ginsenoside, and ZL200610027507.1 discloses 20 (the S)-protopanoxadiols purposes at anti-depression aspect.ZL200510016774.4 discloses Da Ma-20S-24 (S)-epoxy-3 β, 12 β, the synthetic method of 25-triol and the purposes in the medicine of preparation treatment coronary heart disease, myocardial ischemia, ischemic shock, arrhythmia and reperfusion injury thereof, but its purposes in the medicine of preparation treatment or prevention of neurodegenerative diseases unexposed.
Summary of the invention
It is an object of the invention to provide the application in preparation treatment or prevention of neurodegenerative diseases medicine of a kind of 20 (S)-protopanoxadiol derivatives and 20 (S)-Protopanaxatriol derivants.
null20 (S)-protopanoxadiol derivatives and 20 (S)-Protopanaxatriol derivants are conducted in-depth research by the present inventor，Found that，Da Ma-20S-24 (R)-epoxy-3 β,12β,25-triol (dammara-20S-24 (R)-epoxy-3 β,12β,25-triol)、Da Ma-20S-24 (S)-epoxy-3 β,12β,25-triol (dammara-20S-24 (S)-epoxy-3 β,12β,25-triol)、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol (dammara-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol)、And Da Ma-20S-24 (R)-epoxy-3 β,6β,12β,25-tetrol (dammara-20S-24 (R)-epoxy-3 β,6β,12β,25-tetrol) in preparation as exceedingly useful in treatment or prevention of neurodegenerative diseases medicine.
The present invention is provided to Da Ma-20S-24 (R)-epoxy-3 β for the treatment of or prevention of neurodegenerative diseases, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrols or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrols.
The present invention provides Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrols or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrols new application in treatment or prevention of neurodegenerative diseases.
The present invention is provided to treatment or prevention of neurodegenerative diseases contain up to agate-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrols or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, the pharmaceutical composition of 12 β, 25-tetrols.
The present invention provides and contains up to agate-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrols or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, the pharmaceutical composition of 12 β, 25-tetrols purposes in treatment or prevention of neurodegenerative diseases.
Wherein,
The name of protopanoxadiol derivative shown in formula (I) is called Da Ma-20S-24 (R)-epoxy-3 β, 12 β, shown in 25-triol, formula (II), the name of protopanoxadiol derivative is called Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol.
The name of Protopanaxatriol's derivant shown in formula III is called Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, shown in 25-tetrol, formula (IV), the name of Protopanaxatriol's derivant is called Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrols.
Described neurodegenerative diseases includes parkinson disease, alzheimer disease, vascular dementia disease.
Protopanoxadiol derivative of the present invention and Protopanaxatriol's derivant make different preparations from pharmaceutically acceptable carrier, such as oral formulations or parenteral formulation.
Described oral formulations is capsule, tablet, pill, granule, Emulsion, suspensoid.
Described parenteral formulation is injection.
Through pharmacological evaluation, display Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol is at PC12 cell, the H of N2a cell2O2Compared to 20(S)-aglycone protopanaxadiol on damage model, higher anti-oxidation protection effect.
Folder repeatedly closes rats with bilateral common carotid artery coordinates sodium nitroprusside-induced hypotension method to replicate Rat VD model model and bilateral hippocampus injection A β1-42Replicate alzheimer disease animal model and can obviously improve rat space exploration and capacity of orientation.Treatment neurodegenerative diseases such as parkinson disease, alzheimer disease, vascular dementia disease are had potential medical value, there is wide DEVELOPMENT PROSPECT.
Accompanying drawing explanation
Fig. 1 is 20(S of the present invention) protopanoxadiol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols are to H2O2The reversion rate of damage PC12 cell；
Fig. 2 is 20(S of the present invention) protopanoxadiol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols are to H2O2The reversion rate of damage N2a cell；
Fig. 3 is 20(S of the present invention) Protopanaxatriol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols are to H2O2The reversion rate of damage PC12 cell；
Fig. 4 is 20(S of the present invention) Protopanaxatriol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols are to H2O2The reversion rate of damage N2a cell.
Detailed description of the invention
Following example are used for illustrating the present invention, but are not limited to the scope of the present invention.
