WO2018153310A1 - 一种环烯醚萜类化合物及其制备方法和应用 - Google Patents

一种环烯醚萜类化合物及其制备方法和应用 Download PDF

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WO2018153310A1
WO2018153310A1 PCT/CN2018/076529 CN2018076529W WO2018153310A1 WO 2018153310 A1 WO2018153310 A1 WO 2018153310A1 CN 2018076529 W CN2018076529 W CN 2018076529W WO 2018153310 A1 WO2018153310 A1 WO 2018153310A1
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compound
group
methanol
pain
ethanol
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French (fr)
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刘牧龙
左小峰
蔡青青
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深圳曜曦生命科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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)
    • A61K36/74—Rubiaceae (Madder family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products

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  • the invention relates to the technical field of medicine, in particular to an iridoid compound extracted from plants, a preparation method and application thereof.
  • Herba hedyotids chrysotrichae also known as stone penetrating, is used to treat viral hepatitis, bruises, acute nephritis in children, rheumatoid arthritis, sores, and various cancers.
  • the present invention extracts a biologically active iridoid compound from a plant and provides its use in the preparation of a medicament for treating pain or acute inflammation.
  • the present invention provides an iridoid compound having a structure as shown in Formula I:
  • R 2 is COOR 5 , R 3 is hydroxy or alkoxy, may be C 1 -C 6 alkoxy, for example C 1 -C 4 alkoxy or C 1 -C 3 alkoxy, and R 4 is R 6 -OH;
  • R 2 and R 3 are combined as a lactone, and may be a lactone having 5 to 7 ring atoms, for example, a lactone having 5, 6 or 7 ring atoms, and R 4 is a C 1 -C 6 alkylene group.
  • OC(O)R 7 wherein alkylene is, for example, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkylene, such as methylene;
  • R 1 is a glycosyl group, preferably the glycosyl group is selected from the group consisting of glucosyl, galactosyl, mannosyl, arabinose, xylosyl, ribosyl, lysyl, and glucosyl or other polyhydroxyl groups;
  • R 5 is C 1 -C 6 alkyl, such as C 1 -C 4 alkyl or C 1 -C 3 alkyl, such as methyl;
  • R 6 is C 1 -C 6 alkylene, heterocyclylene or sub a phenyl group, such as a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkylene group such as a methylene group;
  • R 7 is a C 1 -C 6 alkyl group or a C 6 -C A 10 aryl group, such as a C 1 -C 4 alkyl group or a C 1 -C 3 alkyl group, such as a methyl group, such as a phenyl group, a naphthyl group.
  • the compound is for example:
  • the compound is Compound 1 and/or Compound 2.
  • the compound is a compound of formula I other than compound 1 and/or compound 2.
  • the invention also provides a preparation method of the above compound, comprising the following steps:
  • the whole grass or effective parts of the roots can be cut into 1-2 cm small sections and refluxed with an aqueous solution of ethanol, for example, by refluxing 10 times with 95% ethanol water for 2 times. For example, each time 2h, the extract is combined, filtered, and the ethanol is recovered. For example, the ethanol is recovered to a volume of about 0.5-1 times the amount of the medicinal material, and the precipitate is allowed to stand and filtered to obtain a filtrate;
  • the aqueous layer is concentrated to dryness, dissolved in methanol, mixed with silica gel, and the methanol is evaporated to dryness.
  • the column is separated on a silica gel column and eluted with a gradient of chloroform-methanol.
  • the fractions containing the main components are collected and combined, for example. For each 50 ml collection, collect the combined fractions 12-25 (comprising compound 1), 29-42 (comprising compound 2), recover the solvent to dryness, dissolve the methanol separately, purify on Sephadex LH-20 column, elute with methanol, collect and combine separately.
  • the fraction containing the main component for example, can be collected every 50 ml, and the combined fractions 4-7 are collected.
  • the collected fraction can be subjected to a thin layer chromatography test (the developing solvent can be chloroform-methanol (4:1). ), vanillin-sulfuric acid reagent), followed by crystallization, for example, can be blown with nitrogen at least in a volume, can be crystallized at 4 ° C, filtered, washed with methanol, crystallized, dissolved in methanol, recrystallized, for example, can be blown with nitrogen At least volume, recrystallized at 4 ° C, filtered, washed with methanol, dried to give the compound, which includes compound 1 and compound 2.
  • the resulting compound can undergo further structural modification and transformation to give structurally similar derivatives.
  • the inventors characterized the structure of the isolated compound by physical and chemical properties and modern spectroscopy (UV, IR, MS, 1 H-NMR, 13 C-NMR and 2D-NMR), and confirmed that the structure is as shown in Formula I.
