CN103961358A - Application of protopanaxadiol derivative and protopanaxatriol derivative in preparation of drugs - Google Patents
Application of protopanaxadiol derivative and protopanaxatriol derivative in preparation of drugs Download PDFInfo
- Publication number
- CN103961358A CN103961358A CN201310044215.9A CN201310044215A CN103961358A CN 103961358 A CN103961358 A CN 103961358A CN 201310044215 A CN201310044215 A CN 201310044215A CN 103961358 A CN103961358 A CN 103961358A
- Authority
- CN
- China
- Prior art keywords
- epoxy
- protopanaxatriol
- derivative
- triol
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- FLBLYRLLJBXAHD-VGOLLOGKSA-N CC(C)([C@H](CC[C@@]1(C)C2CC3)[O]1=[O](C)[C@H](C1)C2[C@]3(C)C(C)(CC2)C1C(C)(CC1)C2C(C)(C)[C@H]1[O](C)=C)[O](C)=C Chemical compound CC(C)([C@H](CC[C@@]1(C)C2CC3)[O]1=[O](C)[C@H](C1)C2[C@]3(C)C(C)(CC2)C1C(C)(CC1)C2C(C)(C)[C@H]1[O](C)=C)[O](C)=C FLBLYRLLJBXAHD-VGOLLOGKSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- 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 an application of a protopanaxadiol derivative and a protopanaxatriol derivative in the preparation of drugs for treating or preventing neurodegenerative diseases. Pharmacological experiment results show that the above derivatives have a stronger anti-oxidation protection effect than 20(S)-protopanaxadiol and 20(S)-protopanaxatriol in H2O2 damage models of PC12 cells and N2a cells. Two vascular dementia models comprising a repeated occlusion rat bilateral vascular carotid cooperation sodium nitroprusside pressure reduction process stimulated dementia model and a bilateral hippocampus injection Abeta1-42 duplicated senile dementia model can improve the rat space exploration and orientation capability.
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 the new purposes of 20 (S)-Protopanaxatriol derivants in pharmacy.Belong to field of medicaments.
Background technology
Neurodegenerative diseases (Degenerative diseases of the central nervoussystem, ND) be one group taking constitutional neuronal degeneration as basic chronic progressive external nervous system disease.Such disease mainly comprise Alzheimer (Alzheimer ' s disease, AD) (be commonly called as alzheimer disease), parkinson disease (Parkinson ' s disease, PD), Huntington chorea (Huntington disease), dissimilar spinocerebellar ataxia (spinal cerebellar ataxias), amyotrophic lateral sclerosis (amyotrophic lateralsclerosis) and spinal cord muscular atrophy (spinal muscular atrophy) etc.
Research is found, ND is caused by multiple different reasons, comprises that neuron or neurogliocyte can not provide that sufficient nutrition, axonal transport function are impaired, glutamate receptor hyperactivity, reactive oxygen species is too high, metabolic pathway is impaired, mitochondrion power generation reduces, folding wrong Protein formation increases or it is insufficient to degrade, the factor such as specific proteins or lipid part merit loss of energy or increase of the course of processing of inflammatory process, viral infection, nucleus or Mitochondrial DNA Mutation and RNA or protein due to incorrect.Be not quite similar although bring out the cause of disease and the diseased region of these diseases, they have a common feature, all have the major injury of neurocyte and cause accelerating dead feature.
A large amount of research has been carried out in mechanism to neurodegenerative diseases and treatment at present; but the method and the medicine that there is no so far effective maturation are prevented and treated this disease, the medicine that exploitation has neuro-protective function is significant to the treatment of neurodegenerative diseases.
20 (S)-protopanoxadiols are one of important aglycons of glycol group ginsenoside, and ZL200610027507.1 discloses the purposes of 20 (S)-protopanoxadiols 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 unexposed its purposes in the medicine of preparation treatment or prevention of neurodegenerative diseases.
Summary of the invention
The object of this invention is 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.
The inventor conducts in-depth research 20 (S)-protopanoxadiol derivatives and 20 (S)-Protopanaxatriol derivants, found that, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol (dammara-20S-24 (R)-epoxy-3 β, 12 β, 25-triol), Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol (dammara-20S-24 (S)-epoxy-3 β, 12 β, 25-triol), Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol (dammara-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol), and Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol (dammara-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol) exceedingly useful aspect preparation conduct treatment or prevention of neurodegenerative diseases medicine.
