WO2022193969A1 - 植醇在制备抗偏头痛药物中的应用 - Google Patents

植醇在制备抗偏头痛药物中的应用 Download PDF

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WO2022193969A1
WO2022193969A1 PCT/CN2022/079445 CN2022079445W WO2022193969A1 WO 2022193969 A1 WO2022193969 A1 WO 2022193969A1 CN 2022079445 W CN2022079445 W CN 2022079445W WO 2022193969 A1 WO2022193969 A1 WO 2022193969A1
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phytol
migraine
silkworm
water
extract
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PCT/CN2022/079445
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French (fr)
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黄相中
李艳红
白溪山
李育晓
李红锐
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云南民族大学
昆明彝草生物科技有限公司
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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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61P25/06—Antimigraine agents

Definitions

  • the invention relates to the use of a diterpenoid compound in the preparation of anti-migraine drugs, in particular to the use of phytol in the preparation of anti-migraine drugs.
  • Migraine is the most common type of headache in clinical practice. Generally, there is no organic disease. The main clinical manifestation is moderate-to-severe, throbbing headache, mainly on one or both sides of the head. Migraine is often related to heredity, and people who are less physically fit, do not like sports and engage in mental work are more prone to migraine. Migraine mainly includes typical migraine, common migraine and cluster migraine. Patients with typical migraine mostly have periodic attacks, which are more common in women. Before the onset of the disease, most patients may have blurred vision, flashes, hallucinations, blind spots, eye swelling, and emotional instability. Almost all patients are afraid of light. After a few minutes, a unilateral headache occurs, most of which are located in the front of the head and the temporal region.
  • migraine The main parts are the abdomen, around the eye socket, temples and so on.
  • the pain generally peaks in 1 to 2 hours and lasts for 4 to 6 hours or more than ten hours, and in severe cases it can last for several days.
  • Common migraine accounts for 80% of migraine patients and is relatively common. There are no obvious aura symptoms before the onset of the disease, and some patients have mental disorders, fatigue, yawning, loss of appetite, general malaise and other symptoms before the onset of the disease.
  • Cluster migraine attacks occur without aura, and each attack occurs at about the same time. Symptoms such as orbital swelling, tearing, conjunctival congestion, nasal congestion, and sweating appear when the disease occurs.
  • migraine also includes neuropsychiatric migraine, abdominal pain migraine, familial hemiplegic migraine, etc. The prevalence of migraine is 15% to 18% in women and 6%-12% in men. In the age sample of 25 to 64 years, the incidence of migraine was 8.1 per 1,000 people per year.
  • the commonly used drugs for the treatment of migraine mainly include ibuprofen, mexiergot, nimodipine, aspirin, ergotamine preparations, sumatriptan, propranolol, amitriptyline, clonidine, flunar Rizine, sodium valproate, and other chemicals.
  • these drugs have a good therapeutic effect on migraine, they also show more serious adverse reactions in clinical application, which can cause harm to the body when used repeatedly or for a long time, and have received great attention in recent years.
  • the main adverse reactions are fatigue, nausea, lethargy, weakness, dry mouth, vomiting, indigestion, gastrointestinal reactions, colitis, mental disorders, blood system damage, liver and kidney damage, etc.
  • Serious adverse events include myocardial infarction, cardiac rhythm Disorders, strokes.
  • anti-migraine treatment drugs with good curative effect and less adverse reactions from natural medicines.
  • the anti-migraine active ingredients of botanicals such as Angelica Radix, Fangfeng, Chuanxiong, Fenfangji, Baiyunhuagen and other botanicals have been studied, and a number of compounds with excellent activity have been obtained, including alkaloids, diterpenes, triterpenes, aromatic Legumes, steroids, volatile oils and other types of compounds. Although more active compounds have been found, there are not many with strong efficacy. At present, there are also anti-migraine drugs or pharmaceutical compositions made from various medicinal plants, but their therapeutic effects are not ideal.
  • CGRP is the most important vasoactive peptide substance released by peripheral nerves.
  • CGRP is the most important vasoactive peptide substance released by peripheral nerves.
  • CGRP and its receptors are widely expressed in the central nervous system, and CGRP-specific binding sites are found in the hypothalamus, midbrain, pons and other regions, which are involved in the occurrence of neurogenic inflammation and pain transmission.
  • CGRP induces vasodilation and mast cell degranulation, further causing neurogenic inflammation, while activating satellite glia, triggering an inflammatory cascade.
  • the increased release of CGRP will lead to an increase in the release of brain-derived neurotrophic factor (BDNF), adenosine triphosphate receptor (P2X3), NO, etc., and aggravate pain (Wang Qingqing, Shen Lan, Zhang Jun, Lin Xiao, Feng Yi.
  • BDNF brain-derived neurotrophic factor
  • P2X3 adenosine triphosphate receptor
  • migraine attacks can be alleviated by reducing CGRP production and release, inhibiting neurogenic inflammation, and interfering with pain signaling.
  • the technical problem to be solved by the present invention is to solve the problem that the compounds in the prior art have poor therapeutic effect on migraine.
  • the present invention provides a use of a diterpenoid phytol in the treatment of migraine, a medicine or a pharmaceutical composition for the treatment of migraine, and a preparation method thereof.
  • the pharmaceutically acceptable carrier or adjuvant comprises oral preparation adjuvant, parenteral route administration or external administration adjuvant
  • the route of administration can be oral, injection, topical administration, etc.
  • the dosage form can be liquid dosage form, solid dosage form, the liquid dosage form can be syrup, injection solution, non-aqueous solution, suspension or emulsion, and the solid dosage form can be Tablets, lozenges, capsules, dropping pills, pills, granules, powders, creams, solutions, suppositories, dispersible powders such as freeze-dried powder injections, aerosols, etc.
