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WO2002067940A1 - Application de derives de phenazynone dans la preparation de medicaments anticancereux et antimetastases - Google Patents

Application de derives de phenazynone dans la preparation de medicaments anticancereux et antimetastases Download PDF

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Publication number
WO2002067940A1
WO2002067940A1 PCT/CN2002/000121 CN0200121W WO02067940A1 WO 2002067940 A1 WO2002067940 A1 WO 2002067940A1 CN 0200121 W CN0200121 W CN 0200121W WO 02067940 A1 WO02067940 A1 WO 02067940A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
phenazinone
cells
tumor
drugs
Prior art date
Application number
PCT/CN2002/000121
Other languages
English (en)
Chinese (zh)
Inventor
Qiwang Xu
Junkang Liu
Zetao Yuan
Original Assignee
Third Military Medical University, Chinese People's Liberation Army, P.R. Of China
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 Third Military Medical University, Chinese People's Liberation Army, P.R. Of China filed Critical Third Military Medical University, Chinese People's Liberation Army, P.R. Of China
Publication of WO2002067940A1 publication Critical patent/WO2002067940A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the use of phenazinone derivatives in the preparation of anti-tumor and anti-tumor metastatic drugs.
  • Tumors are a common and frequently-occurring disease. Among them, malignant tumors are the most serious type of diseases that currently endanger human health. According to statistics, about 5 million people die from cancer each year, and about 900,000 people die from cancer every year in China. Tumors are new organisms formed by the abnormal proliferation of cells in local tissues under the action of various carcinogenic factors in the body, which often appear as local masses. Tumor cells are transformed from normal cells, but when they become tumor cells, they have abnormal morphology, metabolism, and function.
  • Chemotherapy has developed rapidly, and currently many types of anticancer drugs such as cytotoxic drugs, antimetabolites, antibiotics, alkaloids, and hormones have appeared. But at present, there are two problems that cannot be solved by anticancer drugs. The first is efficacy. Chemotherapy drugs can only kill a certain percentage of tumor cells. For example, advanced leukemia has 10 12 tumor cells, even if a certain drug can kill tumor cells. 99. 99%, there are still 10 8 tumor cells, and clinical recurrence can still occur.
  • anticancer drugs also have a certain effect on normal cells, especially normal cells that grow and proliferate. Therefore, after administration of drugs, various adverse reactions may occur. Common are 1 leukocytes and thrombocytopenia; 2 gastrointestinal reactions are nausea, vomiting, diarrhea, oral ulcers, etc .; 3 hair loss; 4 hematuria; 5 decreased immune ability; prone to bacterial or fungal infection.
  • the present invention relates to the use of a phenazinone derivative of the following formula (I) and a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumors and / or tumor metastases
  • the present invention relates to a method of treating tumors and / or tumor metastases, comprising administering to a patient in need thereof a therapeutically effective amount of a halide derivative of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • Pyrosin R-methyl phenazinone of formula (I)
  • Numerous clinical case investigations have shown that P. aeruginosa is rarely found in infectious pathogens of tumor tissues.
  • Tumor cell line Derived from epithelial tissue, connective tissue, and lymphocytes of the blood system.
  • the human trial results show that long-term oral administration of this substance can make the cancer disappear and be used locally, and the cancer tissue will dry up and fall off without affecting the normal tissue.
  • the present invention relates to the application of a phenazinone derivative of the formula (I) and a pharmaceutically acceptable salt thereof to treat various tumors, which can be used as a main active ingredient to prepare an antitumor drug. Because it has been proven that phenazinone derivatives of formula (I) have low toxicity, humans and other mammals can take high doses without significant side effects, and at the same time can effectively inhibit the occurrence and metastasis of tumors and dissipate tumor tissues. The compounds appear to be promising antitumor drugs.
  • Pyocyanin can be fermented from P. aeruginosa or other similar strains according to known methods and isolated and purified from the fermented species.
  • pharmaceutically acceptable salts of phenazinone derivatives of formula (I) mention may be made of those formed with pharmaceutically acceptable acids, such as those formed with inorganic acids, such as hydrochloride, hydrobromide, boron Acid salts, phosphates, sulfates, hydrogen sulfates, and hydrogen phosphates, as well as those formed with organic acids such as citrate, stearic acid, ascorbate, methyl sulfate, naphthalene-2-sulfonate , Picrate, fumarate, maleate, malonate, oxalate, succinate, acetate, tartrate, mesylate, methanylsulfonate, isethionate Salt, ⁇ -ketoglutarate, ⁇ -glyceryl phosphate, and glucose-1-phosphate.
  • pharmaceutically acceptable acids such as those formed with inorganic acids, such as hydrochloride, hydrobromide, boron Acid salts, phosphates, s
  • the compounds of the invention may generally be administered orally, parenterally, sublingually or transdermally, preferably parenterally or orally.
  • the amount of active ingredient administered depends on the nature and severity of the disease being treated and the weight of the patient.
  • the dosage is 100 mg-3000 mg of a oxazinone derivative of the formula (I) per day.
  • the dosage is 500 mg-5000 mg of a hydrazinone derivative of the formula (I) per day.
  • the active ingredient may be administered to animals and humans in the form of an administration unit, such as It is lyophilized or mixed with conventional pharmaceutical carriers.
  • Suitable dosage unit forms include oral forms, such as oral dispersible tablets, capsules, powders, granules and solutions or suspensions, sublingual and buccal forms, subcutaneous, intramuscular or intravenous Administration forms, topical administration forms and rectal administration forms.
  • Formulations for parenteral and oral administration are preferred, especially injectable solutions (for intravenous, intramuscular, subcutaneous injection), tablets and capsules.
  • the solid composition in the form of a tablet is prepared by mixing the main active ingredient with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and the like.
  • a pharmaceutical excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and the like.
  • the tablets may be coated with sucrose or other suitable substances, or they may be treated to have a sustained and delayed effect and to continuously release a predetermined amount of the active ingredient.
  • Formulations in the form of capsules are obtained by mixing the active ingredient with a diluent and filling the resulting mixture into soft or hard capsules.
  • Formulations in the form of syrups or pools may contain the active ingredient and preferably a calorie-free sweetener, methyl paraben and propyl paraben as preservatives, and flavoring agents and suitable colorants.
  • Water-dispersible powders and granules may contain the active ingredient and may be mixed with a dispersing or wetting agent, or a suspending agent such as polyvinylpyrrolidone, and a sweetener or taste modifier.
  • Rectal administration is performed using suppositories, where the suppositories are made with an adhesive that melts at the temperature of the rectum, such as cocoa butter or polyethylene glycol.
  • Parenteral administration can be carried out using injectable sterile aqueous, saline, alcoholic solutions or homogeneous suspensions of the compounds of the present invention. Best Mode of the Invention
  • the following test examples use pyocyanin as an example to demonstrate the antitumor and antitumor metastatic activity of the compound of formula (I) of the present invention.
  • B16 cells were injected into the feet of Kunming mice, and they were administered after growing, and were treated with local injection, intravenous injection, oral gavage, and intramuscular injection. The results are shown in the table below.
  • the experiments include:

