CN1195288A - Use of fluconazole for inhibiting growth of cancers - Google Patents

Use of fluconazole for inhibiting growth of cancers Download PDF

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Publication number
CN1195288A
CN1195288A CN96196682A CN96196682A CN1195288A CN 1195288 A CN1195288 A CN 1195288A CN 96196682 A CN96196682 A CN 96196682A CN 96196682 A CN96196682 A CN 96196682A CN 1195288 A CN1195288 A CN 1195288A
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chemotherapeutics
triazol
propan
tumor
medicine
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J·B·卡姆登
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Procter and Gamble Co
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Procter and Gamble Co
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Priority claimed from US08/674,180 external-priority patent/US5908855A/en
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

A pharmaceutical composition for the treatment of cancers or tumors in mammals is disclosed which comprises 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives. A chemotherapeutic agent can be used in conjunction with 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives as can potentiators. 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-l-yl)propan-2-ol and its derivatives can also be used to treat viral infections, either alone, in conjunction with other anti-viral agents or with a potentiator.

Description

The purposes of fluconazole for inhibiting growth of cancers
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of people especially or homoiothermic animal cancer and tumor, wherein comprise 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol and the derivants thereof of 3-.It can share with other chemotherapeutics and synergist.Said composition also can be used for treating viral infection.
Background of invention
Cancer comprises leukemia, is to cause one of animal and human's main causes of death.The leukemic definite cause of disease is not clear, but for example smoking or to contact carcinogen relevant of the generation that big quantity research has proved some types of leukemia encountered and tumor and some activity.
Verified, many chemotherapeutics are effective to cancer, tumor or leukemia, but are not that all types of cancers and tumor cell are all effective with these medicines.Unfortunately, many these class medicines kill and wound normal cell simultaneously.People always do not understand for the definite mechanism of action of these chemotherapeutics.
Although in cancer and the development to some extent of leukemia treating field, main Therapeutic Method remains radiation and chemotherapy and bone marrow transplantation at present.Embolic chemotherapy is believed to resist especially has invasive cancer.This class is killed cellularity or the cell growth inhibited medicine cancer high to growth index, and promptly cancer is especially effective rapidly for cell division.Up to now, the spendable therapeutic agent of oncologist mainly comprises hormone, especially estrogen, progesterone and testosterone, and by some antibiotic, alkylating agent and the antimetabolite of many microorganisms.It is desirable to those especially only acts on leukemia, cancer and tumor cell specifically and does not have influence on Normocellular cell toxicity medicament.Unfortunately, also do not find this class medicine, and can only replace use especially at the rapid splitted cell medicine of (comprising pathological changes and normal cell simultaneously).
Obviously, develop because of certain unique specificity will be a quantum jump at cancer or leukaemia's material.Perhaps, leukemia or cancer cell had cytotoxicity but it also is that people are required that normal cell is only had the material of slight effect.So, one of purpose of the present invention provide a kind of have treatment leukemia effect but to normal plasma cell action temperature and or adiaphorous pharmaceutical composition.
In particular, one of purpose of the present invention provides a kind of pharmaceutical carrier as herein described and 2-(2,4 difluorobenzene base)-1 of comprising, two (the 1H-1 of 3-, 2,4-triazol-1-yl) compositions of propan-2-ol and derivant thereof, and a kind of method for the treatment of cancer, leukemia and tumor.
With 2-(2,4 difluorobenzene base)-1, it is a kind of new therapy that two (1H-1,2,4-triazol-1-yl) propan-2-ol and the derivants thereof of 3-and other chemotherapeutics with killing tumor cells effect share.2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof can also separately or be used for the treatment of viral infection in the presence of synergist.
Summary of the invention
The invention provides a kind of pharmaceutical composition of suffering from leukemic mammal, especially homoiothermic animal and people that is used for the treatment of, wherein comprise the 2-(2 of pharmaceutical carrier and effective dose, the 4-difluorophenyl)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol (fluconazol) and the derivants thereof of 3-.2-(2,4 difluorobenzene base)-1, two (1H-1,2, the 4-triazol-1-yl) propan-2-ols of 3-have following structural formula:
Give effective dose by oral, rectally, topical or parenteral canal drug administration or vein, these compositionss can be used to suppress the growth of leukemia, tumor and cancer cell in the human or animal body.These compositionss are to the not significant effect of healthy cell.
Synergist is the same with chemotherapeutics, also can and 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof are share.