  • excipients used include: lactose, calcium carbonate, phosphoric acid Calcium, Sodium Phosphate, Starch, Cyclodextrin, Sucrose, Mannitol, Sodium Microcrystalline Cellulose, Calcium Sulfate, Water, Ethanol, Propanol, Glycerin, Propylene Glycol, Isopropan
  • the present invention also provides the use of a diterpenoid phytol as a medicine for reducing the level of calcitonin gene-related peptide (CGRP).
  • CGRP calcitonin gene-related peptide
  • the present invention also provides the use of a diterpenoid phytol as a calcitonin gene-related peptide (CGRP) receptor antagonist in a third aspect.
  • CGRP calcitonin gene-related peptide
  • CGRP calcitonin gene-related peptide
  • a kind of method for the treatment of migraine medicine comprises the administration of phytol, and the structure of described phytol is as follows:
  • the diterpenoid phytol of the present invention can significantly reduce the number of times of head scratching in rats in the nitroglycerin-induced migraine experiment, and down-regulate the content of calcitonin gene-related peptide (CGRP) in the hypothalamus and plasma of migraine rats , suggesting that it has good anti-migraine activity.
  • CGRP calcitonin gene-related peptide
  • the silkworm sand that can be used in the preparation method of phytol of the present invention is rich in domestic resources, and the source of raw materials is simple; and the content of phytol in the present invention is higher in silkworm sand, and is easy to obtain.
  • the present invention finds for the first time that phytol has a good therapeutic effect on migraine.
  • This compound can be used as an anti-migraine active ingredient or a leading compound, and has a good application prospect.
  • Fig. 1 is the active tracing separation flow chart of the diterpenoid phytol of the present invention
  • Fig. 2 is the hydrogen nuclear magnetic resonance spectrum ( 1 H NMR) of phytol of the present invention
  • Fig. 3 is the carbon nuclear magnetic resonance spectrum ( 13 C NMR) of phytol of the present invention.
  • Figure 4 is the mass spectrum (EI-MS) of the phytol of the present invention.
  • the diterpenoid phytol of the present invention may be a naturally occurring compound or a synthetic compound.
  • the anti-migraine component of the present invention can also be an extract obtained by extracting silkworm sand with a solvent; wherein the solvent is 70-100 vol% ethanol/water, 70-100 vol% methanol/water, or 50-80 vol% % acetone/water.
  • Silkworm sand Faeces bombycis is a traditional Chinese medicine, also known as original silkworm sand, silkworm excrement, late silkworm sand, horse Minggan, late silkworm arrow, and second silkworm sand. Mainly produced in Zhejiang, Sichuan, Henan, Jiangsu, Hunan, Jiangxi, Yunnan and other provinces. After nibbling the mulberry leaves, part of the protein, carbohydrates and fats in the mulberry leaves are digested, and most of the effective components in the mulberry leaves are excreted in the feces.
  • the dried silkworm sand is cylindrical in small grains, slightly greenish, black in color, firm and uniform.
  • Silkworm sand is warm in nature, sweet and pungent in taste, enters the liver, spleen and stomach meridians, and has the functions of dispelling wind and dampness, clearing heat and improving eyesight, promoting blood circulation and relieving pain. Indications of wind-heat eye pain, rheumatic heart disease, arthritis, limb numbness, rubella itching, headache, headache and other symptoms, silkworm sand is often used in some compound prescriptions for the treatment of diabetes.
  • the chemical components of silkworm sand are mainly amino acids, chlorophylls, alkaloids, flavonoids, sugars, trace elements, etc. 3): 48; Yan Guiqin, Zhang Shiyuan, Wang Junzhen, etc..
  • the present invention finds that the solvent (such as 95 vol% ethanol/water) extract of silkworm sand has better anti-migraine activity, and under the guidance of biological activity test, the chemical composition of the extract is studied, and the anti-migraine activity is obtained therefrom.
  • the preferred phytol ((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol).
  • the diterpenoid phytol of the present invention has obvious inhibitory effect on nitroglycerin-induced migraine in rats, and the phytol is used in the preparation of anti-migraine drugs or pharmaceutical compositions.
  • the present invention adopts the nitroglycerin-induced migraine model recognized at home and abroad to test the anti-migraine activity of the phytol of the present invention.
  • the experimental results show that phytol can significantly reduce the number of times of head scratching in rats, and down-regulate the content of CGRP in the hypothalamus and plasma of migraine rats, suggesting that phytol has good anti-migraine activity.
  • the present invention also provides a method for preparing the diterpenoid phytol, which comprises preparing the compound from silkworm sand.
  • phytol is prepared from silkworm sand.
  • the method has the following steps:
  • Fr.2 in (4) is subjected to silica gel column chromatography and eluted with a gradient of petroleum ether and ethyl acetate (volume ratio 100:1-10:1) to obtain components Fr.3-1-4.
  • Fr.2-2 adopts silica gel column chromatography, eluted with petroleum ether ethyl acetate (volume ratio 50:1) to obtain diterpenoid phytol ((E)-3,7,11,15-tetramethyl- 2-hexadecen-1-ol).
  • step (1) the available volume percentage of the solvent is 70%-100% ethanol/water, or 70%-100% methanol/water, or 50%-80% acetone/water, and the solvent dosage is Silkworm sand is 6-10 times its weight, the reflux extraction time is 2 hours each time, the reflux extraction is repeated 3 times, and the filtrates are combined to obtain the silkworm sand medicinal material extract solution.
  • the present invention also provides the application of the phytol in the preparation of an anti-migraine drug or a pharmaceutical composition: the phytol is used as an active ingredient and a pharmaceutically acceptable carrier or auxiliary material to prepare an anti-migraine drug or a pharmaceutical composition .