  • An iridoid compound An iridoid compound.
  • Another object of the present invention is to provide a use of a compound of formula I for the manufacture of a medicament for the treatment of pain.
  • the pain is, for example, acute pain, subacute pain, neuropathic pain, systemic pain; the pain is caused, for example, by inflammation.
  • Another object of the present invention is to provide a use of a compound of formula I for the manufacture of a medicament for the treatment or elimination of acute inflammation.
  • Acute inflammation such as serous inflammation, fibrinitis, suppurative inflammation, and hemorrhagic inflammation.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising the compound of the above formula I.
  • the invention also provides a pharmaceutical composition for treating pain or treating or eliminating acute inflammation comprising a therapeutically effective amount of a compound of formula I above and one or more pharmaceutically acceptable carriers.
  • the drug or composition is free of other therapeutically active ingredients other than the compound of formula I.
  • the drug or composition is free of other yellow foxgrass ingredients other than the compound of formula I.
  • Figure 1 is a mass spectrum of Compound 1
  • FIG. 1 is a hydrogen spectrum of Compound 1
  • FIG. 3 is a carbon spectrum of Compound 1
  • Figure 4 is a mass spectrum of Compound 2
  • FIG. 5 is a hydrogen spectrum of Compound 2
  • Figure 6 is a carbon spectrum of Compound 2.
  • the aqueous layer is concentrated to dryness, dissolved in methanol, and mixed with silica gel.
  • the methanol is evaporated to dryness, separated on a silica gel column, and eluted with a gradient of chloroform-methanol.
  • the fractions containing the main components are collected and combined, each 50 ml. Collect and collect the combined fractions 12-25 (comprising compound 1), 29-42 (comprising compound 2), recover the solvent to dryness, dissolve the methanol separately, and purify it on Sephadex LH-20 column, elute with methanol, collect and combine main The fractions of the components were collected every 50 ml, and the combined fractions were collected 4-7.
  • the collected fractions were subjected to thin layer chromatography (developing agent was chloroform-methanol (4:1), vanillin-sulfuric acid Reagent color development; nitrogen gas blowing at least volume, 4 ° C refrigeration crystallizing, filtration, methanol washing and crystallization; crystal multiplexing a little methanol dissolved, nitrogen blowing at least volume, 4 ° C recrystallization, filtration, methanol washing, drying, to obtain compounds, Compound 1 and Compound 2 are included.
  • developer agent was chloroform-methanol (4:1), vanillin-sulfuric acid Reagent color development
  • nitrogen gas blowing at least volume, 4 ° C refrigeration crystallizing, filtration, methanol washing and crystallization crystal multiplexing a little methanol dissolved, nitrogen blowing at least volume, 4 ° C recrystallization, filtration, methanol washing, drying, to obtain compounds, Compound 1 and Compound 2 are included.
  • the molecular weight of Compound 1 was 414.1059, the molecular formula was C 18 H 22 O 11 , and the similarity was 99.14%.
  • the new compound 1 has the same 13 C chemical shift as the compound Asperuloside, and the 13 C chemical shift similarity is 100%.
  • the 13 C chemical shift data is shown in Table 1. Compound 1 was determined to be Asperuloside in combination with 1 H-NMR spectrum.
  • Compound 2 has a molecular weight of 404, a molecular formula of C 17 H 24 O 11 , and a similarity of 99.83%. It was found that Scandoside methyl ester had the same 13 C chemical shift as Compound 2, and the similarity was 100%. The chemical shift data of 13 C are shown in Table 2. In combination with 1 H-NMR spectrum, it was confirmed that Compound 2 was a Scandoside methyl ester.
  • Standard procedure for embryo collection Propagation of zebrafish embryos is carried out in a natural paired mating manner. Prepare 4 to 5 pairs of adult zebrafish for each mating, with an average of 200 to 300 embryos per pair. Embryos were cleaned 6 hours (ie 6 hpf) and 24 hpf (removed dead embryos) and appropriate embryos were selected based on the embryo's developmental stage (Kimmel et al. 1995). Incubate embryos with fish culture water at 28 °C (fish culture water quality: 200 mg of instant sea salt per 1 L of reverse osmosis water, conductivity 480-510 ⁇ S/cm; pH 6.9-7.2; hardness 53.7-71.6 mg/L CaCO3).
  • zebrafish at various developmental stages were treated with tricaine methanesulfonic acid to expose the zebrafish to anesthesia, and the anesthesia was performed in accordance with the requirements of the American Veterinary Medical Association (AVMA) for anesthesia.
