WO2009046635A1 - Utilisation d'alcaloïdes dans la préparation de médicaments traitant la toux - Google Patents

Utilisation d'alcaloïdes dans la préparation de médicaments traitant la toux Download PDF

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Publication number
WO2009046635A1
WO2009046635A1 PCT/CN2008/001690 CN2008001690W WO2009046635A1 WO 2009046635 A1 WO2009046635 A1 WO 2009046635A1 CN 2008001690 W CN2008001690 W CN 2008001690W WO 2009046635 A1 WO2009046635 A1 WO 2009046635A1
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WO
WIPO (PCT)
Prior art keywords
cough
alkaloids
stemospironine
hundred
compound
Prior art date
Application number
PCT/CN2008/001690
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English (en)
Chinese (zh)
Inventor
Yang Ye
Ge Lin
Rensheng Xu
Fan Ge
John Anthony Rudd
Xinzhou Yang
Xiqiang Li
Original Assignee
Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
The Chinese University Of Hong Kong
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 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences, The Chinese University Of Hong Kong filed Critical Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences
Publication of WO2009046635A1 publication Critical patent/WO2009046635A1/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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the invention belongs to the field of medicinal chemistry, and more particularly to an alkaloid compound, stemospironine, which is extracted from a hundred parts, and a pharmaceutical composition thereof for use in the treatment of cough 11 soft. Background technique
  • Cough is a sudden explosive expiratory action to remove substances (sputum) from the airway.
  • Cough itself is a protective reflex that removes sticky secretions, inhaled harmful substances or foreign bodies from the pharynx and the entire respiratory tract.
  • Coughing is an important defense mechanism for the human body. If the cough is weakened or disappeared, it is very harmful. Even fatal.
  • the impact of cough on people's health is dialectical. Long-term frequent cough can affect the patient's breathing, heart and daily life, and work, so it is harmful, and it is also the reason why people often seek medical treatment. According to the US survey, cough is the first cause of medical treatment in patients in the country, and unexplained chronic cough accounts for 10% to 38% of respiratory clinics.
  • the mechanism of cough is generally that the cough receptor receives stimulation, enters the cough center through the gutular nerve and vagus nerve afferent pathway, and then sends an impulse, and then passes along the vagus nerve to the corresponding sensor to produce a series of contraction movements of the respiratory muscle group, causing cough.
  • Cough is usually divided into three categories by time: acute cough, subacute cough, and chronic cough.
  • Acute cough time ⁇ 3 weeks, subacute cough 3 ⁇ 8 weeks, chronic cough ⁇ 8 weeks.
  • Acute cough The common cold is the most common cause of acute cough. Other causes include acute bronchitis, acute sinusitis, allergic rhinitis, acute exacerbation of chronic bronchitis, and bronchial asthma (referred to as asthma).
  • Subacute cough The most common cause is cough after a cold (also known as cough after infection), bacterial Sinusitis, asthma, etc. 3.
  • Chronic cough There are many causes of chronic cough, which can be divided into two categories: One is for those who have a clear lesion on the chest X-ray, such as pneumonia, tuberculosis, and lung cancer. The other type is X-ray chest radiograph without obvious abnormalities, mainly cough, or the only symptom, which is commonly called chronic cough of unknown origin (referred to as chronic cough).
  • Common causes of chronic cough are: cough variant asthma (CVA), postnasal drip syndrome (PNDs), eosinophilic bronchitis (EB), and gastroesophageal reflux cough (GERC), which account for The proportion of chronic cough in respiratory medicine clinics is 70% ⁇ 95%.
  • Other causes are less common, but involve a wide range, such as chronic bronchitis, bronchiectasis, endobronchial tuberculosis, allergic cough (AC), and psychological cough.
  • antitussive drugs for the treatment of cough.
  • central antitussive drugs which are represented by morphine compounds, such as codeine and right. Dextrom ethorphan; one type is a peripheral antitussive, such as benproperine, moguisteine, and the like.
  • morphine compounds such as codeine and right.
  • Dextrom ethorphan one type is a peripheral antitussive, such as benproperine, moguisteine, and the like.
  • these 4 compounds have adverse side effects.
  • the use of morphine compounds can lead to addiction, respiratory depression, inhibition of smooth muscle contraction (such as constipation) and hallucinations.
  • codeine is highly addictive, and dextromethorphan can induce hallucinations, delusions or other psychotic symptoms.
  • drugs with strong antitussive activity such as codeine and methadone have an adverse effect on the central nervous system.
  • japonica ( Blume ) Miq and The underground part of S. tuberosa Lour. Hundreds of them grow under the hillside jungle at 370 - 2240 meters above sea level, on the edge of the river, on the roadside, and in valleys and wet rocks. They are distributed in the Qinling mountains, the provinces south of the Huaihe River, and in Vietnam, Sri, Thailand, and northern India. At present, there have been some reports on the alkaloids related to the leaf and the erect, but there is no report on the antitussive activity of the alkaloids of the alkaloids involved in the present invention.