  • the anti-migraine drug or pharmaceutical composition of the present invention can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intramuscular, nasal, oral mucosa, skin, transdermal, subcutaneous, Intradermal, peritoneal, rectal, intravenous, intramuscular, epidural, intraocular, intracranial, vaginal administration, etc.;
  • the route of administration of the anti-migraine drug or pharmaceutical composition of the present invention can be injection.
  • Injections include intravenous, intramuscular, subcutaneous, intradermal, acupoint, intrathecal, and peritoneal injections.
  • the dosage form for administration can be a liquid dosage form, a solid dosage form.
  • the solution properties of liquid dosage forms can be true solutions, colloids, particulate dosage forms, emulsion dosage forms, and suspension dosage forms.
  • Liquid dosage forms can be syrups, injectable solutions, non-aqueous solutions, suspensions or emulsions; solid dosage forms such as tablets, lozenges, capsules, dropping pills, pills, granules, powders, creams, solutions, suppositories, dispersible Powders such as freeze-dried powder injections, aerosols, etc.
  • the anti-migraine medicine or pharmaceutical composition of the present invention can be made into common preparations, and can also be sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • the pharmaceutically acceptable carrier or adjuvant of the present invention includes oral preparation adjuvant, parenteral route administration or external administration adjuvant.
  • the excipients used include, excipients such as lactose, calcium carbonate, calcium phosphate, sodium phosphate; diluents and absorbents such as starch, cyclodextrin, lactose, sucrose, mannitol, sodium microcrystalline cellulose, calcium sulfate, etc.; wetting agents With binders such as water, ethanol, propanol, glycerin, propylene glycol, isopropanol, syrup, honey, glucose, gelatin pulp, sodium carboxymethyl cellulose, potassium phosphate, etc.; disintegrating agents such as dry starch, agar powder, carbonic acid Calcium, sodium bicarbonate, sodium lauryl sulfonate, methyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil, etc
  • the tablets can also be further prepared as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multi-layer tablets to delay their disintegration and absorption in the gastrointestinal tract , and thus provide a lasting effect over a longer period of time.
  • coated tablets such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multi-layer tablets to delay their disintegration and absorption in the gastrointestinal tract , and thus provide a lasting effect over a longer period of time.
  • the silkworm sand a plant belonging to the genus Silkworm, was collected in Kunming, Yunnan, and was identified as Faeces bombycis by Associate Professor Yang Qingsong of the School of Ethnic Medicine, Yunnan Nationalities University. The specimens are preserved in the Herbarium of the School of Ethnic Medicine, Yunnan Nationalities University.
  • Preparation of silkworm sand extract pulverize the dried silkworm sand to obtain silkworm sand fragments; then reflux the silkworm sand fragments with 95% by volume ethanol/water for 3 times, each time for 2 hours to obtain an extract; The extracts were filtered and concentrated under reduced pressure with a rotary evaporator to form an extract for later use.
  • Each group is followed by: blank control group (distilled water), negative control group (distilled water), positive control group (ibuprofen tablets, 80mg/kg), silkworm sand high, medium and low dose groups (2.0g/kg, 0.5g /kg, 0.13g/kg), continuous administration for 7d. 60 minutes after the last administration, except for the blank group, which was given normal saline, each group was subcutaneously injected with nitroglycerin 10 mg/kg on the right shoulder, with 30 minutes as a time period, and the head scratching times of the rats after modeling were observed in 6 time periods. , and record.
  • the experimental results show that the high and medium dose groups of silkworm extract have significant anti-migraine effects. The results are shown in Table 1.
  • Example 2 Further testing with silkworm sand
  • Example 1 was repeated with 95% by volume methanol/water, 70% ethanol/water and 80% acetone/water as extraction solvents, respectively.
  • the experimental results showed that 95% methanol extract of silkworm, 70% ethanol extract and 80% acetone were obtained by using 95% methanol/water, 70% ethanol/water and 80% acetone/water as extraction solvents, respectively.
  • the extract of /water also has a significant anti-migraine effect on rats, so using different concentrations of ethanol/water, methanol/water or acetone/water as the extraction solvent can also obtain the active components of anti-migraine in silkworm sand.
  • Table 2 The results are shown in Table 2.
  • Example 3 Isolation and identification of anti-migraine active compounds from the whole herb of Silkworm
  • step (2) the ethanol extract obtained in step (1) is filtered through 80-120 micron filter paper and concentrated under reduced pressure with a rotary evaporator at a temperature of 45 ° C, to obtain extract 1129g, for subsequent use;
  • the chemical structures of the compounds of the present invention were identified by nuclear magnetic resonance ( 1 H NMR, 13 C NMR, DEPT, COSY, HSQC, HMBC), EI-MS and IR spectra. According to the spectral data of compound 1, and refer to relevant literature (Shan MD, An TY, Hu LH, Chen ZLDiterpene derivative and chromone from Hypericum perforatum. Natural Product Research, 2004, 18(1): 15-19; Ma Bin, Lou Hongxiang , Kong Lingyi. Study on the chemical constituents of the leaf moss of the hard finger. Chinese Herbal Medicine, 2006, 37(5): 660-662.), identified as the diterpenoid phytol (phytol).
  • the anti-migraine activity of phytol was tested in a nitroglycerin-induced migraine rat model.
  • Male SD rats with a body weight of 180-220 g were selected according to the number of experiments required, and were randomly divided into groups with 10 rats in each group. Each group was in turn: blank control group (distilled water), negative control group (distilled water), sample group (phytol), positive control group (the dose of ibuprofen tablets was 80 mg/kg respectively), which were administered continuously for 7 days. 60 minutes after the last administration, except for the blank group, which was given normal saline, nitroglycerin 10 mg/kg was subcutaneously injected into the right shoulder of each group.
  • the experimental results are shown in Tables 3 and 4.