  • AVMA American Veterinary Medical Association
  • Zebrafish strain wild type AB line
  • Normal control group fish cultured with normal zebrafish
  • Model control group zebrafish was treated with glacial acetic acid to establish a zebrafish pain model
  • Test group The five initial detection concentrations of the test sample were: 1, 10, 100, 250, and 500 ⁇ g/mL; the test sample was treated with a water-soluble sample to treat the pain model zebrafish;
  • Each experimental group was 30 zebrafish and incubated in a 28 ° C incubator;
  • MTC maximum tolerated concentration
  • the test concentration range of the test sample will be expanded, the upper limit is 2000 ⁇ g/mL or the maximum solubility of the test sample, and the lower limit is 0.1 ⁇ g/mL.
  • Number of zebrafish required At least 210 zebrafish are required.
  • Results The results showed that 100, 250 and 500 ⁇ g/mL significantly reduced the abnormal movement of zebrafish caused by glacial acetic acid.
  • Zebrafish strain wild type AB strain
  • Normal control group fish cultured with normal zebrafish
  • Model control group zebrafish was treated with glacial acetic acid to establish a zebrafish pain model
  • Test group According to the experimental results of 1., three concentrations were selected for evaluation (usually 1/9 MTC, 1/3 MTC and MTC); the test sample was treated with water-soluble sample method to treat the pain model zebrafish;
  • Positive drug control group aspirin
  • test article If the test article has an analgesic effect, it will slow down the increase in the number of abnormal movements of zebrafish caused by glacial acetic acid.
  • the zebrafish behavior analyzer was used to detect the number of movements of the zebrafish (N), and the analgesic effect of the test article was evaluated.
  • Inhibition rate (%) (average mean number of movements in the treatment group - mean number of abnormal movements in the model group) / mean number of abnormal movements in the model group.
  • zebrafish was treated with glacial acetic acid to establish a zebrafish pain model.
  • the medium- and high-dose groups of the present invention have a significant inhibitory effect on zebrafish pain caused by glacial acetic acid.
  • the compounds of the invention all exhibit significant analgesic effects.
  • the pain is, for example, acute pain, subacute pain, neuropathic pain, systemic pain; the pain is caused, for example, by inflammation.
  • the zebrafish is used as an experimental object, and the analgesic effect of the zebrafish caused by pain caused by glacial acetic acid is evaluated.
  • the above description is only a preferred embodiment of the present invention, and may also be a mouse or a rat.
  • an analgesic pharmacological activity was studied by an animal model of pain caused by chemical stimulation and thermal stimulation.
  • the iridoid compound in the genus of the genus of the present invention can be combined with a commercially available or commonly used carrier for the preparation of a medicament for preventing, treating and synergistically treating pain.
  • the drug may be in the form of a microemulsion, an injection, a tablet, a capsule, a suppository, an oral solution or the like.
  • SPF Kunming mice body weight 18 ⁇ 22g, male and female half, this experiment using sc administration, the experimental low, medium and high dose concentrations were set to 25, 50, 100mg / kg.
  • Eighty Kunming mice were randomly divided into 8 groups according to their body weight and gender: model control group, hydrocortisone positive control group (25 mg/kg) group, compound 1 low, medium and high dose groups, compound 2 was low, Medium and high dose groups, 10 in each group.
  • the drug was administered once a day for 5 days. After 40 minutes of the last administration, 10 ⁇ L of xylene was uniformly applied to the inside and outside of the right ear of the mouse, and the left ear was coated with the same volume of distilled water as a control.
  • the mass of the right ear piece of the mouse minus the mass of the left ear piece is the swelling degree of the ear piece, and the swelling rate of the ear and the inhibition rate of the ear swelling are calculated.
  • Ear swelling rate (right ear mass - left ear quality) / left ear quality
  • Ear swelling inhibition rate (average swelling rate in the control group - average swelling rate in the administration group) / average swelling rate in the control group
  • the hydrocortisone positive control group the 50, 100 mg/kg group of the compound 1, the 50, 100 mg/kg group of the compound 2 had a significant inhibitory effect on the auricular swelling caused by xylene in mice (p ⁇ 0.05 was a significant difference; p ⁇ 0.01 was a very significant difference.), indicating that 1 and 2 can attenuate xylene-induced ear swelling in mice in a dose-dependent manner, and the results are shown in Table 4.
  • mice The acute inflammation model of mice was used as the research object.
  • the compounds of the invention have a good inhibitory effect on acute inflammatory models.
  • Acute inflammation such as serous inflammation, fibrinitis, suppurative inflammation, and hemorrhagic inflammation.
  • the zebrafish is used as an experimental object, and the analgesic effect of the zebrafish caused by pain caused by glacial acetic acid is evaluated.
