WO2010081266A1 - Utilisation nouvelle de la tétrahydropalmatine - Google Patents

Utilisation nouvelle de la tétrahydropalmatine Download PDF

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Publication number
WO2010081266A1
WO2010081266A1 PCT/CN2009/000563 CN2009000563W WO2010081266A1 WO 2010081266 A1 WO2010081266 A1 WO 2010081266A1 CN 2009000563 W CN2009000563 W CN 2009000563W WO 2010081266 A1 WO2010081266 A1 WO 2010081266A1
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WO
WIPO (PCT)
Prior art keywords
cancer
cells
tumor
tetrahydropalmatine
cell
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PCT/CN2009/000563
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English (en)
Chinese (zh)
Inventor
张虹
金雪
向俊峰
李骞
谭莉
唐亚林
Original Assignee
中国科学院化学研究所
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Application filed by 中国科学院化学研究所 filed Critical 中国科学院化学研究所
Publication of WO2010081266A1 publication Critical patent/WO2010081266A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to new uses of tetrahydropalmatine.
  • Corydalis is the dry tubers of the poppy plant, the genus Corydalis, which has the effect of promoting blood circulation, benefiting gas and relieving pain. Its main chemical component is alkaloid, of which tetrahydropalmatine (structural formula is shown in formula I) is a tertiary amine alkaloid with the strongest analgesic effect, analgesic, sedative, sleep aid and stability, especially for the gastrointestinal system. The resulting dull pain is effective.
  • tetrahydropalmatine has been used as an analgesic and sleepless non-prescription drug, such as tetrahydropalmatine sulfate tablets and Qiangtongning. However, none of them reported on anti-tumor.
  • Lung cancer is a common malignant tumor of the lung, and its mortality rate has been the highest in cancer mortality.
  • Most lung cancers originate from the bronchial mucosa.
  • Chemotherapy can be used alone in advanced lung cancer cases to relieve symptoms or to be combined with surgery and radiotherapy to prevent cancer metastasis, recurrence, and cure.
  • chemotherapeutic drugs are cyclophosphamide, 5-fluorouracil, mitomycin (:, doxorubicin, procarbazine, vincristine, methotrexate, nitrosourea, cisplatin, etc.).
  • mitomycin :, doxorubicin, procarbazine, vincristine, methotrexate, nitrosourea, cisplatin, etc.
  • tetrahydropalmatine provided by the present invention is: the tetrahydropalmatine or the drug thereof of the formula I
  • the tetrahydropalmatine may be a left-handed body, a right-handed body or a racemate, and is preferably a drusen of the formula II;
  • the present invention also protects a drug which inhibits proliferation of eukaryotic tumor cells, and its active ingredient is tetrahydropalmatine of the formula I or a pharmaceutically acceptable salt thereof.
  • the eukaryotic organism described in the present invention is a mammal.
  • the tumor cells are cancer cells; the cancer cells may specifically be breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer A cell, a nasopharyngeal cancer cell, a colon cancer cell, a bladder cancer cell, an anal cancer cell, or a rectal cancer cell; preferably a lung cancer cell.
  • novel use of the tetrahydropalmatine provided by the present invention is also: The use of tetrahydropalmatine or a pharmaceutically acceptable salt thereof represented by the formula (I) for the preparation of a medicament for preventing and/or treating a tumor.
  • the tetrahydropalmatine may be a left-handed body, a right-handed body or a racemate, and is preferably a left-handed tamarindine represented by the formula.
  • the tumor cells are cancer cells; the cancer cells may specifically be breast cancer cells, liver cancer cells, pancreatic cancer cells, lung cancer cells, brain cancer cells, ovarian cancer cells, uterine cancer cells, testicular cancer cells, skin cancer cells, gastric cancer A cell, a nasopharyngeal cancer cell, a colon cancer cell, a bladder cancer cell, an anal cancer cell, or a rectal cancer cell; preferably a lung cancer cell.
  • a tetrahydropalmatine or a pharmaceutically acceptable salt thereof represented by Formula I is also within the scope of the present invention to use a tetrahydropalmatine or a pharmaceutically acceptable salt thereof represented by Formula I as an active ingredient for the prevention and/or treatment of a tumor.
  • the preventive and/or therapeutic tumor drug can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, jetting, nasal drops, eye drops, infiltration, absorption, physical or chemical mediated methods; Other substances are mixed or wrapped and introduced into the body.
  • An antitumor drug containing tetrahydropalmatine or a pharmaceutically acceptable salt thereof as an active ingredient, and if necessary, one or more pharmaceutically acceptable carriers may be added to the above drug.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • the preventive and/or therapeutic tumor drug prepared by using tetrahydropalmatine or a pharmaceutically acceptable salt thereof can be prepared into various forms such as an injection, a tablet, a powder, a granule, a capsule, an oral solution, an ointment, a cream, and the like.
  • the above various dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • Fig. 1 is a schematic diagram showing the tumor size in nude mice of each group on the 28th day after administration, wherein the blank in the positive control group represents tumor disappearance.
  • Tumor cell line human lung cancer cell line A549 (Shanghai Institute of Cell Biology, Chinese Academy of Sciences);
  • Test animals Male BALB/c nude mice (SPF grade, Institute of Experimental Animals, Chinese Academy of Medical Sciences), aged 4-6 weeks, 24 animals;
  • the animal's body weight range at the start of administration 16-18 g, and the animal's initial body weight is not more than or less than 20% of the average body weight;
  • Negative control 0.9% sodium chloride injection (physiological saline).
  • the human lung cancer cell line A549 was suspended and cultured in RPMI 1640 medium (containing penicillin 100 U/mL, streptomycin 100 U /mL) containing 10% calf serum, and placed in a cell culture at 37 ° C, 5% CO 2 . Cultivate in the box.
  • the logarithmic growth phase A549 cells were collected and centrifuged, and counted after staining with a mass percentage of 0.4% trypan blue solution.
  • tumor-bearing murine prepared.
  • the tumor was grown to about lg, and the mice were inoculated to prepare F1 generation tumor-bearing mice.
  • Tumor-bearing animals with strong tumor growth and no ulceration and good health were taken, and tumors were taken under aseptic conditions to prepare 3nmi 3 , which was inoculated into the right axilla of each animal.
  • the tumor growth was observed after inoculation in nude mice.
  • the tumor volume was 100-300 mm 3 , the tumor size and body weight were screened.
  • the tumor volume was too large and no tumorigenicity was selected.
  • Tumor-bearing mice were randomly divided into: negative control group, positive control group and tetrahydropalmatine group, each group
  • Negative control group normal saline was administered
  • Tetrahydropalmatine group L-Tallowhosin (Chengdu Cisco Hua Biotechnology Co., Ltd.), the intragastric dose is lOOmg I kg body weight;
  • Positive control group 0.5 mg I ml of cisplatin solution was administered, and the intraperitoneal dose was: 0.1 ml/lOg body weight.
  • the long diameter, short diameter and body weight of the tumor were measured and recorded by vernier calipers twice a week from the time of grouping and administration, including the first dose and the last dose, the tumor volume was calculated and the tumor growth between the groups was compared.
  • the difference in the curves, the tumor size in the nude mice of each group on the 28th day after administration is shown in Fig. 1.
  • V l/2x long diameter X short diameter 2 ⁇ evaluation of curative effect based on tumor volume
  • Vt daily measurement of tumor volume obtained by tumor
  • T/C% RTV average of the administration group / RTV average of the control group ⁇ 100%
  • tetrahydropalmatine can effectively inhibit tumor growth, and the tumor volume is significantly smaller than the negative control. It can be seen that tetrahydropalmatine, which has been widely used for analgesic action, has excellent antitumor activity, and the results indicate that tetrahydropalmatine can be used for the preparation of a medicament for treating lung cancer.
  • the invention broadens the field of medical application of tetrahydropalmatine.