  • the experimental results show that phytol can significantly reduce the number of head scratching in rats, and down-regulate the content of CGRP in the hypothalamus and plasma of migraine rats, suggesting that phytol has good anti-migraine activity and can be used as an anti-migraine component or lead compound.
  • the prepared phytol was added to the commonly used excipients for tablets, and the tablets were prepared according to the conventional preparation process.
  • the prepared phytol was added to the commonly used auxiliary materials for injections, and the injections were prepared according to the conventional preparation process.
  • the prepared phytol was added to the common auxiliary materials of capsules, and the capsules were prepared according to the conventional preparation process.
  • the prepared phytol was added to the commonly used excipients of poultice, and the poultice was prepared according to the conventional preparation process.

Abstract

本发明涉及二萜类化合物植醇在制备抗偏头痛药物中的用途。本发明的植醇可为天然存在的有机化合物或合成的有机化合物，具有较强的抗偏头痛活性，用其作为活性成分与药学上可接受的载体或辅料制备成抗偏头痛药物或药物组合物。

Description

植醇在制备抗偏头痛药物中的应用 技术领域
本发明涉及一种二萜类化合物在制备抗偏头痛药物中的用途，尤其涉及植醇在制备抗偏头痛药物中的用途。
背景技术
偏头痛是临床上最常见的一种头痛类型，一般无器质性病变，临床以发作性中重度、搏动样头痛为主要表现，以头部一侧或两侧疼痛为主。偏头痛常与遗传有关，身体素质较差、不爱运动和从事脑力劳动的人群更易患偏头痛。偏头痛主要包括典型性偏头痛、普通型偏头痛和丛集性偏头痛三大类。典型性偏头痛病人多呈周期性发作，女性多见。发病前大部分病人可出现视物模糊、闪光、幻视、盲点、眼胀、情绪不稳，几乎所有病人都怕光，数分钟后即出现一侧性头痛，大多数以头前部、颞部、眼眶周围、太阳穴等部位为主。疼痛一般在1～2小时达到高峰，持续4～6小时或十几小时，重者可历时数天。普通型偏头痛占偏头痛患者的80％，比较常见，发病前没有明显的先兆症状，也有部分病人在发病前有精神障碍、疲劳、哈欠、食欲不振、全身不适等表现。丛集性偏头痛发病时没有先兆症状，每次发作的时间大致相同。发病时出现眼眶发胀、流泪、眼结膜充血、鼻塞、出汗等症状。此外，偏头痛还包括神经精神性偏头痛、腹痛性偏头痛、家族偏瘫性偏头痛等。偏头痛的患病率在女性中为15％至18％，而在男性中为6％-12％。在25岁至64岁的年龄样本中，偏头痛的发病率为每千人每年8.1人。
目前治疗偏头痛常用的药物主要有布洛芬、美西麦角、尼莫地平、阿斯匹林、麦角胺制剂、舒马曲坦、普萘洛尔、阿米替林、可乐定、氟桂利嗪、丙戊酸钠、等化学药品。虽然该类药物对偏头痛有较好的 治疗作用，但在临床应用中也表现出较严重的不良反应，多次或长期应用时对机体产生危害，近年来受到高度的重视。其不良反应主要为疲劳、恶心、嗜睡、无力、口干、呕吐、消化不良、胃肠道反应、结肠炎、精神异常、血液系统损害以及肝、肾损伤等，严重不良事件包括心肌梗死、心律失常、卒中。
目前，国内外科研工作者非常重视从天然药物中探索及寻找疗效好且不良反应小的抗偏头痛治疗药物。对香白芷、防风、川芎、粉防己、白云花根等植物药的抗偏头痛活性成分进行了研究，获得了一批活性优良的化合物，包括生物碱类、二萜类、三萜类、香豆素类、甾体类、挥发油等类型的化合物。虽然发现的活性化合物较多，但功效较强的不多。目前也有以多种药用植物为原料制作的抗偏头痛药物或药物组合物，但其治疗效果并不理想。
偏头痛发作时，三叉神经-血管系统被激活，多种与疼痛传导密切相关的神经肽释放增加，且互相促进，发挥协同作用，如CGRP、P物质、缩胆囊肽等。CGRP是血管周围神经释放的最主要的血管活性肽类物质，作为已知的体内作用最强的内源性舒张血管活性肽，其水平的变化能在一定程度上影响偏头痛的病理进程。同时，CGRP及其受体在中枢神经系统内广泛表达，在下丘脑、中脑、脑桥等区域均发现有CGRP特异性结合位点，参与神经源性炎症的发生和痛觉传递。CGRP诱导血管扩张和肥大细胞脱颗粒，进一步引起神经源性炎症，同时激活卫星胶质细胞，触发炎症级联反应。CGRP释放增加，会导致脑源性神经营养因子(BDNF)、三磷酸腺苷受体(P2X3)、NO等释放增加，加剧疼痛(王清清,沈岚,张俊,林晓,冯怡.大川芎方效应组分对偏头痛大鼠降钙素基因相关肽及其受体表达的影响[J].2018,40(1):14-20.)。因此，可通过减少CGRP的生成与释放、抑制神经源性炎症、干扰疼痛信号传导来缓解偏头痛发作。
