WO2014117699A1 - Use of protopanoxadiol derivative and protopanaxatriol derivative in drug preparation - Google Patents
Use of protopanoxadiol derivative and protopanaxatriol derivative in drug preparation Download PDFInfo
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- WO2014117699A1 WO2014117699A1 PCT/CN2014/071497 CN2014071497W WO2014117699A1 WO 2014117699 A1 WO2014117699 A1 WO 2014117699A1 CN 2014071497 W CN2014071497 W CN 2014071497W WO 2014117699 A1 WO2014117699 A1 WO 2014117699A1
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- epoxy
- derivative
- triol
- protopanaxatriol
- dharma
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Classifications
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- 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
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- 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
Definitions
- the present invention relates to the field of application of ginseng glycol compounds, and in particular to a
- Degenerative diseases of the central nervous system are a group of chronic progressive neurological diseases based on primary neuronal degeneration. These diseases mainly include Alzheimer's disease (AD) (commonly known as Alzheimer's disease), Parkinson's disease (PD), Huntington's disease (Huntington disease), and different types of spinal cerebellar ataxia ( Spinal cerebellar ataxias ), amyotrophic lateral sclerosis and spinal muscular atrophy.
- AD Alzheimer's disease
- PD Parkinson's disease
- Huntington's disease Huntington's disease
- spinal cerebellar ataxia Spinal cerebellar ataxias
- amyotrophic lateral sclerosis and spinal muscular atrophy.
- ND is caused by a variety of different reasons, including neuronal or glial cells can not provide adequate nutrition, impaired axonal transmission, excessive glutamate receptor activity, excessive levels of reactive oxygen species, metabolism Damage to pathways, reduced mitochondrial energy production, inadequate folding or reduced protein formation, inflammatory processes, viral infections, nuclear or mitochondrial DNA mutations, and inappropriate protein or lipid partial function due to incorrect processing of RNA or protein Factors such as loss or increase.
- RNA or protein Factors such as loss or increase.
- 20(S)-protopanaxadiol is one of the important aglycones of the diol group ginsenoside
- ZL200610027507.1 discloses the use of 20(S)-protopanaxadiol in antidepressant.
- ZL200510016774.4 discloses a synthetic method of Dama-20S-24(S)-epoxy-3 ⁇ , 12 ⁇ ,25-triol and its preparation for treating coronary heart disease, myocardial ischemia, ischemic shock, arrhythmia and Use in re-infested drugs, but does not disclose its use in the preparation of a medicament for preventing or treating a neurodegenerative disease. Summary of the invention
- An object of the present invention is to provide a 20(S)-protopanaxadiol derivative and a 20(S)-protopanaxatriol derivative for use in the preparation of a medicament for preventing or treating a neurodegenerative disease.
- the present inventors conducted intensive studies on 20(S)-protopanaxadiol derivatives and 20(S)-protopanaxatriol derivatives, and found that Dama-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol (dammara-20S-24(R)-epoxy-3p, 12p, 25-triol), Dharma-20S-24(S)-epoxy-3 ⁇ , 12 ⁇ ,25-triol ( dammara-20S-24(S)-epoxy-3p,12p,25-triol ), Dharma-20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol
- the present invention provides Damar-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ for preventing or treating neurodegenerative diseases. 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ ,25-tetraol, or Dharma-20S-24(R)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ , 25-tetraol.
- the present invention provides Dharma-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma- 20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol, or Dharma-20S-24(R)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol in the prevention or treatment of nerves New uses in degenerative diseases.
- the present invention provides Damar-20S-24(R)-epoxy-3 ⁇ ,12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ for preventing or treating neurodegenerative diseases. , 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol, or Dharma-20S-24(R)-epoxy A pharmaceutical composition of -3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol.
- the present invention provides Dharma-20S-24(R)-epoxy-3 ⁇ ,12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma -20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol, or daruma-20S-24(R)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol pharmaceutical composition Use in the prevention or treatment of neurodegenerative diseases.
- the name of the protopanaxadiol derivative represented by the formula (I) is Dama-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, and the protopanaxadiol derivative represented by the formula (II).
- the name is Dharma-20S-24(S)
- the name of the original ginseng triol derivative represented by formula (III) is Dama-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol
- the original ginseng triol derivative represented by formula (IV) The name of the substance is Dharma-20S-24(R)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol.
- the neurodegenerative diseases include Parkinson's disease, senile dementia, or cerebrovascular dementia.
- the protopanaxadiol derivative and the protopanaxatriol derivative of the present invention are prepared in a different preparation from a pharmaceutically acceptable carrier, such as an oral preparation or a parenteral preparation.
- the oral preparation is a capsule, a tablet, a pill, a granule, a powder, a syrup, a solution, an emulsion or a suspension.
- the parenteral preparation is an injection.
- the solution may be an oral solution.
- the original ginseng diol derivative and the original ginseng triol derivative of the present invention are used in two models of vascular dementia: repeated ratification of bilateral common carotid arteries combined with nitroprus depressurization to replicate vascular dementia model And bilateral hippocampal injection of ⁇ " 2 replication of Alzheimer's disease animal model can significantly improve the spatial exploration and orientation of rats. It has potential medicinal treatment for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and cerebral vascular dementia. Value, has broad development prospects.
- Figure 3 is an experimental example 1 of the present invention, 20 (S)-protopanaxatriol, dammar-20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol against 3 ⁇ 40 2 damage to PC12 cells Reversal rate
- Figure 4 is an experimental example 1 of the present invention, 20 (S)-protopanaxatriol, dammar-20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol against 3 ⁇ 40 2 damage to N2a cells Reversal rate.
- the materials used in the present invention are all conventional materials which can be purchased from the market, and the operation methods not involved are also conventional methods of operation in the art.
- the 70% ethanol used in the examples of the present invention is a volume fraction.
- the name of the protopanaxadiol derivative represented by the formula (I) is Dama-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, and the protopanaxadiol derivative represented by the formula (II).
- the name is Dharma-20S-24(S)-epoxy-3 ⁇ , 12 ⁇ ,25-triol.
- Preparation method Refer to Chinese patent 200510016774.4, accurately weigh 10g 20(S)-protopanaxadiol (Shanghai Traditional Chinese Medicine Innovation Research Center), dissolve in 250ml anhydrous dichloromethane, and add m-chloroperoxybenzoic acid 8g with stirring. . After stirring at room temperature for 24 hours, after completion of the reaction, the reaction solution was washed with 5% sodium hydrogencarbonate solution for 3 times.
- the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness ethyl acetate and petroleum ether 1:10-1 :1 (volume ratio) is an eluent for silica gel column chromatography to obtain the compound Dama-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol 4g (purity 95%), Dharma-20S -24(S)-epoxy-3?, 12?,25-triol 4 g (purity 95%).
- the name of the original ginseng triol derivative represented by formula (III) is Dama-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol
- the original ginseng triol derivative represented by formula (IV) The name of the substance is Dharma-20S-24(R)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol.
- Preparation method Refer to ZL 200410018038.8, accurately weigh 10g 20(S)-protosan ginseng triol (Shanghai Traditional Chinese Medicine Innovation Research Center), dissolve in 250ml anhydrous dichloromethane, and add 8g of m-chloroperoxybenzoic acid with stirring. After stirring at room temperature for 24 hours, the reaction mixture was washed with 5% sodium hydrogencarbonate solution for 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness.
- :1 volume ratio is an eluent for silica gel column chromatography to obtain the compound Dama-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol 4g (purity 95%), Dharma -20S-24(R)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol 4 g (purity 95%).
- excipients examples include: sugars such as lactose, white sugar, glucose, mannitol, sorbitol; corn starch, potato starch, starch derivatives such as X-starch, dextrin, and carboxymethyl starch; crystalline cellulose, Low-substituted hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, calcium carboxymethyl cellulose, cellulose derivatives such as internal cross-linked carboxymethyl cellulose; acacia; dextran; short Wake enzyme polysaccharide; silicates such as light silicic anhydride, synthetic aluminum silicate, aluminum aluminum orthosilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate.
- sugars such as lactose, white sugar, glucose, mannitol, sorbitol
- corn starch potato starch, starch derivatives such as X-starch, dextrin, and carboxymethyl
- binder examples include: a compound represented by the above-mentioned excipient; gelatin; polyvinylpyrrolidone; or polyethylene glycol.