These compositionss are especially effective for resisiting influenza virus.
Describe the A. definition in detail
Herein, " comprise " and refer in pharmaceutical composition of the present invention, can be used in combination multiple components.Accordingly, " mainly by ... constitute " and " by ... formation " forgive among " comprising ".
Herein, the composition of " pharmaceutically approval " is to be applicable to people and/or animal, and with rational curative effect/risk than corresponding, do not have the composition of over-drastic adverse side effect (for example toxicity, zest and anaphylaxis).
Herein, " safe and effective amount " refers to that when using according to the inventive method, the consumption of certain composition is enough to produce required curative effect, and with rational curative effect/risk than corresponding, do not have over-drastic adverse side effect (for example toxicity, zest and anaphylaxis).Obviously, concrete " safe and effective amount " can be according to following factor and difference: the state of an illness to be treated is specifically arranged, the patient's body situation, mammiferous kind to be treated, the course of treatment, the characteristic of the treatment of carrying out (if any) simultaneously, and the concrete prescription that uses and the structure of chemical compound and derivant thereof.
Herein, " 2-(2,4 difluorobenzene base)-1, two (1H-1,2, the 4-triazol-1-yl) propane-2-ol derivatives of 3-" comprise its ester, ether and the salt of pharmaceutically approving.
Herein, " medicine addition salts " is 2-(2,4 difluorobenzene base)-1, the salt that two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and organic or inorganic acid form.The preferred acid-addition salts of this class is chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formates, tartrate, maleate, malate, citrate, benzoate, Salicylate, Ascorbate etc.
Herein, " pharmaceutical carrier " refers to the solvent, suspending agent or the excipient that are used for transmitting to the animal or human anti-leukemia medicine pharmaceutically approved.Carrier can be a liquid or solid, and selects according to predetermined dosage regimen.
Herein, " cancer " or " leukemia " refer to find in mammal, attacks the normal health hemocyte or produce all types of cancers or the tumor or the malignant disease of the bone marrow of hemocyte.
Herein, " virus " is included in morbific virus in the homoiothermic animal, comprises HIV, influenza virus, rhinovirus, herpes etc.
Herein, " 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol and the derivants thereof of 3-" comprise ester, ether and addition salts.
Herein, " synergist " is and 2-(2,4 difluorobenzene base)-1, the material that two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof are share, for example triprolidine and cis-isomer thereof or 1H-benzimidazolyl-2 radicals-propanoic acid.Synergist can act on immune system, perhaps strengthens the curative effect of medicine.
Herein, the medicine that " chemotherapeutics " comprises the medicine that acts on mutually with DNA, antimetabolite, acts on mutually with tubulin, amcinonide and other, for example asparaginase or hydroxyurea.B. 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol and the derivants thereof of 3-
2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof have following structural formula:
Figure A9619668200051
It is the United States Patent (USP) 4,404 according to Richardson, the method preparation described in 216 (1983).
Its derivant comprises the low-carbon carboxylate of propanol base, for example acetic acid, propanoic acid, butanoic acid, valeric acid and alkyl caproate.Good especially is the ester of the following carboxylic acid of 7 carbon atoms, and best is propionic ester.Aromatic carboxylic acid, for example salicylic acid, benzoic acid and relevant acid also can be used for esterification propanol group.7 following alkyl ethers of carbon atom also are useful derivants.
The medicine addition salts is 2-(2,4 difluorobenzene base)-1, the salt that two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and organic or inorganic acid form.This class acid-addition salts preferably is chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formates, tartrate, maleate, malate, citrate, benzoate, Salicylate, Ascorbate etc.
This compounds belongs to the more general class antifungal with following structural formula: R wherein 1Be alkyl, cycloalkyl, aryl, (2, the 4-Dichlorobenzene base) or the aralkyl that can replace arbitrarily, Y 1And Y 2Be=CH-or=N-; And their salt or metal complex and ether or ester.Though these materials can be treated mycosis effectively, wherein some has found to have teratogenecity.So herein, the material that shows this character is inapplicable.C. chemotherapeutics
Usually chemotherapeutics is categorized as the medicine that acts on mutually with DNA, antimetabolite, the medicine that acts on mutually with tubulin, the other medicines of amcinonide and asparaginase or hydroxyurea and so on.Each based chemotherapy agent can also further be distinguished according to active type or type of compounds.With 2-(2,4 difluorobenzene base)-1, the chemotherapeutics that two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof are share comprises the member in all these types.The detailed argumentation of relevant chemotherapeutics and medication thereof can be referring to " cancer chemotherapy handbook (Cancer Chemotherapy Handbook) the 2nd edition, the 15th to 34 page, the Appleton ﹠amp at Dorr. of this incorporated by reference etc.; Lange (Connecticut, 1994).