  • the analgesic effect of the test article is only a preferred embodiment of the present invention, and experiments can also be carried out on mice and rats. Subjects, animal models of pain induced by chemical and thermal stimuli were studied for their analgesic pharmacological activities. In this experiment, an acute inflammation model of mouse ear swelling caused by xylene was used as a subject to evaluate the acute inflammation-eliminating effect of the test article, and it is only a preferred embodiment of the present invention.
  • the iridoid compound in the plant of the genus of the present invention can be combined with a commercially available or commonly used carrier for the preparation of a medicament for preventing, treating, synergistically treating pain or acute inflammation.
  • the drug may be in the form of a microemulsion, an injection, a tablet, a capsule, a suppository, an oral solution or the like.
  • the formulated drug can be administered by a conventional route. It should be noted that those skilled in the art can make several improvements or additions without departing from the principles of the invention, and such improvements or additions should also be considered as the scope of the invention.

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Abstract

本发明公开了一种环烯醚萜类化合物及其制备方法和应用。制法：（1）全草乙醇水回流提取，回收乙醇，静置沉淀，过滤，得过滤液；（2）过滤液依次用三氯甲烷、醋酸乙酯萃取，得萃取后水层液。（3）水层液浓缩至干，硅胶、Sephadex LH-20等色谱柱分离纯化，结晶，得到本发明化合物。本发明所述化合物具有良好的镇痛作用和消除急性炎症反应的作用。

Description

一种环烯醚萜类化合物及其制备方法和应用 技术领域
本发明涉及医药技术领域，特别涉及从植物中提取的环烯醚萜化合物及其制备方法和应用。
背景技术
茜草科耳草属植物在我国有50多种，其20多种药用，大多为清热解毒类中药，用于治疗感冒，多种炎症及癌症。黄毛耳草(Herba hedyotids chrysotrichae)又名石打穿，用于治疗病毒性肝炎、跌打损伤、小儿急性肾炎、风湿性关节炎、疮疔肿痛和各种癌症。
发明内容
本发明从植物中提取出具有生物活性的环烯醚萜类化合物，并提供了其在制备治疗疼痛或急性炎症的药物中的应用。具体地说，本发明提供了环烯醚萜类化合物，其结构如式I所示：
Figure PCTCN2018076529-appb-000001
或其可药用盐
其中：
R 2为COOR 5，R 3为羟基或烷氧基，可以是C 1-C 6烷氧基，例如C 1-C 4烷氧基或C 1-C 3烷氧基，且R 4为R 6-OH；
或者R 2、R 3结合为内酯，可以是具有5-7个环原子的内酯，例如具有5、6或7个环原子的内酯，且R 4为C 1-C 6亚烷基OC(O)R 7，其中的亚烷基例如C 1、C 2、C 3、C 4、C 5、C 6亚烷基，如亚甲基；
R 1为糖基，优选糖基选自葡萄糖基、半乳糖基、甘露糖基、阿拉伯糖基、木糖基、核糖基、来苏糖基和夫糖基或其他多羟基化合物基团；