发明内容
(一)要解决的技术问题
本发明要解决的技术问题是解决现有技术中的化合物对于偏头痛治疗效果不好的问题。
(二)技术方案
为了解决现有技术中存在的上述问题，本发明提供一种二萜类化合物植醇在治疗偏头痛中的用途、用于治疗偏头痛的药物或药物组合物及其制备方法。
(1)植醇用于制备抗偏头痛药物的用途，所述植醇的结构如下：
Figure PCTCN2022079445-appb-000001
(2)根据(1)所述的用途，其中所述的植醇存在于用溶剂提取蚕沙而得到的浸膏中并以该浸膏的形式使用；其中所述溶剂为70-100体积％的乙醇/水、70-100体积％的甲醇/水、或50-80体积％的丙酮/水，其中所述蚕沙为蚕蛾科昆虫家蚕幼虫的干燥粪便。
(3)根据(1)-(2)中所述的用途，其中所述植醇作为活性成分与药学上可接受的载体或辅料制备成药物组合物。
(4)根据(1)-(3)中任一项所述的用途，所述的药物组合物选自片剂、胶囊、丸剂、注射剂。
(5)根据(1)-(4)中任一项所述的用途，所述的药物组合物选自缓释制剂或控释制剂。
(6)根据(1)-(5)中任一项所述的用途，其中所述的药学上可接受的载体或辅料包括口服制剂辅料、胃肠外途径给药或外用给药的辅料，给药途径可以是口服、注射、外用局部给药等；给药剂型可以是液体剂型、固体剂型，液体剂型形式可以是糖浆剂、注射溶液、非水溶液、悬浮液或乳剂，固体剂型形式可以是片剂、锭剂、胶囊、滴丸、丸剂、粒剂、粉剂、霜剂、溶液剂、栓剂、可分散粉剂如冻干粉针剂、气雾剂等；所用辅料包括：乳糖、碳酸钙、磷酸钙、磷酸钠、淀粉、环糊 精、蔗糖、甘露醇、微晶纤维素钠、硫酸钙、水、乙醇、丙醇、甘油、丙二醇、异丙醇、糖浆、蜂蜜、葡萄糖、明胶浆、羧甲基纤维素钠、磷酸钾、干燥淀粉、琼脂粉、碳酸钙、碳酸氢钠、十二烷基磺酸钠、甲基纤维素、三硬脂酸甘油酯、可可脂、氢化油、季铵盐、滑石粉、三乙胺硬脂酸镁、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡。
本发明在第二方面还提供一种二萜类化合物植醇作为降低降钙素基因相关肽(CGRP)水平的药物的用途。
(7)植醇用于制备降低降钙素基因相关肽(CGRP)水平的药物的用途，所述植醇的结构如下：
Figure PCTCN2022079445-appb-000002
本发明在第三方面还提供一种二萜类化合物植醇作为降钙素基因相关肽(CGRP)受体拮抗剂的用途。
(8)植醇用于制备降钙素基因相关肽(CGRP)受体拮抗剂的用途，所述植醇的结构如下：
Figure PCTCN2022079445-appb-000003
(9)一种治疗偏头痛药物的方法，所述方法包括给药植醇，所述植醇的结构如下：
Figure PCTCN2022079445-appb-000004
(三)有益效果
本发明的上述技术方案具有如下优点：
(1)本发明的二萜类化合物植醇在硝酸甘油致偏头痛实验中能显 著减少大鼠挠头的次数，下调偏头痛大鼠下丘脑及血浆中降钙素基因相关肽(CGRP)的含量，提示其具有良好的抗偏头痛活性。
(2)本发明的植醇的制备方法中可采用的蚕沙在国内资源丰富，原料来源简单；而且本发明中的植醇在蚕沙中含量较高，容易得到。
(3)本发明的植醇的制备方法中可采用常规柱层析制备方法，化合物制备操作流程简单，所获得的化合物纯度高，随后的工业化生产很容易实现。
(4)本发明首次发现植醇对偏头痛具有较好的治疗作用。这一化合物可以作为抗偏头痛活性成分或先导化合物，有着很好的应用前景。
附图说明
图1为本发明所述的二萜类化合物植醇的活性追踪分离流程图；
图2为本发明植醇的核磁共振氢谱( 1H NMR)；
图3为本发明植醇的核磁共振碳谱( 13C NMR)；
图4为本发明植醇的质谱(EI-MS)。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明的二萜类化合物植醇可以是天然存在的化合物，也可以是人工合成的化合物。
本发明所述抗偏头痛成分也可以是用溶剂提取蚕沙而得到的浸膏；其中溶剂为70-100体积％的乙醇/水、70-100体积％的甲醇/水、或50-80体积％的丙酮/水。
蚕沙Faeces bombycis是一种传统中药，又称原蚕沙、蚕屎、晚蚕 沙、马鸣肝、晚蚕矢、二蚕沙，为蚕蛾科昆虫家蚕蛾Bombyx mori L.幼虫的干燥粪便，主产于浙江、四川、河南、江苏、湖南、江西、云南等省。蚕食桑叶后消化了桑叶中的部份蛋白质、糖类和脂肪类物质，而桑叶中的大部分有效成份随粪便排泄到体外。干燥的蚕沙呈圆柱型小粒，微有青草气，色黑、坚实，均匀。蚕沙性温，味甘、辛，入肝、脾、胃经，有祛风除湿、清热明目、活血定痛的功能。主治风热目痛、风湿性心脏病、关节炎、肢体麻木、风疹瘙痒、头痛头风等症，在一些治疗糖尿病的复方中常使用蚕沙。蚕沙的化学成分主要是氨基酸、叶绿素类、生物碱类、黄酮类、糖类、微量元素等(李秀艳,陈国定,谢德松等.蚕蛾蚕粪的氨基酸组成与分析.蚕桑通报.1987,18(3):48；严桂芹,章世元,王俊棽等.蚕沙叶绿素的提取及分析测定.林业科技.2008,33(4):60-62；周光雄,阮杰武,黄美燕等.蚕沙中生物碱成分研究.中药材.2007,30(11):1384-1385；朱祥瑞,蒋振东,唐孟成.蚕沙中黄酮类化合物的研究.蚕业科学.1996,2(22):90-92；吕顺霖,徐俊良,臧荣春.蚕粪中水溶性单糖和双糖的测定.蚕桑通报.1989,20(1):54-55)。除此之外，还有大量的类胡萝卜素、果胶、叶蛋白等成分(崔锡强,李杏翠,王磊,陈若芸.蚕沙化学成分研究.中国中药杂志.2008,33(21):2493-2496)。药理学试验证实，蚕沙具有降血糖、改善和治疗贫血、消炎抑菌、促进创伤愈合、抗氧化、抗溃疡和抗肿瘤等作用(刘峻池,徐立,梁杨,黄先智.蚕沙的药理研究及临床应用研究进展.蚕学通讯.2010,30(3):14-17)。