The invention provides and be used for the treatment of or Da Ma-20S-24 (R)-epoxy-3 β of prevention of neurodegenerative diseases, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol.
The invention provides Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, the new purposes of 25-tetrol in treatment or prevention of neurodegenerative diseases.
The invention provides be used for the treatment of or prevention of neurodegenerative diseases comprise Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, the pharmaceutical composition of 25-tetrol.
The invention provides and comprise Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol or Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, the purposes of the pharmaceutical composition of 25-tetrol 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, the name of protopanoxadiol derivative shown in 25-triol, formula (II) is called Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol.
The name of the derivant of Protopanaxatriol shown in formula III is called Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, the name of Protopanaxatriol's derivant shown in 25-tetrol, formula (IV) is called Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol.
Described neurodegenerative diseases comprises parkinson disease, alzheimer disease, vascular dementia disease.
Protopanoxadiol derivative of the present invention and Protopanaxatriol's derivant are made 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, show Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol is at PC12 cell, the H of N2a cell
2o
2on damage model than 20(S)-aglycone protopanaxadiol, stronger anti-oxidation protection effect.
Folder is repeatedly closed to rats with bilateral common carotid artery to be coordinated sodium nitroprusside-induced hypotension method to copy to intend vascular dementia model and bilateral hippocampus injection A β
1-42copy alzheimer disease animal model and can obviously improve rat space exploration and capacity of orientation.Treatment neurodegenerative diseases, as parkinson disease, alzheimer disease, vascular dementia disease have potential medical value, is had to wide DEVELOPMENT PROSPECT.
Brief description of the drawings
Fig. 1 is 20(S of the present invention) protopanoxadiol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25 triols are to H
2o
2the 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 H
2o
2the 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 H
2o
2the 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 H
2o
2the reversion rate of damage N2a cell.
Detailed description of the invention
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the 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, the name of protopanoxadiol derivative shown in 25-triol, formula (II) is called Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol.
It can be manufactured by disclosed method in ZL200510016774.4 or the method based on the method.The synthetic method of specifically taking is:
Preparation method, with reference to Chinese patent 200510016774.7, accurately weighs 10g20 (S)-protopanoxadiol (Shanghai Chinese Medicine Creation Research Center), is dissolved in 250ml anhydrous methylene chloride, adds metachloroperbenzoic acid 8g under stirring.Under room temperature, stir 24 hours, after completion of the reaction, 5% sodium bicarbonate solution washing 3 times for reactant liquor, organic facies is dry with being concentrated into after anhydrous sodium sulfate drying, taking ethyl acetate and petroleum ether 1:10-1:1(volume ratio) carry out silica gel column chromatography as 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 measuring by ESI-MS and NMR, the materialization data of formula (I) compound determination are as follows:
ESI-MS m/z:477.47(M+H)
-1H NMR(300MHz,CDCl
3):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).
13C NMR(300MHz,CDCl
3):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 materialization data of formula (II) compound determination are as follows:
ESI-MS m/z:477.47(M+H)
-1H NMR(300MHz,CDCl
3):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).
13C NMR(300MHz,CDCl
3):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 the derivant of Protopanaxatriol shown in formula III is called Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, the name of Protopanaxatriol's derivant shown in 25-tetrol, formula (IV) is called Da Ma-20S-24 (R)-epoxy-3 β, 6 β, 12 β, 25-tetrol.
Preparation method, with reference to ZL200410018038.8, accurately weighs 10g20 (S)-Protopanaxatriol (Shanghai Chinese Medicine Creation Research Center), is dissolved in 250ml anhydrous methylene chloride, adds metachloroperbenzoic acid 8g under stirring.Under room temperature, stir 24 hours, after completion of the reaction, reactant liquor washs 3 times with 5% sodium bicarbonate solution, organic facies is dry with being concentrated into after anhydrous sodium sulfate drying, taking ethyl acetate and petroleum ether 1:10-1:1(volume ratio) as eluant carries out silica gel column chromatography, 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 measuring by ESI-MS and NMR, the materialization data of formula III compound determination are as follows:
ESI-MS m/z:493.40(M+H)
-1H NMR(300MHz,CDCl
3):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).
13C NMR(300MHz,CDCl
3):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 materialization data of formula IV compound determination are as follows:
ESI-MS m/z:493.40(M+H)
-1H NMR(300MHz,CDCl
3):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).