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

Abstract

L'invention porte sur l'application de dérivés de phénazynone de formule (I) dans la préparation de médicaments anticancéreux et antimétastases. Les composés de formule (I) inhibent la croissance de cellules tumorales en régulant le métabolisme de ces cellules, empêchent la croissance de cellules métastasées, et par là même agissent en qualité d'antimétastases. Ces composés se sont avérés très efficaces lors d'études menées dans des laboratoires et lors de tests effectués sur des animaux et des êtres humains.
PCT/CN2002/000121 2001-02-28 2002-02-28 Application de derives de phenazynone dans la preparation de medicaments anticancereux et antimetastases WO2002067940A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNB011048948A CN1162155C (zh) 2001-02-28 2001-02-28 吩嗪酮衍生物在制备抗肿瘤以及抗肿瘤转移的药物中的应用
CN01104894.8 2001-02-28

Publications (1)

Publication Number Publication Date
WO2002067940A1 true WO2002067940A1 (fr) 2002-09-06

Family

ID=4654079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2002/000121 WO2002067940A1 (fr) 2001-02-28 2002-02-28 Application de derives de phenazynone dans la preparation de medicaments anticancereux et antimetastases

Country Status (2)

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CN (1) CN1162155C (fr)
WO (1) WO2002067940A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103360329B (zh) * 2013-07-18 2015-11-18 中国科学院南海海洋研究所 一类吩嗪化合物及其在制备抗肿瘤药物中的应用
CN105418519B (zh) * 2015-11-25 2018-10-02 高小春 具有抗肿瘤活性的吩嗪酰胺类化合物的合成及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845222A (en) * 1986-08-12 1989-07-04 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Pyocyanine derivatives and process for their manufacture
CN1156025A (zh) * 1996-12-27 1997-08-06 中国人民解放军第三军医大学 吩嗪酮在制备营养药物制剂中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4845222A (en) * 1986-08-12 1989-07-04 Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) Pyocyanine derivatives and process for their manufacture
CN1156025A (zh) * 1996-12-27 1997-08-06 中国人民解放军第三军医大学 吩嗪酮在制备营养药物制剂中的应用

Also Published As

Publication number Publication date
CN1372927A (zh) 2002-10-09
CN1162155C (zh) 2004-08-18

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