本发明发现蚕沙的溶剂(如95体积％的乙醇/水)提取物具有较好的抗偏头痛活性，并在生物活性测试指导下对提取物进行化学成分研究，从中获得了抗偏头痛活性较好的植醇((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol)。
植醇((2E,7R,11R)-3,7,11,15-四甲基-2-十六碳烯-1-醇)((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol)的结构式为：
Figure PCTCN2022079445-appb-000005
本发明所述的二萜类化合物植醇对硝酸甘油诱导的大鼠偏头痛具有明显的抑制作用，所述的植醇在制备抗偏头痛药物或药物组合物中的应用。
本发明采用目前国内外公认的硝酸甘油致偏头痛模型，对本发明所述的植醇进行抗偏头痛活性测试。实验结果表明植醇能显著减少大鼠挠头的次数，下调偏头痛大鼠下丘脑及血浆中CGRP的含量，提示植醇具有良好的抗偏头痛活性。
本发明还提供二萜类化合物植醇的制备方法，该方法包括从蚕沙中制备所述化合物。优选的是，从蚕沙中制备植醇。优选的是，所述方法具有下述步骤：
(1)将蚕沙粉碎后用溶剂提取，合并提取液；
(2)减压浓缩(1)中的提取液得浸膏；
(3)将(2)中的浸膏混悬于水中，依次用石油醚、乙酸乙酯以及正丁醇进行萃取，再用旋转蒸发仪蒸去溶剂，分别得石油醚、乙酸乙酯以及正丁醇萃取物；
(4)将(3)中的石油醚萃取物经硅胶柱层析分离，用石油醚乙酸乙酯(体积比200:1～0:1)梯度洗脱得到10个组分(Fr.1～10)。
(5)将(4)中的Fr.2经硅胶柱色谱，以石油醚乙酸乙酯(体积比100:1～10:1)梯度洗脱，得到组分Fr.3-1～4。Fr.2-2采用硅胶柱色谱，经石油醚乙酸乙酯(体积比50:1)洗脱，得到二萜类化合物植醇((E)-3,7,11,15-四甲基-2-十六碳烯-1-醇)。
在步骤(1)中，所述的溶剂可用体积百分比为70％-100％的乙醇/水、或70％-100％的甲醇/水、或50％-80％的丙酮/水，溶剂用量为蚕沙6-10倍重量，回流提取时间为每次2小时，回流提取重复3次，合并滤液即得到蚕沙药材提取物溶液。
本发明还提供所述的植醇在制备抗偏头痛药物或药物组合物中的 应用：所述的植醇作为活性成分与药学上可接受的载体或辅料制备成抗偏头痛药物或药物组合物。
本发明所述的抗偏头痛药物或药物组合物可以单位剂量形式给药，给药途径可以为肠道、或非肠道，如口服、肌肉、鼻腔、口腔黏膜、皮肤、透皮、皮下、皮内、腹膜、直肠、静脉内、肌内、硬膜外、眼内、颅内、阴道给药等；
本发明所述的抗偏头痛药物或药物组合物的给药途径可以为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射、穴位注射、鞘内注射和腹膜注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型的溶液性质可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。液体剂型形式可以是糖浆剂、注射溶液、非水溶液、悬浮液或乳剂；固体剂型例如片剂、锭剂、胶囊、滴丸、丸剂、粒剂、粉剂、霜剂、溶液剂、栓剂、可分散粉剂如冻干粉针剂、气雾剂等。
本发明所述的抗偏头痛药物或药物组合物可以制成普通制剂，也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
本发明所述的药学上可接受的载体或辅料包括口服制剂辅料、胃肠外途径给药或外用给药的辅料。所用辅料包括，赋形剂如乳糖、碳酸钙、磷酸钙、磷酸钠；稀释剂与吸收剂如淀粉、环糊精、乳糖、蔗糖、甘露醇、微晶纤维素钠、硫酸钙等；湿润剂与粘合剂如水、乙醇、丙醇、甘油、丙二醇、异丙醇、糖浆、蜂蜜、葡萄糖、明胶浆、羧甲基纤维素钠、磷酸钾等；崩解剂如干燥淀粉、琼脂粉、碳酸钙、碳酸氢钠、十二烷基磺酸钠、甲基纤维素等；崩解抑制剂如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂如季铵盐、十二烷基硫酸钠等；润滑剂如滑石粉、三乙胺硬脂酸镁、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡等。还可以将片剂进一步制备成包衣片，如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片，以延迟其在胃肠道中的崩解和吸收，并由此提供在较长时间内的持续作用。
为了更好的理解本发明，以下通过具体实施例进一步解释或说明本发明内容，但这些例子不应被理解为对本发明保护范围的限制。
具体实施例
为了更好的理解本发明，以下通过具体实施例进一步解释或说明本发明内容，但这些例子不应被理解为对本发明保护范围的限制。
实施例1：蚕沙提取物抗偏头痛活性测试
材料来源：所属蚕沙属植物蚕沙采于云南昆明，经云南民族大学民族医药学院杨青松副教授鉴定为Faeces bombycis。标本保存于云南民族大学民族医药学院标本馆。
