WO2011017905A1 - Utilisation de senkyunolide i dans la fabrication d'un médicament destiné à combattre la dépression, et à traiter la migraine et autres maladies liées au système sérotonergique - Google Patents

Utilisation de senkyunolide i dans la fabrication d'un médicament destiné à combattre la dépression, et à traiter la migraine et autres maladies liées au système sérotonergique Download PDF

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Publication number
WO2011017905A1
WO2011017905A1 PCT/CN2010/001145 CN2010001145W WO2011017905A1 WO 2011017905 A1 WO2011017905 A1 WO 2011017905A1 CN 2010001145 W CN2010001145 W CN 2010001145W WO 2011017905 A1 WO2011017905 A1 WO 2011017905A1
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WO
WIPO (PCT)
Prior art keywords
group
yangchuan
azlactone
depression
plasma
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PCT/CN2010/001145
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English (en)
Chinese (zh)
Inventor
冯怡
徐德生
梁爽
Original Assignee
上海张江中药现代制剂技术工程研究中心
上海中医药大学
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Application filed by 上海张江中药现代制剂技术工程研究中心, 上海中医药大学 filed Critical 上海张江中药现代制剂技术工程研究中心
Publication of WO2011017905A1 publication Critical patent/WO2011017905A1/fr

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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
    • A61K31/365—Lactones
    • 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
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to the field of traditional Chinese medicine chemistry and medical technology, and specifically relates to Chuanxiong
  • Chuanxiong is a traditional Chinese medicine in China. It has the effect of promoting blood circulation and relieving pain.
  • the Eastern Han Dynasty Shennong Bencao Jing is listed as the top grade and is a commonly used traditional Chinese medicine for treating depression and migraine.
  • Benzoquinones are a class of compounds found in Chuanxiong and have been shown to be active in cardiovascular, blood and smooth muscle.
  • butylphthalide which has been studied more, has many activities such as anti-cerebral ischemia and protection of brain trauma tissue, and can be considered as one of the material basis of the efficacy of Chuanxiong.
  • Senkynolide l (Formula 1) is a benzoquinone compound isolated from Chuanxiong. It has good fat solubility and water solubility, and can rapidly enter blood and cerebrospinal fluid. It has certain potential for developing new drugs. . However, there are few reports on its pharmacological effects.
  • the technical problem to be solved by the present invention is to propose an anti-supplementation product of sylvestre lactone I (senkyunolide I).
  • sylvestre lactone I serotonergic system related diseases.
  • the inventors extracted and isolated a sufficient amount of Isoproterenol I from Chuanxiong, and confirmed by pharmacological experiments that the drug can be used for the treatment of depression and migraine, as well as other serotonin system-related diseases, thus completing this invention.
  • the extraction and separation of the indole lactone I of the present invention comprises the following steps:
  • pre-treatment step removing the impurities of the Chuanxiong decoction piece to be extracted and pulverizing into a powder
  • the inventors used animal models to study the effects of lanthanide 13 on monoamine transmitters in plasma and brain tissue of rats, the effect of lansyl lactone I on NO and plasma of rat brain and brain.
  • the effect of the pain threshold in mice, the subsequent examples and their pharmacological results will confirm that the steroidal lactone I regulates the content of monoamine transmitters, especially serotonin (5-HT) in plasma and brain tissue, , Yangchuan azlactone I can be used to prepare drugs for the prevention and treatment of depression and migraine, as well as other serotonergic system related diseases.
  • the present invention will be further illustrated by the pharmacological activity test and results of the indole lactone I by the examples.
  • Modeling method Except for the normal group subcutaneous injection of absolute ethanol Aml'kg- 1 , the other groups were subcutaneously injected with nitroglycerin 10mg/kg. Dosing was performed 30 minutes after modeling.
  • the positive drug group was given 1.23 mg'kg ergotamine caffeine tablet solution; the high, middle and low dose groups of chuanchuan azlactone I were intragastrically administered with 72 mg, kg-36 mg-kg ISmg.kg- 1 aqueous solution of yoghurt lactone I, and the rest. Each group was given an equal volume of distilled water. Blood was taken from the abdominal aorta 4 h after administration, and injected into a centrifuge tube to which heparin sodium was added, and centrifuged at 4 000 r'mirT 1 for 10 min to separate the plasma; the brain stem was separated on an ice tray and stored at -80 ° C for use.
  • the filter paper is wiped and weighed, poured into a glass homogenizer, rotated up and down several times, fully ground to homogenize (about 6 ⁇ 8min); transfer the homogenate into the centrifuge tube, add O ⁇ moH 1 high chlorine Appropriate amount of acid solution, vortex for 2 min, centrifuge at 10 000 r'min- 1 for 15 min in a refrigerated centrifuge (4 °C); transfer the supernatant after centrifugation into a centrifuge tube, and centrifuge again for 10 min at 10 000 rmirT 1 , 0.4 mol 1 supernatant with perchloric acid to lml of volume, vortex mixing, a sample solution.
  • the content of serotonin (5-HT), 5-hydroxytryptamine (5-HTP) and 5-hydroxyindoleacetic acid (5-HIAA) in blood and brain stems were determined by high performance liquid chromatography-fluorescence detector. Chromatographic conditions: Kromasil C18 column (4.6 mm * 250 mm, 5 ⁇ ); mobile phase: O.lmol-L of NaAc (containing O.lmmol-L EDTA-2Na), pH 5.1 with HAc, take this buffer It was mixed with methanol at 9:1, filtered through a 0.45 ⁇ m microporous membrane, ultrasonically degassed at a flow rate of 1.0 ml/min ; an emission wavelength of 330 nm and an excitation wavelength of 290 nm.
  • the determination method of NO in rat plasma is as follows:
  • the steps for determining the NO content in rat brain tissue are as follows:
  • Unit - mol gprot 1 Yangchuan azlactone I can inhibit the increase of NO content in plasma and brain tissue during the onset of migraine.
  • the results are shown in Table 5.
  • Kunming mice weighing 18 ⁇ 22g, female, placed on a hot plate at 55 ⁇ 56°C, recording the foot contact hot plate to the hind paw, kicking foot or jumping time, ie the hot plate reaction latency As a pain threshold indicator.
  • the basal pain threshold of each group of rats was first determined, and the pain threshold was less than 5 s or more than 30 s.
  • Rats meeting the criteria of 3 ⁇ 4 ⁇ were randomly divided into 5 groups, 6 in each group. They were: blank control group, Qiangtongding group, and Chuanxionglide I high, medium and low dose groups.
  • a single intragastric administration is as follows:
  • Blank control group normal saline, intragastric administration O.lmHOg - Qiangtongding group: SJmg'mr 1 strong pain-fixing tablet aqueous solution, intragastric O.lmHOg- 1 ; Yangchuan azlactone I high-dose group: Yangchuan a lactone I aqueous solution, each intragastric administration of O.lmHOg-Yanchuan azlactone I medium dose group: l mg'mr 1 Yangchuan azlactone I aqueous solution, each intragastric O.lmHOg; Yangchuan azlactone I low Dosage group: ⁇ . ⁇ 1 aqueous solution of yoghurt lactone I, O.lmHOg per stomach - the pain threshold was measured at 0.33, 2, 3, 4, 6 h after gavage.
  • the pain thresholds of each group of mice were statistically analyzed using the SPSS software package. The results showed that, except for the low dose group, the pain threshold of each group was higher than that of the blank group, which was statistically significant, and was best in the high dose group for 4 hours. The results are shown in Table 6.
  • Inhibition rate % (the average of the writhing body of the blank group and the writhing mean of the reagent group) / the mean of the writhing body of the blank group x l00%.
  • the number of writhings in each group of mice from 0 to 15 min was statistically analyzed using the SPSS software package.
  • Yangchuan Azlactone I has been initially established as an essential condition for the effective preparation of antidepressant drugs, migraine drugs, and other diseases related to serotonin system. Therefore, the present invention can be used for the effective preparation of an antidepressant drug, a migraine drug, and other serotonergic system related diseases.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne l'utilisation de senkyunolide I dans la fabrication d'un médicament destiné à combattre la dépression, et à traiter la migraine et autres maladies liées au système sérotonergique.
PCT/CN2010/001145 2009-08-12 2010-07-29 Utilisation de senkyunolide i dans la fabrication d'un médicament destiné à combattre la dépression, et à traiter la migraine et autres maladies liées au système sérotonergique WO2011017905A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910057749.9 2009-08-12
CN2009100577499A CN101991568B (zh) 2009-08-12 2009-08-12 洋川芎内酯i在制备抗抑郁症药物、偏头痛药物及其他5-羟色胺能系统相关疾病药物中的应用