13C NMR(300MHz,CDCl
3):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 above-mentioned Protopanaxatriol's derivant that there is the protopanoxadiol derivative of formula (I), (II) structure and there is formula III, (IV) structure, while being used for preparation treatment neurodegenerative diseases medicine, can carry out administration with itself; Or the preparation (such as tablet, capsule, granule, powder, syrup, solution, Emulsion, suspensoid, injection etc.) making as mixing with the suitable upper acceptable excipient of pharmacology, diluent etc. carries out administration.Prevention of the present invention or therapeutic agent can be taken orally or parenteral.
Above-mentioned preparation, can adopt known method, uses excipient, binding agent, disintegrating agent, lubricant, stabilizing agent, taste masking to rectify and smells agent, emulsifying agent, suspending agent, diluent, the additives such as solvent for preparation.
The example of excipient comprises: 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 comprises: as the compound shown in above-mentioned excipient; Gelatin; Polyvinylpyrrolidone; Or Polyethylene Glycol.
The example of disintegrating agent comprises: as the compound shown in above-mentioned excipient; Or cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, crospolyvinylpyrrolidone etc. are through starch or the cellulose derivative of chemical modification.
The example of lubricant comprises: Talcum; Stearic acid; The Metallic stearates such as calcium stearate, magnesium stearate; Colloidal silica; Aluminium-magnesium silicate; The wax such as Cera Flava, spermaceti class; 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 such as silicic acid anhydride, hydrate of silicic acid class; Or, the starch derivatives in above-mentioned excipient.
The example of stabilizing agent comprises: the parabenses 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 can be for example: conventional sweetening material, acid flavoring or spice.
Emulsifying agent can be for example: tween or span etc.
Suspending agent can be for example: Tween 80 or sodium carboxymethyl cellulose.
Preparation with solvent can be for example: water, ethanol or glycerol.
Embodiment 1
10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, adds 20g lactose, mixes, and taking 70% ethanol as binding agent, granulates, and incapsulates, and obtains capsule, and 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, mixes, and taking 70% ethanol as binding agent, granulates, and incapsulates, and obtains capsule, and every containing 20 (S)-protopanoxadiol derivative 20mg.
Embodiment 3
10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol, adds 20g lactose, mix, taking 70% ethanol as binding agent, granulate, dry, add 5g magnesium stearate, tabletting, obtains tablet, and 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, mix, taking 70% ethanol as binding agent, granulate, dry, add 5g magnesium stearate, tabletting, obtains tablet, and 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-triol, grinds and makes colostrum, then add water to 1000ml, obtains 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, grinds and makes colostrum, then add water to 1000ml, obtains oral liquid.
Embodiment 7
10g tween, is dissolved in water for injection, adds 10g Da Ma-20S-24 (R)-epoxy-3 β, 12 β, and 25-triol, grinds and makes colostrum, then inject water to 5000ml, and through filtering, sterilizing, obtains injection after embedding.
Evaluate pharmacology pharmacodynamic effect of the present invention by this area model experiment model below, but pharmacology pharmacodynamic effect of the present invention is not limited to evaluate by following method.
Experimental example 1 derivant is to H
2o
2the protection of the neurocyte of damage
In Hydroperoxide injury model, detect Da Ma-20S-24 (R)-epoxy-3 β with mtt assay, 12 β, 25 triols, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25 tetrols are to H
2o
2the 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 CO
2incubator (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 (GIBCO Lot NO.460302), trypsin GIBCO Lot NO.F20020705), hyclone (GIBCO LotNO.721229), MTT (Sino-A-Biotel Lot NO.0793), DMSO (traditional Chinese medicines group), DMSO (Sigma Lot NO.038K2391), hydrogen peroxide (LotNO.20080610 of traditional Chinese medicines group)
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
Get in one bottle, cell in good condition exponential phase of growth, make cell suspension, and cell density is diluted to 1 × 10
5individual/ml, obtained cell suspension is inoculated on 96 orifice plates, puts constant temperature CO
2in incubator, cultivate 24 hours; add the tested medicine of variable concentrations; making ultimate density is 6 multiple holes of the each concentration of 0.1-100 μ M, cultivates 6 hours, continues to add hydrogen peroxide; every hole 10 μ l; final concentration is that 75 μ M-100 μ M, cultivate in incubator 16 hours; be light absorption value that 570nm place measure every hole with enzyme-linked immunosorbent assay instrument at wavelength according to mtt assay, and calculate the protection effect (reversion rate) of cell.
Protection effect %(reversion rate)=(not administration of model 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, the protective effect of N2a, and result is as Figure 1-4.