- disintegrant examples include: a compound represented by the above-mentioned excipient; or a chemically modified starch or cellulose such as croscarmellose sodium, sodium carboxymethyl starch, or crosslinked polyvinylpyrrolidone; derivative.
- lubricant examples include: talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; magnesium aluminum silicate; waxes such as beeswax and cetyl wax; boric acid; ;
- dodecyl sulfate such as sodium dodecyl sulfate, magnesium sulfonate
- silicic acid such as silicic anhydride or silicic acid hydrate; or a starch derivative in the above excipient.
- the stabilizer examples include: parabens such as methylparaben, hydroxypropylpropyl ester; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; ; acetic anhydride; or sorbic acid.
- Flavoring odorants can be, for example, commonly used sweeteners, sours or flavors.
- the emulsifier may be, for example, Tween or Span.
- the suspending agent can be, for example, Tween 80 or sodium carboxymethylcellulose.
- the solvent for formulation may be, for example, water, ethanol or glycerin.
- RPMI1640 medium (GIBCO Lot NO.460302), trypsin (GIBCO Lot NO.F20020705), fetal bovine serum (GIBCO Lot N0.721229), MTT (Sino-A-Biotel Lot NO.0793), DMSO Group), DMSO (Sigma Lot NO.038K2391), hydrogen peroxide (National Pharmaceutical Group Lot ⁇ 20080610).
- the cell strain was provided by the cells of the Chinese Academy of Sciences.
- % protective effect (reversal rate) (cell inhibition rate in model non-administered group - cell inhibition rate in model drug sensitivity group) / cell inhibition rate in model drug sensitivity group ⁇ ⁇ %
- MTT assay was used to detect 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, Dharma-20S-24(R)- Epoxy-3 ⁇ ,12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol protective effect on nerve cells, found: Dharma-20S- 24(R)-epoxy-3 ⁇ ,12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ ,6 ⁇ ,12 ⁇ ,25-tetraol ratio 20 (S)-protopanaxadiol , 20 ( S ) - Pro-ginseng triol has stronger neuroprotective effects and can be used as an active ingredient in neurodegenerative diseases.
- Derivatives replicated the model of the vascular dementia model by repeatedly clamping the bilateral common carotid arteries in combination with the nitroprus down-pressure method.
- Test sample Dharma-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol Prepared according to the above method of the present invention. Positive control drug (Amway).
- Each group was started 3 days after model establishment, and the sham operation group and the model group were given saline injection.
- the compound treatment group was treated with 1 mg/kg (low dose), 5 mg/kg (middle dose), 25 mg/kg (high dose).
- Anritsu was administered with 1.667 mg/kg by intragastric administration. Behavioral testing was performed 28 days after modeling.
- Test sample Dharma-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol, Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol Prepared according to the above method of the present invention. Positive control drug (Amway).
- Healthy male SD rats weighing (300 ⁇ 10) g, were modeled after one week of adaptive feeding, and were randomly divided into 9 groups, sham operation group (Sham), model group (Model), Arisheng group (DNP), ⁇ -20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol low-dose treatment group (S01-L), Dharma-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ , 25-three Alcohol medium dose treatment group (S01-M), Dharma-20S-24(R)-epoxy-3 ⁇ , 12 ⁇ ,25-triol high dose treatment group (S01-H), Dharma-20S-24 (S )-Epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol low-dose treatment group (S02-L), Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-tetraol Treatment group (S02-M), Dharma-20S-24(S)-epoxy-3 ⁇ , 6 ⁇ , 12 ⁇ , 25-t
- Each group was started 3 days after model establishment, and the sham operation group and the model group were given saline injection.
- the compound treatment group was treated with 1 mg/kg (low dose), 5 mg/kg (middle dose), 25 mg/kg (high dose).
- Anritsu was administered with 1.667 mg/kg by intragastric administration. Behavioral testing was performed 28 days after modeling.
- the present invention provides an application of a protopanaxadiol derivative and a protopanaxatriol derivative for the preparation of a medicament for preventing or treating a neurodegenerative disease.
- Pharmacological experiments showed that the above derivatives showed stronger antioxidant activity in the 3 ⁇ 40 2 damage model of PC12 cells and N2a cells than 20(S)-protopanaxadiol, 20(S)-protopanaxatriol.
- the protopanaxadiol derivative and the protopanaxatriol derivative of the present invention have broad medicinal value for treating neurodegenerative diseases such as Parkinson's disease, senile dementia or cerebrovascular dementia diseases, and have broad development prospect.
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Abstract
Provided are uses of a protopanoxadiol derivative and protopanaxatriol derivative in the preparation of drugs for preventing or treating degenerative diseases of the central nervous system (ND). The protopanoxadiol derivative and protopanaxatriol derivative of the present invention have potential medicinal value for treating NDs such as Parkinson's disease (PD), Alzheimer's disease (AD), cerebrovascular dementia disease and the like, and have a great prospect for development.
Description
原人参二醇衍生物、 原人参三醇衍生物在制药中的应用 技术领域 Application of protopanaxadiol derivative and protopanaxatriol derivative in pharmaceutical industry
本发明涉及人参二醇类化合物的应用领域， 具体地说， 涉及一种 The present invention relates to the field of application of ginseng glycol compounds, and in particular to a
20(S)-原人参二醇衍生物及 20(S)-原人参三醇衍生物在制药中的新用 途； 属于医药领域。 背景技术 The new use of 20(S)-protopanaxadiol derivatives and 20(S)-protopanaxatriol derivatives in pharmaceuticals; Background technique
神经退行性疾病 ( Degenerative diseases of the central nervous system, ND )是一组以原发性神经元变性为基础的慢性进行性神经 系统疾病。 该类疾病主要包括阿尔茨海默氏病 （Alzheimer's disease, AD ) (俗称老年性痴呆）、 帕金森病 （Parkinson's disease , PD )、 Huntington舞蹈病 （ Huntington disease )、 不同类型脊髓小脑共济失调 ( spinal cerebellar ataxias ), 肌萎缩侧索硬化症 ( amyotrophic lateral sclerosis )及脊骨邃肌萎缩症 ( spinal muscular atrophy ) 等。 Degenerative diseases of the central nervous system (ND) are a group of chronic progressive neurological diseases based on primary neuronal degeneration. These diseases mainly include Alzheimer's disease (AD) (commonly known as Alzheimer's disease), Parkinson's disease (PD), Huntington's disease (Huntington disease), and different types of spinal cerebellar ataxia ( Spinal cerebellar ataxias ), amyotrophic lateral sclerosis and spinal muscular atrophy.
研究发现， ND是由多种不同原因导致的， 包括神经元或神经胶 质细胞不能提供充分的营养、 轴突传递功能受损、 谷氨酸受体活性过 高、 活性氧水平过高、 代谢通路受损、 线粒体能量产生减少、 折叠错 误的蛋白质形成增加或降解不充分、 炎症过程、 病毒感染、 细胞核或 线粒体 DNA突变以及 RNA或蛋白质的加工过程不正确所致的特殊蛋 白质或脂质部分功能的损失或增加等因素。虽然诱发这些疾病的病因 和病变部位不尽相同， 但它们都有一个共同的特征， 即都存在神经细 胞的严重损伤并导致加速死亡的特点。 The study found that ND is caused by a variety of different reasons, including neuronal or glial cells can not provide adequate nutrition, impaired axonal transmission, excessive glutamate receptor activity, excessive levels of reactive oxygen species, metabolism Damage to pathways, reduced mitochondrial energy production, inadequate folding or reduced protein formation, inflammatory processes, viral infections, nuclear or mitochondrial DNA mutations, and inappropriate protein or lipid partial function due to incorrect processing of RNA or protein Factors such as loss or increase. Although the causes and lesions of these diseases are different, they all have a common feature, that is, there are serious damages of nerve cells and lead to accelerated death.
目前对神经退行性疾病的机理及治疗已进行了大量的研究，但至 今尚无有效成熟的方法和药物来防治这种疾病，开发具有神经元保护 功能的药物对神经退行性疾病的治疗具有重大的意义。 At present, a lot of researches have been done on the mechanism and treatment of neurodegenerative diseases, but so far there are no effective mature methods and drugs to prevent and treat this disease. The development of drugs with neuroprotective functions is of great significance for the treatment of neurodegenerative diseases. The meaning.