Comprise alkylating agent with the medicine that DNA acts on mutually, for example cisplatin, cyclophosphamide, altretamine; DNA chain interruption agent, for example bleomycin; Embedding human nature topoisomerase II inhibitor, for example actinomycin D and amycin; Non-embeddability topoisomerase II inhibitor, for example etoposide and teniposide; With DNA minor groove binding plicamycin.
Alkylating agent and cell DNA, RNA and protein molecule are with less aminoacid, glutathion and so on compound formation covalent chemical addition product.Usually, the nucleophilicity atom in this class alkylating agent and certain cellular component, for example amino in nucleic acid, protein, aminoacid or the glutathion, carboxyl, phosphate ester, sulfydryl reaction.These alkylating agents in treatment of cancer mechanism and effect and imperfectly understand.Typical alkylating agent comprises:
Nitrogen mustards, for example chlorambucil, cyclophosphamide, Isofamide, chlormethine, melphalan, uracil mustard;
Aziridine, for example plug is for group;
Methanesulfonates, for example busulfan;
Nitroso ureas, for example carmustine, lomustine, streptozocin;
Platinum complex, for example cisplatin, carboplatin;
The biological reducing alkylating agent, for example mitomycin and procarbazine, dacarbazine and altretamine;
DNA chain interruption agent is comprising bleomycin;
DNA topoisomerase II inhibitor, comprising:
Intercalator, for example amsacrine, actinomycin D, daunorubicin, amycin, idarubicin and rice
The holder anthraquinone;
Non-intercalator, for example etoposide and teniposide;
The DNA minor groove binding is a plicamycin.
Antimetabolite is by the generation of one of two kinds of main mechanism interfere RNA.Some suppresses the generation as the triphosphoric acid dezyribonucleoside of the synthetic direct precursor of DNA in this type of medicine, suppresses duplicating of DNA thus.Some and purine and pyrimidine are enough similar and can replace in the nucleotide route of synthesis in this compounds.The normal counterpart that these analog can replace them then enters DNA and RNA.The antimetabolite of Shi Yonging comprises herein:
Antifol, for example methotrexate and trimetrexate;
Pyrimidine antagonist, for example fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytosine arabinoside, floxuridine;
Purine antagonist comprises mercaptopurine, 6-thioguanine, fludarabine, pentostatin;
Sugar-modified analog comprises Cyctrabine, fludarabine;
The ribonucleotide reductase inhibitor comprises hydroxyurea.
The medicine that acts on mutually with tubulin is by working in conjunction with the special site on the microcosmic albumen, and microcosmic albumen is a kind of protein that forms the cell microtubule by polymerization.Microtubule is important cellularity unit.When medicine that acts on mutually and protein bound, cell just can not form microtubule.Comprise these two kinds of vincristine and vinblastine, alkaloid and paclitaxel with medicine that microtubule acts on mutually.
Amcinonide also can be used for the treatment of cancer and tumor.They are used to the hormone-sensitive tumor, and usually derived from natural origin.Comprising:
Estrogen, conjugated estrogen hormone and ethinylestradiol and diethylstilbestrol, chlorotrianisene and Idenestrol;
Progestational hormone, for example delalutin, medroxyprogesterone and megestrol;
Androgen, testosterone for example, Androfort; Fluoxymesterone, methyltestosterone;
Adrenocorticosteroid is derived from natural hydrocortisone or hydrocortisone.Use them to be because their antiinflammatory action, and wherein some inhibition mitosis that has and the synthetic ability of blocking dna.This compounds comprises prednisone, dexamethasone, methylprednisolone and prednisolone.
Luteinizing hormone-releasing hormone class medicine or gonadotropin-releasing hormone antagonist are mainly used in the treatment carcinoma of prostate.Comprising acetic acid shell third Rayleigh and acetic acid goserelin.In test, they stop the biosynthesis of steroidal.
Hormone antagonist class medicated bag is drawn together:
Antiestrogen, for example tamoxifen;
Antiandrogen, for example flutamide; With
Antiadrenergic drug, for example mitotane and aminoglutethimide.