R 5为C 1-C 6烷基，例如C 1-C 4烷基或C 1-C 3烷基，如甲基；R 6为C 1-C 6亚烷基、亚杂环基或亚苯基，所述亚烷基例如C 1、C 2、C 3、C 4、C 5、C 6亚烷基，如亚甲基；R 7为C 1-C 6烷基或 C 6-C 10芳基，所述烷基例如C 1-C 4烷基或C 1-C 3烷基，如甲基，所述芳基例如苯基、萘基。
所述化合物例如：
Figure PCTCN2018076529-appb-000002
化合物1
Figure PCTCN2018076529-appb-000003
化合物2
在一个实施方案中，所述化合物是化合物1和/或化合物2。
在另一个实施方案中，所述化合物是化合物1和/或化合物2以外的式I化合物。
本发明还提供了上述化合物的制备方法，包括如下步骤：
(1)黄毛耳草带根全草或有效部位，如根、茎、叶，可以剪成1-2cm小段，用乙醇水溶液回流提取，例如用10倍量95％乙醇水回流提取2次，例如每次2h，合并提取液，过滤，回收乙醇，例如回收乙醇至0.5-1倍量药材体积左右，静置沉淀，过滤，得过滤液；
(2)过滤液依次用三氯甲烷、醋酸乙酯萃取，例如萃取3次，例如每次100ml，合并相同萃取液，得萃取后水层液。
(3)水层液浓缩至干，加甲醇溶解，硅胶拌样，挥发甲醇至干，上硅胶色谱柱分离，三氯甲烷-甲醇梯度洗脱，分别收集并合并含主要成分的馏分，例如可以每50ml收集，收集合并馏分12-25(含化合物1)，29-42(含化合物2)，回收溶剂至干，甲醇分别溶解后上Sephadex LH-20柱纯化，以甲醇洗脱，分别收集合并含主要成分的馏分，例如可以每50ml收集，收集合并馏分4-7，在收集馏分的过程中，可以对收集的馏分进行薄层色谱试验(展开剂可以为三氯甲烷-甲醇(4∶1)，香草醛-硫酸试剂显色)，随后结晶，例如可以用氮气 吹至少量体积，可在4℃冷藏结晶，过滤，甲醇清洗结晶；结晶复用甲醇溶解，重结晶，例如可以用氮气吹至少量体积，可在4℃重结晶，过滤，甲醇冲洗，干燥，得化合物，其中包括化合物1和化合物2。所得化合物可进行进一步的结构修饰和转化，得到结构类似的衍生物。
发明人通过理化性质和现代波谱学手段(UV、IR、MS、 1H-NMR、 13C-NMR和2D-NMR)对分离得到的化合物进行了结构鉴定，证实其为结构如式I所示的环烯醚萜化合物。
本发明的另一个目的在于提供一种式I所示化合物在制备治疗疼痛药物中的应用。所述疼痛例如急性疼痛、亚急性疼痛、神经性疼痛、全身性疼痛；所述疼痛例如由炎症引起。
本发明的另一个目的在于提供一种式I所示化合物在制备治疗或消除急性炎症药物中的应用。急性炎症例如浆液性炎、纤维素性炎、化脓性炎和出血性炎。
本发明的再一个目的在于提供一种药物组合物，包含上述式I所示化合物。
本发明还提供了一种治疗疼痛或者治疗或消除急性炎症的药物组合物，含有治疗有效量的上述式I化合物以及一种或多种药学上可接受的载体。
在一个实施方案中，所述药物或组合物不含除所述式I化合物以外的其它治疗活性成分。
在一个实施方案中，所述药物或组合物不含除所述式I化合物以外的其它的黄毛耳草成分。
附图说明
图1是化合物1的质谱；
图2是化合物1的氢谱；
图3是化合物1的碳谱；
图4是化合物2的质谱；
图5是化合物2的氢谱；
图6是化合物2的碳谱。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实施例1本发明化合物的制备
(1)干燥的黄毛耳草带根全草，剪成1-2cm小段，10倍量95％乙醇水回流提取2次，每次2 h，合并提取液，过滤；回收乙醇至0.5-1倍量药材体积左右，静置沉淀，过滤，得过滤液；
(2)过滤液依次用三氯甲烷、醋酸乙酯萃取，萃取3次，每次100ml，合并相同萃取液，得萃取后水层液；
(3)水层液浓缩至干，加甲醇溶解，硅胶拌样，挥发甲醇至干，上硅胶色谱柱分离，三氯甲烷-甲醇梯度洗脱，分别收集并合并含主要成分的馏分，每50ml收集，收集合并馏分12-25(含化合物1)，29-42(含化合物2)，回收溶剂至干，甲醇分别溶解后上Sephadex LH-20柱纯化，以甲醇洗脱，分别收集合并含主要成分的馏分，每50ml收集，收集合并馏分4-7，在收集馏分的过程中，对收集的馏分进行薄层色谱试验(展开剂为三氯甲烷-甲醇(4∶1)，香草醛-硫酸试剂显色)；氮气吹至少量体积，4℃冷藏结晶，过滤，甲醇清洗结晶；结晶复用少许甲醇溶解，氮气吹至少量体积，4℃重结晶，过滤，甲醇冲洗，干燥，得化合物，包括化合物1和化合物2。
实施例2本发明化合物的结构鉴定
化合物1：ESI-MS m/z：437.1059[M+Na] +。 1H-NMR(500MHz，CD 30D)δ：7.30(1H，d，J＝2.05Hz，H-3)，5.95(1H，d，J＝1.05Hz，H-1)，5.73(1H，s，H-7)，5.56(1H，d，J＝6.6Hz，H-6)，4.79(1H，dd，J＝1.0，14.3Hz，H-1′)，4.68-4.64(2H，t，H-10a，10b)，3.92(1H，dd，J＝2.1，11.85Hz，H-6′a)，3.68-3.65(2H，m，H-6′b，5)，3.39-3.17(5H，m，H-3′，5′，4′，9，2′)，2.07(3H，s，CH3COO)； 13C-NMR(500MHz，CD 30D)δ：172.56(C-11)，172.23(CH3CO)，150.27(C-3)，144.29(C-8)，128.93(C-7)，106.18(C-4)，100.02(C-1′)，93.31(C-1)，86.30(C-6)，78.38(C-3′)，77.889(C-5′)，74.65(C-2′)，71.60(C-4′)，62.80(C-6′)，61.91(C-10)，45.27(C-9)，37.45(C-5)，20.62(CH 3)。