20(S)-原人参二醇是二醇组人参皂苷的重要苷元之一， ZL200610027507.1公开了 20(S)-原人参二醇在抗抑郁方面的用途。
ZL200510016774.4公开了达玛 -20S-24(S)-环氧 -3β,12β,25-三醇的合成 方法及其在制备治疗冠心病、 心肌缺血、 缺血性休克、 心律不齐和再 灌损伤的药物中的用途，但是未公开其在制备预防或治疗神经退行性 疾病的药物中的用途。 发明内容 20(S)-protopanaxadiol is one of the important aglycones of the diol group ginsenoside, and ZL200610027507.1 discloses the use of 20(S)-protopanaxadiol in antidepressant. ZL200510016774.4 discloses a synthetic method of Dama-20S-24(S)-epoxy-3β, 12β,25-triol and its preparation for treating coronary heart disease, myocardial ischemia, ischemic shock, arrhythmia and Use in re-infested drugs, but does not disclose its use in the preparation of a medicament for preventing or treating a neurodegenerative disease. Summary of the invention
本发明的目的是提供一种 20(S)-原人参二醇衍生物以及 20(S)-原 人参三醇衍生物在制备预防或治疗神经退行性疾病药物中的应用。 SUMMARY OF THE INVENTION An object of the present invention is to provide a 20(S)-protopanaxadiol derivative and a 20(S)-protopanaxatriol derivative for use in the preparation of a medicament for preventing or treating a neurodegenerative disease.
本发明人对 20(S)-原人参二醇衍生物以及 20(S)-原人参三醇衍生 物进行了深入的研究， 结果发现， 达玛 -20S-24(R)-环氧 -3β,12β,25-三 醇 （dammara-20S-24(R)-epoxy-3p,12p,25-triol )、 达玛 -20S-24(S)-环氧 -3β,12β,25-三醇 （ dammara-20S-24(S)-epoxy-3p,12p,25-triol )、 达玛 -20S-24(S)- 环 氧 -3β,6β,12β,25- 四 醇 The present inventors conducted intensive studies on 20(S)-protopanaxadiol derivatives and 20(S)-protopanaxatriol derivatives, and found that Dama-20S-24(R)-epoxy-3β , 12β,25-triol (dammara-20S-24(R)-epoxy-3p, 12p, 25-triol), Dharma-20S-24(S)-epoxy-3β, 12β,25-triol ( dammara-20S-24(S)-epoxy-3p,12p,25-triol ), Dharma-20S-24(S)-epoxy-3β,6β,12β,25-tetraol
( dammara-20S-24(S)-epoxy-3 ,6 ,12 ,25-tetrol ) , 以 及 达 玛 -20S-24(R)- 环 氧 -3β,6β,12β,25- 四 醇(dammara-20S-24(S)-epoxy-3,6,12,25-tetrol), and 达玛-20S-24(R)-epoxy-3β,6β,12β,25-tetraol
( dammara-20S-24(R)-epoxy-3 ,6 ,12 ,25-tetrol )在制备作为预防或治 疗神经退行性疾病药物方面极其有用。 (dammara-20S-24(R)-epoxy-3,6,12,25-tetrol) is extremely useful in the preparation of a medicament for preventing or treating a neurodegenerative disease.
本发明提供用于预防或治疗神经退行性疾病的达玛 -20S-24(R)- 环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇、 或达玛 -20S-24(R)-环氧 -3β,6β,12β,25-四醇。 The present invention provides Damar-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β for preventing or treating neurodegenerative diseases. 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β, 12β,25-tetraol, or Dharma-20S-24(R)-epoxy-3β,6β,12β , 25-tetraol.
本发明提供达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25- 四醇、 或达玛 -20S-24(R)-环氧 -3β,6β,12β,25-四醇在预防或治疗神经退 行性疾病中的新用途。 The present invention provides Dharma-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 12β,25-triol, Dharma- 20S-24(S)-epoxy-3β,6β,12β,25-tetraol, or Dharma-20S-24(R)-epoxy-3β,6β,12β,25-tetraol in the prevention or treatment of nerves New uses in degenerative diseases.
本发明提供用于预防或治疗神经退行性疾病的包含达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,12β,25-三 醇、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇、 或达玛 -20S-24(R)-环氧
-3β,6β,12β,25-四醇的药物组合物。 The present invention provides Damar-20S-24(R)-epoxy-3β,12β,25-triol, Dharma-20S-24(S)-epoxy-3β for preventing or treating neurodegenerative diseases. , 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol, or Dharma-20S-24(R)-epoxy A pharmaceutical composition of -3β, 6β, 12β, 25-tetraol.
本发明提供包含达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,12β,25-三醇、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25- 四醇、 或达玛 -20S-24(R)-环氧 -3β,6β,12β,25-四醇的药物组合物在预防 或治疗神经退行性疾病中的用途。 The present invention provides Dharma-20S-24(R)-epoxy-3β,12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 12β,25-triol, Dharma -20S-24(S)-epoxy-3β,6β,12β,25-tetraol, or daruma-20S-24(R)-epoxy-3β,6β,12β,25-tetraol pharmaceutical composition Use in the prevention or treatment of neurodegenerative diseases.
其中， among them,
式（I)所示原人参二醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 式（II)所示原人参二醇衍生物的名称为达玛 -20S-24(S The name of the protopanaxadiol derivative represented by the formula (I) is Dama-20S-24(R)-epoxy-3β, 12β,25-triol, and the protopanaxadiol derivative represented by the formula (II). The name is Dharma-20S-24(S
式 (III)所示原人参三醇衍生物的名称为达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇、 式（IV)所示原人参三醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,6β, 12β,25-四醇。 The name of the original ginseng triol derivative represented by formula (III) is Dama-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol, and the original ginseng triol derivative represented by formula (IV) The name of the substance is Dharma-20S-24(R)-epoxy-3β, 6β, 12β, 25-tetraol.
所述神经退行性疾病包括帕金森病、老年性痴呆或脑血管性痴呆 疾病。 The neurodegenerative diseases include Parkinson's disease, senile dementia, or cerebrovascular dementia.
本发明所述原人参二醇衍生物及原人参三醇衍生物与药学上可 接受的载体制成不同的制剂， 比如口服制剂或胃肠外制剂。 The protopanaxadiol derivative and the protopanaxatriol derivative of the present invention are prepared in a different preparation from a pharmaceutically acceptable carrier, such as an oral preparation or a parenteral preparation.
所述口服制剂为胶囊剂、 片剂、 丸剂、 颗粒剂、 散剂、 糖浆剂、 溶液剂、 乳剂或混悬剂。
所述胃肠外制剂为注射剂。 The oral preparation is a capsule, a tablet, a pill, a granule, a powder, a syrup, a solution, an emulsion or a suspension. The parenteral preparation is an injection.
所述溶液剂可以为口服液。 The solution may be an oral solution.
经药理实验， 显示达玛 -20S-24(R)-环氧 -3β,12β,25-三醇， 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇在 PC12细胞， N2a细胞的 ¾02损伤 模型上相比于 20 ( S ) -原人参二醇， 表现出更强的抗氧化保护效果。 Pharmacological experiments show that Dama-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol In PC12 cells, the 3⁄40 2 damage model of N2a cells showed stronger antioxidant protection than 20(S)-protopanaxadiol.
本发明所述原人参二醇衍生物及原人参三醇衍生物，在两种血管 性痴呆模型：对反复夹闭大鼠双侧颈总动脉配合硝普纳降压法复制拟 血管性痴呆模型和双侧海马注射 Αβ"2复制老年性痴呆动物模型可 明显改善大鼠空间探索和定向能力。对治疗神经退行性疾病如帕金森 病、 老年性痴呆、 脑血管性痴呆疾病具有潜在的药用价值， 具有广阔 的开发前景。 附图说明 The original ginseng diol derivative and the original ginseng triol derivative of the present invention are used in two models of vascular dementia: repeated ratification of bilateral common carotid arteries combined with nitroprus depressurization to replicate vascular dementia model And bilateral hippocampal injection of Αβ" 2 replication of Alzheimer's disease animal model can significantly improve the spatial exploration and orientation of rats. It has potential medicinal treatment for neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and cerebral vascular dementia. Value, has broad development prospects.
