WO2016086842A1 - 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途 - Google Patents

二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途 Download PDF

Info

Publication number
WO2016086842A1
WO2016086842A1 PCT/CN2015/096134 CN2015096134W WO2016086842A1 WO 2016086842 A1 WO2016086842 A1 WO 2016086842A1 CN 2015096134 W CN2015096134 W CN 2015096134W WO 2016086842 A1 WO2016086842 A1 WO 2016086842A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
extract
preparation
health care
Prior art date
Application number
PCT/CN2015/096134
Other languages
English (en)
French (fr)
Inventor
赵维民
章海燕
宁若男
王维
张如隽
雷芸
朱应栋
刘双柱
Original Assignee
中国科学院上海药物研究所
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 中国科学院上海药物研究所 filed Critical 中国科学院上海药物研究所
Publication of WO2016086842A1 publication Critical patent/WO2016086842A1/zh

Links

Images

Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/37—Celastraceae (Staff-tree or Bittersweet family), e.g. tripterygium or spindletree
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of biomedicine, and in particular, to the dihydro- ⁇ -amptofuran-type sesquiterpenoids, processes for their preparation and use.
  • AD Alzheimer's disease
  • a ⁇ 25-35 a synthetic polypeptide fragment, has the same ⁇ -sheet structure as full-length A ⁇ , capable of forming fibers and retaining its biological activity.
  • a ⁇ 25-35 is often used as a nerve damaging agent for screening against A ⁇ toxic compounds.
  • Oxidative stress also plays an important role in the development of AD. There is currently no effective means for the prevention and treatment of AD, and those skilled in the art have been working to develop new compounds that have a better therapeutic effect on neurological function improvement.
  • Euonymus sinensis is a medicinal plant with many medicinal plants, such as lamp vine, southern snake vine, Qingjiang vine, bitter vine and locust southern snake vine. Commonly used to treat bone and muscle pain, rheumatoid arthritis, bruises, bruises and so on. Some plants also have insect antifeedant activity. Among them, Celastrus orbiculatus Thunb. is a perennial deciduous climbing shrub born in hills, ravines and hillside shrubs. The roots, stems, leaves and fruits of the plant can be used as medicine. The roots and stems have the effect of phlegm and blood circulation, reducing swelling and relieving pain. The folks are mostly used to treat rheumatoid arthritis, low back pain and so on.
  • Celastrus angulatus Maxim Also known as bitter bark, horse-breaking intestine, tiger-hemp, thorn-like southern snake vine, bitter-skinned tree, old-striped vine, perennial vine; bark fiber can be used for paper and rayon raw materials
  • the peel and seeds contain oil for industrial use, and the root bark and bark are insecticides and sterilizing agents.
  • Celastrus flagellaris is a deciduous vine. Also known as the thorny southern snake vine, thorn south snake vine, its roots and fruits can be used as medicine, attending rheumatoid arthritis and bruises.
  • the natural active ingredients in the genus Nannosaurus are not clear, and those skilled in the art are working to clarify the material basis of their medicinal activities.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are each independently selected from: H, OH, halogen, carboxyl, substituted or unsubstituted C 2 -C 20 ester group, substituted or unsubstituted C 1 -C 10 An alkyl group, a substituted or unsubstituted C2-C8 alkenyl group and a substituted or unsubstituted C2 to C8 alkynyl group;
  • R 7 is selected from the group consisting of H, OH and halogen.
  • R 1 and R 5 are each independently selected from the group consisting of: OH, OBz, OCin, ONic, OFu, OCOR a ;
  • R 2 , R 3 , R 4 , R 6 are each independently selected from the group consisting of: H, OH, OBz, OCin, ONic, OFu, OCOR a ;
  • R 7 is selected from the group consisting of: H, OH;
  • R a is selected from a C1-C5 alkyl group, a C6-C10 aryl group, a C2-C6 alkenyl group, and a 5- to 10-membered heteroaryl C2-C6 alkenyl group.
  • heteroaryl group contains 1 to 3 selected from the group consisting of O, N and S;
  • R 1 is selected from the group consisting of: H, OH, C2 to C10 ester groups.
  • R 1 is selected from the group consisting of: OH, (acetoxy), (benzoyloxy), (cinnamoyloxy).
  • R 2 is selected from the group consisting of: H, OH, C2 to C6 ester groups, (benzoyloxy), (cinnamoyloxy).
  • R 2 is selected from the group consisting of: H, OH, (acetoxy), (butyryloxy), (hexanoyloxy), (benzoyloxy), (cinnamoyloxy).
  • R 3 is selected from the group consisting of: H, (acetoxy), (benzoyloxy), (cinnamoyloxy).
  • R 4 is selected from the group consisting of: H, OH, C2 to C6 ester groups, (benzoyloxy), (cinnamoyloxy).
  • R 4 is selected from the group consisting of: H, OH, (acetoxy), (butyryloxy), (benzoyloxy).
  • R 5 is selected from the group consisting of (acetoxy), (benzoyloxy), (cinnamoyloxy).
  • R 6 is selected from the group consisting of: H, (acetoxy), (benzoyloxy), (cinnamoyloxy).
  • R 7 is H.
  • the compound is selected from the individual compounds of Table 1.
  • the compound is selected from the group consisting of:
  • the compound is selected from the individual compounds of Table 2.
  • the compound is selected from the group consisting of:
  • the additional condition is: when R 1 is an acetoxy group and R 4 is When (benzoyloxy), R 2 is not (benzoyloxy).
  • the additional condition is:
  • R 4 is H
  • R 2 is not H
  • R 6 is H
  • R 2 is not (benzoyloxy
  • R 2 and R 3 are different groups, and when R 2 is When (cinnamoyloxy), R 3 is not H.
  • a pharmaceutical composition comprising the compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a third aspect of the invention provides the use of a compound according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • the object is a human.
  • the neuronal damage disease includes, but is not limited to, Alzheimer's disease.
  • composition according to the third aspect of the invention the use being selected from the group consisting of:
  • a plant extract of Celastrus containing a dihydro- ⁇ -amptofuran-type sesquiterpenoid compound selected from the group consisting of:
  • the structure of the dihydro- ⁇ -amptofuran-type sesquiterpenoid compound is as shown in Formula I.
  • the extract contains at least one compound of the first aspect of the invention.
  • the extract is water or an organic solvent extract.
  • the extract is a fruit or seed extract.
  • the southern snake plant is selected from the group consisting of: Celstrus orbiculatus Thunb., Celastrus angulatus Maxim., and Celastrus flagellaris.
  • the extract is an extract of Celastrus orbiculatus Thunb., the extract comprising one or more compounds selected from the group consisting of:
  • the extract is an extract of Celestris angulatus Maxim., the extract comprising one or more compounds selected from the group consisting of:
  • KPT-12b, KPT-13, KPT-13b, KPT-4, KPT-15a, KPT-15b, and KPT-12a the structures of the respective compounds are shown in Table 2.
  • the extract is an extract of Celastrus flagellaris, the extract comprising one or more compounds selected from the group consisting of:
  • a sixth aspect of the invention provides a method of improving memory, comprising: administering to a subject in need thereof an effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof;
  • An effective amount of a Celastrus plant extract containing a dihydro-[beta]-amptofuran-type sesquiterpenoid compound is administered to a subject in need thereof.
  • a method for preventing or treating a neuronal injury disease comprising: administering to a subject in need thereof an effective amount of the compound of the first aspect of the invention, or a pharmaceutically acceptable compound thereof Salt; or
  • An effective amount of a Celastrus plant extract containing a dihydro-[beta]-amptofuran-type sesquiterpenoid compound is administered to a subject in need thereof.
  • Figure 1 shows the extraction and separation of compounds from the seeds of Southern snake vine.
  • Figure 2 shows the extraction and isolation of compounds from the fruit of the scutellaria.
  • Figure 3 shows the extraction and separation of compounds from the fruit of the southern snake vine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of C1-C10 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, hydroxy. And a carboxyl group (-COOH), a C1-C10 carbonyl group, a C1-C10 amide group, a C2-C20 ester group, a C6-C30 aryl group, a fluorine group and a thioether group.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • C1-C10 alkyl refers to a straight or branched alkyl group having from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, Tert-butyl, or a similar group.
  • C2-C8 alkenyl means a straight or branched alkenyl group having 2-8 carbon atoms, such as ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butyl Dienyl, or a similar group.
  • C2-C8 alkynyl refers to a straight or branched alkynyl group having 2 to 8 carbon atoms, for example ethynyl, propynyl, isopropynyl, butynyl , isobutynyl, sec-butynyl, tert-butynyl, or the like.
  • C3-C10 cycloalkyl refers to a cycloalkyl group having 3 to 10 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cycloheptyl group, or the like.
  • C1-C10 alkoxy refers to a straight or branched alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso Butoxy, sec-butoxy, tert-butoxy, or the like.
  • carbonyl means having A group; for example, "C1 to 10 carbonyl” means a carbonyl group having 1 to 10 carbon atoms.
  • amido refers to having A group; for example, "C1 to 10 amide group” means an amide group having 1 to 10 carbon atoms.
  • C2-C20 ester group means having a hydrocarbyl-COO-(acyloxy) structure or having a -COO-hydrocarbyl structure, wherein the hydrocarbyl group may be an aryl group, an arylalkenyl group, an alkyl group, an alkenyl group, an alkynyl group;
  • the base, alkenyl, alkynyl group may be straight or branched, and may be substituted or unsubstituted;
  • the aryl group is preferably a phenyl group, may be substituted or unsubstituted;
  • the arylalkenyl group is preferably a styryl group , may be substituted or unsubstituted.
  • the C2-C20 ester group may be a group having a C1-C10 alkyl-COO- structure, such as CH 3 COO-, C 2 H 5 COO-, C 3 H. 8 COO-, (CH 3 ) 2 CHCOO-, nC 4 H 9 COO-, tC 4 H 9 COO-, or the like. Or having a -COO-C1 - C19 alkyl structure, for example -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 8 or -COO-(CH 2 )n-CH 3 , n is an integer from 0 to 18.
  • aryl preferably having 6 to 30 carbon atoms, refers to a monocyclic or bicyclic aromatic group having 6 to 12 carbon atoms in the ring moiety, for example, phenyl, biphenyl, naphthyl. Or a similar group in which each carbon atom can be optionally substituted. Preferably, it has 1 to 3 substituents selected from the group consisting of halogen, C1-C10 alkyl, cyano, OH, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, and amino.
  • halogenated compound means a compound formed by substituting at least one H atom of an organic compound with a halogen.
  • halogen means fluoro, chloro, bromo, iodo.
  • halogenated means fluoro, chloro, bromo, iodo.
  • Each group of the present invention may be unsubstituted or substituted, and the substituted means substituted with a substituent selected from the group consisting of a hydroxyl group, a halogen, an aryl group, a C1-C6 alkyl group, and a halogenated C1 ⁇ .
  • the substituents may be substituted at various positions of each group.
  • R 1 and R 5 are each independently selected from the group consisting of: OH, OBz, OCin, ONic, OFu, OCOR a ;
  • R 2 , R 4 , R 6 , and R 3 are each independently selected from the group consisting of: H, OH, OBz, OCin, ONic, OFu, OCOR a ;
  • R 7 is selected from the group consisting of: H, OH;
  • heteroaryl group contains 1 to 3 selected from the group consisting of O, N and S.
  • the compound of the present invention can be produced by a chemical synthesis method, or can be obtained by extracting from a plant of the genus Nansui, preferably by extracting from the fruit or seed of the plant.
  • the southern snake plant includes Celastrus orbiculatus Thunb., Celastrus angulatus Maxim., and Celastrus flagellaris.
  • the process of extracting the compound of the present invention from the fruit or seed of the genus Nannosper comprises: pulverizing the fruit or seed, using ethanol leaching, concentrating and using a chromatographic method (eg, The macroporous adsorption resin, silica gel column chromatography) is subjected to separation and purification to obtain a monomer compound or to obtain a composition containing a plurality of compounds.
  • a chromatographic method eg, The macroporous adsorption resin, silica gel column chromatography
  • the invention provides the use of a Celastrus plant extract selected from the group consisting of:
  • the extract contains at least one of the compounds of Table 1 or Table 2 of the present invention.
  • the extract is a fruit or seed extract of the genus Nansui, preferably an organic solvent or an aqueous extract, more preferably an ethanol extract.
  • the compounds of the invention may be used as neuroprotective agents, to prevent or treat nerve damage and/or to improve memory.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a safe and effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier or excipient.
  • the amount of the compound of the present invention is usually from 10 ⁇ g to 100 mg per dose, preferably from 100 to 1000 ⁇ g per dose.
  • an effective dose is from about 0.01 mg/kg to 1000 mg/kg, preferably from 0.1 mg/kg to 500 mg/kg of body weight of the compound of the invention.
  • the compounds of the invention may be used alone or in combination with other therapeutic agents (e.g., formulated in the same pharmaceutical composition).
  • the pharmaceutical composition may also contain a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier refers to a carrier for the administration of a therapeutic agent.
  • pharmaceutical carriers which do not themselves induce the production of antibodies harmful to the individual receiving the composition and which are not excessively toxic after administration. These vectors are well known to those of ordinary skill in the art. A thorough discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub. Co., N. J. 1991).
  • Such carriers include, but are not limited to, saline, buffer, dextrose, water, glycerol, ethanol, adjuvants, and combinations thereof.
  • the pharmaceutically acceptable carrier in the therapeutic composition may contain a liquid such as water, saline, glycerol and ethanol.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering substances and the like may also be present in these carriers.
  • the therapeutic compositions can be formulated as injectables, such as liquid solutions or suspensions; solid forms such as liquid carriers, which may be formulated in solution or suspension prior to injection.
  • composition of the invention can be administered by conventional routes including, but not limited to, intramuscular, intravenous, subcutaneous, intradermal or topical administration.
  • the subject to be prevented or treated may be an animal; especially a human.
  • a pharmaceutical composition of various dosage forms may be employed depending on the use. It is preferably an injection.
  • compositions can be formulated by mixing, diluting or dissolving according to conventional methods, and occasionally adding suitable pharmaceutical additives such as excipients, disintegrating agents, binders, lubricants, diluents, buffers, isotonicity Isotonicities, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers and solubilizers, and the formulation process can be carried out in a customary manner depending on the dosage form.
  • suitable pharmaceutical additives such as excipients, disintegrating agents, binders, lubricants, diluents, buffers, isotonicity Isotonicities, preservatives, wetting agents, emulsifiers, dispersing agents, stabilizers and solubilizers, and the formulation process can be carried out in a customary manner depending on the dosage form.
  • suitable pharmaceutical additives such as excipients, disintegrating agents, binders, lubricants, diluents, buffer
  • the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient may be based on the weight of each subject (patient) to be prevented or treated, Age, gender, and degree of symptoms are reasonably determined.
  • the compounds and pharmaceutical compositions according to the invention may be used to treat neurologically impaired diseases including, but not limited to, Alzheimer's disease.
  • a pharmaceutical composition containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient has a remarkable neuroprotective function. It has been confirmed by animal experiments that the compounds of the present invention can improve the memory function of animals.
  • PE-34 MF: C 28 H 36 O 9 , MW: 516; white amorphous powder; ESIMS m/z 539.2 [M+Na] + ;
  • CB-4A MF: C 35 H 40 O 9 , MW: 604; white amorphous powder; ESIMS m/z 627.3 [M+Na] + ;
  • the assay measures cell viability using the thiazolyl blue (MTT) colorimetric assay.
  • MTT thiazolyl blue
  • Human bone marrow neuroblastoma cell line (SH-SY5Y cells) was purchased from ATCC and cultured in a MEM/F12 medium containing 10% fetal calf serum in a 37 ° C, 5% CO 2 incubator. When the cells were grown to a density of 80-90%, they were digested with 0.125% trypsin, seeded at a density of 2.5*10 4 cells/well in a 96-well culture plate, and cultured in an incubator for 24 hours.
  • the different groups were treated as follows: After 24 hours of cell seeding, the culture medium was changed to serum-free MEM/F12 medium, and each compound was added (final concentration: 10 ⁇ M), and the model group was added with an equal volume of solvent control. After 2 hours of culture, each treatment group was added with A ⁇ 25-35 at a final concentration of 10 ⁇ M, and an equal volume of the culture solution was added to the control group, and the culture was continued for 22 hours.
  • the positive control uses EGCG (epigallocatechin gallate), which is a catechin monomer isolated from tea. It has anti-oxidation and is resistant to A ⁇ 25-35-induced cytotoxicity. It is commonly used for anti-A ⁇ .
  • EGCG epigallocatechin gallate
  • Positive drug for toxic compound screening [Choi S M., Kim B C., et al. Effects of Flavonoid Compounds on ⁇ -amyloid-peptide-induced Neuronal Death in Cultured Mouse Cortical Neurons, Chonnam Medicinal Journal. 2014, 50, 45-51 [Lin C L, Chen T F, et al.
  • EGCG Epigallocatechin gallate
  • mice were orally administered with different doses of the test drugs, the blank control group and the model group were given a solvent control, and the positive control group was given huperzine A.
  • mice in each group were intraperitoneally injected with scopolamine (4.5 mg/kg), and the blank control group was given an equal dose of normal saline.
  • each group of mice was placed in a water maze to record the time of landing on the platform and The number of times to enter the blind end before arriving at the platform (60 seconds without reaching the platform within 60 seconds).
  • the escape time and number of errors of the model group animals were determined to be 100%, and the escape time and number of errors of the animals in each administration group were expressed as a percentage of the model group.
  • the blank control mice were able to quickly find the platform to escape, with fewer errors during the period.
  • the mice in the model group need to find the platform for a long time, and the number of errors is high.
  • the escape time was significantly shorter than that in the model group, and the number of errors was significantly reduced, which was equivalent to the positive compound huperzine A, which showed obvious improvement in memory impairment.
  • Differences between groups were tested by one-way ANOVA in combination with LSD and Duancan's.
  • the compounds of the present invention were significantly different from the blank control group and the model group.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Biotechnology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途,本发明的二氢-β-沉香呋喃型倍半萜类化合物具有对抗胞外淀粉样蛋白(Aβ)诱导神经细胞损伤和改善东莨菪碱引起记忆和行为损害的功能,在制备神经保护药物和改善记忆药物中具有广阔的应用前景。