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WO2011017905A1 true WO2011017905A1 (fr) 2011-02-17

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WO (1) WO2011017905A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9420288B2 (en) 2012-03-26 2016-08-16 Koninklijke Philips N.V. Brightness region-based apparatuses and methods for HDR image encoding and decoding

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103830227A (zh) * 2014-02-27 2014-06-04 中南大学湘雅医院 洋川芎内酯i在治疗疾病方面的用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101015552A (zh) * 2006-12-29 2007-08-15 天津大学 一种川芎内酯提取物及其制备方法和应用
WO2008017491A1 (fr) * 2006-08-11 2008-02-14 Dsm Ip Assets B.V. Dérivés de ligustilide pour le traitement des troubles du système nerveux central
CN101184484A (zh) * 2005-05-24 2008-05-21 帝斯曼知识产权资产管理有限公司 用于治疗炎性失调的藁本内酯衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1977838A (zh) * 2005-12-05 2007-06-13 江西青峰药业有限公司 洋川芎内酯a的制药用途及含有它的药物组合物与制备方法
CN1989984B (zh) * 2005-12-31 2011-05-18 天津天士力制药股份有限公司 川芎有效组分、制备方法及其制剂与用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101184484A (zh) * 2005-05-24 2008-05-21 帝斯曼知识产权资产管理有限公司 用于治疗炎性失调的藁本内酯衍生物
WO2008017491A1 (fr) * 2006-08-11 2008-02-14 Dsm Ip Assets B.V. Dérivés de ligustilide pour le traitement des troubles du système nerveux central
CN101015552A (zh) * 2006-12-29 2007-08-15 天津大学 一种川芎内酯提取物及其制备方法和应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9420288B2 (en) 2012-03-26 2016-08-16 Koninklijke Philips N.V. Brightness region-based apparatuses and methods for HDR image encoding and decoding

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CN101991568A (zh) 2011-03-30

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