Abstract

L'invention concerne une utilisation nouvelle de la tétrahydropalmatine, consistant à utiliser la tétrahydropalmatine de formule (I) ou ses sels pharmaceutiquement acceptables pour préparer un médicament destiné à inhiber la prolifération des cellules tumorales dans un eucaryon et pour préparer un médicament destiné à empêcher l'apparition et/ou traiter une tumeur. Les résultats de l'essai chez les souris Nude montrent que la tétrahydropalmatine peut inhiber de manière efficace la croissance tumorale et que le volume de la tumeur est sensiblement plus faible par rapport au témoin négatif. De fait la tétrahydropalmatine, déjà largement employée pour lutter contre la douleur, fait preuve d'une excellente activité anti-tumorale et peut être utilisée pour préparer des médicaments contre le cancer, en particulier le cancer du poumon. Cette invention étend le champ des applications pharmaceutiques de la tétrahydropalmatine.
PCT/CN2009/000563 2009-01-14 2009-05-22 Utilisation nouvelle de la tétrahydropalmatine WO2010081266A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910076383A CN101773499A (zh) 2009-01-14 2009-01-14 延胡索乙素的新用途
CN200910076383.X 2009-01-14

Publications (1)

Publication Number Publication Date
WO2010081266A1 true WO2010081266A1 (fr) 2010-07-22

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WO (1) WO2010081266A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020139999A1 (fr) * 2018-12-28 2020-07-02 Addanki Pratap Kumar Traitement du cancer du pancréas
CN112755045A (zh) * 2021-02-04 2021-05-07 新疆医科大学 芜菁中性多糖在制备肺癌a549细胞调控的药物中的应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104327068B (zh) * 2014-09-17 2017-02-15 深圳福山生物科技有限公司 一种用于抗癌镇痛的含硒化合物及其制备方法和用途
CN104490877B (zh) * 2014-12-10 2017-04-12 中国科学院化学研究所 左旋延胡索乙素衍生物的新用途
CN105330708B (zh) * 2015-11-13 2018-11-13 中国科学院化学研究所 延胡索乙素衍生物及其制备方法、用途

Citations (1)

* Cited by examiner, † Cited by third party
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CN101327214A (zh) * 2008-07-18 2008-12-24 中国药科大学 异喹啉生物碱类作为组织因子抑制剂的医药用途

Patent Citations (1)

* Cited by examiner, † Cited by third party
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CN101327214A (zh) * 2008-07-18 2008-12-24 中国药科大学 异喹啉生物碱类作为组织因子抑制剂的医药用途

Non-Patent Citations (2)

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CUI, WENHUA ET AL.: "Potential Cancer Chemopreventive Activity of Simple Isoquinolines, 1-Benzylisoquinolines, and Protoberberines.", PHYTOCHEMISTRY, vol. 67, no. 1, 2006, pages 70 - 79 *
ITO, CHIHIRO ET AL.: "Chemopreventive Activity of Isoquinoline Alkaloids fro Corydalis Plants.", PLANTA MEDICA, vol. 67, no. 5, 2001, pages 473 - 475 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020139999A1 (fr) * 2018-12-28 2020-07-02 Addanki Pratap Kumar Traitement du cancer du pancréas
CN112755045A (zh) * 2021-02-04 2021-05-07 新疆医科大学 芜菁中性多糖在制备肺癌a549细胞调控的药物中的应用
CN112755045B (zh) * 2021-02-04 2022-08-26 新疆医科大学 芜菁中性多糖在制备肺癌a549细胞调控的药物中的应用

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