As if hydroxyurea mainly work by suppressing ribonucleotide reductase.
Asparaginase is a kind of non-functional aspartic acid and synthetic enzyme of blocking protein thus of in tumor agedoite being changed into.
Paclitaxel is a kind of chemotherapeutics preferably.D. synergist
" synergist " is improvement or strengthens the effectiveness of pharmaceutical composition or act on immune any material.One of this class synergist is triprolidine and cis-isomer thereof, their quilts and chemotherapeutics and 2-(2,4 difluorobenzene base)-1, and two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof are share.Relevant triprolidine can be referring to United States Patent (USP) 5,114, and 951 (1992).Another kind of synergist is a procodazole, 1H-benzimidazolyl-2 radicals-propanoic acid; [β-(2-benzimidazole) propanoic acid; 2-(2-carboxy ethyl) benzimidazole; Propazol].Procodazole is a kind of non-specific active immunity protective agent, and antiviral and bacterial infection can share with the compositions of this paper.When it only with 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof are share, and can effectively treat cancer, tumor, leukemia and viral infection when perhaps share with chemotherapeutics.
Propanoic acid and salt thereof and ester also can share with pharmaceutical composition of the present invention.
In this paper compositions, can also add the antioxidant biostearin, for example vitamin A, C and E, and beta-carotene.E. dosage
Can use any proper dosage in the methods of the invention.The type of chemical compound and carrier and consumption will be with homoiothermic animal or people's kinds, and body weight has the type of cancer to be treated or tumor or viral infection that a great difference is arranged.Usually, to 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol and derivant or the chemotherapeutics of 3-, proper dosage is 1 milligram of every approximately kg body weight extremely between 1000 milligrams of every approximately kg body weight.Be preferably and use about 15 to 800 milligrams of every kg body weight.Usually, human dosage is lower than small-sized homoiothermic animal, for example mice.Dosage unit can comprise a kind of unification compound or with the mixture of other chemical compound or other cancer inhibitor.This dosage unit can also comprise diluent, expand agent, carrier, liposome etc.Dosage unit can be solid or gel form, for example pill, tablet, capsule etc., or be suitable for oral, rectally, topical, intravenous injection or parenteral canal drug administration, or be injected in the bone marrow or liquid form on every side.2-(2,4 difluorobenzene base)-1, the scope of two (1H-1,2, the 4-triazol-1-yl) propan-2-ols of 3-and derivant and chemotherapeutics and ratio depend on cancer to be treated or tumor type and the concrete chemotherapeutics that uses.F. form of administration
Chemotherapeutics, 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof and optional synergist mix with the carrier of pharmaceutically approving usually.This carrier can be solid or liquid, and its type is selected according to the administration type that adopts usually.Active drug can be with tablet or capsule, and the form co-administered of liposome is perhaps with blended powder or liquid form.The example of suitable solid carrier comprises lactose, sucrose, gelatin and agar.Capsule or tablet formulation are convenient, and easy-to-swallow and chew; Other solid dosage forms comprises granule and loose powder.Tablet can comprise suitable bonding, lubricant, diluent, disintegrating agent, coloring agent, tax flavor agent, fluidizer and flux.Suitable liquid dosage form is included in water, pharmaceutically approval is fatty and oily, alcohol or other organic solvent, comprising solution that forms in the ester or suspending agent, suspension that Emulsion, syrup or elixir, suspending agent, solution and/or the regeneration of non-effervescency granule form and the effervescent that forms by the regeneration of effervescency granule.This liquid dosage form can comprise for example suitable solvent, antiseptic, emulsifying agent, suspending agent, diluent, sweeting agent, thickening agent and flux.Peroral dosage form can randomly comprise composes flavor agent and coloring agent.Parenteral road and intravenous dosage forms also comprise injection or compatible mineral and other material of drug-supplying system type that makes it and select for use.