图 1为本发明实验例 1中， 20 ( S ) -原人参二醇，达玛 -20S-24(R)- 环氧 -3β,12β, 25-三醇对 Η202损伤 PC12细胞的逆转率； Figure 1 of the present invention in Experimental Example 1, 20 (S) - protopanaxadiol, dammar -20S-24 (R) - epoxy -3β, 12β, 25- triol of Η 2 0 2 in PC12 cells Reversal rate
图 2为本发明实验例 1中， 20 ( S ) -原人参二醇，达玛 -20S-24(R)- 环氧 -3β,12β,25-三醇对 ¾02损伤 N2a细胞的逆转率； 2 is a reversal rate of 20(S)-protopanaxadiol, dammar-20S-24(R)-epoxy-3β, 12β,25-triol on 3⁄40 2 damaged N2a cells in Experimental Example 1 of the present invention. ;
图 3为本发明实验例 1中， 20 ( S ) -原人参三醇，达玛 -20S-24(S)- 环氧 -3β,6β,12β,25-四醇对 ¾02损伤 PC12细胞的逆转率； Figure 3 is an experimental example 1 of the present invention, 20 (S)-protopanaxatriol, dammar-20S-24(S)-epoxy-3β,6β,12β,25-tetraol against 3⁄40 2 damage to PC12 cells Reversal rate
图 4为本发明实验例 1中， 20 ( S ) -原人参三醇，达玛 -20S-24(S)- 环氧 -3β,6β,12β,25-四醇对 ¾02损伤 N2a细胞的逆转率。 Figure 4 is an experimental example 1 of the present invention, 20 (S)-protopanaxatriol, dammar-20S-24(S)-epoxy-3β,6β,12β,25-tetraol against 3⁄40 2 damage to N2a cells Reversal rate.
图 1~4中， 每组的柱形中， 左边柱相应地表示 20 ( S ) -原人参 二醇或 20 ( S ) -原人参三醇， 右边柱相应地表示达玛 -20S-24(R)-环氧 -3β,12β,25-三醇或达玛 -20S-24(S)-环氧 -3β,6β, 12β,25-四醇。 具体实施方式 In Figures 1 to 4, among the columns of each group, the left column correspondingly represents 20 (S)-proto-ginseng diol or 20 (S)-protopanaxatriol, and the right column correspondingly represents Dharma-20S-24 ( R)-Epoxy-3β, 12β,25-triol or Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol. detailed description
以下实施例用于说明本发明， 但不用来限制本发明的范围。 The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
本发明所用物料均为可以从巿场上购买得到的常规物料，未涉及 的操作方法也为本领域常规的操作方法。 The materials used in the present invention are all conventional materials which can be purchased from the market, and the operation methods not involved are also conventional methods of operation in the art.
本发明实施例所用 70%乙醇为体积分数。
本 The 70% ethanol used in the examples of the present invention is a volume fraction. this
式（I)所示原人参二醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 式（II)所示原人参二醇衍生物的名称为达玛 -20S-24(S)-环氧 -3β,12β,25-三醇。 The name of the protopanaxadiol derivative represented by the formula (I) is Dama-20S-24(R)-epoxy-3β, 12β,25-triol, and the protopanaxadiol derivative represented by the formula (II). The name is Dharma-20S-24(S)-epoxy-3β, 12β,25-triol.
其可以通过 ZL 200510016774.4中公开的方法或基于该方法的方 法来制造。 具体釆取的合成方法为： It can be produced by the method disclosed in ZL 200510016774.4 or the method based on the method. The specific synthesis method is:
制备方法参考中国专利 200510016774.4, 准确称量 10g 20(S)-原 人参二醇 （上海中药创新研究中心）， 溶于 250ml无水二氯甲垸中， 搅拌下加入间氯过氧苯甲酸 8 g。于室温下搅拌 24小时，反应完毕后， 反应液用 5%的碳酸氢纳溶液洗涤 3遍， 有机相用无水硫酸纳干燥后 浓缩至干， 以乙酸乙酯和石油醚 1 :10-1:1 (体积比）为洗脱剂进行硅 胶柱层析， 得化合物达玛 -20S-24(R)-环氧 -3β,12β,25-三醇 4g (纯度 95% ), 达玛 -20S-24(S)-环氧 -3β,12β,25-三醇 4g (纯度 95% )。 Preparation method Refer to Chinese patent 200510016774.4, accurately weigh 10g 20(S)-protopanaxadiol (Shanghai Traditional Chinese Medicine Innovation Research Center), dissolve in 250ml anhydrous dichloromethane, and add m-chloroperoxybenzoic acid 8g with stirring. . After stirring at room temperature for 24 hours, after completion of the reaction, the reaction solution was washed with 5% sodium hydrogencarbonate solution for 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness ethyl acetate and petroleum ether 1:10-1 :1 (volume ratio) is an eluent for silica gel column chromatography to obtain the compound Dama-20S-24(R)-epoxy-3β, 12β,25-triol 4g (purity 95%), Dharma-20S -24(S)-epoxy-3?, 12?,25-triol 4 g (purity 95%).
通过 ESI-MS和 NMR测定后，式 (I)化合物测定的物化数据如下： The physicochemical data determined by the compound of formula (I) after determination by ESI-MS and NMR are as follows:
ESI-MS m/z:477.47(M+H)" ¾ NMR (300 MHz, CDC13): δ 0.77 (s, 3 H),0.85(s, 3H), 0.90(s, 3 H), 0.97(s, 3 H), 0.98 (s, 3 H), 1.10(s, 3 H), 1.27 (s, 3 H), 1.28 (s, 3 H), 1.30-2.23(m,22H),3.40(d, 1H), 3.52(m, 1H), 3.84(d, 1H).13C NMR (300 MHz, CDC13): δ 33.5(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).
式 (II)化合物测定的物化数据如下： ESI-MS m / z: 477.47 (M + H) "¾ NMR (300 MHz, CDC1 3): δ 0.77 (s, 3 H), 0.85 (s, 3H), 0.90 (s, 3 H), 0.97 ( s, 3 H), 0.98 (s, 3 H), 1.10(s, 3 H), 1.27 (s, 3 H), 1.28 (s, 3 H), 1.30-2.23 (m, 22H), 3.40 (d , 1H), 3.52 (m, 1H), 3.84 (d, 1H). 13 C NMR (300 MHz, CDC1 3 ): δ 33.5 (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 determined by the compound of formula (II) are as follows:
ESI-MS m/z:477.47(M+H)" ¾ NMR (300 MHz, CDC13): δ 0.77 (s, 3 H),0.85(s, 3H), 0.90(s, 3 H), 0.97(s, 3 H), 0.98 (s, 3 H), 1.10(s, 3 H), 1.27 (s, 3 H), 1.28 (s, 3 H), 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 (300 MHz, CDC13): δ 33.5(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). ESI-MS m / z: 477.47 (M + H) "¾ NMR (300 MHz, CDC1 3): δ 0.77 (s, 3 H), 0.85 (s, 3H), 0.90 (s, 3 H), 0.97 ( s, 3 H), 0.98 (s, 3 H), 1.10(s, 3 H), 1.27 (s, 3 H), 1.28 (s, 3 H), 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). 13 C NMR (300 MHz, CDC1 3 ): δ 33.5 (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).
本 Ben
式 (III)所示原人参三醇衍生物的名称为达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇、 式（IV)所示原人参三醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,6β, 12β,25-四醇。 The name of the original ginseng triol derivative represented by formula (III) is Dama-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol, and the original ginseng triol derivative represented by formula (IV) The name of the substance is Dharma-20S-24(R)-epoxy-3β, 6β, 12β, 25-tetraol.
制备方法参考 ZL 200410018038.8,准确称量 10g 20(S)-原人参三 醇 （上海中药创新研究中心）， 溶于 250ml无水二氯甲垸中， 搅拌下 加入间氯过氧苯甲酸 8 g。 于室温下搅拌 24小时， 反应完毕后， 反应 液用 5%的碳酸氢纳溶液洗涤 3遍， 有机相用无水硫酸纳干燥后浓缩 至干， 以乙酸乙酯和石油醚 1:10-1:1 (体积比）为洗脱剂进行硅胶柱 层析， 得化合物达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇 4g (纯度 95% ), 达玛 -20S-24(R)-环氧 -3β,6β,12β,25-四醇 4g (纯度 95% )。 Preparation method Refer to ZL 200410018038.8, accurately weigh 10g 20(S)-protosan ginseng triol (Shanghai Traditional Chinese Medicine Innovation Research Center), dissolve in 250ml anhydrous dichloromethane, and add 8g of m-chloroperoxybenzoic acid with stirring. After stirring at room temperature for 24 hours, the reaction mixture was washed with 5% sodium hydrogencarbonate solution for 3 times. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness. :1 (volume ratio) is an eluent for silica gel column chromatography to obtain the compound Dama-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol 4g (purity 95%), Dharma -20S-24(R)-epoxy-3β, 6β, 12β, 25-tetraol 4 g (purity 95%).