高分辨质谱分子量分析，化合物1分子量为414.1059，分子式为C 18H 22O 11，相似度99.14％。经查新化合物1与化合物Asperuloside(车叶草苷)有相同的 13C化学位移， 13C化学位移相似度100％， 13C化学位移数据见表1。结合 1H-NMR谱，确定化合物1为Asperuloside(车叶草苷)。
表1化合物1与Asperuloside(车叶草苷) 13C化学位移比较
Figure PCTCN2018076529-appb-000004
Figure PCTCN2018076529-appb-000005
化合物1 Asperuloside(车叶草苷)
化合物2：ESI-MS m/z：427.1213[M+Na] +。 1H-NMR(500MHz，CD 30D)δ：7.54(1H，s，H-3)，5.83(1H，s，H-7)，5.22(1H，d，J＝6.0Hz，H-1)，4.70(1H，d，J＝8.0Hz，H-1′)，4.58(1H，t，J＝1.0Hz，H-6)，4.37(1H，d，J＝15.2Hz，H-10a)，4.22(1H，d，J＝15.0Hz，H-10)，3.90(1H，d，J＝11.0Hz，H-6′a)，3.66(1H，dd，J＝5.0，11.0Hz，H-6′b)，3.78(3H，s，OCH 3)，3.22～3.41(4H，m，H-2′，3′，4′，5′)，3.01～3.08(2H，m，H-5，9)； 13C-NMR(500MHz，CD 30D)δ：170.301(C-11)，153.848(C-3)，147.518(C-8)，130.147(C-7)，110.836(C-4)，100.335(C-1′)，98.367(C-1)，82.302(C-6)，78.424(C-3′)，77.902(C-5′)，74.801(C-2′)，71.555(C-4′)，62.708(C-6′)，61.046(C-10)，52.042(OCH 3)，47.164(C-9)，45.637(C-5)。
高分辨质谱分子量分析，化合物2分子量为404，分子式为C 17H 24O 11，相似度99.83％。经查新发现Scandoside methyl ester(鸡矢藤次苷甲酯)与化合物2有相同的 13C化学位移，相似度为100％， 13C化学位移数据见表2。结合 1H-NMR谱，确定化合物2为 Scandoside methyl ester(鸡矢藤次苷甲酯)。
表2化合物2与Scandoside methyl ester(鸡矢藤次苷甲酯) 13C化学位移比较
Figure PCTCN2018076529-appb-000006
Figure PCTCN2018076529-appb-000007
化合物2 Scandoside methyl ester(鸡矢藤次苷甲酯)
实施例3本发明化合物治疗疼痛药物检测
胚胎收集的标准步骤：斑马鱼胚胎的繁殖以自然成对交配的方式进行。每次交配准备4～5对成年斑马鱼，平均每对能产200～300个胚胎。在受精后6小时(即6hpf)和24hpf对胚胎进行清理(移除已死亡胚胎)，并根据胚胎的发育阶段挑选合适的胚胎(Kimmel et al.1995)。在28℃条件下用养鱼用水孵育胚胎(养鱼用水水质：每1L反渗透水中加入200mg速溶海盐，电导率为480～510μS/cm；pH为6.9～7.2；硬度为53.7～71.6mg/L CaCO3)。因为胚胎可以从自身的卵黄囊中获取营养物质，所以在受精后9天内(9dpf)不需要喂食。用三卡因甲磺酸对各个发育阶段的斑马鱼进行过度暴露处理，从而将斑马鱼麻醉 处死，麻醉处死的操作步骤符合美国兽医协会(AVMA)对动物麻醉处死的规范要求。
1.确定化合物的最大耐受浓度(MTC)
斑马鱼品系：野生型AB系；
正常对照组：养鱼用水处理正常斑马鱼；
模型对照组：用冰乙酸处理斑马鱼，建立斑马鱼疼痛模型；
供试品组：供试品的五个初始检测浓度分别为：1、10、100、250和500μg/mL；供试品以水溶给样方式处理疼痛模型斑马鱼；
每个实验组均为30尾斑马鱼，在28℃培养箱中孵育；
供试品处理结束后，统计各实验组的斑马鱼死亡数量与毒性情况，确定供试品的最大耐受浓度(MTC)；
如果在最初的浓度检测实验中不能得到MTC，将扩大供试品的检测浓度范围，上限为2000μg/mL或供试品最大溶解度，下限为0.1μg/mL。
所需斑马鱼数目：至少需要210尾斑马鱼.