JIUYUE in 1975 was issued to have described in the United States Patent (USP) 3,903,297 of Robert and can be used for preparing the pharmaceutically carrier of approval of peroral dosage form of the present invention and the instantiation of excipient on the 2nd.Below with reference to having described technology and the composition that is used to make the used dosage form of the present invention in the document: 7 " modern pharmaceutical " (7 ModernPharmaceutics), the 9th and the 10th chapter (Banker ﹠amp; Rhodes compiles, and 1979); Lieberman etc., " pharmaceutical dosage form: tablet " (Pharmaceutical Dosage Forms:Tablets) (1981); And Ansel, " pharmaceutical dosage form introduction " Introduction to (Pharmaceutical Dosage Froms) the 2nd edition) 1976.G. Therapeutic Method
Therapeutic Method can be any in concrete cancer of treatment or tumor type effective appropriate method.Therapeutic Method can be oral, rectum, part, parenteral road or intravenously administrable, or is expelled in tumor or the cancer.Use the method for effective dose medicine to depend on that also leukemia to be treated, cancer, tumor or virus are arranged.It is believed that, the method preferably that homoiothermic animal is given chemical compound is non-intestines and stomach treatment, promptly press down the diluent 2-(2 formulated together of chemical compound for treating cancer or assistance administration with suitable carriers, additional one or more by vein, subcutaneous or intramuscular use, the 4-difluorophenyl)-1, two (the 1H-1 of 3-, 2, the 4-triazol-1-yl) propan-2-ol and derivant thereof.
Except using chemotherapeutics and synergist, 2-(2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ols of 3-and derivant thereof can also be share with antifungal, herbicide or other antiviral agents.Herbicide and antifungal comprise carbendazim, fluoconazole, benomyl, glyphosate and propicodazole preferably.
When this pharmaceutical composition was used to treat viral infection, they can share with other antiviral agents.The antiviral evaluation that utilizes the human influenza virus to carry out
When use is received be 5 to 7 the week ages female CD mice (Charles River Breeding Laboratories, Portage, MI).When the test beginning, mice was about for 6 to 9 ages in week, heavily about 20 to 28 grams.Each Mus of using in the research, the age differs and is no more than 10 days.Per 6 mices pass is had in the careless cage of pad at one.Allow mice ad lib Mus eat 5002 (PMI, St.Louis Missouri).Make its ad lib fresh water.
Attack mice with human influenza strain AT2/Taiwan/1/64.This strain is kept at-70 ℃ approximately.Before infectivity was attacked, first freezing thing thawing with virus was incorporated in and is diluted to suitable concentration in the normal saline buffer solution.Use the halothane anesthesia mice, intranasal is given the virus attack dosage of 50 microlitres.
Use for the examination material according to following concentration and volume.At the 1st day to the 14th day, every group of 10 mices were for the lavation of examination thing per os.Normal saline control animal (10) is accepted and the normal saline that supplies examination thing administration mice respective volume.Finish for the administration that tries thing according to 24 hours interval.At the 0th day, to give for the second time for examination thing or normal saline after about 4 hours, each Mus is with it is calculated that the virus of the infective dose that can cause about 90% mortality rate attacks in intranasal.In 21 days after infectivity is attacked, the fatality rate or the dying rate of observing animal every day.In vitro tests for dead percentage ratio fluconazol 350 0 fluconazol of examination agent amount (mg/kg) 700 30% normal saline-100% amantadines 75 0% people's tumor colony forming units
The solid tumor that to take from the patient is cut into 2 to 5 millimeters small pieces, is placed on immediately to add 10% and add among the McCoyShi culture medium 5A of 1% penicillin/streptomycin through heat-inactivated new-born calf serum.In 4 hours,, and under pressure, filter stainless steel mesh and No. 25 syringe needles of No. 100, wash with aforementioned McCoyShi culture medium then with shearing machine tool these solid tumors that dissociate.Utilize routine techniques to obtain ascites, hydrothorax, pericardial fluid and bone marrow.These body fluid or bone marrow are placed sterile chamber, contained the antiseptic that every milliliter of pernicious body fluid or bone marrow 10 units do not have heparin in the container.After centrifugal 10 minutes with 150 * g, collecting cell, and wash through the McCoyShi of heat-inactivated calf serum culture medium 5A with adding 10%.Utilize the trypan blue method on blood-counter system, to measure the vigor of cell suspending liquid.
The cell suspension of clone's usefulness in 0.3% agar with the preparation of enrichment CMRL1066 culture medium, has been replenished 15% through heat-inactivated horse serum, penicillin (100 units per ml), streptomycin (2 mg/ml), glutamine (2 millimolar concentration), insulin (3 units per ml), agedoite (0.6 mg/ml) and HEPES buffer (2 millimolar concentration) in the culture medium.In order to carry out continuous exposure test, each test compound is added in the said mixture.In 35 millimeters culture dishs, cell is layered on the agar of top layer, has one deck to be used to prevent the agar of fibroblastic growth under this layer.Be 3 flat boards of each data point preparation.Flat board is placed in 37 ℃ the incubator, took out, count the colony number on each plate at the 14th day.With 3 colonies that in the flat board of compound treatment, form (being defined as 50 cells) number and 3 comparisons that contrast on the flat boards, the survival colony percentage ratio under each compound concentration can be made table then.Measure survival rate with 3 positive control flat boards.With 200 mcg/ml sodium vanadates as positive control.If the colony number in the positive control is lower than 30% of non-processing contrast, can estimate test.