The structural formula of 20 (the S)-protopanoxadiol derivatives that the present invention relates to is as follows:
The name of protopanoxadiol derivative shown in formula (I) is called Da Ma-20S-24 (R)-epoxy-3 β, 12 β, shown in 25-triol, formula (II), the name of protopanoxadiol derivative is called Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol.
It can the method by the method disclosed in ZL200510016774.4 or based on the method manufacture.The synthetic method specifically taked is:
Preparation method, with reference to Chinese patent 200510016774.7, precise 10g20 (S)-protopanoxadiol (Shanghai Chinese Medicine Creation Research Center), is dissolved in 250ml anhydrous methylene chloride, and stirring is lower adds metachloroperbenzoic acid 8g.Stir 24 hours under room temperature, after completion of the reaction, reactant liquor washs 3 times with the sodium bicarbonate solution of 5%, and organic facies anhydrous sodium sulfate is concentrated into dry after drying, with ethyl acetate and petroleum ether 1:10-1:1(volume ratio) carry out silica gel column chromatography for eluant, obtain compound Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol 4g(purity 95%), Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol 4g(purity 95%).
After being measured by ESI-MS and NMR, the physicochemical data of formula (I) compound determination is as follows:
ESI-MSm/z:477.47(M+H)-1HNMR(300MHz,CDCl3):δ0.77(s,3H),0.85(s,3H),0.90(s,3H),0.97(s,3H),0.98(s,3H),1.10(s,3H),1.27(s,3H),1.28(s,3H),1.30-2.23(m,22H),3.40(d,1H),3.52(m,1H),3.84(d,1H).13CNMR(300MHz,CDCl3):δ33.5(C1),25.4(C2),76.0(C3),37.5(C4),49.5(C5),18.2(C6),34.6(C7),39.9(C8),50.0(C9),37.2(C10),31.6(C11),70.5(C12),48.7(C13),52.2(C14),32.1(C15),28.5(C16),48.8(C17),15.4(C18),16.1(C19),87.3(C20),28.8(C21),31.5(C22),25.0(C23),87.1(C24),70.1(C25),24.1(C26),27.8(C27),28.3(C28),22.0(C29),17.2(C30).
The physicochemical data of formula (II) compound determination is as follows:
ESI-MSm/z:477.47(M+H)-1HNMR(300MHz,CDCl3):δ0.77(s,3H),0.85(s,3H),0.90(s,3H),0.97(s,3H),0.98(s,3H),1.10(s,3H),1.27(s,3H),1.28(s,3H),1.30-2.23(m,22H),3.16-3.21(m,1H),3.48-3.56(m,1H),3.84-3.89(d,1H),4.08-4.16(m,1H).13CNMR(300MHz,CDCl3):δ33.5(C1),25.4(C2),76.0(C3),37.5(C4),49.5(C5),77.4(C6),34.6(C7),39.9(C8),50.0(C9),37.2(C10),31.6(C11),70.5(C12), 48.7(C13),52.2(C14),32.1(C15),28.5(C16),48.8(C17),15.4(C18),16.1(C19),87.3(C20),28.8(C21),31.5(C22),25.0(C23),85.3(C24),70.5(C25),26.0(C26),27.8(C27),28.3(C28),22.0(C29),18.2(C30).
The structural formula of 20 (the S)-Protopanaxatriol derivants that the present invention relates to is as follows:
The name of Protopanaxatriol's derivant shown in formula III is called Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, shown in 25-tetrol, formula (IV), the name of Protopanaxatriol's derivant is called Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrols.
Preparation method, with reference to ZL200410018038.8, precise 10g20 (S)-Protopanaxatriol (Shanghai Chinese Medicine Creation Research Center), is dissolved in 250ml anhydrous methylene chloride, and stirring is lower adds metachloroperbenzoic acid 8g.Stirring 24 hours under room temperature, after completion of the reaction, reactant liquor washs 3 times with the sodium bicarbonate solution of 5%, organic facies anhydrous sodium sulfate is concentrated into dry after drying, with ethyl acetate and petroleum ether 1:10-1:1(volume ratio) carry out silica gel column chromatography for eluant, obtain compound Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol 4g(purity 95%), Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol 4g(purity 95%).