Description

二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途 技术领域
本发明属于生物医药领域，具体地说，本发明涉及二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途。
背景技术
阿尔茨海默症(Alzheimer's disease，AD)是一种不可逆的、多因素的、进行性神经退行性病变，临床表现为认知障碍和记忆力丧失。AD的的主要病理学特征包括胞内神经纤维缠结和胞外淀粉样蛋白(Aβ)沉积。尽管AD的发病机理并不清楚，一系列证据表明AD和过量的Aβ沉积相关。Aβ发挥神经毒性的机制涉及很多方面，包括氧化应激、诱导神经细胞凋亡等。Aβ25-35，是一种合成多肽片段，与全长的Aβ具有相同的β-折叠结构，能够形成纤维，保持了其生物活性。因此，Aβ25-35常作为神经损伤剂用于对抗Aβ毒性化合物的筛选。氧化应激在AD的发生发展中也起着重要作用。目前关于AD的预防和治疗仍然缺乏有效的手段，本领域技术人员一直致力于开发新的对神经系统功能改善有更好疗效的化合物。
卫矛科南蛇藤属入药植物较多，如灯油藤，南蛇藤，青江藤，苦皮藤和刺苞南蛇藤。常用于治疗筋骨疼痛，风湿性关节炎，跌打损伤，痈肿疮疡等病症。一些植物还有昆虫拒食活性。其中，南蛇藤(Celastrus orbiculatus Thunb.)为多年生落叶攀援灌木，生于丘陵，山沟及山坡的灌木丛中。该植物的根，茎，叶，果均可入药，根和茎具有祛风活血，消肿止痛之功效，民间多用来治疗风湿性关节炎，腰腿痛等。苦皮藤(Celastrus angulatus Maxim.)又名苦树皮，马断肠、老虎麻，棱枝南蛇藤，苦皮树、老麻藤，为多年生藤本植物；树皮纤维可以供造纸及人造棉原料，果皮及种子含油脂可供工业用，根皮及茎皮为杀虫剂和灭菌剂。刺苞南蛇藤(Celastrus flagellaris)为落叶藤本植物。又名刺叶南蛇藤，刺南蛇藤，其根茎和果实皆可入药，主治风湿性关节炎和跌打损伤等。目前，南蛇藤属植物中的天然活性成分还不明确，本领域技术人员致力于阐明其药物活性的物质基础。
发明内容
本发明的目的在于提供新型的二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途。
本发明的第一方面，提供了一种化合物，所述化合物的结构如式I所示：
Figure PCTCN2015096134-appb-000001
式I中，
R1,R2,R3,R4,R5,R6分别独立地选自：H、OH、卤素、羧基、取代或未取代的C2～C20酯基、取代或未取代的C1～C10烷基、取代或未取代的C2-C8烯基和取代或未取代的C2～C8炔基；
R7选自：H、OH和卤素。
在另一优选例中，R1,R5分别独立地选自：OH,OBz,OCin,ONic,OFu,OCORa；
R2,R3,R4,R6,分别独立地选自：H,OH,OBz,OCin,ONic,OFu,OCORa；
R7选自：H,OH；
Ra选自C1～C5烷基，C6～C10芳基，C2～C6烯基，5～10元杂芳基C2～C6烯基，
其中，所述杂芳基含有选自O、N和S中的1至3个；
Bz为
Figure PCTCN2015096134-appb-000002
Cin为
Figure PCTCN2015096134-appb-000003
Nic为
Figure PCTCN2015096134-appb-000004
Fu为
Figure PCTCN2015096134-appb-000005
Ac为
Figure PCTCN2015096134-appb-000006
But为
Figure PCTCN2015096134-appb-000007
Hex为
Figure PCTCN2015096134-appb-000008
在另一优选例中，R1选自：H、OH、C2～C10酯基。
在另一优选例中，R1选自：OH、
Figure PCTCN2015096134-appb-000009
(乙酰氧基)、
Figure PCTCN2015096134-appb-000010
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000011
(肉桂酰氧基)。
在另一优选例中，R2选自：H、OH、C2～C6酯基、
Figure PCTCN2015096134-appb-000012
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000013
(肉桂酰氧基)。
在另一优选例中，R2选自：H、OH、
Figure PCTCN2015096134-appb-000014
(乙酰氧基)、
Figure PCTCN2015096134-appb-000015
(丁酰氧基)、
Figure PCTCN2015096134-appb-000016
(己酰氧基)、
Figure PCTCN2015096134-appb-000017
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000018
(肉桂酰氧基)。
在另一优选例中，R3选自：H、
Figure PCTCN2015096134-appb-000019
(乙酰氧基)、
Figure PCTCN2015096134-appb-000020
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000021
(肉桂酰氧基)。
在另一优选例中，R4选自：H、OH、C2～C6酯基、
Figure PCTCN2015096134-appb-000022
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000023
(肉桂酰氧基)。
在另一优选例中，R4选自：H、OH、
Figure PCTCN2015096134-appb-000024
(乙酰氧基)、
Figure PCTCN2015096134-appb-000025
(丁酰氧基)、
Figure PCTCN2015096134-appb-000026
(苯甲酰氧基)。
在另一优选例中，R5选自：
Figure PCTCN2015096134-appb-000027
(乙酰氧基)、
Figure PCTCN2015096134-appb-000028
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000029
(肉桂酰氧基)。
在另一优选例中，R6选自：H、
Figure PCTCN2015096134-appb-000030
(乙酰氧基)、
Figure PCTCN2015096134-appb-000031
(苯甲酰氧基)、
Figure PCTCN2015096134-appb-000032
(肉桂酰氧基)。
在另一优选例中，R7为H。
在另一优选例中，所述化合物选自表1中的各化合物。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2015096134-appb-000033
在另一优选例中，所述化合物选自表2中的各化合物。
在另一优选例中，所述化合物选自下组：
Figure PCTCN2015096134-appb-000034
Figure PCTCN2015096134-appb-000035
Bz、Cin、Ac、Nic、But、Hex的定义如上。在另一优选例中，附加条件是：当R1为乙酰氧基并且R4为
Figure PCTCN2015096134-appb-000036
(苯甲酰氧基)时，R2不为
Figure PCTCN2015096134-appb-000037
(苯甲酰氧基)。
在另一优选例中，附加条件是：
(1)当R4为H时，R2不为H，并且当R6为H时R2不为
Figure PCTCN2015096134-appb-000038
(苯甲酰氧基)；
(2)在满足(1)的条件下，R2和R3为不同的基团，并且当R2为
Figure PCTCN2015096134-appb-000039
(肉桂酰氧基)时R3不为H。
本发明的第二方面，提供了一种药物组合物，所述药物组合物含有本发明第一方面所述的化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
本发明的第三方面，提供了如本发明第一方面所述的化合物或其药学上可接受的盐的用途，所述用途选自下组：
(a)用于制备神经保护的药物或保健产品；和/或
(b)用于制备预防或治疗神经细胞损伤疾病的药物或保健产品；和/或
(c)用于制备改善记忆的药物或保健产品。
在另一优选例中，所述的对象是人。
在另一优选例中，所述的神经细胞损伤疾病包括但不限于阿尔茨海默病。
本发明的第四方面，提供了如本发明第三方面所述的组合物的用途，所述用途选自下组：
(a)用于制备神经保护的药物或保健产品；和/或
(b)用于制备预防或治疗神经细胞损伤疾病的药物或保健产品；和/或
(c)用于制备改善记忆的药物或保健产品。
本发明的第五方面，提供了含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物的用途，所述用途选自下组：
(a)用于制备神经保护的药物或保健产品；和/或
(b)用于制备预防或治疗神经细胞损伤疾病的药物或保健产品；和/或
(c)用于制备改善记忆的药物或保健产品。
在另一优选例中，所述二氢-β-沉香呋喃型倍半萜类化合物结构如式I所示。
在另一优选例中，所述提取物中含有本发明第一方面所述的至少一种化合物。
在另一优选例中，所述提取物为水或有机溶剂提取物。
在另一优选例中，所述提取物为果实或种子提取物。
在另一优选例中，所述南蛇藤属植物选自：南蛇藤(Celastrus orbiculatus Thunb.)、苦皮藤(Celastrus angulatus Maxim.)、刺苞南蛇藤(Celastrus flagellaris)。
在另一优选例中，所述提取物为南蛇藤(Celastrus orbiculatus Thunb.)提取物，所述提取物中含有选自下组的一种或多种化合物：
PE-11、PE-13、PE-4221、PE-17、PE-34、PE-221、PE-4212、PE-331、和PE-232，各化合物结构如表2中所示。
在另一优选例中，所述提取物为苦皮藤(Celastrus angulatus Maxim.)提取物，所述提取物中含有选自下组的一种或多种化合物：
KPT-12b、KPT-13、KPT-13b、KPT-4、KPT-15a、KPT-15b、和KPT-12a，各化合物结构如表2中所示。
在另一优选例中，所述提取物为刺苞南蛇藤(Celastrus flagellaris)提取物，所述提取物中含有选自下组的一种或多种化合物：
CB-5I、CB-2H、CB-2D、CB-4E、CB-4R、CB-4A、CB-4C、CB-5D2、CB-4S、和CB-4D，各化合物结构如表2中所示。
本发明的第六方面，提供了一种改善记忆的方法，所述方法包括：给需要的对象施用有效量的本发明第一方面所述的化合物，或其药学上可接受的盐；或者
给需要的对象施用有效量的本发明第二方面所述的药物组合物；或者
给需要的对象施用有效量的含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物。
本发明的第七方面，提供了一种预防或治疗神经细胞损伤疾病的方法，所述方法包括：给需要的对象施用有效量的本发明第一方面所述的化合物，或其药学上可接受的盐；或者
给需要的对象施用有效量的本发明第二方面所述的药物组合物；或者
给需要的对象施用有效量的含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了南蛇藤种子中化合物的提取和分离。
图2显示了苦皮藤果实中化合物的提取与分离。
图3显示了刺苞南蛇藤果实中化合物的提取与分离。
具体实施方式
本发明人通过广泛而深入的研究，在南蛇藤属植物中获得一类结构新颖的二氢-β-沉香呋喃型倍半萜类化合物，经过生物活性实验意外地发现，此类化合物具有显著的神经细胞保护活性和改善记忆功能。在此基础上完成了本发明。
术语
如本文所用，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：C1～C10烷基、C3～C10环烷基、C1～C10烷氧基、羟基、羧基(-COOH)、C1～C10羰基、C1～C10酰胺基、C2～C20酯基、C6～C30芳基、氟基和硫醚基。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
术语“C1～C10烷基”指具有1～10个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
术语“C2-C8烯基”是指具有2-8个碳原子的直链或支链烯基，例如乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
在本发明优选的实施方式中，术语“C2-C8炔基”指具有2～8个碳原子的直链或支链炔基，例如乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
术语“C3～C10环烷基”指具有3～10个碳原子的环烷基，例如环丙基、环丁基、环戊基、环庚基、或类似基团。
术语“C1～C10烷氧基”指具有1-10个碳原子的直链或支链烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、或类似基团。
术语“羰基”指具有
Figure PCTCN2015096134-appb-000040
的基团；例如“C1～10羰基”是指具有1～10个碳原子的羰基。
术语“酰胺基”指具有
Figure PCTCN2015096134-appb-000041
的基团；例如“C1～10酰胺基”是指具有1～10个碳原子的酰胺基。