结果：结果显示，100、250和500μg/mL可明显减少冰乙酸导致的斑马鱼异常运动。
2.评价化合物的镇痛作用
斑马鱼品系：野生型AB品系；
正常对照组：养鱼用水处理正常斑马鱼；
模型对照组：用冰乙酸处理斑马鱼，建立斑马鱼疼痛模型；
供试品组：依据1.的实验结果，选取3个浓度进行评价(通常为1/9MTC、1/3MTC和MTC)；供试品以水溶给样方式处理疼痛模型斑马鱼；
阳性药物对照组：阿司匹林；
每个实验组均处理30尾斑马鱼，28℃培养箱中孵育；
若供试品有镇痛效果，则会减缓冰乙酸所致疼痛引起的斑马鱼异常运动次数增加。供试品处理结束后，利用斑马鱼行为分析仪检测斑马鱼的运动次数(N)，评价供试品的镇痛作用，统计学处理结果以
Figure PCTCN2018076529-appb-000008
表示；
供试品对疼痛缓解作用计算公式如下：
Figure PCTCN2018076529-appb-000009
统计学分析采用方差分析和Dunnett’s T-检验，p＜0.05为显著性差异；p＜0.01为极显著性差异。
3.结果
在冰乙酸所致疼痛引起的斑马鱼异常运动次数实验中，与模型对照组相比，化合物1和2中、高剂量对冰乙酸所致疼痛引起的斑马鱼有明显的抑制作用。模型对照组、阳性对照药组、化合物1和2低、中、高剂量组的斑马鱼冰乙酸异常运动实验结果见表3：
抑制率(％)＝(用药组异常运动均数-模型组异常运动均数)/模型组异常运动均数。
表3.化合物对斑马鱼疼痛的影响(
Figure PCTCN2018076529-appb-000010
n＝10)
Figure PCTCN2018076529-appb-000011
与模型对照组比较，*p＜0.05，**p＜0.01.
4.结论
本实验以用冰乙酸处理斑马鱼，建立斑马鱼疼痛模型，本发明化合物中、高剂量组对冰乙酸引起斑马鱼疼痛具有明显的抑制作用。本发明化合物均表现出明显的镇痛作用。所述疼痛例如急性疼痛、亚急性疼痛、神经性疼痛、全身性疼痛；所述疼痛例如由炎症引起。
本发明以斑马鱼为实验对象，冰乙酸所致疼痛引起的斑马鱼异常运动次数来评价供试品的镇痛作用，以上所述仅是本发明的优选实施方式，还可以小鼠、大鼠等为实验对象，通过化学刺激和热刺激引发疼痛的动物模型对其镇痛药理活性进行研究。本发明制备得到的耳草属植物中环烯醚萜化合物可与市售或者常用的载体结合，用于制备预防、治疗、协同治疗疼痛的药物。所述药物可以为微乳、注射剂、片剂、胶囊剂、栓剂、口服液等形式。
实施例4本发明化合物消除急性炎症反应药物检测
1.对二甲苯所致小鼠耳廓肿胀炎症模型的作用
SPF级昆明小鼠，体质量18～22g，雌雄各半，本实验采用sc给药方式，实验低、中、高3个剂量浓度分别设置为25、50、100mg/kg。昆明种小鼠80只，根据体质量和性别随机分为8组：模型对照组，氢化可的松阳性对照组(25mg/kg)组，化合物1低、中、高剂量组，化合物2低、中、高剂量组，每组10只。每天给药1次，连续给药5d。最后一次给药40min后，10μL二甲苯均匀涂于小鼠右耳内外侧，左耳涂以同样体积的蒸馏水作 对照。40min后重复一次，再过40min后脱颈处死小鼠，沿耳廓基线剪下双耳，用直径8mm的打孔器分别在两耳同一部位打下圆耳片，迅速用电子天平秤质量，每只小鼠右耳片减去左耳片质量即为耳片炎症肿胀度，计算耳肿胀率和耳肿胀抑制率。
耳肿胀率＝(右耳片质量-左耳片质量)/左耳片质量
耳肿胀抑制率＝(对照组平均肿胀率-给药组平均肿胀率)/对照组平均肿胀率
2.结果
与模型对照组比较，氢化可的松阳性对照组，化合物1的50、100mg/kg组，化合物2的50、100mg/kg组对二甲苯所致小鼠耳廓肿胀具有明显的抑制作用(p＜0.05为显著性差异；p＜0.01为极显著性差异。)，表明化1和化2可以剂量依赖性的改善二甲苯所致小鼠耳廓肿胀，结果见表4。
表4.化合物对二甲苯所致小鼠耳廓肿胀的拮抗作用(
Figure PCTCN2018076529-appb-000012
n＝10)
Figure PCTCN2018076529-appb-000013
与模型对照组比较，*p＜0.05，**p＜0.01.