  • a phloem alkaloid compound having a structural formula of the following formula and a pharmaceutical composition thereof for use in the preparation of a medicament for treating cough, which compound can alleviate and/or inhibit cough 11 softness, Cough 11 soft inhibitor.
  • the present invention provides an alkaloid compound, a part of alkaloids, which is extracted from a leaf or an upright hundred part having a cough-reducing activity, and has a structure represented by the following structural formula:
  • FIG 1 shows the results of the antitussive activity of stemospironine.
  • the present invention provides an alkaloid compound, a basal base, and a pharmaceutical composition thereof, which are isolated from Stemona tuberosa and Stemona sessilifolia, in the treatment of cough. Application in .
  • the therapeutic cough activity according to the present invention means that cough can be alleviated and/or inhibited.
  • the present invention provides an alkaloid compound having cough-reducing activity, which has the structure shown by the following structural formula:
  • Thin layer chromatography (TLC) silica gel plates and column chromatography silica gel (200 ⁇ 300 mesh) were produced by Qingdao Haiyang Chemical Plant; thin layer chromatography spots were sprayed with vanillin sulfate ethanol solution for color development.
  • the stem roots of Stemona tuberosa and sessilifolia used in the experiment were collected from Hainan province, China, and identified by Associate Professor Shen Jingui of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Stemona tuberosa and Stemona sessilifolia. Evidence samples of these two plant materials were deposited with the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
  • the ratio of solvents involved is a volume ratio.
  • the total alkaloid extract was separated by silica gel (100 ⁇ 200 mesh) column chromatography (silica gel in lkg), petroleum ether: ethyl acetate (7:1), (6:1), (5:1), ( 4:1), (3:1), (2:1), (1:1), (1:2), and (1:3) are eluents, and the eluent volume of each gradient is 10L. , each 500mL concentration is a fraction. Each gradient of the eluate was combined and concentrated to give a total of 9 sites of 1-9.
  • the total alkaloid extract was separated by silica gel (100 ⁇ 200 mesh) column chromatography (1.5 kg silica gel), petroleum ether: ethyl acetate (6:1), (5:1), (4:1), (3:1), (2:1), (1:1) and (1:2) are eluents.
  • the eluent volume of each gradient is 10L, and each 500mL concentration is a fraction.
  • Each gradient of the eluate was combined and concentrated to obtain 7 parts from 1 to 7.
  • the fraction 4 that is, the mobile phase was petroleum ether: ethyl acetate (3:1), the eluted fraction (12.0 g) was concentrated, and the solution was allowed to stand at room temperature to precipitate crystals, which were filtered and then recrystallized from ethyl acetate.
  • a citric acid-induced guinea pig cough model was used (Gallico et al., 1994; Chung et al., 2003). Guinea pigs were randomly divided into different groups, each group containing at least 5 guinea pigs, individually placed in a sealed transparent plexiglass chamber (25 x cm x 12 cm x 12 cm), and passed through an atomized 0.5 M aqueous citric acid solution, approximately 0.5 ml per minute. The atomized citric acid solution was changed to a particle aerosol having an average diameter of 1-5 ⁇ m for 8 minutes using an ultrasonic atomizer (OMRONNE-U12, Tokyo, Japan).
  • the paroxysmal cough was monitored within 8 minutes, and the coughing sound was recorded and amplified by a microphone placed indoors.
  • the sound waves were analyzed by Cool Edit 2000 software (Synxrillium, Phenix, USA), and the sound data was counted by computer software (CoughCount-CUHK-2003 -Copyright) to count the number of coughs.
  • Each group of guinea pigs was administered intraperitoneally or orally in a single dose 30 minutes prior to citric acid stimulation.
  • the three doses administered intraperitoneally were: 30, 50, 100 mg/kg, and the oral dose was 100 mg/kg.
  • Antitussive cough frequency and with the control group of animals administered group to give the corresponding volume of saline) to reduce the number of cough counts 11 soft compared.
  • the actual use of common antitussives is acceptable because the positive control to verify the guinea pig cough model, intraperitoneal administration of 30 mg / kg codeine cough inhibition rate of 86%, demonstrating the feasibility of this model.
  • Codeine as a positive control drug has a clear dose-effect relationship with its antitussive activity, and this model can well represent the town of codeine. Coughing ' ⁇ ' is born.
  • Figure 1 shows the results of the antitussive activity of stemospironine.
  • stemospironine showed a good dose-dependent antitussive activity in the peritoneal administration.
  • oral administration 100 mg/kg
  • stemospironine also showed strong antitussive activity (about 83% inhibition rate)
  • statistical analysis showed the same There was no significant difference in the antitussive activity between the intraperitoneal and oral doses.