通过 ESI-MS和 NMR测定后， 式 (III)化合物测定的物化数据如 下：
L
The physicochemical data determined by the compound of formula (III) after determination by ESI-MS and NMR are as follows: L
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'(HI ΐ -9 ΐ
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669JI/ OZ OAV
剂等添加物。 669JI/ OZ OAV Additives such as agents.
赋形剂的例子包括： 乳糖、 白糖、 葡萄糖、 甘露醇、 山梨糖醇等 糖类； 玉米淀粉、 马铃薯淀粉、 （X-淀粉、 糊精、 羧甲基淀粉等淀粉衍 生物； 结晶纤维素、 低取代羟丙基纤维素、 羟丙甲纤维素、 羧甲基纤 维素、 羧甲基纤维素钙、 内部交联羧甲基纤维素纳等纤维素衍生物； 阿拉伯树胶； 葡聚糖； 短醒酶多糖； 轻质硅酸酐、 合成硅酸铝、 铝正 硅酸镁等硅酸盐类； 磷酸钙等磷酸盐类； 碳酸钙等碳酸盐类； 或者硫 酸钙等硫酸盐类。 Examples of the excipient include: sugars such as lactose, white sugar, glucose, mannitol, sorbitol; corn starch, potato starch, starch derivatives such as X-starch, dextrin, and carboxymethyl starch; crystalline cellulose, Low-substituted hydroxypropyl cellulose, hypromellose, carboxymethyl cellulose, calcium carboxymethyl cellulose, cellulose derivatives such as internal cross-linked carboxymethyl cellulose; acacia; dextran; short Wake enzyme polysaccharide; silicates such as light silicic anhydride, synthetic aluminum silicate, aluminum aluminum orthosilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate.
粘合剂的例子包括： 作为上述的赋形剂所示的化合物； 明胶； 聚 乙烯吡咯垸酮； 或者聚乙二醇。 Examples of the binder include: a compound represented by the above-mentioned excipient; gelatin; polyvinylpyrrolidone; or polyethylene glycol.
崩解剂的例子包括： 作为上述的赋形剂所示的化合物； 或者， 交 联羧甲纤维素纳、 羧甲基淀粉纳、 交联聚乙烯吡咯垸酮等经化学修饰 的淀粉或纤维素衍生物。 Examples of the disintegrant include: a compound represented by the above-mentioned excipient; or a chemically modified starch or cellulose such as croscarmellose sodium, sodium carboxymethyl starch, or crosslinked polyvinylpyrrolidone; derivative.
润滑剂的例子包括： 滑石； 硬脂酸； 硬脂酸钙、 硬脂酸镁等硬脂 酸金属盐； 胶态硅石； 硅酸镁铝； 蜂蜡、 鲸蜡等蜡类； 硼酸； 乙二醇； Examples of the lubricant include: talc; stearic acid; stearic acid metal salts such as calcium stearate and magnesium stearate; colloidal silica; magnesium aluminum silicate; waxes such as beeswax and cetyl wax; boric acid; ;
亮氨酸； 十二垸基硫酸纳、 十二垸基硫酸镁等十二垸基硫酸盐； 硅酸 酐、 硅酸水合物等硅酸类； 或者， 上述赋形剂中的淀粉衍生物。 Leucine; dodecyl sulfate such as sodium dodecyl sulfate, magnesium sulfonate; silicic acid such as silicic anhydride or silicic acid hydrate; or a starch derivative in the above excipient.
稳定剂的例子包括： 羟苯甲酯、 羟苯丙酯等对羟基苯甲酸酯类； 氯丁醇、 苄醇、 苯乙醇等醇类； 苯扎氯铵； 苯酚、 甲酚等酚类； 硫柳 汞； 乙酸酐； 或者山梨酸。 Examples of the stabilizer include: parabens such as methylparaben, hydroxypropylpropyl ester; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; ; acetic anhydride; or sorbic acid.
矫味矫嗅剂例如可以是： 常用的甜味料、 酸味料或香料。 Flavoring odorants can be, for example, commonly used sweeteners, sours or flavors.
乳化剂例如可以是： 吐温或司盘等。 The emulsifier may be, for example, Tween or Span.
悬浮剂例如可以是： 吐温 80或羧甲基纤维素纳。 The suspending agent can be, for example, Tween 80 or sodium carboxymethylcellulose.
制剂用溶剂例如可以是： 水、 乙醇或甘油。 The solvent for formulation may be, for example, water, ethanol or glycerin.
实施例 1 Example 1
10g达玛 -20S-24(R)-环氧 -3β,12β,25-三醇， 力 P20g乳糖， 混匀， 以
70%乙醇为粘合剂， 制粒， 装入胶囊， 即得胶囊剂， 每粒含 20(S)-原 人参二醇衍生物 20mg。 10g Dharma-20S-24(R)-epoxy-3β,12β,25-triol, force P20g lactose, mix, 70% ethanol is used as a binder, granulated, and encapsulated into capsules, each containing 20 mg of 20 (S)-protopanaxadiol derivative.
实施例 2 Example 2
10g达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇， 加 20g乳糖, 混匀， 以 70%乙醇为粘合剂， 制粒， 装入胶囊， 即得胶囊剂， 每粒含 20(S)- 原人参三醇衍生物 20mg。 10g Dama-20S-24(S)-epoxy-3β,6β,12β,25-tetraol, add 20g lactose, mix, use 70% ethanol as binder, granulate, capsule, get A capsule containing 20 mg of 20 (S)-protopanaxatriol derivative per capsule.
实施例 3 Example 3
10g达玛 -20S-24(R)-环氧 -3β,12β,25-三醇， 加 20g乳糖, 混匀， 以 70%乙醇为粘合剂， 制粒， 干燥， 加入 5g硬脂酸镁， 压片， 即得片剂， 每片含 20(S)-原人参二醇衍生物 50mg。 10g Dama-20S-24(R)-epoxy-3β,12β,25-triol, add 20g lactose, mix, use 70% ethanol as binder, granulate, dry, add 5g magnesium stearate , tableting, that is, tablets, each containing 20 (S) - protopanaxadiol derivative 50mg.
实施例 4 Example 4
10g达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇， 加 20g乳糖, 混匀， 以 70%乙醇为粘合剂， 制粒， 干燥， 加入 5g硬脂酸镁， 压片， 即得片 剂， 每片含 20(S)-原人参三醇衍生物 50mg。 10g Dama-20S-24(S)-epoxy-3β,6β,12β,25-tetraol, add 20g lactose, mix, use 70% ethanol as binder, granulate, dry, add 5g stearin Magnesium, tablets, tablets, each containing 20 (S) - protopanaxatriol derivative 50 mg.
实施例 5 Example 5
10g吐温， 溶于水中， 加入 10g达玛 -20S-24(R)-环氧 -3β,12β,25-三 醇， 研磨制成初乳， 再加水至 1000ml, 即得口服液。 10 g of Tween, dissolved in water, added 10 g of Dama -20S-24(R)-epoxy-3β, 12β,25-triol, ground to make colostrum, and then add water to 1000 ml, which is an oral solution.
实施例 6 Example 6
10g吐温， 溶于水中， 加入 10g达玛 -20S-24(S)-环氧 -3β,6β,12β,25- 四醇， 研磨制成初乳， 再加水至 1000ml, 即得口服液。 10g Tween, dissolved in water, adding 10g of Dama -20S-24(S)-epoxy-3β,6β,12β,25-tetraol, ground to make colostrum, add water to 1000ml, that is, get oral liquid.
实施例 7 Example 7
10g吐温，溶于注射用水，加入 10g达玛 -20S-24(R)-环氧 -3β,12β,25- 三醇， 研磨制成初乳， 再加注射用水至 5000ml, 经过过滤， 灭菌， 灌 封后即得注射液。 10g Tween, dissolved in water for injection, add 10g Dama-20S-24(R)-epoxy-3β, 12β,25-triol, grind to make colostrum, add water for injection to 5000ml, filter, extinction Bacteria, after the potting, the injection is obtained.
以下通过本领域典型实验模型来评价本发明的药理药效学效果， 但本发明的药理药效学效果不限于用下述方法来评价。
实验例 1 The pharmacological effects of the present invention are evaluated by a typical experimental model in the art, but the pharmacodynamic effects of the present invention are not limited to evaluation by the following methods. Experimental example 1
衍生物对 ¾02损伤的神经细胞的保护 Protection of 3⁄40 2 damaged nerve cells by derivatives
在过氧化氢损伤模型中， 用 MTT 法检测达玛 -20S-24(R)-环氧 -3β,12β,25-三醇，达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇对 ¾02损伤 的 PC12细胞， N2a细胞的保护作用。 In the hydrogen peroxide damage model, DMT-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β were detected by MTT assay. , 12β, 25-tetraol on the protection of 3⁄40 2 damaged PC12 cells, N2a cells.
1、 实验材料： 1. Experimental materials:
①仪器： 洁净工作台 (上海淀山湖净化设备厂)， 恒温 C02培养箱 (美国 Forma ) ,酶联免疫检测仪 (美国 BioTek),倒置生物显微镜（重 庆光学仪器）， 台式恒温摇床 (太仓巿科教器材厂)。 1 Instruments: Clean Workbench (Shanghai Dianshan Lake Purification Equipment Factory), constant temperature C0 2 incubator (American Forma), enzyme-linked immunosorbent assay (BioTek, USA), inverted biological microscope (Chongqing optical instrument), bench-top constant temperature shaker (Taicang)巿Science and Education Equipment Factory).
②试剂： RPMI1640培养基（GIBCO Lot NO.460302 ), 胰蛋白 酶 （ GIBCO Lot NO.F20020705 ) , 胎牛血清 （ GIBCO Lot N0.721229 ), MTT(Sino-A-Biotel Lot NO.0793), DMSO 国药集 团）， DMSO (Sigma Lot NO.038K2391), 过氧化氢 （国药集团 Lot ΝΟ·20080610 )。 2 Reagents: RPMI1640 medium (GIBCO Lot NO.460302), trypsin (GIBCO Lot NO.F20020705), fetal bovine serum (GIBCO Lot N0.721229), MTT (Sino-A-Biotel Lot NO.0793), DMSO Group), DMSO (Sigma Lot NO.038K2391), hydrogen peroxide (National Pharmaceutical Group Lot ΝΟ·20080610).
③细胞株： 细胞株由中科院细胞所提供。 3 cell strain: The cell strain was provided by the cells of the Chinese Academy of Sciences.
2、 实验样品： 2. Experimental samples:
20 ( S ) -原人参二醇， 20 ( S ) -原人参三醇， 达玛 -20S-24(R)-环 氧 -3β, 12β, 25-三醇， 达玛 -20S-24(S)-环氧 -3β, 6β, 12β, 25-四醇。 各化合物经 DMSO溶解后中， 稀释 4°C保存。 20 ( S ) - Protopanaxadiol, 20 ( S ) - Protopanaxatriol, Dharma-20S-24(R)-Epoxy-3β, 12β, 25-triol, Dharma-20S-24(S )-epoxy-3β, 6β, 12β, 25-tetraol. Each compound was dissolved in DMSO and stored at 4 ° C.
3、 实验方法 3. Experimental methods
取处于指数生长期状态良好的细胞一瓶， 制成细胞悬液， 并将细 胞密度稀释至 lxlO5个 /ml,取细胞悬液接种于 96孔板上，置恒温 C02 培养箱中培养 24 小时， 加入不同浓度的受试药物， 使最终浓度为 0.1-100μΜ每个浓度 6个复孔， 培养 6小时， 继续加入过氧化氢， 每 孔 ΙΟμΙ, 终浓度为, 75μΜ-100μΜ, 培养箱中培养 16小时,按照 ΜΤΤ 法用酶联免疫检测仪在波长为 570nm处测定每孔的吸光值， 并计算 细胞的保护效果（逆转率）。
保护效果％ (逆转率） = (模型不给药组细胞抑制率 -模型药敏组 细胞抑制率） /模型药敏组细胞抑制率 χ ΐοο% Take a bottle of cells in good exponential growth phase, make a cell suspension, and dilute the cell density to lxlO 5 / ml, inoculate the cell suspension in 96-well plate, and culture in a constant temperature C0 2 incubator. Hours, add different concentrations of test drugs, the final concentration is 0.1-100μΜ 6 replicates per concentration, culture for 6 hours, continue to add hydrogen peroxide, each well ΙΟμΙ, the final concentration is 75μΜ-100μΜ, in the incubator After culturing for 16 hours, the absorbance of each well was measured by an enzyme-linked immunosorbent assay at a wavelength of 570 nm, and the protective effect (reversal rate) of the cells was calculated. % protective effect (reversal rate) = (cell inhibition rate in model non-administered group - cell inhibition rate in model drug sensitivity group) / cell inhibition rate in model drug sensitivity group χ ΐοο%
4、 实验结果 4, the experimental results
根据 MTT法测试结果， 计算 20 ( S ) -原人参二醇， 20 ( S ) -原 人参三醇， 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇， 达玛 -20S-24(S)-环 氧 -3β,6β,12β,25-四醇对过氧化氢损伤高分化 PC12细胞， N2a的保护 作用， 结果如图 1-4所示。 According to the MTT test results, calculate 20 (S)-protopanaxadiol, 20 (S)-protopanaxatriol, Dharma-20S-24(R)-epoxy-3β, 12β,25-triol, up to Ma-20S-24(S)-epoxy-3β,6β,12β,25-tetraol inhibited the protective effect of hydrogen peroxide on highly differentiated PC12 cells and N2a. The results are shown in Figure 1-4.
5、 结论 5 Conclusion
在过氧化氢高分化 PC12细胞， N2a细胞的损伤模型中， 用 MTT 法检测 20 ( S ) -原人参二醇， 20 ( S ) -原人参三醇， 达玛 -20S-24(R)- 环氧 -3β,12β,25-三醇， 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇对神经 细胞的保护作用， 结果发现： 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇， 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇比 20 ( S ) -原人参二醇, 20 ( S ) -原人参三醇具有更强神经细胞保护效果， 可以作为神经退行性疾病 药物的有效成分。 In the damage model of hydrogen peroxide-differentiated PC12 cells and N2a cells, MTT assay was used to detect 20(S)-protopanaxadiol, 20(S)-protopanaxatriol, Dharma-20S-24(R)- Epoxy-3β,12β,25-triol, Dharma-20S-24(S)-epoxy-3β,6β,12β,25-tetraol protective effect on nerve cells, found: Dharma-20S- 24(R)-epoxy-3β,12β,25-triol, Dharma-20S-24(S)-epoxy-3β,6β,12β,25-tetraol ratio 20 (S)-protopanaxadiol , 20 ( S ) - Pro-ginseng triol has stronger neuroprotective effects and can be used as an active ingredient in neurodegenerative diseases.
实验例 2 Experimental example 2
衍生物对反复夹闭大鼠双侧颈总动脉配合硝普纳降压法复制拟 血管性痴呆模型的作用。 Derivatives replicated the model of the vascular dementia model by repeatedly clamping the bilateral common carotid arteries in combination with the nitroprus down-pressure method.
1、 实验动物 1. Experimental animals
品系： 清洁级昆明小鼠， 性别： 雄性， 体重： 18-22g, 来源： 上 海斯莱克实验动物有 限责任公司 提供 ， 许可证号 ： SCXK (沪) 2007-0005。 Line: Clean-grade Kunming mice, gender: male, weight: 18-22g, source: Shanghai Slack Laboratory Animals Limited Liability Company, License No.: SCXK (Shanghai) 2007-0005.
2、 药品 2, drugs
受试样品：达玛 -20S-24(R)-环氧 -3β,12β,25-三醇，达玛 -20S-24(S)- 环氧 -3β,6β,12β,25-四醇， 按本发明上述方法制备。 阳性对照药 (安理 中）。 Test sample: Dharma-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol Prepared according to the above method of the present invention. Positive control drug (Amway).
3、 实验方法
健康雄性 SD大鼠， 体重 （300±10 ) g, 适应性喂养一周后造模， 3. Experimental methods Healthy male Sprague-Dawley rats, weighing (300±10) g, were modeled after one week of adaptive feeding.
并随机分为 9组，假手术组（ Sham )、模型组（ Model )、安理申组（ DNP )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇低剂量治疗组 （S01-L )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇中剂量治疗组 （ S01-M )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇高剂量治疗组 ( S01-H )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇低剂量治疗组 （ S02-L )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇中剂量治疗组 （ S02-M )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇高剂量治疗组 ( S02-H ), 每组 15 只。 各组分别于造模后 3天开始给药， 假手术组和模型组给予生理盐 水注射，化合物治疗组按 lmg/kg (低剂量）、 5mg/kg(中剂量）、25mg/kg (高剂量）进行腹腔注射， 安理申给予 1.667mg/kg灌胃给药。 造模 后 28天进行行为学检测。 They were randomly divided into 9 groups: Sham, Model, DRP, Dharma-20S-24(R)-Epoxy-3β, 12β,25-triol low dose. Treatment group (S01-L), Dharma-20S-24(R)-epoxy-3β, 12β,25-triol medium dose treatment group (S01-M), Dharma-20S-24(R)-ring Oxygen-3β, 12β, 25-triol high-dose treatment group (S01-H), Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol low-dose treatment group (S02- L), Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol medium dose treatment group (S02-M), Dharma-20S-24(S)-epoxy-3β , 6β, 12β, 25-tetraol high-dose treatment group (S02-H), 15 in each group. Each group was started 3 days after model establishment, and the sham operation group and the model group were given saline injection. The compound treatment group was treated with 1 mg/kg (low dose), 5 mg/kg (middle dose), 25 mg/kg (high dose). For intraperitoneal injection, Anritsu was administered with 1.667 mg/kg by intragastric administration. Behavioral testing was performed 28 days after modeling.
4、 实验结果 假手术组 模型组 DNP S01-L S01-M S01-H S02-L S02-M S02-H 4. Experimental results Sham operation group Model group DNP S01-L S01-M S01-H S02-L S02-M S02-H
13.89±3.41 36.22±9.41* 17.75±3.72** 22.61±9.12* 16.64±7.27* 15.24±3.83* 30.80±1.65 20.92±6.12* 17.26±9.54* 潜伏期 13.89±3.41 36.22±9.41* 17.75±3.72** 22.61±9.12* 16.64±7.27* 15.24±3.83* 30.80±1.65 20.92±6.12* 17.26±9.54* Latency
204.24±68.42 533.22±78.78* 241.76±75.31* 231.87±10.84 214.89i45.45* 207.63±55.59* 298.06±166.38 237.22±61.95* 230.58±62.01* 总路程 204.24±68.42 533.22±78.78* 241.76±75.31* 231.87±10.84 214.89i45.45* 207.63±55.59* 298.06±166.38 237.22±61.95* 230.58±62.01* Total distance
目标象限 34.22±3.73 13.25±2.83* 26.32±6.90* 20.77±2.83* 27.78±4.84* 30.03^.20** 23.89±1.93** 25.21±6.77** 27.29±2.51* 停留时间 Target quadrant 34.22±3.73 13.25±2.83* 26.32±6.90* 20.77±2.83* 27.78±4.84* 30.03^.20** 23.89±1.93** 25.21±6.77** 27.29±2.51* Residence time
9 2.58 4±0.82* 6±1.67* 6.25±2.06* 6.6±0.89* 7.4±0.89* 5±1* 6±2* 7.5±1 * 注： 与相应对照的组别比较， < 0.05, * < 0.01 9 2.58 4±0.82* 6±1.67* 6.25±2.06* 6.6±0.89* 7.4±0.89* 5±1* 6±2* 7.5±1 * Note: Compared with the corresponding control group, < 0.05, * < 0.01
从模型实验结果看， 逃避潜伏期实验结果显示， 模型组逃避潜伏 From the experimental results of the model, the results of the escape latency experiment show that the model group escapes the latent
期时间明显高于假手术组（P < 0.05 ), 提示造模成功。 阳性对照药安 理申组 （DNP ) 的治疗结果与模型组相比有显著性差异（Ρ < 0.05 )。 各用药组中， 化合物 S01和 S02各剂量与模型组比较，逃避潜伏期时 间均显著下降， 游泳总路程均明显缩短； 各剂量目标象限停留时间显 著提高， 穿台次数显著增加， 可明显改善大鼠空间探索和定向能力。 且中高剂量组效果优于阳性对照药安理申组， 具有显著药理活性。
实验例 3 The time was significantly higher than that of the sham operation group (P < 0.05), suggesting that the model was successful. There was a significant difference in the treatment outcome of the positive control drug (RNP) compared with the model group (Ρ < 0.05). In each drug group, compared with the model group, the doses of the compounds S01 and S02 were significantly decreased, and the total swimming distance was significantly shortened. The dwell time of each dose target quadrant was significantly increased, the number of piercings was significantly increased, and the rats were significantly improved. Space exploration and orientation capabilities. And the middle and high dose group was better than the positive control drug An Lishen group, and had significant pharmacological activity. Experimental example 3
衍生物对双侧海马注射 Αβ"2复制老年性痴呆动物模型的作用Effect of Derivatives on Bilateral Hippocampal Injection of Αβ" 2 Replication of Animal Model of Alzheimer's Disease
1、 实验动物 1. Experimental animals
品系： 清洁级昆明小鼠， 性别： 雄性， 体重： 18-22g, 来源： 上 海斯莱克实验动物有 限责任公司 提供 ， 许可证号 ： SCXK (沪) 2007-0005。 Line: Clean-grade Kunming mice, gender: male, weight: 18-22g, source: Shanghai Slack Laboratory Animals Limited Liability Company, License No.: SCXK (Shanghai) 2007-0005.
2、 药品 2, drugs
受试样品：达玛 -20S-24(R)-环氧 -3β,12β,25-三醇，达玛 -20S-24(S)- 环氧 -3β,6β,12β,25-四醇， 按本发明上述方法制备。 阳性对照药 (安理 中）。 Test sample: Dharma-20S-24(R)-epoxy-3β, 12β,25-triol, Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol Prepared according to the above method of the present invention. Positive control drug (Amway).
3、 实验方法 3. Experimental methods
健康雄性 SD大鼠， 体重 （300±10 ) g, 适应性喂养一周后造模， 并随机分为 9组，假手术组（ Sham )、模型组（ Model )、安理申组（ DNP )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇低剂量治疗组 （S01-L )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇中剂量治疗组 （ S01-M )、 达玛 -20S-24(R)-环氧 -3β,12β,25-三醇高剂量治疗组 ( S01-H )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇低剂量治疗组 （ S02-L )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇中剂量治疗组 （ S02-M )、 达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇高剂量治疗组 ( S02-H ), 每组 15 只。 各组分别于造模后 3天开始给药， 假手术组和模型组给予生理盐 水注射，化合物治疗组按 lmg/kg (低剂量）、 5mg/kg(中剂量）、25mg/kg (高剂量）进行腹腔注射， 安理申给予 1.667mg/kg灌胃给药。 造模 后 28天进行行为学检测。 Healthy male SD rats, weighing (300±10) g, were modeled after one week of adaptive feeding, and were randomly divided into 9 groups, sham operation group (Sham), model group (Model), Arisheng group (DNP),玛-20S-24(R)-epoxy-3β, 12β,25-triol low-dose treatment group (S01-L), Dharma-20S-24(R)-epoxy-3β, 12β, 25-three Alcohol medium dose treatment group (S01-M), Dharma-20S-24(R)-epoxy-3β, 12β,25-triol high dose treatment group (S01-H), Dharma-20S-24 (S )-Epoxy-3β, 6β, 12β, 25-tetraol low-dose treatment group (S02-L), Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol Treatment group (S02-M), Dharma-20S-24(S)-epoxy-3β, 6β, 12β, 25-tetraol high-dose treatment group (S02-H), 15 rats in each group. Each group was started 3 days after model establishment, and the sham operation group and the model group were given saline injection. The compound treatment group was treated with 1 mg/kg (low dose), 5 mg/kg (middle dose), 25 mg/kg (high dose). For intraperitoneal injection, Anritsu was administered with 1.667 mg/kg by intragastric administration. Behavioral testing was performed 28 days after modeling.