In exposure test or single dose are tested continuously, the fluconazol antitumor of 0.5 and 5.0 mcg/ml invalid (being respectively 0/3 and 0/13).In continuous exposure test, the fluconazol of 50.0 mcg/ml is especially effective for lung non-small cell carcinoma and ovarian cancer.Always have 4/13 appearance 50% or following survival rate.

Claims (9)

1. treat cancer, tumor and medicine for treating viral infections compositions for one kind, wherein comprise a kind of material that about 1 mg/kg body weight to 800 mg/kg body weight is selected from down the group material, this group comprises 2-(2, the 4-difluorophenyl)-1, two (the 1H-1 of 3-, 2,4-triazol-1-yl) propan-2-ol and derivant thereof and their mixture and the pharmaceutically carrier of approval.
2. pharmaceutical composition according to claim 1 wherein also comprises the chemotherapeutics of safe and effective amount.
3. medicine, amcinonide, asparaginase or hydroxyurea that pharmaceutical composition according to claim 1 and 2, wherein said chemotherapeutics are selected from the medicine that acts on mutually with DNA, antimetabolite, are used as mutually with tubulin.
4. according to claim 1,2 or 3 described pharmaceutical compositions, wherein said chemotherapeutics is selected from asparaginase, hydroxyurea, cisplatin, cyclophosphamide, altretamine, bleomycin, actinomycin D, amycin, etoposide, teniposide and plicamycin.
5. according to claim 1,2 or 3 described pharmaceutical compositions, wherein said chemotherapeutics is selected from paclitaxel, methotrexate, fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytosine arabinoside, floxuridine, mercaptopurine, 6-thioguanine, fludarabine, pentostatin, Cyctrabine and fludarabine.
6. according to claim 1,2,3,4 or 5 described pharmaceutical compositions, wherein also comprise synergist.
7. method for the treatment of homoiothermic animal cancer or tumor, this method comprises claim 1,2,3,4, the 5 or 6 described compositionss of giving safe and effective amount.
8. method for the treatment of the homoiothermic animal viral infection, this method comprises claim 1,2,3,4, the 5 or 6 described compositionss of giving safe and effective amount.
9. according to claim 7 or 8 described methods, wherein by oral or through intestinal, vein, through the abdominal cavity or in tumor the described 2-of injection (2,4 difluorobenzene base)-1, two (1H-1,2,4-triazol-1-yl) propan-2-ol and the derivants thereof of 3-.
CN96196682A 1995-08-04 1996-07-30 Use of fluconazole for inhibiting growth of cancers Pending CN1195288A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US188995P 1995-08-04 1995-08-04
US60/001,889 1996-07-16
US08/674,180 1996-07-16
US08/674,180 US5908855A (en) 1996-07-16 1996-07-16 Compositions for treating viral infections

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US6380232B1 (en) 2000-09-26 2002-04-30 The Procter & Gamble Company Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof
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KR19990036138A (en) 1999-05-25
NZ503921A (en) 2002-03-01
CZ33798A3 (en) 1998-06-17
NZ315184A (en) 2000-05-26
AU6683396A (en) 1997-03-05
AU711966B2 (en) 1999-10-28
CA2229024A1 (en) 1997-02-20
WO1997005873A2 (en) 1997-02-20
NO980473D0 (en) 1998-02-03
IL123095A0 (en) 1998-09-24
JPH11510187A (en) 1999-09-07
TR199801739T2 (en) 1998-12-21
TR199800270T1 (en) 1998-05-21
BR9609966A (en) 1999-02-02
NO980473L (en) 1998-04-03
HUP9903420A3 (en) 2001-12-28
AR003175A1 (en) 1998-07-08
PL324904A1 (en) 1998-06-22
SK14198A3 (en) 1999-03-12
MX9800998A (en) 1998-04-30
WO1997005873A3 (en) 1997-03-27
EP0841921A2 (en) 1998-05-20
HUP9903420A2 (en) 2000-03-28

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