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

Abstract

Cette invention concerne l'utilisation de la stemospironine dans la préparation de médicaments traitant (c'est-à-dire réduisant et/ou supprimant) la toux, et la composition pharmaceutique comprenant le composé. La stemospironine représentée par la formule structurelle suivante est extraite de Stemona tuberosa et de Stemona sessilifolia, plantes de la famille des Stemonaceae, et a une activité antitussive constante.
PCT/CN2008/001690 2007-09-28 2008-09-28 Utilisation d'alcaloïdes dans la préparation de médicaments traitant la toux WO2009046635A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2007100465812A CN101396359A (zh) 2007-09-28 2007-09-28 一种生物碱类化合物在制备治疗咳嗽药物中的用途
CN200710046581.2 2007-09-28

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Publication Number Publication Date
WO2009046635A1 true WO2009046635A1 (fr) 2009-04-16

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019055294A1 (fr) * 2017-09-12 2019-03-21 Yang Ye Formes solides de stémospironine et ses sels

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1453279A (zh) * 2002-04-24 2003-11-05 香港中文大学 具有镇咳活性的植物提取物和生物碱
CN1931171A (zh) * 2005-09-12 2007-03-21 香港赛马会中药研究院有限公司 制备镇咳药及缓解咳嗽的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1453279A (zh) * 2002-04-24 2003-11-05 香港中文大学 具有镇咳活性的植物提取物和生物碱
CN1931171A (zh) * 2005-09-12 2007-03-21 香港赛马会中药研究院有限公司 制备镇咳药及缓解咳嗽的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORIMOTO-Y ET AL.: "An efficient approach toward pyrrolidinyllactone system characteristic of the Stemona alkaloids. Lewis acid catalyzed stereoselective reaction of N-benzyloxycarbonyl- 2-methoxypyrrolidine with 3-methyl-2-trimethylsilyloxyfuran.", TETRAHEDRON-LETTERS., vol. 34, no. 36, 1993, pages 5773 - 5776 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019055294A1 (fr) * 2017-09-12 2019-03-21 Yang Ye Formes solides de stémospironine et ses sels
CN111565723A (zh) * 2017-09-12 2020-08-21 叶阳 百部螺碱及其盐的固体形式
JP2020536951A (ja) * 2017-09-12 2020-12-17 イェ，ヤン ステモスピロニン及びその塩の固体形態
EP3681506A4 (fr) * 2017-09-12 2021-09-22 Yang Ye Formes solides de stémospironine et ses sels
US11414427B2 (en) 2017-09-12 2022-08-16 Yang Ye Solid forms of stemospironine and its salts

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