蚕沙提取物的制备：将干燥的蚕沙粉碎，得蚕沙碎块；然后将蚕沙的碎块用95体积％乙醇/水回流提取3次，每次2小时得提取液；将蚕沙提取液分别过滤并用旋转蒸发仪减压浓缩成浸膏备用。
采用硝酸甘油致偏头痛大鼠模型(可参见科技文献：Zhang Xiao-Fan,Zhang Wen-Jun,Dong Cui-Lan et al.Analgesia effect of baicalein against NTG-induced migraine in rats[J].Biomed.Pharmacother.,2017,90:116-121)测试了蚕沙95％乙醇提取物的抗偏头痛活性。取雄性健康SD大鼠60只，体重180～220g，随机分为6组，每组10只。各组依次为：空白对照组(蒸馏水)、阴性对照组(蒸馏水)，阳性对照组(布洛芬片，80mg/kg)，蚕沙高、中、低剂量组(2.0g/kg，0.5g/kg，0.13g/kg)，连续给药7d。末次给药60min后，除空白组给予生理盐水外，各组分别于右肩皮下注射硝酸甘油10mg/kg，以30min为一个时间段，观察造模后大鼠在6个时间段中的挠头次数，并记录。实验结果表明蚕沙提取物高、中剂量组具有显著的抗偏头痛作用。结果见表1。
表1 蚕沙95％乙醇提取物对偏头痛大鼠挠头次数的影响
Figure PCTCN2022079445-appb-000006
Figure PCTCN2022079445-appb-000007
n＝10
注： #与空白对照组比较，P<0.05， ##与空白对照组比较，P<0.01； *与阴性对照组比较，P<0.05， **与阴性对照组比较，P<0.01。
实施例2：用蚕沙进一步试验
分别用体积百分比为95％的甲醇/水、70％的乙醇/水和80％的丙酮/水作提取溶剂，重复实施例1。实验结果表明用95％的甲醇/水、70％的乙醇/水和80％的丙酮/水作提取溶剂分别所获得的蚕沙95％甲醇提取物、蚕沙70％乙醇提取物以及80％丙酮/水的提取物同样对大鼠具有显著的抗偏头痛作用，因此用不同浓度的乙醇/水、甲醇/水或丙酮/水作提取溶剂同样可以获得蚕沙中抗偏头痛的活性成分。结果见表2。
表2 蚕沙不同溶剂提取物对偏头痛大鼠挠头次数的影响
Figure PCTCN2022079445-appb-000008
n＝10
注： #与空白对照组比较，P<0.05， ##与空白对照组比较，P<0.01； *与阴性对照组比较，P<0.05， **与阴性对照组比较，P<0.01。
实施例3：从蚕沙全草中分离鉴定抗偏头痛活性化合物
(1)将10Kg蚕沙晾干粉碎成粒径0.1cm大小的颗粒，得蚕沙粉，将蚕沙粉在70～74℃的温度下每次用60Kg 95％浓度的乙醇超声提取4次，每次2小时，合并乙醇提取液，备用；
(2)将步骤(1)制得的乙醇提取液经80-120微米滤纸过滤并在45℃的温度下用旋转蒸发仪进行减压浓缩，得浸膏1129g，备用；
(3)将(2)中的1129g浸膏混悬于4500ml水中，依次用4500ml石油醚、4500ml乙酸乙酯以及4500ml正丁醇进行萃取，每种溶剂萃取5次，再用旋转蒸发仪蒸去溶剂，分别得石油醚萃取物(207g)、乙酸乙酯萃取物(214g)以及正丁醇萃取物(406g)；
(4)将(3)中制得的石油醚萃取物经100-200目硅胶柱色谱，用石油醚–乙酸乙酯(体积比200:1～0:1)梯度洗脱，得到10个组分(Fr.1～10)。取Fr.2(33.0g)经200-300目硅胶柱色谱，以石油醚–乙酸乙酯(体积比100:1～10:1)梯度洗脱，得到组分Fr.2-1～4。Fr.2-2经硅胶柱色谱，以石油醚–乙酸乙酯(体积比50:1)洗脱，反复纯化得到二萜类化合物植醇(3.6g)。蚕沙中抗偏头痛活性成分的分离鉴定流程见图1。
本发明的化合物的化学结构用核磁共振谱( 1H NMR, 13C NMR,DEPT,COSY,HSQC,HMBC)、EI-MS及IR等波谱图鉴定。根据分析化合物1的波谱数据，并参考相关文献(Shan M.D.,An T.Y.,Hu L.H., Chen Z.L.Diterpene derivative and chromone from Hypericum perforatum.Natural Product Research,2004,18(1):15-19；马斌,娄红祥,孔令义.硬指叶苔化学成分的研究.中草药,2006,37(5):660-662.)，鉴定为二萜类化合物植醇(phytol)。
化合物1的理化数据：化合物(植醇)为无色粘稠状液体，EI-MS m/z:278[M–H 2O] +(8％),123(56％),109(27％),95(75％),81(72％),71(93％),57(76％),43(100％)，推测分子式为C 20H 40O。 1H NMR(400MHz,CDCl 3)δ H:4.15(2H,d,J＝7.2Hz,H-1),5.41(1H,t,J＝7.2Hz,H-2),1.99(2H,t,J＝7.2Hz,H-4),1.67(3H,s,H-20),0.83–0.87(12H,H-16–H-19),0.95–1.60(19H,m,H-5–H-15)； 13C NMR(100MHz,CDCl 3)δ C:59.6(C-1),123.2(C-2),140.5(C-3),40.0(C-4),25.3(C-5),36.8(C-6),32.9(C-7),37.5(C-8),24.6(C-9),37.6(C-10),32.8(C-11),37.4(C-12),25.0(C-13),39.5(C-14),28.1(C-15),22.8(C-16),22.9(C-17),19.9(C-18,19),16.3(C-20).