术语“C2～C20酯基”指具有烃基-COO-(酰氧基)结构或者具有-COO-烃基结构，其中烃基可以为芳基、芳基烯基、烷基、烯基、炔基；烷基、烯基、炔基可以为直链或支链的，可以是取代的或未取代的；芳基优选为苯基，可以是取代的或未取代的；芳基烯基优选为苯乙烯基，可以是取代的或未取代的。在本发明的一个优选的实施方式中，所述C2～C20酯基可以为具有C1～C10烷基-COO-结构的基团，例如CH3COO-、C2H5COO-、C3H8COO-、(CH3)2CHCOO-、n-C4H9COO-、t-C4H9COO-，或类似基团。或者具有-COO-C1～C19烷基结构，例如-COOCH3、-COOC2H5、-COOC3H8或-COO-(CH2)n-CH3，n为0～18的整数。
术语“芳基”，优选为具有6～30个碳原子，是指在环内部分具有6～12个碳原子的单环或双环芳香性基团，例如：苯基、联苯基、萘基、或类似基团，其中的每个碳原子均可以被任意取代。优选具有1～3个取代基，所述取代基选自：卤素、C1～C10烷基、氰基、OH、硝基、C3～C10环烷基、C1～C10烷氧基、氨基。
术语“卤代化合物”，指有机化合物中的至少一个H原子被卤素取代后形成的化合物。
术语“卤素”是指氟、氯、溴、碘。术语“卤代的”是指氟代的、氯代的、溴代的、碘代的。
本发明的各个基团可以为未取代的或取代的，所述取代的是指被选自下组的取代基所取代：羟基、卤素、芳基、C1～C6烷基、卤代的C1～C6烷基、C1～C6烷氧基、卤代的C1～C6烷氧基、氰基、叔丁氨甲酰基、-O-(CH2)n-O-；其中，n为1～3之间的整数。所述取代基可取代在各基团的各个位置上。
本发明化合物的结构如式I所示：
Figure PCTCN2015096134-appb-000042
式I中，R1,R5分别独立地选自：OH,OBz,OCin,ONic,OFu,OCORa；
R2,R4,R6,R3分别独立地选自：H,OH,OBz,OCin,ONic,OFu,OCORa；
R7选自：H,OH；
Ra选自CnH2n+1(n＝1-5)，C6-C10芳基，C6-C10芳基，C2-C6烯基，5-10元杂芳基C2-C6烯基，
其中，所述杂芳基含有选自O、N和S中的1至3个。
上述Bz为
Figure PCTCN2015096134-appb-000043
Cin为
Figure PCTCN2015096134-appb-000044
Nic为
Figure PCTCN2015096134-appb-000045
Fu为
Figure PCTCN2015096134-appb-000046
Ac为
Figure PCTCN2015096134-appb-000047
But为
Figure PCTCN2015096134-appb-000048
Hex为
Figure PCTCN2015096134-appb-000049
表1本发明优选的化合物
Figure PCTCN2015096134-appb-000050
Figure PCTCN2015096134-appb-000051
表2本发明优选的部分化合物
Figure PCTCN2015096134-appb-000052
Figure PCTCN2015096134-appb-000053
注：表2中Bz为
Figure PCTCN2015096134-appb-000054
Cin为
Figure PCTCN2015096134-appb-000055
Nic为
Figure PCTCN2015096134-appb-000056
Fu为
Figure PCTCN2015096134-appb-000057
Ac为
Figure PCTCN2015096134-appb-000058
But为
Figure PCTCN2015096134-appb-000059
Hex为
Figure PCTCN2015096134-appb-000060
制备方法
本发明的化合物可以以化学合成的方法制得，也可以从南蛇藤属植物中提取制得，优选地从南蛇藤属植物的果实或种子中提取制得。
在本发明的一个优选地实施方式中，所述南蛇藤属植物包括南蛇藤(Celastrus orbiculatus Thunb.)、苦皮藤(Celastrus angulatus Maxim.)、刺苞南蛇藤(Celastrus flagellaris)。
在本发明的一个优选地实施方式中，从南蛇藤属植物的果实或种子中提取本发明化合物的过程包括：将果实或种子粉碎后使用乙醇浸提，浓缩后使用色谱方法(如 大孔吸附树脂、硅胶柱色谱)进行分离纯化获得单体化合物或者得到含有多种化合物的组合物。
在本发明的一个优选地实施方式中，本发明提供了南蛇藤属(Celastrus)植物提取物的用途，所述用途选自下组：
(a)用于制备神经保护的药物；和/或
(b)用于制备预防或治疗神经细胞损伤疾病的药物；和/或
(c)用于制备改善记忆的药物。
在另一优选例中，所述提取物中含有本发明的至少一种表1或表2中的化合物。
在另一优选例中，所述提取物为南蛇藤属植物的果实或种子提取物，优选地为有机溶剂或水提取物，更优选地为乙醇提取物。
药物组合物和施用方法
本发明的化合物可以用作神经保护剂、预防或治疗神经损伤和/或用于改善记忆。
一方面，本发明提供了一种药物组合物，它含有(a)安全有效量的本发明化合物或其药学上可接受的盐；以及(b)药学上可接受的载体或赋形剂。本发明化合物的数量通常为10微克-100毫克/剂，较佳地为100-1000微克/剂。
为了本发明的目的，有效的剂量为给予个体约0.01毫克/千克至1000毫克/千克，较佳地0.1毫克/千克至500毫克/千克体重的本发明化合物。此外，本发明的化合物可以单用，也可与其他治疗剂一起使用(如配制在同一药物组合物中)。
药物组合物还可含有药学上可接受的载体。术语“药学上可接受的载体”指用于治疗剂给药的载体。该术语指这样一些药剂载体：它们本身不诱导产生对接受该组合物的个体有害的抗体，且给药后没有过分的毒性。这些载体是本领域普通技术人员所熟知的。在Remington's Pharmaceutical Sciences(Mack Pub.Co.，N.J.1991)中可找到关于药学上可接受的赋形剂的充分讨论。这类载体包括(但并不限于)：盐水、缓冲液、葡萄糖、水、甘油、乙醇、佐剂及其组合。
治疗性组合物中药学上可接受的载体可含有液体，如水、盐水、甘油和乙醇。另外，这些载体中还可能存在辅助性的物质，如润湿剂或乳化剂、pH缓冲物质等。
通常，可将治疗性组合物制成可注射剂，例如液体溶液或悬液；还可制成在注射前适合配入溶液或悬液中、液体载体的固体形式。
一旦配成本发明的组合物，可将其通过常规途径进行给药，其中包括(但并不限于)：肌内、静脉内、皮下、皮内或局部给药。待预防或治疗的对象可以是动物；尤其是人。
当本发明的药物组合物被用于实际治疗时，可根据使用情况而采用各种不同剂型的药物组合物。较佳地为注射剂。
这些药物组合物可根据常规方法通过混合、稀释或溶解而进行配制，并且偶尔添加合适的药物添加剂，如赋形剂、崩解剂、粘合剂、润滑剂、稀释剂、缓冲剂、等渗剂(isotonicities)、防腐剂、润湿剂、乳化剂、分散剂、稳定剂和助溶剂，而且该配制过程可根据剂型用惯常方式进行。本发明的药物组合物还可以缓释剂形式给药。
当本发明的药物组合物被用于预防或治疗时，作为活性成分的本发明的化合物或其药学上可接受的盐的剂量，可根据待预防或治疗的每个对象(病人)的体重、年龄、性别、症状程度而合理地加以确定。
根据本发明的化合物和药物组合物可以用于治疗神经损伤疾病，包括但不限于：阿尔茨海默病。
工业应用性
含有本发明化合物或其药学上可接受盐作为活性成分的药物组合物，具有显著的神经细胞保护功能。经动物试验证实，本发明化合物可以改善动物的记忆功能。
本发明的主要优点在于：
(1)首次揭示了一类结构新颖的南蛇藤属植物中的活性化合物；
(2)首次发现了本发明化合物在神经保护、治疗神经损伤、改善记忆上的功能。
(3)首次发现了南蛇藤属植物提取物在神经保护、治疗神经损伤、改善记忆上的功能。
下面结合具体实施例，进一步详陈本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。除非另外说明，否则百分比和份数按重量计算。
实施例1化合物的制备和结构鉴定
南蛇藤种子中化合物的提取和分离
将阴干、粉碎的南蛇藤种子(C.orbiculatus)(10.0kg)用95％工业乙醇室温渗漉三次(25L×3，3天/次)，滤液减压浓缩至小量，加H2O悬浮，以石油醚、乙酸乙酯和正丁醇(2L×3,each)依次连续萃取，分别得到石油醚部位(1.1kg),乙酸乙酯部位(20.5g)和正丁醇部位(100.0g)。各部位具体分离流程见图1。
苦皮藤果实中化合物的提取与分离
苦皮藤(C.angulatus)果实1.8Kg经粉碎后，以95％乙醇室温浸提三次(10L×3)，减压蒸除乙醇得到总浸膏(300g)，总浸膏直接硅胶拌样，硅胶柱色谱分离，石油醚-丙酮(1:0，20:1，15:1，10:1，5:1，2:1，1:1，0:1)梯度洗脱，得到6个馏分(Fr.A-Fr.F)；具体分离流程图见图2。
刺苞南蛇藤果实中化合物的提取与分离
刺苞南蛇藤(Celastrus flagellaris)果实98g经粉碎后，以二氯甲烷超声提取五次(1L×5)，减压蒸除二氯甲烷得到总浸膏(36g)，总浸膏直接硅胶拌样，硅胶柱色谱分离，石油醚-丙酮(1:0，20:1，15:1，10:1，5:1，2:1，1:1，0:1)梯度洗脱，得到6个馏分(Fr.1-Fr.6)；具体分离流程图见图3。
化合物理化性质和波谱数据
KPT-13：白色无定形粉末；
Figure PCTCN2015096134-appb-000061
-164.3(c 0.14,MeOH)；UV(MeOH)λmax(logε)227(4.48),264(3.63)nm；IR(KBr)νmax 2991,1743,1720,1603,1591,1450,1367,1292,1271,1244,1115,1084,1026,854,712cm-1；1H NMR(500MHz,Pyridine-d5)δH 1.92(s,3H)(AcO-1),1.81(s,3H)(AcO-2),BzO-8and BzO-9[8.34(d,2H,J＝7.2Hz),7.48(t,2H,J＝7.2Hz),7.56(t,1H,J＝7.2Hz),7.97(d,2H,J＝7.2Hz),6.95(t,2H,J＝7.2Hz),7.23(overlapped,1H)],NicO-15[9.54(brs,1H),8.77(brd,1H,J＝4.8Hz),8.39(brd,1H,J＝8.0Hz),7.23(overlapped,1H)],6.17(d,1H,J＝2.7Hz,H-1),5.82(dd,1H,J＝5.7,2.7Hz,H-2),1.79,2.49(m,each 1H,H-3),2.00(m,1H,H-4),2.17(dd,1H,J＝13.4,3.2Hz,H-6a),2.98(d,1H,J＝13.4Hz,H-6b),2.53(brt,1H,J＝3.7Hz,H-7),6.13(dd,1H,J＝5.4,3.4Hz,H-8),6.20(d,1H,J＝5.4Hz,H-9),1.50(s,3H,H-12),1.24(s,3H,H-13),1.41(d,3H,J＝8.0 Hz,H-14),5.47,5.97(d,each 1H,J＝12.0Hz,H-15)；13C NMR(125MHz,Pyridine-d5)δC 78.5(d,C-1),71.0(d,C-2),32.3(t,C-3),40.0(d,C-4),88.7(s,C-5),32.5(t,C-6),48.8(d,C-7),71.9(d,C-8),75.1(d,C-9),50.3(s,C-10),81.7(s,C-11),23.2(q,C-12),29.9(q,C-13),19.9(q,C-14),65.2(t,C-15),AcO-1[171.2(s),21.5(q)],AcO-2[170.5(s),21.5(q)],BzO-8and BzO-9[166.5(s),130.7(s),130.6(d),129.4(d),134.2(d),165.9(s),130.1(s),130.2(d),128.9(d),133.8(d)],NicO-15[166.2(s),126.8(s),151.9(d),154.4(d),137.5(d),123.5(d)]；HRESIMS m/z 722.2588(calcd for C39H41O11NNa,722.2577)；
KPT-13b：白色无定形粉末；
Figure PCTCN2015096134-appb-000062
-37.9(c 0.14,MeOH)；UV(MeOH)λmax(logε)226(4.38),264(3.58)nm；IR(KBr)νmax 2929,1728,1603,1591,1452,1369,1288,1269,1230,1095,1026,860,712cm-1；1H NMR(400MHz,CDCl3)δH1.52(s,3H)(AcO-1),2.14(s,3H)(AcO-6),BzO-8and BzO-9[7.77(d,2H,J＝7.2Hz),7.10(t,2H,J＝7.2Hz),7.34(t,1H,J＝7.2Hz),7.95(d,2H,J＝7.2Hz),7.30(t,2H,J＝7.2Hz),7.48(t,1H,J＝7.2Hz)],NicO-15[9.22(brs,1H),8.63(brd,1H,J＝4.6Hz),8.26(brd,1H,J＝8.0Hz),7.11(dd,1H,J＝8.0,4.6Hz)],5.57(dd,1H,J＝10.1,6.3Hz,H-1),1.80(m,1H,H-2a),1.83(m,1H,H-2b),2.30(m,1H,H-3a),1.50(m,1H,H-3b),2.37(m,1H,H-4),6.45(s,1H,H-6),2.78(d,1H,J＝4.0Hz,H-7),5.77(dd,1H,J＝5.8,4.0Hz,H-8),5.8(d,1H,J＝5.8Hz,H-9),1.67(s,3H,H-12),1.49(s,3H,H-13),1.14(d,3H,J＝8.0Hz,H-14),5.00,5.36(d,each 1H,J＝13.2Hz,H-15)；13C NMR(100MHz,CDCl3)δC AcO-1[170.0(s),21.0(q)],AcO-6[170.3(s),21.5(q)],BzO-8and BzO-9[166.4(s),129.8(s),129.7(d),128.3(d),133.1(d),165.1(s),129.4(s),129.9(d),128.7(d),133.5(d)],NicO-15[165.6(s),125.7(s),151.4(d),153.6(d),137.6(d),123.2(d)],79.4(d,C-1),23.5(t,C-2),26.8(t,C-3),33.7(d,C-4),90.6(s,C-5),75.4(d,C-6),53.0(d,C-7),71.8(d,C-8),73.3(d,C-9),51.5(s,C-10),81.7(s,C-11),24.8(q,C-12),30.8(q,C-13),16.2(q,C-14),62.5(t,C-15)；HRESIMS m/z 700.2757(calcd for C39H42O11N,700.2758)；