5, conclusion
At hydrogen peroxide differentiated PC12 cell, in the damage model of N2a cell, detect 20(S 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 of 25 tetrols to neurocyte, 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 stronger neurocyte protection effect, can be used as the effective ingredient of neurodegenerative diseases medicine.
Experimental example 2
Derivant is closed rats with bilateral common carotid artery to folder repeatedly and is coordinated sodium nitroprusside-induced hypotension method to copy the effect of intending vascular dementia model.
1, laboratory animal
Strain: clean level 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-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol.Preparation 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
Healthy male SD rat, body weight (300 ± 10) g, adaptability is fed modeling after a week, and be divided at random 9 groups, sham operated rats (Sham), model group (Model), aricept group (DNP), Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol low dose therapy group (S01-L), Da Ma-20S-24 (R)-epoxy-3 β, 12 β, dosage treatment group (S01-M) in 25-triol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol high-dose therapy group (S01-H), Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol low dose therapy group (S02-L), Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, dosage treatment group (S02-M) in 25-tetrol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol high-dose therapy group (S02-H), every group 15.Each group respectively at beginning administration in 3 days after modeling, be administered once 8 of every mornings, sham operated rats and model group give normal saline injection, and compounds for treating group is carried 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, the demonstration of escape latency experimental result, 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 S 01 and S02 and model group comparison, its escape latency time all significantly declines, total distance of swimming all obviously shortens, the target quadrant time of staying significantly improves, wearing platform number of times significantly increases, and middle high dose group effect is better than positive control drug aricept group, has remarkable pharmacologically active.
Experimental example 3
Derivant is to bilateral hippocampus injection A β
1-42copy the effect of alzheimer disease animal model
1, laboratory animal
Strain: clean level 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-triol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol.Preparation 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
Healthy male SD rat, body weight (300 ± 10) g, adaptability is fed modeling after a week, and be divided at random 9 groups, sham operated rats (Sham), model group (Model), aricept group (DNP), Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol low dose therapy group (S01-L), Da Ma-20S-24 (R)-epoxy-3 β, 12 β, dosage treatment group (S01-M) in 25-triol, Da Ma-20S-24 (R)-epoxy-3 β, 12 β, 25-triol high-dose therapy group (S01-H), Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol low dose therapy group (S02-L), Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, dosage treatment group (S02-M) in 25-tetrol, Da Ma-20S-24 (S)-epoxy-3 β, 6 β, 12 β, 25-tetrol high-dose therapy group (S02-H), every group 15.Each group respectively at beginning administration in 3 days after modeling, be administered once 8 of every mornings, sham operated rats and model group give normal saline injection, and compounds for treating group is carried 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, the demonstration of escape latency experimental result, 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 S 01 and S02 and model group comparison, its escape latency time all significantly declines, total distance of swimming all obviously shortens, the target quadrant time of staying significantly improves, wearing platform number of times significantly increases, and middle high dose group effect is better than positive control drug aricept group, has remarkable pharmacologically active.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore these amendments of, making without departing from theon the basis of the spirit of the present invention or. improve, all belong to the scope of protection of present invention.
Claims (6)
1. there is the protopanoxadiol derivative of formula (I), (II) structure in the application of preparing in treatment or prevention of neurodegenerative diseases medicine,
The name of the protopanoxadiol derivative shown in formula (I) is called Da Ma-20S-24 (R)-epoxy-3 β, 12 β, the name of the protopanoxadiol derivative shown in 25-triol, formula II is called Da Ma-20S-24 (S)-epoxy-3 β, 12 β, 25-triol.
2. there is Protopanaxatriol's derivant of formula III, (IV) structure in the application of preparing in treatment or prevention of neurodegenerative diseases medicine,
formula III
formula IV
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, the name of the Protopanaxatriol's derivant shown in 25-tetrol, 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, is characterized in that, described neurodegenerative diseases comprises parkinson disease, alzheimer disease or vascular dementia disease.
4. application according to claim 1 and 2, is characterized in that, described protopanoxadiol derivative or Protopanaxatriol's derivant and pharmaceutically acceptable carrier are made oral formulations or parenteral formulation.
5. application according to claim 4, is characterized in that, described oral formulations is capsule, tablet, pill, granule, Emulsion or suspensoid.