实施例4：所述植醇的抗偏头痛活性测试
采用硝酸甘油致偏头痛大鼠模型测试植醇的抗偏头痛活性。按实验需要数量取雄性SD大鼠，体重180～220g，随机分组，每组10只。各组依次为：空白对照组(蒸馏水)，阴性对照组(蒸馏水)，样品组(植醇)，阳性对照组(布洛芬片的剂量分别为80mg/kg)，连续给药7d。末次给药60min后，除空白组给予生理盐水外，各组分别于右肩皮下注射硝酸甘油10mg/kg。注射硝酸甘油后，以30min为一个时间段，观察造模后大鼠在6个时间段中的挠头次数，并记录。大鼠皮下注射硝酸 甘油4h后，用10％水合氯醛麻醉，打开腹腔，腹主动脉取血，4℃下离心15min(1000g/min)，分离血浆；断头取脑，分离下丘脑，-80℃保存，酶联免疫吸附法(ELISA)检测偏头痛大鼠下丘脑及血浆中降钙素基因相关肽(CGRP)的含量。计量资料以均数±标准差
Figure PCTCN2022079445-appb-000009
表示，采用prism 6统计软件进行统计处理。实验结果见表3和4。实验结果表明，植醇能显著减少大鼠挠头的次数，下调偏头痛大鼠下丘脑及血浆中CGRP的含量，提示植醇具有良好的抗偏头痛活性，可以作为抗偏头痛成分或先导化合物。
表3 植醇对偏头痛大鼠挠头次数的影响
Figure PCTCN2022079445-appb-000010
n＝10
注： #与空白对照组比较，P<0.05， ##与空白对照组比较，P<0.01， ###与空白对照组比较，P<0.001； *与阴性对照组比较，P<0.05， **与阴性对照组比较，P<0.01， ***与阴性对照组比较，P<0.001。
表4 植醇对偏头痛大鼠下丘脑及血浆中CGRP含量的影响
Figure PCTCN2022079445-appb-000011
Figure PCTCN2022079445-appb-000012
n＝10
注： #与空白对照组比较，P<0.05， ##与空白对照组比较，P<0.01， ###与空白对照组比较，P<0.001； *与阴性对照组比较，P<0.05， **与阴性对照组比较，P<0.01， ***与阴性对照组比较，P<0.001。
实施例5
按实施例3所述方法，制备获得的植醇加入片剂常用辅料，按常规制备工艺制备成片剂。
实施例6
按实施例3所述方法，制备获得的植醇加入注射剂常用辅料，按常规制备工艺制备成注射剂。
实施例7
按实施例3所述方法，制备获得的植醇加入胶囊剂常用辅料，按常规制备工艺制备成胶囊剂。
实施例8
按实施例3所述方法，制备获得的植醇加入巴布剂常用辅料，按常规制备工艺制备成巴布剂。
最后应说明的是：以上实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。

Claims (10)

  1. 植醇用于制备抗偏头痛药物的用途，其特征在于，所述植醇的结构如下：
    Figure PCTCN2022079445-appb-100001
  2. 根据权利要求1所述的用途，其中所述的植醇存在于用溶剂提取蚕沙而得到的浸膏中并以该浸膏的形式使用；其中所述溶剂为70-100体积％的乙醇/水、70-100体积％的甲醇/水、或50-80体积％的丙酮/水。其中所述蚕沙为蚕蛾科昆虫家蚕幼虫的干燥粪便。
  3. 根据权利要求1-2中任一项所述的用途，其中所述植醇作为活性成分与药学上可接受的载体或辅料制备成药物组合物。
  4. 根据权利要求1-3中任一项所述的用途，其特征在于，所述的药物组合物选自片剂、胶囊、丸剂、注射剂。
  5. 根据权利要求1-4中任一项所述的用途，其特征在于，所述的药物组合物选自缓释制剂或控释制剂。
  6. 根据权利要求1-5中任一项所述的用途，其中所述的药学上可接受的载体或辅料包括口服制剂辅料、胃肠外途径给药或外用给药的辅料，给药途径可以是口服、注射、外用局部给药等；给药剂型可以是液体剂型、固体剂型，液体剂型形式可以是糖浆剂、注射溶液、非水溶液、悬浮液或乳剂，固体剂型形式可以是片剂、锭剂、胶囊、滴丸、丸剂、粒剂、粉剂、霜剂、溶液剂、栓剂、可分散粉剂如冻干粉针剂、气雾剂等；所用辅料包括：乳糖、碳酸钙、磷酸钙、磷酸钠、淀粉、环糊精、蔗糖、甘露醇、微晶纤维素钠、硫酸钙、水、乙醇、丙醇、甘油、丙二醇、异丙醇、糖浆、蜂蜜、葡萄糖、明胶浆、羧甲 基纤维素钠、磷酸钾、干燥淀粉、琼脂粉、碳酸钙、碳酸氢钠、十二烷基磺酸钠、甲基纤维素、三硬脂酸甘油酯、可可脂、氢化油、季铵盐、滑石粉、三乙胺硬脂酸镁、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡。
  7. 植醇用于制备降低降钙素基因相关肽(CGRP)水平的药物的用途，所述植醇的结构如下：
    Figure PCTCN2022079445-appb-100002
  8. 植醇用于制备降钙素基因相关肽(CGRP)受体拮抗剂的用途，所述植醇的结构如下：
    Figure PCTCN2022079445-appb-100003
  9. 根据权利要求7或8所述的用途，其中所述的植醇存在于用溶剂提取蚕沙而得到的浸膏中并以该浸膏的形式使用；其中所述溶剂为70-100体积％的乙醇/水、70-100体积％的甲醇/水、或50-80体积％的丙酮/水，其中所述蚕沙为蚕蛾科昆虫家蚕幼虫的干燥粪便。
  10. 一种治疗偏头痛药物的方法，所述方法包括给药植醇，所述植醇的结构如下：
    Figure PCTCN2022079445-appb-100004
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