CB-5I：无色晶体；熔点:218-220℃；
Figure PCTCN2015096134-appb-000063
+143.2(c 0.08,CHCl3)；UVλmax(Methanol)219(4.4)nm,223(4.4)nm,279(4.4)nm；IR(KBr)νmax 1742,1713,1636,1452,1367,1274,1227,1165,720cm-1；1H NMR(CDCl3)δ1.77(3H,s,AcO-1),2.17(3H,s,AcO-15),BzO-2and CinO-9[8.13(d,2H,J＝7.0Hz),7.69(d,1H,J＝16.0Hz),7.57(m,3H),7.50(t,2H,J＝7.5Hz),7.39(m,3H),6.39(d,1H,J＝16.0Hz)],5.80(brs,1H,H-1),5.80(m,1H,H-2),2.56(ddd,1H,J＝15.2,6.9,3.2Hz,H-3a),1.94(dd,1H,J＝15.2,3.2Hz,H-3b),1.98(t,1H,J＝6.9Hz,H-4),2.13(m,1H,H-6a),2.31(m,1H,H-6b),2.11(m,1H,H-7),2.28(m,1H,H-8a),2.12(m,1H,H-8b),5.23(d,1H,J＝6.9Hz,H-9),1.41(s,3H,H-12),1.23(s,3H,H-13),1.32(d,3H,J＝7.0Hz,H-14),5.12,4.48(d,each 1H,J＝12.1Hz,H-15)；13C NMR(CDCl3)δ AcO-1[20.9(q),170.0(s)],AcO-15[21.5(q),170.9(s)],BzO-2and CinO-9[118.2(d),128.4x2(d),128.8x2(d),129.0x2(d),130.0(s),130.0x2(d),130.5(d),133.3(d),134.5(s),145.6(d),166.2(s),166.3(s)],71.3(d,C-1),71.3(d,C-2),31.1(t,C-3),39.4(d,C-4),86.7(s,C-5),36.4(t,C-6),43.8(d,C-7),34.1(t,C-8),69.6(d,C-9),50.5(s,C-10),82.4(s,C-11),24.3(q,C-12),30.3(q,C-13),19.2(q,C-14),66.2(t,C-15)；HRTOFMS  m/z 627.2579[M+Na]+(calcd for C35H40O9Na,627.2570).
CB-4E：白色无定形粉末；
Figure PCTCN2015096134-appb-000064
+150.0(c 0.08,CHCl3)；UVλmax(Methanol)218(4.0)nm,279(4.1)nm；IR(KBr)νmax 1742,1712,1639,1450,1367,1261,1226,1162,1013,769cm-1；1H NMR(CDCl3)δ1.80(3H,s,AcO-1),2.18(3H,s,AcO-15),CinO-2and CinO-9[7.76(d,1H,J＝16.2Hz),7.69(d,1H,J＝16.0Hz),7.64(m,2H),7.55(m,2H),7.39(m,6H),6.43(d,1H,J＝16.2Hz),6.39(d,1H,J＝16.2Hz)],5.75(d,1H,J＝3.4Hz,H-1),5.66(dd,1H,J＝7.5,3.4Hz,H-2),2.50(ddd,1H,J＝15.0,7.1,3.5Hz,H-3a),1.88(dd,1H,J＝15.0,3.5Hz,H-3b),2.40(t,1H,J＝7.7Hz,H-4),2.11(m,1H,H-6a),2.29(m,1H,H-6b),2.11(m,1H,H-7),2.27(m,1H,H-8a),2.11(m,1H,H-8b),5.24(d,1H,J＝6.8Hz,H-9),1.40(s,3H,H-12),1.22(s,3H,H-13),1.30(d,3H,J＝7.0Hz,H-14),5.03,4.49(d,each 1H,J＝12.6Hz,H-15)；13C NMR(CDCl3)δ AcO-1[20.9(q),170.0(s)],AcO-15[21.6(q),170.8(s)],CinO-2and CinO-9[118.2x2(d),128.4x4(d),129.0x4(d),130.5x2(d),134.5x2(s),145.3(d),145.6(d),166.2x2(s)],71.4(d,C-1),70.8(d,C-2),31.1(t,C-3),39.4(d,C-4),86.7(s,C-5),36.4(t,C-6),43.7(d,C-7),34.1(t,C-8),69.6(d,C-9),50.6(s,C-10),82.3(s,C-11),24.3(q,C-12),30.3(q,C-13),19.1(q,C-14),65.9(t,C-15)；HRTOFMS m/z 653.2739[M+Na]+(calcd for C37H42O9Na,653.2727).
CB-4C：白色无定形粉末；
Figure PCTCN2015096134-appb-000065
+210.0(c 0.10,CHCl3)；UVλmax(Methanol)218(3.9)nm,279(4.0)nm；IR(KBr)νmax 1745,1711,1637,1450,1367,1234,1165,1016,767cm-1；1H NMR(CDCl3)δ1.81(3H,s,AcO-1),2.13(3H,s,AcO-6),CinO-2and CinO-9[7.67(d,1H,J＝16.5Hz),7.63(d,1H,J＝16.5Hz),7.53(m,4H),7.38(m,6H),6.38(d,1H,J＝16.5Hz),6.37(d,1H,J＝16.5Hz)],5.65(d,1H,J＝3.9Hz,H-1),5.70(dd,1H,J＝7.8,3.9Hz,H-2),2.44(m,1H,H-3a),1.89(dd,1H,J＝15.0,3.0Hz,H-3b),2.37(t,1H,J＝7.5Hz,H-4),5.42(s,1H,H-6),2.23(brs,1H,H-7),2.23(m,1H,H-8a),2.16(m,1H,H-8b),4.77(d,1H,J＝7.0Hz,H-9),1.42(s,3H,H-12),1.41(s,3H,H-13),1.27(d,3H,J＝7.0Hz,H-14),1.52(s,3H,H-15)；13C NMR(CDCl3)δAcO-1[20.9(q),170.2(s)],AcO-6[21.6(q),170.3(s)],CinO-2and CinO-9[118.1(d),118.4(d),128.2x2(d),128.4x2(d),129.0x2(d),129.1x2(d),130.5x2(d),134.4(s),134.5(s),145.1(d),145.7(d),166.2(s),166.3(s)],71.1(d,C-1),70.4(d,C-2),31.2(t,C-3),33.9(d,C-4),89.6(s,C-5),79.3(d,C-6),48.9(d,C-7),31.6(t,C-8),72.9(d,C-9),49.9(s,C-10),83.0(s,C-11),26.1(q,C-12),30.8(q,C-13),18.9(q,C-14),20.6(q,C-15)；HRTOFMS m/z 653.2742[M+Na]+(calcd for C37H42O9Na,653.2727).
CB-4S：白色无定形粉末；
Figure PCTCN2015096134-appb-000066
+87.0(c 0.10,CHCl3)；UVλmax(Methanol)218(4.2)nm,223(4.1)nm,276(4.2)nm；IR(KBr)νmax 1742,1713,1639,1392,1366,1280,1227,1100,1015,709cm-1；1H NMR(CDCl3)δ1.62(3H,s,AcO-1),2.13(3H,s,AcO-6),BzO-9and CinO-2[8.06(d,2H,J＝7.4Hz),7.63(d,1H,J＝16.1Hz),7.56(t,1H,J＝7.0Hz),7.51(m,2H),7.44(t,2H),7.39(m,3H),6.37(d,1H,J＝16.1Hz)],5.65(d,1H,J＝3.2Hz,H-1),5.73(dd,1H,J＝7.5,3.2Hz,H-2),2.49(m,1H,H-3a),1.90(dd,1H,J＝15.1,3.3Hz,H-3b),2.40(t,1H,J＝7.7Hz,H-4),5.46(s,1H,H-6),2.26(t,1H,J＝7.0Hz,H-7),2.20(m,1H,H-8a),2.16(m,1H,H-8b),4.99(d,1H,J＝6.9Hz, H-9),1.43(s,3H,H-12),1.42(s,3H,H-13),1.27(d,3H,J＝7.2Hz,H-14),1.55(s,3H,H-15)；13C NMR(CDCl3)δ AcO-1[20.6(q),169.8(s)],AcO-15[21.6(q),170.3(s)],BzO-9and CinO-2[118.3(d),128.3x2(d),128.4x2(d),129.1x2(d),129.6(s),130.2x2(d),130.6(d),133.4(d),134.4(s),145.1(d),165.7(s),166.3(s)],71.4(d,C-1),70.3(d,C-2),31.7(t,C-3),33.9(d,C-4),89.7(s,C-5),79.4(d,C-6),49.0(d,C-7),31.2(t,C-8),73.2(d,C-9),50.0(s,C-10),83.1(s,C-11),26.2(q,C-12),30.8(q,C-13),18.9(q,C-14),20.7(q,C-15)；HRTOFMS m/z 627.2588[M+Na]+(calcd for C35H40O9Na,627.2570).
CB-2H：白色无定形粉末；
Figure PCTCN2015096134-appb-000067
+72.3(c 0.08,CHCl3)；UVλmax(Methanol)218(4.1)nm,223(4.1)nm,277(4.2)nm；IR(KBr)νmax 1747,1718,1641,1456,1362,1233,1133,1013,878,770cm-1；1H NMR(pyridine-d5)δ1.97(3H,s,AcO-1),HexO-2[2.36(t,2H,J＝7.2Hz),2.11(m,2H),1.66(m,2H),1.27(m,2H),0.85(t,3H,J＝7.1Hz)],CinO-9[8.03(d,1H,J＝16.0Hz),7.56(m,2H),7.32(m,3H),6.78(d,1H,J＝16.0Hz)],5.96(d,1H,J＝3.4Hz,H-1),6.00(dd,1H,J＝7.4,3.4Hz,H-2),2.49(ddd,1H,J＝15.0,6.8,3.2Hz,H-3a),1.77(dd,1H,J＝15.0,3.2Hz,H-3b),1.99(m,1H,H-4),2.06(m,1H,H-6a),2.02(m,1H,H-6b),1.92(m,1H,H-7),2.21(m,1H,H-8a),2.14(m,1H,H-8b),5.13(d,1H,J＝6.8Hz,H-9),1.55(s,3H,H-12),1.24(s,3H,H-13),1.29(d,3H,J＝7.0Hz,H-14),1.46(s,3H,H-15)；13C NMR(pyridine-d5)δ AcO-1[21.3(q),170.7(s)],HexO-2[14.5(q),23.0(t),25.4(t),32.0(t),35.2(t),173.4(s)],CinO-9[119.7(d),129.1x2(d),129.7x2(d),131.1(d),136.3(s),145.6(d),166.6(s)],72.2(d,C-1),70.9(d,C-2),31.7(t,C-3),40.3(d,C-4),88.1(s,C-5),36.5(t,C-6),44.5(d,C-7),31.8(t,C-8),74.3(d,C-9),47.9(s,C-10),83.0(s,C-11),24.9(q,C-12),30.9(q,C-13),19.8(q,C-14),20.6(q,C-15)；HRTOFMS m/z 563.2996[M+Na]+(calcd for C32H44O7Na,563.2985).