6. application according to claim 4, is characterized in that, described parenteral formulation is injection.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310044215.9A CN103961358B (en) | 2013-01-31 | 2013-01-31 | Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant |
| PCT/CN2014/071497 WO2014117699A1 (en) | 2013-01-31 | 2014-01-26 | Use of protopanoxadiol derivative and protopanaxatriol derivative in drug preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310044215.9A CN103961358B (en) | 2013-01-31 | 2013-01-31 | Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103961358A true CN103961358A (en) | 2014-08-06 |
| CN103961358B CN103961358B (en) | 2016-07-06 |
Family
ID=51231681
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310044215.9A Active CN103961358B (en) | 2013-01-31 | 2013-01-31 | Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103961358B (en) |
| WO (1) | WO2014117699A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074597A (en) * | 2016-06-13 | 2016-11-09 | 中山大学 | Sodium nitroprusside is as the purposes of indole amine 2,3-dioxygenase-1 inhibitor |
| CN107778340A (en) * | 2017-10-18 | 2018-03-09 | 中国科学院昆明植物研究所 | (20S, 24R) 20,24 epoxy dammarane 3 β, 12 β, 25 triols and its application |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2013
- 2013-01-31 CN CN201310044215.9A patent/CN103961358B/en active Active
-
2014
- 2014-01-26 WO PCT/CN2014/071497 patent/WO2014117699A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 刘金平: "国产西洋参茎叶皂苷分离.结构修饰及其生物活性研究", 《中国博士学位论文全文数据库.医药卫生辑》, 31 January 2007 (2007-01-31), pages 53 - 66 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074597A (en) * | 2016-06-13 | 2016-11-09 | 中山大学 | Sodium nitroprusside is as the purposes of indole amine 2,3-dioxygenase-1 inhibitor |
| CN107778340A (en) * | 2017-10-18 | 2018-03-09 | 中国科学院昆明植物研究所 | (20S, 24R) 20,24 epoxy dammarane 3 β, 12 β, 25 triols and its application |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014117699A1 (en) | 2014-08-07 |
| CN103961358B (en) | 2016-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2496144T5 (en) | Pirfenidone capsule formulation and pharmaceutically acceptable excipients | |
| TW200306801A (en) | Farnesoid X-activated receptor agonists | |
| US10869875B2 (en) | Oxysterols and Hedgehog signaling | |
| CN105859814A (en) | Obeticholic acid compound and pharmaceutical composition thereof | |
| CN108635332A (en) | A kind of preparation method of voglibose particle | |
| CN101775058A (en) | Preparation and application of pharmaceutic preparation of 11-carbonyl-betal- acetyl mastic acid and derivatives thereof extracted from frankincense | |
| CN103961358B (en) | Protopanoxadiol derivative, the application in pharmacy of Protopanaxatriol's derivant | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN104017045A (en) | Novel prodrug of steroid CYP 17 inhibitor as well as application and preparation method thereof | |
| CN102971296B (en) | Comprise the pharmaceutical composition of N-(4-(2-amino-3-chloropyridine-4-base oxygen base)-3-fluorophenyl)-4-oxyethyl group-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid amides | |
| CN111333694B (en) | Application of hederagenin derivative in medicine for resisting myocardial anoxia reoxygenation injury | |
| CN101597272A (en) | The potassium salt compound of Ailamode, its preparation method and medicinal application | |
| JPH01197438A (en) | Drug preparation for treatment of climacteric disturbance and hormone dependence tumor and for use as contraceptive, and production thereof | |
| EP3368543B1 (en) | Oxysterols and hedgehog signaling | |
| CN110590779B (en) | 3, 10 di-p-chlorophenyl 6, 12 diazatetracubane compound, and synthetic method, application and pharmaceutical composition thereof | |
| US20220133731A1 (en) | Acyl-coa synthetase 4 (acsl4) inhibitory compound | |
| CN104224796B (en) | Application of oleanane triterpene ester derivative in preparation for anti-neurodegeneration medicine | |
| CN108785317B (en) | Use of cortex Periplocae Radicis C21 steroid compound in preparation of IDO inhibitor | |
| CN108785322A (en) | Purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor | |
| CN113292621A (en) | Pharmaceutical crystal form of progesterone and application thereof | |
| CN110051680A (en) | It is a kind of for preventing and/or treating the drug, combination product and its application of Alzheimer disease | |
| CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| JP2657614B2 (en) | Aromatase inhibitor | |
| CN103860486A (en) | Letrozole orally disintegrating tablets and preparation method | |
| CN106188030A (en) | N (5 piperonyl thiazole 2 base) chlorinated amide derivant |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |