WO2013174245A1 - Dérivé d'hédéragénine et procédé de préparation et utilisations associés - Google Patents

Dérivé d'hédéragénine et procédé de préparation et utilisations associés Download PDF

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Publication number
WO2013174245A1
WO2013174245A1 PCT/CN2013/075876 CN2013075876W WO2013174245A1 WO 2013174245 A1 WO2013174245 A1 WO 2013174245A1 CN 2013075876 W CN2013075876 W CN 2013075876W WO 2013174245 A1 WO2013174245 A1 WO 2013174245A1
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WO
WIPO (PCT)
Prior art keywords
salt
ivy
saponin derivative
ivy saponin
derivative
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PCT/CN2013/075876
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English (en)
Chinese (zh)
Inventor
马仁强
石清慧
周瑞明
周清
黄娟
Original Assignee
广州博济医药生物技术股份有限公司
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Publication of WO2013174245A1 publication Critical patent/WO2013174245A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to an ivy saponin derivative, a preparation method and application thereof.
  • Ivy saponin is a common aglycone in Chinese medicinal materials, mainly found in continuation, pre-existing, wood, honeysuckle and so on. Ivy saponin is a white powder with low polarity, slightly soluble in methanol and ethanol, and hardly soluble in water. It has been reported that Ivy saponin has the function of protein tyrosine phosphatase PTP1B inhibitor, which can form anti-diabetic drugs and health care products, and can provide for prevention, diagnosis, detection, protection, treatment and research of depression and its directly related diseases. A new source of medicine.
  • the present invention changes or enhances the biological activity by changing the structure.
  • Chinese patent CN200810032325.2 discloses the use of an ivy saponin and a derivative thereof for preparing an antidepressant product, but the ivy saponin derivative thereof refers to an ivy saponin salt derivative (referred to as sodium) Salt or potassium salt) is prepared by dissolving ivy saponin in an ethanol solution, reacting with a corresponding alkali solution, and obtaining a salt upon recrystallization. The role in antidepressant was demonstrated by an in vitro activity test.
  • a primary object of the present invention is to provide an ivy saponin derivative.
  • Another object of the present invention is to provide a process for the preparation of an ivy saponin derivative.
  • R' in R 2 contains a carboxyl group
  • the carboxyl group may further react with a base to form one or more salts.
  • R' is -COCH 3 or -CO(CH 2 ) 2 COOH.
  • the preparation method of the ivy saponin derivative of the invention is obtained by using an ivy saponin as a raw material by an acylation reaction, an esterification reaction or a transesterification reaction, and the specific method is as follows:
  • the solvent in the above preparation method is pyridine or toluene; the catalyst is pyridine or triethylamine in the acylation reaction, and concentrated sulfuric acid or p-toluenesulfonic acid in the esterification or transesterification reaction.
  • the ivy saponin of the present invention can be extracted from a Chinese medicinal material by a known preparation method or directly obtained from the market.
  • an ivy saponin derivative is obtained by using an ivy saponin as a raw material by an acylation reaction, an esterification reaction or a transesterification reaction, and the derivative can be further reacted with a base to obtain a salt thereof.
  • the method has the advantages of high yield and purity of ivy saponin derivatives semi-synthesized from ivy saponins, which can reach more than 95%, simple preparation process, high conversion rate of raw materials, suitable for industrial production, and easy to popularize and apply.
  • the salt of the ivy saponin derivative of the present invention may be a single salt, a double salt or a poly salt. It can be prepared by dissolving the ivy saponin derivative in 95% ethanol, adding 1-10% alkali solution at -10 to 30 ° C to adjust the pH to 9-11, and cooling the precipitated solid to obtain the ivy saponin. a salt of a meta-derivative.
  • the salt of the ivy saponin derivative may be an ivy saponin derivative sodium salt, an ivy saponin derivative potassium salt or an ivy saponin derivative ammonium salt.
  • the salt of the ivy saponin derivative is a sodium salt of an ivy saponin derivative or a potassium salt of an ivy saponin derivative.
  • the present invention also provides the use of an Ivy saponin derivative or a salt thereof for the preparation of an antidepressant.
  • the pharmaceutically acceptable carrier is prepared by adding a pharmaceutically acceptable carrier to a pharmaceutically acceptable carrier by using a saponin derivative or a salt thereof as a main active ingredient, and adding a pharmaceutically acceptable carrier; Crystalline cellulose, hydroxypropylmethylcellulose, gelatin, starch, dextrin, magnesium stearate, lactose, glucose, talc, sodium chloride, phosphate buffered saline, glycerol, ethanol, etc.; the dosage form may be a tablet Agents, capsules, granules, oral liquids, injections, and the like.
  • the dose of the medicament of the present invention may vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the daily dose may be preferably from 100 to 600 mg.
  • the present invention further verifies the pharmacological activity of the ivy saponin derivative or a salt thereof, and the experiment shows that the activity of the ivy saponin derivative or its salt is higher than that of the aglycon and aglycone, and the pharmacological activity thereof has It is obviously improved, has obvious therapeutic effects on depression, has obvious pharmacological effects, and is stable in nature, and can be used for preparing antidepressant drugs.
  • Ivy saponin-3,23-disuccinate was prepared according to Example 1, and 10 g of ivy saponin-3,23-disuccinate was weighed and dissolved in 100 ml of absolute ethanol, and added at about 10 °C. Adjust the pH to about 11 with 3% sodium hydroxide solution, cool the precipitated solid, filter it, wash it with absolute ethanol, and dry it to get the disodium of ivy saponin-3,23-disuccinate.
  • each tablet contains 60mg of the main drug, the theoretical weight of 200mg.
  • the above-mentioned raw and auxiliary materials are first passed through a 80 mesh sieve, and the ivy saponin derivative, microcrystalline cellulose starch, sodium carboxymethyl starch is uniformly mixed according to the prescription amount, and the mixture is uniformly mixed, and the soft material is made of 80% medicinal ethanol, and 24 mesh is used.
  • the granules were sieved, dried at 60 ° C for 1 hour, sieved through 20 mesh, and added to the micro-silica gel, and filled into capsules to obtain 950 capsules of ivy saponin-3,23-disuccinate capsule.
  • each tablet contains 300mg of the main drug, the theoretical weight of 360mg.
  • the above-mentioned raw and auxiliary materials are respectively passed through a 100-mesh sieve, and the main drug, hydroxypropylmethylcellulose, microcrystalline cellulose, and polyethylene glycol are weighed according to the prescription amount, and uniformly mixed, and the soft material is made of 95% medicinal ethanol.
  • the mesh was granulated, dried at 60 ° C for 4 hours, sieved through 20 mesh, and added with magnesium stearate and compressed to obtain 912 tablets of ivy saponin-3,23-disuccinate sustained-release tablet.
  • Example 10 Therapeutic effect of Ivy saponin derivatives on two depression model mice
  • Test drug Ivy saponin derivative (HEDS), produced by Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., batch number: 20100413; Ivy saponin (HED), produced by Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd. Provided, batch number: 20101031; Ivy saponin sodium (HEDN), produced by Guangzhou Boji Pharmaceutical Biotechnology Co., Ltd., batch number: 20100901.
  • Western medicine reference drug amitriptyline hydrochloride (Source: Changzhou Si Yao Pharmaceutical Co., Ltd., Specification: 25mg/tablet, batch number:
  • Modeling drugs Reserpine injection (Source: Guangdong Bangmin Pharmaceutical Factory Co., Ltd., specifications lmg * lml-l, batch number 090717
  • mice were randomly divided into 8 groups according to body weight, and 10 rats in each group were administered according to the following methods.
  • the administration volume was 0.2 ml/10 g.
  • each mouse was intraperitoneally injected with reserpine 2.5 mg. /kg.
  • Normal group Normal feeding, no medication.
  • Model group Distilled water was given by gavage once a day for 7 days.
  • Chinese patent medicine control group A pre-formulated Chinese medicine solution was administered by gavage, and was administered at a dose of 296 mg/kg once a day for 7 days.
  • HEDS high-dose group HEDS solution was administered by gavage at a dose of 60 mg/kg once daily for 7 days.
  • Low dose group of HEDS HEDS solution was administered by gavage at a dose of 30 mg/kg once daily for 7 days.
  • HEDN group HEDN solution was administered by gavage at a dose of 60 mg/kg once daily for 7 days.
  • HED group HED solution was administered by gavage at a dose of 60 mg/kg once daily for 7 days.
  • mice were placed in a circle of 7.5 cm in diameter for 15 s, and the circle-out rate of each group of mice was calculated. The results are shown in Table 1. 2.2.3 Observation of drooping eyelids After intraperitoneal injection of reserpine for 1 h, the number of animals with more than half of the eyelids closed in each group was observed. The results are shown in Table 1.
  • mice The decrease of anal temperature in mice was expressed as mean ⁇ standard deviation ( ⁇ s)).
  • the measurement data were analyzed by one-way analysis of variance for completely randomized design.
  • Statistical software SPSS13.0 was used for statistical analysis.
  • P ⁇ 0.05 was considered statistically significant.
  • mice were randomly divided into 8 groups according to body weight, and 10 rats in each group were administered according to the following methods, and the administration volume was 0.4 ml/10 g.
  • Normal group Normal feeding, no medication was given.
  • Model group Distilled water was given by gavage once a day for 14 days.
  • Chinese patent medicine control group The pre-formulated Chinese medicine solution was administered by gavage, and was administered at a dose of 296 mg/kg once a day for 14 days.
  • HEDS high-dose group HEDS solution was administered by gavage at a dose of 60 mg/kg once daily for 14 days.
  • HEDS solution was administered by gavage at a dose of 30 mg/kg once daily for 14 days.
  • HEDN group HEDN solution was administered by gavage at a dose of 60 mg/kg once daily for 14 days.
  • Hi-D fR HED solution was administered by gavage at a dose of 60 mg/kg once daily for 14 days.
  • each group was placed in an opaque glass jar with a height of 20 cm, h Vv. 10 cm, water depth of 10 cm and water temperature of about 20 ° C after the last administration for 1 h. : 00-10: 00 time period strong side swimming 5mm, forced swimming for 14d.
  • the normal group of mice were not treated except for the necessary squirrel cage cleaning. On the ld, 7d, and 14d, the swimming time of each group was observed (the mice were swimming for 6 min, and the immobility time was 4 min after the accumulation).
  • Table 3 The test results are shown in Table 3.
  • Reserpine is a vesicle reuptake inhibitor that leaves the transmitter outside the vesicle and is easily degraded by monoamine oxidase, thereby depleting catecholamines (norepinephrine, adrenaline, dopamine, and 5-HT), causing behavior And physiological changes.
  • catecholamines nodepinephrine, adrenaline, dopamine, and 5-HT
  • t]1] may be associated with agonistic alpha-adrenergic effects.
  • Both high and low doses of HEDS can reduce the body drop of reserpine, suggesting that the drug can also act through stimulating ⁇ -adrenergic dysmenorrhea.
  • the absolute swimming experiment is based on the pathogenesis theory of environmental factors, using the classic mouse depression model established by desperate behavior, for the preliminary evaluation of the efficacy of antidepressants.
  • Our experimental results show that high and low dose HEDS can significantly reduce the duration of desperate motion in mice forced swimming, suggesting that HEDS has a better therapeutic effect.
  • HEDS showed a stronger antidepressant effect than HEDN and HED at the same dose, especially with respect to HED.