CB-4R：白色无定形粉末；
Figure PCTCN2015096134-appb-000068
+100.2(c 0.07,CHCl3)；UVλmax(Methanol)206(4.4)nm,218(4.4)nm,279(4.6)nm；IR(KBr)νmax 1746,1719,1643,1452,1365,1223,1162,1134,1012,879,767,710cm-1；1H NMR(CDCl3)δ1.78(3H,s,AcO-1),2.16(3H,s,AcO-15),ButO-2[2.33(m,2H),1.69(m,2H),0.96(t,3H,J＝7.0Hz)],CinO-9[7.67(d,1H,J＝16.0Hz),7.54(m,2H),7.38(m,3H),6.36(d,1H,J＝16.0Hz)],5.68(d,1H,J＝3.2Hz,H-1),5.56(dd,1H,J＝7.3,3.2Hz,H-2),2.46(ddd,1H,J＝15.0,6.9,3.0Hz,H-3a),1.75(dd,1H,J＝15.0,3.0Hz,H-3b),1.92(t,1H,J＝6.9Hz,H-4),2.06(m,1H,H-6a),2.33(m,1H,H-6b),2.11(m,1H,H-7),2.24(m,1H,H-8a),2.08(m,1H,H-8b),5.17(d,1H,J＝7.0Hz,H-9),1.38(s,3H,H-12),1.20(s,3H,H-13),1.26(d,3H,J＝7.0Hz,H-14),4.84,4.40(d,each 1H,J＝12.7Hz,H-15)；13C NMR(CDCl3)δ AcO-1[20.9(q),169.8(s)],AcO-15[21.6(q),170.8(s)],ButO-2[13.8(q),18.5(t),36.8(t),172.9(s)],CinO-9[118.2(d),128.4x2(d),129.0x2(d),130.5(d),134.5(s),145.5(d),166.2(s)],71.4(d,C-1),70.1(d,C-2),31.2(t,C-3),39.5(d,C-4),86.7(s,C-5),36.4(t,C-6),43.7(d,C-7),34.2(t,C-8),69.6(d,C-9),50.6(s,C-10),82.2(s,C-11),24.3(q,C-12),30.3(q,C-13),18.9(q,C-14),65.8(t,C-15)；HRTOFMS m/z563.2734[M+Na]+(calcd for C32H42O9Na,593.2727).
本发明中其它化合物的波谱数据如下：
PE-11:MF:C33H38O7，MW:546；白色无定形粉末；ESIMS m/z 547.3[M+H]+；1H NMR(CDCl3,400MHz)δ AcO-1[1.62(3H,s)],CinO-6[6.47,7.71(each lH,d,J＝16.1Hz),7.42(3H,m),7.55(2H,m)],BzO-9[7.45(2H,brt,J＝6.8Hz),7.57(1H,brt,J＝6.8Hz),8.08(2H,brd,J＝6.8Hz)],5.52(dd,1H,J＝12.2,4.4Hz,H-1),1.53(m,1H,H-2a),1.90(ddd,1H,J＝12.2,8.3,3.9Hz,H-2b),1.46(m,1H,m,H-3a),2.26(m,1H,H-3b),2.37(q,1H,J＝7.3Hz,H-4),5.47(brs,1H,H-6),2.32(m,1H,H-7),2.48(ddd,2H,J＝16.6,6.8,3.3Hz,H-8),5.02(d,1H,J＝6.8Hz,H-9),1.43(s,3H,H-12),1.45(s,3H,H-13),1.03(d,3H,J＝7.3Hz,H-14),1.37(s,3H,H-15)；
PE-13:MF:C31H36O8，MW:536；白色无定形粉末；ESIMS m/z 559.2[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-6[2.13(3H,s)],BzO-8,BzO-9[8.10(2H,d,J＝7.5Hz),8.03(2H,d,J＝7.5Hz),7.87(2H,d,J＝7.5Hz),7.54(m,2H),7.50(m,3H),7.44(t,2H,J＝7.3Hz),7.25(2H,t,J＝7.3Hz)],4.14(dd,1H,J＝10.7,5.1Hz,H-1),1.57,1.94(m,each 1H,H-2),1.49,2.29(m,each1H,H-3),2.40(m,1H,H-4),6.19(brs,1H,H-6),2.57(m,1H,H-7),5.83(ddd,1H,J＝5.1,3.7Hz,H-8),5.77(d,1H,J＝5.1Hz,H-9),1.73(s,3H,H-12),1.55(s,3H,H-13),1.05(d,3H,J＝7.3Hz,H-14),1.31(s,3H,H-15)；
PE-17:MF:C33H38O8，MW:562；白色无定形粉末；ESIMS m/z 585.2[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-6[2.15(3H,s)],CinO-1[6.92(2H,d,J＝7.5Hz),7.16(2H,t,J＝7.5Hz),7.25(1H,t,J＝7.5Hz),5.68(1H,d,J＝15.9Hz),7.22(1H,d,J＝15.9Hz)],BzO-9[7.93(2H,d,J＝7.8Hz),7.19(2H,t,J＝7.8Hz),and 7.27(1H,t,J＝7.8Hz)],5.36(dd,1H,J＝11.0,4.8Hz,H-1),1.64,1.68(m,each 1H,H-2),1.42,2.12(m,each 1H,H-3),2.19(m,1H,H-4),6.15(brs,1H,H-6),2.43(d,1H,J＝4.4Hz,H-7),4.35(t,2H,J＝4.4Hz,H-8),5.50(d,1H,J＝4.4Hz,H-9),1.46(s,3H,H-12),1.39(s,3H,H-13),1.02(d,3H,J＝7.1Hz,H-14),1.56(s,3H,H-15)；
PE-34:MF:C28H36O9，MW:516；白色无定形粉末；ESIMS m/z 539.2[M+Na]+；
1H NMR(CDCl3,400MHz)δ AcO-1,AcO-6,AcO-8[1.60,2.15,2.10(each 3H,s)],BzO-9[7.44(2H,brt,J＝7.2Hz),7.56(1H,brt,J＝7.2Hz),8.04(2H,brd,J＝7.2Hz)],5.41(dd,1H,J＝12.2,4.4Hz,H-1),1.60(m,1H,H-2a),1.89(m,1H,H-2b),1.44(m,1H,m,H-3a),2.22(m,1H,H-3b),2.26(q,1H,J＝7.6Hz,H-4),5.73(brs,1H,H-6),2.45(d,1H,J＝4.4Hz,H-7),5.26(t,2H,J＝4.4Hz,H-8),5.03(s,1H,H-9),1.46(s,3H,H-12),1.40(s,3H,H-13),1.03(d,3H,J＝7.0Hz,H-14),1.46(s,3H,H-15)；
PE-221:MF:C26H34O5，MW:426；白色无定形粉末；ESIMS m/z 459.2[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-1[1.83(3H,s)],CinO-9[6.47,7.71(each lH,d,J＝16.1Hz),7.42(3H,m),7.55(2H,m)],5.43(dd,1H,J＝12.2,4.4Hz,H-1),1.60(m,1H,H-2a),1.89(m,1H,H-2b),1.50,2.22(m,each 1H,H-3),2.26(m,1H,H-4),2.12(m,1H,H-6),2.07(m,1H,H-7),1.92,2.54(m,each1H,H-8b),4.82(d,1H,J＝6.4Hz,H-9),1.20(s,3H,H-12),1.38(s,3H,H-13),1.06(d,3H,J＝7.6Hz,H-14),1.20(s,3H,H-15)；
PE-232:MF:C31H36O7，MW:520；白色无定形粉末；ESIMS m/z 546.2[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-1[1.63(3H,s)],BzO-6,BzO-9[8.10(2H,d,J＝7.5Hz),8.03(2H,d,J＝7.5Hz),7.87(2H,d,J＝7.5Hz),7.54(m,2H),7.50(m,3H),7.44(t,2H,J＝7.5Hz),7.35(2H,t,J＝7.5Hz)],5.52(dd,1H,J＝12.2,4.4Hz,H-1),1.65,1.91(m,each 1H,H-2),1.53,2.25(m,each1H,H-3),2.29(m,1H,H-4),5.57(s,1H,H-6),2.07(m,1H,H-7),1.92,2.32(m,each 1H,H-8),5.07(d,1H,J＝7.4Hz,H-9),1.44(s,3H,H-12),1.45(s,3H,H-13),1.03(d,3H,J＝7.6Hz,H-14),1.39(s,3H,H-15)；
PE-331:MF:C26H34O7，MW:458；白色无定形粉末；ESIMS m/z 459.2[M+H]+；1H NMR(CDCl3,400MHz)δ AcO-6,AcO-9[2.15,2.10(each 3H,s,),BzO-1[7.24(2H,brt,J＝7.2Hz),7.56(1H,brt,J＝7.2Hz),8.04(2H,brd,J＝7.2Hz)],5.43(dd,1H,J＝11.0,4.4Hz,H-1),1.50,1.89(m,each 1H,H-2),1.44,2.22(m,each 1H,H-3),2.36(m,1H,H-4),5.28(brs,1H,H-6),2.16(m,1H,H-7),1.90,2.32(m,each 1H,H-8),4.98(dd,1H,J＝6.1,1.0Hz,H-9),1.36(s,3H,H-12),1.38(s,3H,H-13),0.98(d,3H,J＝7.0Hz,H-14),1.30(s,3H,H-15)；
PE-4212:MF:C26H34O7，MW:606；白色无定形粉末；ESIMS m/z 629.3[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-6[2.12(3H,s)],BzO-1[7.61(2H,d,J＝7.4Hz),6.92(2H,t,J＝7.4Hz),and 7.18(1H,t,J＝7.4Hz)],ButO-8[2.34(2H,t,J＝7.6Hz),1.62(2H,m),and 0.88(3H,t,J＝7.6Hz)],BzO-9[7.59(2H,d,J＝7.4Hz),7.10(2H,t,J＝7.4Hz),and 7.32(1H,t,J＝7.4Hz)],5.54(dd,1H,J＝11.2,4.0Hz,H-1),1.78,1.80(m,each 1H,H-2),1.48,2.20(m,each 1H,H-3),2.26(m,1H,H-4),5.96(brs,1H,H-6),2.48(d,1H,J＝4.4Hz,H-7),5.53(brs,2H,H-8),5.67(d,1H,J＝4.4Hz,H-9),1.59(s,3H,H-12),1.42(s,3H,H-13),1.10(d,3H,J＝7.0Hz,H-14),1.61(s,3H,H-15)；
PE-4221:MF:C28H36O9，MW:516；白色无定形粉末；ESIMS m/z 539.3[M+Na]+；1H NMR(CDCl3,400MHz)δ AcO-1,AcO-6,and AcO-15[1.54,2.09,2.24(each3H,s,)],BzO-1[7.24(2H,brt,J＝7.2Hz),7.56(1H,brt,J＝7.2Hz),8.04(2H,brd,J＝7.2Hz)],5.60(dd,1H,J＝12.5,4.0Hz,H-1),1.42,1.52(m,each 1H,H-2b),1.43,2.26(m,each 1H,H-3),2.30(m,1H,H-4),5.93(brs,1H,H-6),2.19(d,1H,J＝4.4Hz,H-7),2.48(brs,2H,H-8),5.38(d,1H,J＝7.5Hz,H-9),1.44(s,3H,H-12),1.41(s,3H,H-13),0.99(d,3H,J＝7.0Hz,H-14),4.43,4.67(d,each 2H,J＝11.7Hz,H-15)；
KPT-4：MF:C37H40O9N，MW:642；白色无定形粉末；ESIMS m/z 665.3[M+Na]+；1H NMR(400MHz,CDCl3)δH 1.57(s,3H)(AcO-1),BzO-8and BzO-9[7.93(d,2H,J＝8.2Hz),7.35(t,2H,J＝8.2Hz),7.48(t,1H,J＝8.2Hz),7.80(d,2H,J＝8.2Hz),7.26(t,2H,J＝8.2Hz),7.42(t,1H,J＝8.2Hz)],NicO-15[9.46(brs,1H),8.88(brs),8.53(brd,1H,J＝7.8Hz),7.53(dd,1H,J＝7.8,4.8Hz)],5.52(dd,1H,J＝12.0,4.0Hz,H-1),1.84(m,1H,H-2a),1.52(m,1H,H-2b),2.29(m,1H,H-3a),1.50(m,1H,H-3b),1.92(m,1H,H-4),2.20(dd,1H,J＝12.9,4.8Hz,H-6a),2.76(d,1H,J＝12.9Hz,H-6b),2.60(brt,1H,J＝3.8Hz,H-7),5.83(dd,1H,J＝9.7,3.2Hz,H-8),6.29(d,1H,J＝ 9.7Hz,H-9),1.69(s,3H,H-12),1.22(s,3H,H-13),1.20(d,3H,J＝7.9Hz,H-14),5.06,4.98(d,each 1H,J＝12.7Hz,H-15)；