3.结论
本实验以小鼠急性炎症模型为研究对象，50、100mg/kg的化合物1和2对二甲苯引起的小鼠耳廓肿胀的急性炎症均具有明显的抑制作用，抑制率分别为26.3％、51.5％；24.3％，44.5％。本发明化合物对于急性炎症模型有较好的抑制作用。急性炎症例如浆液性炎、纤维素性炎、化脓性炎和出血性炎。
本发明以斑马鱼为实验对象，冰乙酸所致疼痛引起的斑马鱼异常运动次数来评价供试品的镇痛作用，仅是本发明的优选实施方式，还可以小鼠、大鼠等为实验对象，通过化学刺激和热刺激引发疼痛的动物模型对其镇痛药理活性进行研究。本实验以二甲苯引起的小鼠耳廓肿胀的急性炎症模型为研究对象来评价供试品的急性炎症消除作用，仅是本发明的优选实施方式。
本发明制备得到的耳草属植物中环烯醚萜化合物可与市售或者常用的载体结合，用于制备预防、治疗、协同治疗疼痛的药物或急性炎症的药物。所述药物可以为微乳、注射剂、片剂、胶囊剂、栓剂、口服液等形式。配制好的药物可以通过常规途径给药。应当指 出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进或补充，这些改进或补充也应视为本发明的保护范围。
尽管本文较多地使用了术语，但并不排除使用其它术语的可能性。使用这些术语仅仅是为了更方便地描述和解释本发明的本质；把它们解释成任何一种附加的限制都是与本发明精神相违背的。

Claims (10)

  1. 一种环烯醚萜类化合物，其结构如式I所示：
    Figure PCTCN2018076529-appb-100001
    或其可药用盐
    其中：
    R 2为COOR 5，R 5为C 1-C 6烷基，R 3为羟基或C 1-C 6烷氧基，且R 4为R 6-OH，R 6为C 1-C 6亚烷基、亚杂环基或亚苯基；
    或者R 2、R 3结合为具有5-7个环原子的内酯，且R 4为C 1-C 6亚烷基OC(O)R 7，R 7为C 1-C 6烷基或C 6-C 10芳基；
    R 1为糖基，优选糖基选自葡萄糖基、半乳糖基、甘露糖基、阿拉伯糖基、木糖基、核糖基、来苏糖基和夫糖基或其他多羟基化合物基团。
  2. 根据权利要求1中所述的化合物，R 5为C 1-C 4烷基；R 3为C 1-C 4烷氧基；其中R 5+R 3的碳链总数为3～7。
  3. 根据权利要求1中所述的化合物，R 7为C 1-C 3烷基。
  4. 权利要求1所述化合物的制备方法，其特征在于，包括以下步骤：
    (1)黄毛耳草带根全草或有效部位，如根、茎、叶，用乙醇水溶液回流提取，合并提取液，过滤，回收乙醇，静置沉淀，过滤，得过滤液；
    (2)过滤液依次用三氯甲烷、醋酸乙酯萃取，合并相同萃取液，得萃取后水层液；
    (3)水层液浓缩至干，加甲醇溶解，硅胶拌样，挥发甲醇至干，上硅胶色谱柱分离，三氯甲烷-甲醇梯度洗脱，分别收集并合并含主要成分的馏分，回收溶剂至干，甲醇分别溶解后上Sephadex LH-20柱纯化，以甲醇洗脱，分别收集合并含主要成分的馏分，结晶，过滤，甲醇清洗结晶；结晶复用甲醇溶解，重结晶，过滤，甲醇冲洗，干燥，得化合物，其中包括化合物1和化合物2：
    Figure PCTCN2018076529-appb-100002
  5. 根据权利要求4所述的制备方法，其特征在于，步骤(1)乙醇水溶液为0-100％乙醇水溶液。
  6. 权利要求1所述化合物在制备治疗疼痛的药物中的应用。
  7. 权利要求1所述化合物在制备治疗或消除急性炎症药物中的应用。
  8. 一种药物组合物，其特征在于，包含权利要求1所述化合物。
  9. 一种用于治疗疼痛药物组合物，其特征在于，含有治疗有效量的权利要求1所述化合物和药学上可接受的载体。
  10. 一种用于治疗或消除急性炎症药物组合物，其特征在于，含有治疗有效量的权利要求1所述化合物和药学上可接受的载体。
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