Abstract

La présente invention concerne un dérivé d'hédéragénine ainsi que le procédé de préparation et les utilisations associés, et la formule générale du dérivé est (I). Le procédé de préparation est le suivant : le dérivé peut être obtenu par l'intermédiaire de l'acylation et l'estérification ou la transestérification à l'aide d'hédéragénine comme matière première. A la fois le rendement et la pureté du dérivé d'hédéragénine de la présente invention obtenu par la semi-synthèse de l'hédéragénine sont très élevés, jusqu'à plus de 95 %. Le procédé de préparation est simple ; le taux de conversion des matières premières est élevé ; le procédé convient à la production industrielle et est donc facile à populariser et à appliquer. Les expériences pharmacologiques montrent que le dérivé ou ses sels ont un effet thérapeutique évident sur la dépression, de telle sorte que l'invention offre une nouvelle source de médicament pour le traitement et l'étude de la dépression.
PCT/CN2013/075876 2012-05-21 2013-05-20 Dérivé d'hédéragénine et procédé de préparation et utilisations associés WO2013174245A1 (fr)

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CN201210157859.4 2012-05-21
CN201210157859.4A CN102659905B (zh) 2012-05-21 2012-05-21 一种常春藤皂苷元衍生物及其制备方法和应用

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WO2016193309A1 (fr) * 2015-06-01 2016-12-08 Dsm Ip Assets B.V. Nouveaux bis-esters de sapogénines de lierre pour ruminants

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CN102659905B (zh) * 2012-05-21 2014-07-30 广州博济医药生物技术股份有限公司 一种常春藤皂苷元衍生物及其制备方法和应用
CN105481935B (zh) * 2015-11-21 2019-06-07 吉林省中医药科学院 常春藤皂苷元衍生物及其在制备防治老年痴呆的药物中的应用

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Publication number Priority date Publication date Assignee Title
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