After being measured by ESI-MS and NMR, the physicochemical data of formula III compound determination is as follows:
ESI-MSm/z:493.40(M+H)-1HNMR(300MHz,CDCl3):δ0.77(s,3H),0.85(s,3H),0.90(s,3H),0.97(s,3H),0.98(s,3H),1.10(s,3H),1.27(s,3H),1.28(s,3H),1.30-2.23(m,22H),2.68-2.79(m,1H),3.50-3.59(m,1H),3.84-3.89(m,1H),3.97-4.06(m,1H).13CNMR(300MHz,CDCl3):δ33.5(C1),25.4(C2),76.0(C3),37.5(C4),49.5(C5),77.4(C6),34.6(C7),39.9(C8),50.0(C9),37.2(C10),31.6(C11),70.5(C12),48.7(C13),52.2(C14),32.1(C15),28.5(C16),48.8(C17),15.4(C18), 16.1(C19),87.3(C20),28.8(C21),31.5(C22),25.0(C23),87.1(C24),70.1(C25),24.1(C26),27.8(C27),28.3(C28),22.0(C29),17.2(C30).
The physicochemical data of formula IV compound determination is as follows:
ESI-MSm/z:493.40(M+H)-1HNMR(300MHz,CDCl3):δ0.77(s,3H),0.85(s,3H),0.90(s,3H),0.97(s,3H),0.98(s,3H),1.10(s,3H),1.27(s,3H),1.28(s,3H),1.30-2.23(m,22H),3.16-3.21(m,1H),3.48-3.56(m,1H),3.84-3.89(d,1H),4.08-4.16(m,1H).13CNMR(300MHz,CDCl3):δ33.5(C1),25.4(C2),76.0(C3),37.5(C4),49.5(C5),77.4(C6),34.6(C7),39.9(C8),50.0(C9),37.2(C10),31.6(C11),70.5(C12),48.7(C13),52.2(C14),32.1(C15),28.5(C16),48.8(C17),15.4(C18),16.1(C19),87.3(C20),28.8(C21),31.5(C22),25.0(C23),85.3(C24),70.5(C25),26.0(C26),27.8(C27),28.3(C28),22.0(C29),18.2(C30).
Above-mentioned have formula (I), the protopanoxadiol derivative of (II) structure and have Protopanaxatriol's derivant of formula III, (IV) structure, when being used for preparing treatment neurodegenerative diseases medicine, it is possible to be administered with itself；Or the preparation (such as tablet, capsule, granule, powder, syrup, solution, Emulsion, suspensoid, injection etc.) prepared as mixing with suitable pharmacologically acceptable excipient, diluent etc. is administered.The prevention of the present invention or therapeutic agent can be taken orally or parenteral.
Above-mentioned preparation, it is possible to adopt known method, uses excipient, binding agent, disintegrating agent, lubricant, stabilizer, taste masking to rectify and smells the additives such as agent, emulsifying agent, suspending agent, diluent, preparation solvent.
The example of excipient includes: the saccharides such as lactose, white sugar, glucose, mannitol, Sorbitol；The starch derivatives such as corn starch, potato starch, alphalise starch, dextrin, carboxymethyl starch；The cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, carboxymethylcellulose calcium, internal crosslinking sodium carboxymethyl cellulose；Radix Acaciae senegalis；Glucosan；Short awake enzyme polysaccharide；The silicates such as light silicon anhydride, synthetic aluminium silicate, the positive magnesium silicate of aluminum；The phosphoric acid salts such as calcium phosphate；The carbonates such as calcium carbonate；Or the Sulfateses such as calcium sulfate.
The example of binding agent includes: as the compound shown in above-mentioned excipient；Gelatin；Polyvinylpyrrolidone；Or Polyethylene Glycol.
The example of disintegrating agent includes: as the compound shown in above-mentioned excipient；Or, cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, crospolyvinylpyrrolidone etc. are through the starch of chemical modification or cellulose derivative.
The example of lubricant includes: Talcum；Stearic acid；The Metallic stearates such as calcium stearate, magnesium stearate；Colloidal silica；Aluminium-magnesium silicate；The wax class such as Cera Flava, spermaceti；Boric acid；Ethylene glycol；The carboxylic acids such as fumaric acid, adipic acid；The carboxylic acid sodium salts such as sodium benzoate；The sulfate such as sodium sulfate；Leucine；The lauryl sulfate such as sodium lauryl sulphate, Stepanol MG；The silicic acid class such as silicic acid anhydride, hydrate of silicic acid；Or, the starch derivatives in above-mentioned excipient.