KPT-12b：MF:C35H40O12，MW:652；白色无定形粉末；ESIMS m/z 675.2[M+Na]+；1H NMR(400MHz,CDCl3)δH 1.61(s,3H)(AcO-1),2.13(s,3H)(AcO-6),1.91(s,3H)(AcO-15),BzO-8and BzO-9[7.96(d,2H,J＝7.4Hz),7.94(d,2H,J＝7.4Hz),7.53(t,2H,J＝7.4Hz),7.39(t,2H,J＝7.4Hz),7.37(t,2H,J＝7.4Hz)],δH 5.57(d,1H,J＝3.5Hz,H-1),4.19(br m,1H,H-2),2.37(m,1H,H-3a),1.86(m,1H,H-3b),2.32(m,1H,H-4),6.86(s,1H,H-6),2.67(d,2H,J＝3.7Hz,H-7),5.78(dd,1H,J＝6.0,3.7Hz,H-8),5.73(d,1H,J＝6.0Hz,H-9),1.62(s,3H,H-12),1.47(s,3H,H-13),1.22(d,3H,J＝7.5Hz,H-14),5.44,4.77(d,each 1H,J＝13.2Hz,H-15)；
KPT-15a:MF:C42H44O13，MW:756；白色无定形粉末；ESIMS m/z 779.3[M+Na]+；1H NMR(CDCl3,400MHz):δ AcO-1,AcO-6and AcO-15[2.18,1.92,1.54(each3H,s)],BzO-2,BzO-8and BzO-9[8.10(2H,d,J＝7.5Hz),8.03(2H,d,J＝7.5Hz),7.87(2H,d,J＝7.5Hz),7.54(m,2H),7.50(m,3H),7.44(t,2H,J＝7.5Hz),7.35(2H,t,J＝7.5Hz)],5.77(brs,1H,H-1),5.77(brs,1H,H-2),2.62,1.95(m,2H,H-3),2.44(m,1H,H-4),6.92(s,1H,H-6),2.71(d,1H,J＝3.9Hz,H-7),5.82(m,1H,H-8),5.83(m,1H,H-9),1.68(s,3H,H-12),1.53(s,3H,H-13),1.27(d,3H,J＝7.8Hz,H-14),5.61,4.62(d,each 1H,J＝13.2Hz,H-15)；
KPT-15b
MF:C47H46O13，MW:818；白色无定形粉末；ESIMS m/z 841.3[M+Na]+；1H NMR(CDCl3,400MHz):δ AcO-6and AcO-15[2.19,1.94(each 3H,s)],BzO-1,BzO-2,BzO-8and BzO-9[8.08(2H,d,J＝7.6Hz),8.03(2H,d,J＝7.6Hz),7.40–7.60(m,10H),7.32(1H,t,J＝7.6Hz),7.14(1H,t,J＝7.6Hz),7.05(2H,t,J＝7.6Hz),6.85(2H,t,J＝7.6Hz)],6.06(d,1H,J＝4.0Hz,H-1),5.86(m,1H,H-2),1.69,2.04(m,2H,H-3),2.48(m,1H,H-4),6.92(s,1H,H-6),2.74(d,1H,J＝4.0Hz,H-7),5.82(dd,1H,J＝6.0,4.0Hz,H-8),5.91(d,1H,J＝6.0Hz,H-9),1.71(s,3H,H-12),1.54(s,3H,H-13),1.30(d,3H,J＝8.0Hz,H-14),4.83,5.79(d,each 1H,J＝12.8Hz,H-15)；
KPT-12a
MF:C31H36O9，MW:552；白色无定形粉末；ESIMS m/z 575.2[M+Na]+；1H NMR(CDCl3,400MHz):δ AcO-6[2.14(each 3H,s)],BzO-8and BzO-9[8.10(2H,d,J＝7.2Hz),7.90(2H,d,J＝7.2Hz),7.61(1H,t,J＝7.2Hz),7.40-7.60(m,3H),7.34(2H,t,J＝7.2Hz)],4.07(brs,1H,H-1),4.11(dd,1H,J＝6.2,3.6Hz,H-2),2.33(m,1H,H-3a),1.89(d,1H,J＝15.0,H-3b),2.20(m,1H,H-4),6.30(s,1H,H-6),2.63(d,1H,J＝3.6Hz,H-7),5.84(dd,1H,J＝5.2,4.2Hz,H-8),5.75(d,1H,J＝5.2Hz,H-9),1.62(s,3H,H-12),1.47(s,3H,H-13),1.34(d,3H,J＝7.6Hz,H-14),1.67(s,3H,H-15)；
CB-5D2：MF:C30H38O9，MW:542；白色无定形粉末；ESIMS m/z 543.3[M+H]+；1H NMR(CDCl3,400MHz):δ AcO-1,AcO-2and AcO-6[1.80,2.04,2.12(each 3H,s)],[CinO-9[7.67(1H,d,J＝16.0Hz),7.54(m,2H),7.38(m,3H),6.36(1H, d,J＝16.0Hz)],5.57(brs,1H,H-1),5.57(brs,1H,H-2),1.78,2.32(m,each 1H,H-3),2.40(m,1H,H-4),5.37(s,1H,H-6),2.21(m,1H,H-7),2.13(dd,1H,J＝15.6,2.5Hz,H-8a),2.42(m,1H,H-8b),4.74(d,1H,J＝6.9Hz,H-9),1.39(s,3H,H-12),1.40(s,3H,H-13),1.21(d,3H,J＝7.8Hz,H-14),1.44(s,3H,H-15)；
CB-4D：MF:C35H40O7，MW:572；白色无定形粉末；ESIMS m/z 573.2[M+H]+；1H NMR(CDCl3,400MHz):δ AcO-1[1.83(3H,s)],CinO-2and CinO-9[7.67(1H,d,J＝16.0Hz),7.60(1H,d,J＝16.0Hz),7.54(m,4H),7.38(m,6H),6.42(d,1H,J＝16.0Hz),6.38(d,1H,J＝16.0Hz)],5.62(d,1H,J＝3.4Hz,H-1),5.68(dd,1H,J＝3.4,6.6Hz,H-2),4.78(d,1H,J＝6.9Hz,H-9),1.39(s,3H,H-12),1.42(s,3H,H-13),1.31(d,3H,J＝7.8Hz,H-14),1.22(s,3H,H-15)；
CB-2D：MF:C33H38O7，MW:546；白色无定形粉末；ESIMS m/z 547.3[M+H]+；
1H NMR(CDCl3,400MHz):δ AcO-1[1.83(3H,s)],BzO-2[7.45(2H,brt,J＝7.6Hz),7.56(lH,br t,J＝7.6),8.00(2H,br d,J＝7.6)],CinO-9[6.40,7.67(each lH,d,J＝16.l),7.37(3H,rn),7.55(2H,rn)],5.68(d,1H,J＝3.4Hz,H-1),5.83(ddd,1H,J＝6.4,3.4,3.2Hz,H-2),1.91,2.20(m,each1H,H-3),1.97(m,1H,H-4),2.12(m,1H,H-6),2.07(m,1H,H-7),1.92(m,1H,H-8a),2.54(ddd,1H,J＝10.2,6.4,3.9Hz,H-8b),4.78(d,1H,J＝6.5Hz,H-9),1.40(s,3H,H-12),1.23(s,3H,H-13),1.33(d,3H,J＝7.8Hz,H-14),1.47(s,3H,H-15)；
CB-4A：MF:C35H40O9，MW:604；白色无定形粉末；ESIMS m/z 627.3[M+Na]+；
1H NMR(CDCl3,400MHz):δ AcO-1,AcO-6and AcO-15[2.12,1.80(each 3H,s)],BzO-2[7.98(2H,d,J＝8.0Hz),7.45(2H,t,J＝8.0Hz),and 7.56(1H,t,J＝8.0Hz)],CinO-9[7.55(2H,m),7.38(2H,m),7.38(1H,m),6.38(1H,d,J＝16.0Hz),7.70(1H,d,J＝16.0Hz)],5.71(1H,d,J＝3.7Hz,H-1),5.85(1H,brd,J＝3.0Hz,H-2),1.95,2.40(each 1H,m,H-3),2.39(1H,m,H-4),5.44(1H,s,H-6),2.23(1H,brs,H-7),2.18,2.55(each 1H,m,H-8),4.78(1H,d,J＝7.1Hz,H-9),1.41(3H,s,H-12),1.42(3H,s,H-13),1.28(3H,d,J＝7.2Hz,H-14),1.58(3H,s,H-15)；
实施例2本发明化合物保护SH-SY5Y细胞免受Aβ25-35损伤
本测定采用噻唑蓝(MTT)比色试验法测定细胞存活率。人骨髓神经母细胞瘤细胞株(SH-SY5Y细胞)从ATCC购买，以含10％的胎牛血清的MEM/F12培养液，在37℃、5％CO2培养箱中培养。当细胞生长至80-90％密度时，用0.125％的胰蛋白酶消化，以2.5*104个/孔的密度接种在96孔培养板中，于培养箱中继续培养24小时。不同组处理如下：细胞接种24小时后，将培养液更换为不含血清的MEM/F12培养液，并分别加入各化合物(终浓度为10μM)，模型组加入等体积的溶剂对照。培养2小时后，各处理组加入终浓度为10μM的Aβ25-35，对照组加入等体积的培养液,继续培养22小时。处理完成后，每孔加入10μL MTT(5mg/mL)，37℃孵育3小时后，小心吸出培养板中的液体，每孔加入100μL DMSO，室温振荡5分钟，使紫蓝色甲瓒(formazan)结晶充分溶解，在酶标仪上490nm波长处测定各孔OD值，根据下式计算给药后细胞的存活率：
存活率＝(OD给药组-OD空白组)/(OD正常组-OD空白组)×100％。
阳性对照使用EGCG(表没食子儿茶素没食子酸酯)，该化合物是从茶叶中分离得到的儿茶素类单体，具有抗氧化作用，能够对抗Aβ25-35诱发的细胞毒性，常用于抗Aβ毒性化合物筛选的阳性药[Choi S M.,Kim B C.,et al.Effects of Flavonoid Compounds onβ-amyloid-peptide-induced Neuronal Death in Cultured Mouse Cortical Neurons,Chonnam Medicinal Journal.2014,50,45-51.][Lin C L,Chen T F,et al.Epigallocatechin gallate(EGCG)suppresses beta-amyloid-induced neurotoxicity through inhibiting c-Abl/FE65nuclear translocation and GSK3_activation.Neurobiology of Aging.2009,30,81-92.]
实验结果：统计结果显示，Aβ25-35处理后SH-SY5Y细胞的存活率显著下降，而给予目标化合物后，细胞存活率得到明显恢复，药效与阳性化合物相当，部分化合物药效强于阳性化合物。每组6孔，独立重复实验3次。结果如图1所示。
表3部分本发明化合物的神经保护活性检测(Aβ模型)结果
Figure PCTCN2015096134-appb-000069
实施例3动物记忆障碍模型实验
采用通道式水迷宫(黑色有机玻璃制成,80cm×50cm×20cm，参考文献[Jing L,Zhang H Y,et al.Effects of synthetic(-)-huperzine A on cholinesterase activities and mouse water maze performance.Acta Pharmacologica Sinica,1998,19,413-416])进行行为学测试。分别将各小鼠鼻朝宫壁方向轻放入水,同时开始记录各小 鼠游抵平台的时间及到达平台前进入盲端的次数,作为评价各小鼠的记忆成绩。训练4天,每天上午、下午各训练一次,以最后3次训练成绩在25秒以内,错误次数在2次以下作为标准,选出记忆成绩合格小鼠,随机分组,进行药物测试。小鼠按组别分别口服不同剂量受试药物，空白对照组和模型组给予溶剂对照，阳性对照组给予石杉碱甲。40分钟后给予各组小鼠腹腔注射东莨菪碱(4.5mg/kg)，空白对照组给予等剂量生理盐水,20分钟后将各组小鼠放入水迷宫内测试,记录其游抵平台的时间以及抵达平台前进入盲端的次数(60秒内未抵达平台按60秒算)。将模型组动物的逃脱时间和错误次数定为100％，各给药组动物的逃脱时间和错误次数表示为模型组的百分比。
实验结果如下：
空白对照组小鼠能够很快找到平台逃脱，期间错误次数较少。模型组小鼠则需用较长时间找到平台，且期间错误次数较多。给药组小鼠给予不同化合物后，逃脱时间较模型组小鼠明显缩短，错误次数明显降低，与阳性化合物石杉碱甲作用相当，体现出明显的改善记忆障碍作用。组间差异采用单因素方差(one-way ANOVA)结合LSD和Duancan’s进行检验，本发明化合物相比于空白对照组和模型组均有显著差异。
表4部分本发明化合物的动物记忆障碍模型实验结果
Figure PCTCN2015096134-appb-000070
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (15)

  1. 一种化合物，其特征在于，所述化合物的结构如式I所示：
    Figure PCTCN2015096134-appb-100001
    式I中，
    R1,R2,R3,R4,R5,R6分别独立地选自：H、OH、卤素、羧基、取代或未取代的C2～C20酯基、取代或未取代的C1～C10烷基、取代或未取代的C2-C8烯基和取代或未取代的C2～C8炔基；
    R7选自：H、OH和卤素。
  2. 如权利要求1所述的化合物，其中，R1,R5分别独立地选自：OH,OBz,OCin,ONic,OFu,OCORa；
    R2,R3,R4,R6,分别独立地选自：H,OH,OBz,OCin,ONic,OFu,OCORa；
    R7选自：H,OH；
    Ra选自C1～C5烷基，C6～C10芳基，C2～C6烯基，5～10元杂芳基C2～C6烯基，
    其中，所述杂芳基含有选自O、N和S中的1至3个；
    Bz为
    Figure PCTCN2015096134-appb-100002
    Cin为
    Figure PCTCN2015096134-appb-100003
    Nic为
    Figure PCTCN2015096134-appb-100004
    Fu为
    Figure PCTCN2015096134-appb-100005
    Ac为
    Figure PCTCN2015096134-appb-100006
    But为
    Figure PCTCN2015096134-appb-100007
    Hex为
    Figure PCTCN2015096134-appb-100008
  3. 如权利要求1所述的化合物，其中，所述化合物选自下组：
    Figure PCTCN2015096134-appb-100009
    Figure PCTCN2015096134-appb-100010
  4. 如权利要求1所述的化合物，其中，所述化合物选自下组：
    Figure PCTCN2015096134-appb-100011
    Figure PCTCN2015096134-appb-100012
    Bz、Cin、Ac、Nic、But、Hex的定义如上。
  5. 一种药物组合物，其特征在于，所述药物组合物含有权利要求1-4中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
  6. 如权利要求1-4中任一项所述的化合物或其药学上可接受的盐的用途，其特征在于，所述用途选自下组：
    (a)用于制备神经保护的药物或保健产品；和/或
    (b)用于制备预防或治疗神经细胞损伤疾病(优选地如阿尔茨海默病)的药物或保健产品；和/或
    (c)用于制备改善记忆的药物或保健产品。
  7. 如权利要求5所述的组合物的用途，其特征在于，所述用途选自下组：
    (a)用于制备神经保护的药物或保健产品；和/或
    (b)用于制备预防或治疗神经细胞损伤疾病(优选地如阿尔茨海默病)的药物或保健产品；和/或
    (c)用于制备改善记忆的药物或保健产品。
  8. 含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物的用途，其特征在于，所述用途选自下组：
    (a)用于制备神经保护的药物或保健产品；和/或
    (b)用于制备预防或治疗神经细胞损伤疾病的药物或保健产品；和/或
    (c)用于制备改善记忆的药物或保健产品。
  9. 如权利要求8所述的用途，其中，所述提取物中含有权利要求1中所述的至少一种化合物。
  10. 如权利要求8所述的用途，其中，所述提取物为南蛇藤(Celastrus orbiculatus Thunb.)提取物，所述提取物中含有选自下组的一种或多种化合物：
    PE-11、PE-13、PE-4221、PE-17、PE-34、PE-221、PE-4212、PE-331、和PE-232；或者
    所述提取物为苦皮藤(Celastrus angulatus Maxim.)提取物，所述提取物中含有选自下组的一种或多种化合物：
    KPT-12b、KPT-13、KPT-13b、KPT-4、KPT-15a、KPT-15b、和KPT-12a；或者
    所述提取物为刺苞南蛇藤(Celastrus flagellaris)提取物，所述提取物中含有选自下组的一种或多种化合物：
    CB-5I、CB-2H、CB-2D、CB-4E、CB-4R、CB-4A、CB-4C、CB-5D2、CB-4S、和CB-4D；
    各化合物结构如表2中所示。
  11. 如权利要求8所述的用途，其中，所述提取物为果实或种子提取物。
  12. 如权利要求8所述的用途，其中，所述南蛇藤属植物选自：南蛇藤(Celastrus orbiculatus Thunb.)、苦皮藤(Celastrus angulatus Maxim.)、和刺苞南蛇藤(Celastrus flagellaris)。
  13. 如权利要求8所述的用途，其中，所述的神经细胞损伤疾病包括但不限于阿尔茨海默病。
  14. 一种改善记忆的方法，其特征在于，所述方法包括：给需要的对象施用有效量的权利要求1所述的化合物，或其药学上可接受的盐；或者
    给需要的对象施用有效量的权利要求5所述的药物组合物；或者
    给需要的对象施用有效量的含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物。
  15. 一种预防或治疗神经细胞损伤疾病的方法，其特征在于，所述方法包括：给需要的对象施用治疗有效量的权利要求1所述的化合物，或其药学上可接受的盐；或者
    给需要的对象施用治疗有效量的权利要求5所述的药物组合物；或者
    给需要的对象施用治疗有效量的含有二氢-β-沉香呋喃型倍半萜类化合物的南蛇藤属(Celastrus)植物提取物。
PCT/CN2015/096134 2014-12-02 2015-12-01 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途 WO2016086842A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410723529.6 2014-12-02
CN201410723529.6A CN105712982B (zh) 2014-12-02 2014-12-02 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途