4、 实验结果
假手术组 模型组 DNP S01-L S01-M S01-H S02-L S02-M S02-H 逃避 4, the experimental results Sham operation group model group DNP S01-L S01-M S01-H S02-L S02-M S02-H escape
L 13.86±11.73 32.56±13.20 19.35±10.95* 18.92±5.52* 18.67±6.38* 16.90±2.83* 21.67±5.88 15.55±13.91* 13.32±5.43* 潜伏期 L 13.86±11.73 32.56±13.20 19.35±10.95* 18.92±5.52* 18.67±6.38* 16.90±2.83* 21.67±5.88 15.55±13.91* 13.32±5.43* Incubation period
游泳 Swim
134.80±60.12 707.84±374.65 477.48±337.88* 380.37±172.56* 292.28±72.01 * 243.20±92.81* 478.85±162.62 401.98±309.03* 356.63±63.48* 总路程 134.80±60.12 707.84±374.65 477.48±337.88* 380.37±172.56* 292.28±72.01 * 243.20±92.81* 478.85±162.62 401.98±309.03* 356.63±63.48*
目标象限 Target quadrant
37.15±2.43 17.46±3.45 25.10±2.86* 23.79±3.38* 27.45±6.41 ** 30.51±4.28** 21.39±3.57* 26.77±1.16* 29.55±2.36* 停留时间 37.15±2.43 17.46±3.45 25.10±2.86* 23.79±3.38* 27.45±6.41 ** 30.51±4.28** 21.39±3.57* 26.77±1.16* 29.55±2.36* Residence time
穿^ ·次 Wear ^ · times
4.25±1.26 2.57±1.13 3±2.37* 2.86±0.90* 3.75±1.91 5.29±1.83** 3.43±2.37* 3.75±1.26 5.75±1.50** _^ 4.25±1.26 2.57±1.13 3±2.37* 2.86±0.90* 3.75±1.91 5.29±1.83** 3.43±2.37* 3.75±1.26 5.75±1.50** _^
注： 与相应对照的组别比较 0.05， *> < 0.01 Note: Comparison with the corresponding control group 0.05, *> < 0.01
从模型实验结果看， 逃避潜伏期实验结果显示， 模型组逃避潜伏 期时间明显高于假手术组（P < 0.05 ), 提示造模成功。 阳性对照药安 理申组 （DNP ) 的治疗结果与模型组相比有显著性差异（Ρ < 0.05 )。 各用药组中， 化合物 S01和 S02各剂量与模型组比较，逃避潜伏期时 间均显著下降， 游泳总路程均明显缩短； 而各剂量目标象限停留时间 显著提高，穿台次数显著增加，可明显改善大鼠空间探索和定向能力。 且中高剂量组效果优于阳性对照药安理申组， 具有显著药理活性。 From the experimental results of the model, the results of the escape latency test showed that the escape time of the model group was significantly higher than that of the sham operation group (P < 0.05), suggesting that the model was successful. The positive control group (DNP) treatment results were significantly different from the model group (Ρ < 0.05). In each drug group, compared with the model group, the doses of the compounds S01 and S02 were significantly decreased, and the total swimming distance was significantly shortened. The dwell time of each dose target was significantly increased, and the number of piercings was significantly increased, which could significantly improve. Mouse space exploration and orientation capabilities. And the middle and high dose group was better than the positive control drug An Lishen group, and had significant pharmacological activity.
而达玛 -20S-24(S)-环氧 -3β,12β,25-三醇与达玛 -20S-24(R)-环氧 Dama -20S-24(S)-epoxy-3β,12β,25-triol and Dharma-20S-24(R)-epoxy
-3β,12β,25-三醇的效果类似，达玛 -20S-24(R)-环氧 -3β,6β,12β,25-四醇" 的活性与达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇的效果类似。 工业实用性 The effect of -3β, 12β,25-triol is similar, and the activity of Dharma-20S-24(R)-epoxy-3β, 6β, 12β, 25-tetraol” and Dama-20S-24(S)- Epoxy-3β, 6β, 12β, 25-tetraol have similar effects. Industrial Applicability
本发明提供了一种原人参二醇衍生物及原人参三醇衍生物在制 备预防或治疗神经退行性疾病药物中的应用。 经药理实验结果显示， 上述衍生物在 PC12细胞， N2a细胞的 ¾02损伤模型上相比于 20( S ) -原人参二醇， 20(S)-原人参三醇表现出更强的抗氧化保护效果； 在两 种血管性痴呆模型：反复夹闭大鼠双侧颈总动脉配合硝普纳降压法复 制拟血管性痴呆模型和双侧海马注射 APi_ 42复制老年性痴呆动物模 型可改善大鼠空间探索和定向能力。本发明所述原人参二醇衍生物及 原人参三醇衍生物， 对治疗神经退行性疾病如帕金森病、 老年性痴呆 或脑血管性痴呆疾病等具有潜在的药用价值， 具有广阔的开发前景。
The present invention provides an application of a protopanaxadiol derivative and a protopanaxatriol derivative for the preparation of a medicament for preventing or treating a neurodegenerative disease. Pharmacological experiments showed that the above derivatives showed stronger antioxidant activity in the 3⁄40 2 damage model of PC12 cells and N2a cells than 20(S)-protopanaxadiol, 20(S)-protopanaxatriol. protective effect; in both vascular dementia model: bilateral carotid occlusion is repeated with copy nitroprusside artery vascular dementia depressurization model copy 42 and senile dementia animal model of bilateral hippocampal injections can improve large APi_ Mouse space exploration and orientation capabilities. The protopanaxadiol derivative and the protopanaxatriol derivative of the present invention have broad medicinal value for treating neurodegenerative diseases such as Parkinson's disease, senile dementia or cerebrovascular dementia diseases, and have broad development prospect.
Claims
1、具有式 (1)、（Π)结构的原人参二醇衍生物在制备预防或治疗神 经退行性疾 1. Protopanaxadiol derivatives with structures of formula (1) and (Π) are used in the preparation of preventing or treating neurodegenerative diseases.
式 (I)所示的原人参二醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,12β,25-三醇、 式（Π )所示的原人参二醇衍生物的名称为达玛 -20S-24(S)-环氧 -3β,12β,25-三醇。 The name of the protopanaxadiol derivative represented by formula (I) is damar-20S-24(R)-epoxy-3β,12β,25-triol, and the protopanaxadiol derivative represented by formula (II) The name of the substance is damar-20S-24(S)-epoxy-3β,12β,25-triol.
2、 具有式 (ΠΙ)、 （IV)结构的原人参三醇衍生物在制备预防或治疗 神经退 2. Preparation of protopanaxatriol derivatives with structures of formulas (ΠI) and (IV) for preventing or treating neurodegeneration
式 (III)所示的原人参三醇衍生物的名称为达玛 -20S-24(S)-环氧 -3β,6β,12β,25-四醇、 式（IV)所示的原人参三醇衍生物的名称为达玛 -20S-24(R)-环氧 -3β,6β, 12β,25-四醇。 The name of the protopanaxatriol derivative represented by the formula (III) is dama-20S-24(S)-epoxy-3β,6β,12β,25-tetraol, and the protopanaxatriol derivative represented by the formula (IV). The name of the alcohol derivative is damar-20S-24(R)-epoxy-3β,6β,12β,25-tetraol.
3、 根据权利要求 1或 2所述的应用， 其特征在于， 所述神经退 行性疾病包括帕金森病、 老年性痴呆或脑血管性痴呆疾病。 3. The application according to claim 1 or 2, characterized in that the neurodegenerative disease includes Parkinson's disease, Alzheimer's disease or cerebrovascular dementia.
4、 根据权利要求 1或 2所述的应用， 其特征在于， 所述原人参 二醇衍生物或原人参三醇衍生物与药学上可接受的载体制成口服制 剂或胃肠外制剂。 4. The application according to claim 1 or 2, characterized in that the protopanaxadiol derivative or protopanaxatriol derivative and a pharmaceutically acceptable carrier are made into an oral preparation or a parenteral preparation.
5、 根据权利要求 4所述的应用， 其特征在于， 所述口服制剂为 胶囊剂、 片剂、 丸剂、 颗粒剂、 散剂、 糖浆剂、 溶液剂、 乳剂或混悬
剂。 5. Application according to claim 4, characterized in that the oral preparation is a capsule, tablet, pill, granule, powder, syrup, solution, emulsion or suspension agent.
6、 根据权利要求 4所述的应用， 其特征在于， 所述胃肠外制剂 为注射剂。 6. The application according to claim 4, characterized in that the parenteral preparation is an injection.
7、 根据权利要求 5所述的应用， 其特征在于， 所述溶液剂为口
7. Application according to claim 5, characterized in that the solution is oral
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| 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 |
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| CN100438876C (en) * | 2006-06-09 | 2008-12-03 | 上海中药创新研究中心 | Use of 20(S)-protopanoxadiol in preparation of antidepressant medicine |
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| LIU, JINPING: "Studies on Isolation, Structure Modification and Pharmacological Activities of Saponins from the Leaves and Stems of Panax Quiquefolium L. Cultivated in China", MEDICINE & PUBLIC HEALTH, CHINA DOCTORAL DISSERTATIONS FULL-TEXT DATABASE, vol. E057-23, 31 January 2007 (2007-01-31), pages 66 * |
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