The example of stabilizer includes: the parabens such as methyl hydroxybenzoate, propyl hydroxybenzoate；The alcohols such as methaform, benzylalcohol, phenethanol；Benzalkonium chloride；The phenols such as phenol, cresol；Thimerosal；Acetic anhydride；Or sorbic acid.
Taste masking is rectified and is smelt agent and such as may is that conventional sweetening material, acid flavoring or spice.
Emulsifying agent such as may is that tween or span etc..
Suspending agents is as may is that Tween 80 or sodium carboxymethyl cellulose.
Preparation solvent such as may is that water, ethanol or glycerol.
Embodiment 1
10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, add 20g lactose, mixing, with 70% ethanol for binding agent, granulate, load capsule, obtain capsule, every containing 20 (S)-protopanoxadiol derivative 20mg.
Embodiment 2
10g Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol, adds 20g lactose, mixing, with 70% ethanol for binding agent, granulates, loads capsule, obtain capsule, and every containing 20 (S)-protopanoxadiol derivative 20mg.
Embodiment 3
10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, add 20g lactose, mixing, with 70% ethanol for binding agent, granulates, dry, adding 5g magnesium stearate, tabletting, obtain tablet, every containing 20 (S)-protopanoxadiol derivative 50mg.
Embodiment 4
10g Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol, adds 20g lactose, mixing, with 70% ethanol for binding agent, granulates, dry, adding 5g magnesium stearate, tabletting, obtain tablet, every containing 20 (S)-protopanoxadiol derivative 50mg.
Embodiment 5
10g tween, soluble in water, add 10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, grind and make colostrum, add water to 1000ml, obtain oral liquid.
Embodiment 6
10g tween, soluble in water, add 10g Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol, grind and make colostrum, add water to 1000ml, obtain oral liquid.
Embodiment 7
10g tween, is dissolved in water for injection, adds 10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, grinds and make colostrum, then inject water to 5000ml, through filtering, and sterilizing, namely obtain injection after embedding.
Evaluate the pharmacology pharmacodynamic effect of the present invention below by way of this area model experiment model, but the pharmacology pharmacodynamic effect of the present invention is not limited to evaluate by following method.
Experimental example 1 derivant is to H2O2The protection of the neurocyte of damage
In Hydroperoxide injury model, detecting Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols with mtt assay, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols are to H2O2The PC12 cell of damage, the protective effect of N2a cell.
1, experiment material:
1. instrument: clean bench (Microcystins in The Dianshan Lake cleaning equipment factory), constant temperature CO2Incubator (U.S. Forma), enzyme-linked immunosorbent assay instrument (U.S. BioTek), inverted biological microscope (Chongqing optical instrument), desk-top constant-temperature table (Taicang science and education equipment factory)
2. reagent: RPMI1640 culture medium (GIBCOLotNO.460302), trypsin GIBCOLotNO.F20020705), hyclone (GIBCOLotNO.721229), MTT (Sino-A-BiotelLotNO.0793), DMSO (traditional Chinese medicines group), DMSO (SigmaLotNO.038K2391), hydrogen peroxide (traditional Chinese medicines group LotNO.20080610)
3. cell strain: cell strain is provided by Chinese Academy of Sciences's cell.
2, laboratory sample:
20(S) protopanoxadiol, 20(S) Protopanaxatriol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols.Each compound through DMSO dissolve after in, dilute 4 DEG C of preservations.
3, experimental technique
Take and be in one bottle of cell in good condition exponential phase of growth, make cell suspension, and cell density is diluted to 1 × 105Individual/ml, obtained cell suspension is inoculated on 96 orifice plates, puts constant temperature CO2Incubator is cultivated 24 hours; add the test medicine of variable concentrations; making ultimate density is the multiple hole of 0.1-100 μM of each concentration 6, cultivates 6 hours, continuously adds hydrogen peroxide; every hole 10 μ l; final concentration of, 75 μMs-100 μMs, incubator is cultivated 16 hours; according to mtt assay enzyme-linked immunosorbent assay instrument at the light absorption value that wavelength is the every hole of mensuration, 570nm place, and calculate the protected effect (reversion rate) of cell.
Protected effect %(reversion rate)=(model is not administered group cell inhibitory rate-model susceptibility group cell inhibitory rate)/model susceptibility group cell inhibitory rate × 100%
4, experimental result
According to mtt assay test result; calculate 20(S) protopanoxadiol, 20(S) Protopanaxatriol, Da Ma-20S-24 (R)-epoxy-3 β; 12 β; 25 triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β; 12 β; 25 tetrols are to Hydroperoxide injury differentiated PC12 cell, and the protective effect of N2a, result is as Figure 1-4.
5, conclusion
At hydrogen peroxide differentiated PC12 cell, in the damage model of N2a cell, 20(S is detected with mtt assay) protopanoxadiol, 20(S) Protopanaxatriol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, the protective effect to neurocyte of 25 tetrols, found that: Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols are than 20(S) protopanoxadiol, 20(S) Protopanaxatriol has higher neurocyte protection effect, can as the effective ingredient of neurodegenerative diseases medicine.
Experimental example 2
Folder repeatedly is closed rats with bilateral common carotid artery and coordinates sodium nitroprusside-induced hypotension method to replicate the effect of Rat VD model model by derivant.
1, laboratory animal
Strain: cleaning grade kunming mice, sex: male, body weight: 18-22g, source: Shanghai Slac Experimental Animal Co., Ltd. provides, credit number: SCXK (Shanghai) 2007-0005.
2, medicine
Given the test agent: Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol.Prepare as stated above.Positive control drug (aricept), configuration: medicated powder is dissolved in the solvent of 0.3%CMCNa, makes suspension, ultrasonic dissolution assisting.
3, experimental technique
nullHealthy male SD rat，Body weight (300 ± 10) g，Adaptability feed one week after modeling，And it is randomly divided into 9 groups，Sham operated rats (Sham)、Model group (Model)、Aricept group (DNP)、Da Ma-20S-24 (R)-epoxy-3 β,12β,25-triol low dose therapy group (S01-L)、Da Ma-20S-24 (R)-epoxy-3 β,12β,Dosage treatment group (S01-M) in 25-triol、Da Ma-20S-24 (R)-epoxy-3 β,12β,25-triol high-dose therapy group (S01-H)、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol low dose therapy group (S02-L)、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,Dosage treatment group (S02-M) in 25-tetrol、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol high-dose therapy group (S02-H)，Often group 15.Each group starts administration for 3 days after modeling, every morning 8 is administered once, sham operated rats and model group give physiological saline, and compounds for treating group carries out lumbar injection by 1mg/kg, 5mg/kg, 25mg/kg, and aricept gives 1.667mg/kg gastric infusion.Within after modeling 28 days, carry out behavioristics's detection.
4, experimental result
Note: compare with model group (model)*P < 0.05,**P < 0.01
From model experiment results, escape latency experimental result shows, the model group escape latency time, prompting modeling was successful apparently higher than sham operated rats (P < 0.05).The therapeutic outcome of positive control drug aricept group (DNP) has significant difference (P < 0.05) compared with model group.In each medication group, the each dosage of compound S01 and S02 compares with model group, its escape latency time is all remarkably decreased, total distance of swimming all substantially shortens, the target quadrant time of staying significantly improves, wearing platform number of times to dramatically increase, middle high dose group effect is better than positive control drug aricept group, has notable pharmacologically active.
Experimental example 3
Bilateral hippocampus is injected A β by derivant1-42Replicate the effect of alzheimer disease animal model
1, laboratory animal
Strain: cleaning grade kunming mice, sex: male, body weight: 18-22g, source: Shanghai Slac Experimental Animal Co., Ltd. provides, credit number: SCXK (Shanghai) 2007-0005.
2, medicine
Given the test agent: Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol.Prepare as stated above.Positive control drug (aricept), configuration: medicated powder is dissolved in the solvent of 0.3%CMCNa, makes suspension, ultrasonic dissolution assisting.