Publications (1)

Publication Number Publication Date
WO2016086842A1 true WO2016086842A1 (zh) 2016-06-09

Family

ID=56091025

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/096134 WO2016086842A1 (zh) 2014-12-02 2015-12-01 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途

Country Status (2)

Country Link
CN (1) CN105712982B (zh)
WO (1) WO2016086842A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108645948A (zh) * 2018-05-31 2018-10-12 贵阳中医学院 一种苦皮藤药材中儿茶素的含量测定方法
TWI778243B (zh) * 2019-03-14 2022-09-21 三顧股份有限公司 沉香萃取物之用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010075282A1 (en) * 2008-12-22 2010-07-01 University Of Washington Molecular inhibitors of the wnt/beta-catenin pathway
CN103109813A (zh) * 2013-01-29 2013-05-22 河南省科高植物天然产物开发工程技术有限公司 一种4-h-苦皮藤素原药及其制备方法和质量检测方法
CN103134827A (zh) * 2013-01-29 2013-06-05 河南省科高植物天然产物开发工程技术有限公司 一种鉴别苦皮藤种子药材的方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010075282A1 (en) * 2008-12-22 2010-07-01 University Of Washington Molecular inhibitors of the wnt/beta-catenin pathway
CN103109813A (zh) * 2013-01-29 2013-05-22 河南省科高植物天然产物开发工程技术有限公司 一种4-h-苦皮藤素原药及其制备方法和质量检测方法
CN103134827A (zh) * 2013-01-29 2013-06-05 河南省科高植物天然产物开发工程技术有限公司 一种鉴别苦皮藤种子药材的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NING, RUONAN ET AL.: "Natural beta-Dihydro agarofuran-Type Sesquiterpenoids as Cognition-Enhancing and Neuroprotective Agents from Medicinal Plants of the Genus Celastrus", JOURNAL OF NATURAL PRODUCTS, vol. 78, 21 August 2015 (2015-08-21), pages 2175 - 2186 *
TORRES-ROMERO, D. ET AL.: "Dihydro-beta-agarofuran sesquiterpenes isolated from Celastrus vulcanicola as potential anti-Mycobacterium tuberculosis multidrug-resistant agents", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, no. 7, 26 February 2011 (2011-02-26), pages 2182 - 2189 *

Also Published As

Publication number Publication date
CN105712982A (zh) 2016-06-29
CN105712982B (zh) 2020-06-30

Similar Documents

Publication Publication Date Title
Valcic et al. Lignans from Chilean propolis
Mengarda et al. Antiparasitic activity of piplartine (piperlongumine) in a mouse model of schistosomiasis
Geetha Anti-psoriatic activity of flavonoids from Cassia tora leaves using the rat ultraviolet B ray photodermatitis model
Vilegas et al. Isolation and structure elucidation of two new flavonoid glycosides from the infusion of Maytenus aquifolium leaves. Evaluation of the antiulcer activity of the infusion
KR20220056256A (ko) 뼈 장애, 연골 장애, 또는 이 둘 다의 관리 또는 개선을 위한 조성물 및 방법
Pitchaipillai et al. In vitro antidiabetic activity of ethanolic leaf extract of bruguiera Cylindrica L.–glucose uptake by yeast cells method
KR20200018724A (ko) 관절 건강을 위한 조성물 및 방법
Swamy et al. Phytochemical analysis of Vernonia adoensis leaves and roots used as a traditional medicinal plant in Kenya
US20040052879A1 (en) Method for the extraction of pharmaceutically active products from spermatophyte plants, products thus obtained and their use in the medical field, in particular as substances with anti-tumoral activity
Xiao et al. Natural neuroprotective alkaloids from Stephania japonica (Thunb.) Miers
CN110167574A (zh) 包含芫花树花提取物或其分离物作为有效成分的神经退行性疾病预防或者治疗用药学组合物
CN102458414B (zh) 川楝素或楝树提取物在痴呆预防和治疗上的用途
KR100524373B1 (ko) 삼백초 추출물을 함유하는 항암제용 약학조성물 및 그의제조방법
CN106619674A (zh) 栀子有效部位或有效成分在制备治疗异质性及多因性阿尔茨海默病药物或保健食品中的应用
KR102121915B1 (ko) 결명 새싹 유래 나프토파이론 유도체를 포함하는 신경세포 보호용 조성물
Mehta et al. In-vitro anthelmintic activity of seeds of Zanthoxylum armatum DC. against Pheretima Posthuma
EP3461486B1 (en) Pharmaceutical composition for preventing or treating dementia and improving cognitive function, comprising acanthoside b extracted from glasswort
WO2016086842A1 (zh) 二氢-β-沉香呋喃型倍半萜类化合物、其制法和用途
Ko et al. Synergistic effect of two major components of Malva verticillata in the recovery of alloxan-damaged pancreatic islet cells in zebrafish
Maciel et al. Pharmacological and biochemical profiling of lead compounds from traditional remedies: the case of Croton cajucara
KR101811048B1 (ko) 지노스테마 론기페스 vk1 추출물 또는 이로부터 분리한 론기페노사이드 a 화합물을 유효성분으로 포함하는 인지기능장애 예방 또는 치료용 조성물
Riris et al. Isolation and Structure Elucidation of Bioactive Compounds Chemical as Inhibitor of The Enzime α-Glucosidase Raru Bark Ethanol Extract (Vatica Pauciflora Blume)
KR100481684B1 (ko) 피누솔리드 유도체를 유효성분으로 포함하는 퇴행성뇌신경계 질환의 예방 및 치료제
Mejin Isolation, structural elucidation and antibacterial activity of the chemical constituents of Scaevola spinescens.
Sazed et al. Phytochemical, biological and computational investigations of Erythrina fusca Lour. to assess antimalarial property against Plasmodium falciparum

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15865479

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15865479

Country of ref document: EP

Kind code of ref document: A1