3, experimental technique
nullHealthy male SD rat，Body weight (300 ± 10) g，Adaptability feed one week after modeling，And it is randomly divided into 9 groups，Sham operated rats (Sham)、Model group (Model)、Aricept group (DNP)、Da Ma-20S-24 (R)-epoxy-3 β,12β,25-triol low dose therapy group (S01-L)、Da Ma-20S-24 (R)-epoxy-3 β,12β,Dosage treatment group (S01-M) in 25-triol、Da Ma-20S-24 (R)-epoxy-3 β,12β,25-triol high-dose therapy group (S01-H)、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol low dose therapy group (S02-L)、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,Dosage treatment group (S02-M) in 25-tetrol、Da Ma-20S-24 (S)-epoxy-3 β,6β,12β,25-tetrol high-dose therapy group (S02-H)，Often group 15.Each group starts administration for 3 days after modeling, every morning 8 is administered once, sham operated rats and model group give physiological saline, and compounds for treating group carries out lumbar injection by 1mg/kg, 5mg/kg, 25mg/kg, and aricept gives 1.667mg/kg gastric infusion.Within after modeling 28 days, carry out behavioristics's detection.
4, experimental result
Note: compare with model group (model)*P < 0.05,**P < 0.01
From model experiment results, escape latency experimental result shows, the model group escape latency time, prompting modeling was successful apparently higher than sham operated rats (P < 0.05).The therapeutic outcome of positive control drug aricept group (DNP) has significant difference (P < 0.05) compared with model group.In each medication group, the each dosage of compound S01 and S02 compares with model group, its escape latency time is all remarkably decreased, total distance of swimming all substantially shortens, the target quadrant time of staying significantly improves, wearing platform number of times to dramatically increase, middle high dose group effect is better than positive control drug aricept group, has notable pharmacologically active.
Although, above the present invention is described in detail with a general description of the specific embodiments, but on basis of the present invention, it is possible to it is made some modifications or improvements, and this will be apparent to those skilled in the art.Therefore, make without departing from theon the basis of the spirit of the present invention these amendment or. improve, belong to the scope of protection of present invention.
Claims (6)
1. the protopanoxadiol derivative with formula (I) or (II) structure is preparing the application treated or in prevention of neurodegenerative diseases medicine,
The name of the protopanoxadiol derivative shown in formula (I) is called Da Ma-20S-24 (R)-epoxy-3 beta, 12 beta, 25-triol；The name of the protopanoxadiol derivative shown in formula II is called Da Ma-20S-24 (S)-epoxy-3 beta, 12 beta, 25-triol.
2. Protopanaxatriol's derivant with formula III or (IV) structure is preparing the application treated or in prevention of neurodegenerative diseases medicine,
The name of the Protopanaxatriol's derivant shown in formula III is called Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol；The name of the Protopanaxatriol's derivant shown in formula IV is called Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol.
3. application according to claim 1 and 2, it is characterised in that described neurodegenerative diseases includes parkinson disease, alzheimer disease or vascular dementia disease.
4. application according to claim 1 and 2, it is characterised in that described protopanoxadiol derivative or Protopanaxatriol's derivant make oral formulations or parenteral formulation with pharmaceutically acceptable carrier.
5. application according to claim 4, it is characterised in that described oral formulations is capsule, tablet, pill, granule, Emulsion or suspensoid.
6. application according to claim 4, it is characterised in that described parenteral formulation is injection.
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| CN1569882A (en) * | 2004-04-29 | 2005-01-26 | 上海中药创新研究中心 | Process for preparing protopanoxadiol and protopanaxatriol |
| CN1895256A (en) * | 2006-06-09 | 2007-01-17 | 上海中药创新研究中心 | Use of 20(S)-protopanoxadiol in preparation of antidepressant medicine |
| CN102018716A (en) * | 2009-09-14 | 2011-04-20 | 王泽君 | Medical application of protopanaxatriol and protopanaxadiol in nervous system diseases |
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| CN1569882A (en) * | 2004-04-29 | 2005-01-26 | 上海中药创新研究中心 | Process for preparing protopanoxadiol and protopanaxatriol |
| CN1895256A (en) * | 2006-06-09 | 2007-01-17 | 上海中药创新研究中心 | Use of 20(S)-protopanoxadiol in preparation of antidepressant medicine |
| CN102018716A (en) * | 2009-09-14 | 2011-04-20 | 王泽君 | Medical application of protopanaxatriol and protopanaxadiol in nervous system diseases |
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| 国产西洋参茎叶皂苷分离.结构修饰及其生物活性研究;刘金平;《中国博士学位论文全文数据库.医药卫生辑》;20070131;第53，66页 * |
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