MXPA98000998A - Use of fluconazole to inhibit the growth of cance - Google Patents

Abstract

A pharmaceutical composition for the treatment of cancers or tumors in mammals comprising 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2 is described. 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-1-yl) propan-2-ol and its derivatives as it may be the enhancers. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives can also be used to treat viral infections, either alone or in combination with other antiviral agents or with a potentiated

Description

FLUOROZOL U.80 FOR INHIBITING CANCER GROWTH FIELD OF THE INVENTION This invention is a pharmaceutical composition that is useful for the treatment of cancers and tumors, particularly in humans and warm blooded animals containing 2- (2,4-difluorophenyl) - 1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives. It can be used in combination with other chemotherapeutic agents and enhancers. The same composition can be used to treat viral infections.

BACKGROUND OF THE INVENTION Cancers, including leukemia, are the main cause of death in animals and humans. The exact cause of the leukemia is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of leukemia and tumors have been shown by a number of researchers. Many types of chemotherapeutic agents have been shown to be effective against cancers, tumors and leukemia, but not all types of cancer and tumor cells respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for action is not always known P569 these chemotherapeutic agents. Despite advances in the field of cancer and leukemia treatments, the main therapies to date are radiation and chemotherapy and bone marrow transplants. The chemotherapeutic approaches are to fight cancers that are particularly aggressive. These cytocidal or cytostatic agents work best in cancers with large growth factors, ie those whose cells divide rapidly. To date, hormones, particularly estrogen, progesterone, and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the majority of the therapies available in oncologists. Ideally cytotoxic agents that have specificity for leukemia, cancer and tumor cells, while not affecting normal cells, will be extremely desirable. Unfortunately, none has been found and instead agents have been used which especially target rapidly dividing cells (both diseased and normal). Clearly, it would be an advancement in the development of materials that target cancer or leukemia cells, due to some unique specificity for them. alternatively, materials that were P569 cytotoxic to leukemia or cancer cells, while exerting mild or moderate effects on normal cells. Therefore, it is an object of this invention to provide a pharmaceutical composition that is effective in the treatment of leukemia with mild or no effects on normal blood cells. More specifically, it is an object of this invention to provide a composition comprising a pharmaceutical carrier and a 2- (2,4-difluorophenyl) -1,3-bis (lH-1, 2,4-triazol-1-yl) ) propan-2-ol and its derivatives as defined herein along with a method for treating cancer, leukemia and tumors. The use of 2- (2,4-difluorophenyl) -l, 3-bis (lH-1, 2,4-triazol-1-yl) propan-2-ol and its derivatives in combination with other chemotherapeutic agents that are effective In the destruction of the tumor, it is a new method of treatment. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives can also be used to treat viral infections either alone or in the presence of an enhancer.

SUMMARY OF THE INVENTION A pharmaceutical composition for the treatment of mammals, and in particular, warm-blooded animals and humans, which are affected by the leukemia that P5b9 comprises a pharmaceutical carrier and an effective amount of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol (Fluconazole *) and Their derivatives. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol has the formula: These compositions can be used to inhibit the growth of leukemia, tumors and cancer cells, in humans or animals by the administration of an effective amount either orally, rectally, topically or parenterally or intravenously. These compositions do not significantly affect healthy cells. The enhancers can also be used in combination with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives as they can be the chemotherapeutic agents. These compositions are particularly effective against the influenza virus.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions: As used herein, the term "comprising" means several components that can be used together in the pharmaceutical composition of this invention. Accordingly, the terms "consisting essentially of", "consisting of" are incorporated into the term comprising. As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without the adverse, undesirable side effects (such as toxicity, irritation, or allergic response) corresponding with a favorable ratio. of benefit / risk. As used herein, the term "safe and effective amount" refers to the amount of a component that is sufficient to produce a desirable therapeutic response without side effects, adverse, undesirable, such as allergic toxicity, irritation or response) corresponding with a reasonable benefit / risk ratio when used in the manner of this invention. The specific "safe and effective amount" will obviously vary with factors such as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of the concurrent therapy (if any), and the specific formulations used and the structure of the compounds or their derivatives. As used herein, a "derivative of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol" includes its esters and ethers and their pharmaceutically acceptable salts. As used herein, a "pharmaceutical addition salt" is that of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan- 2-ol with an organic and inorganic acid. Preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, dispersing agent or vehicle for distributing the anti-leukemia agent to the animal or human. The carrier can be liquid or solid selected in the planned manner of administration in mind. As used herein, "cancer" or "leukemia" refers to all types of cancers or neoplasm or malignant disease that attacks healthy, normal blood cells or the bone marrow that produces the blood cells found in the mammals.

As used herein, "virus" includes viruses that cause disease in warm-blooded animals including HIV, influenza, rhinovirus, herpes, and the like. As used herein, "2- (2,4-difluorophenyl) -1,3-bis (1H-1, 2, -triazol-1-yl) propan-2-ol and its derivatives" includes esters and ethers as well as the acid addition salts. As used herein "enhancers" are materials such as triprolidine and its cis-isomer or lH-benzimidazole acid, which are used in combination with 2- (2,4-difluorophenyl) -1,3-bis (1H-) 1, 2, 4-triazol-1-yl) propan-2-ol and its derivatives. The enhancers can affect the immune system or improve the effectiveness of the drugs. As used herein, "chemotherapeutic agents" includes agents interactive with DNA, anti-metabolites, Interactive Agents with Tubulin, Hormonal agents and others, such as Asparaginase or hydroxyurea. b, 2- (2,4-difluorophenyl) -l, 3-bis (1H-1, 2,4-triazol-1-yl) propan-2-ol x its derivatives 2- (2,4-difluorophenyl) -1, 3 Bis (1H-1, 2,4-triazol-1-yl) propan-2-ol and its derivatives has the following formula: It is prepared according to the method described in the North American Patent No. 4,404,216 issued Richardson (1983). The derivatives include the lower esters of carboxylic acids of the propanol group, for example, acetyl, propanoyl, butyl, pentyl and hexyl esters. Particularly preferred are esters of carboxylic acids having less than seven carbon atoms, and more preferably propyl esters. The aryl carboxylic acids such as salicylic acid, benzoic acid, and related acids can also be used to esterify the propanol group. Alkyl esters having less than seven carbon atoms are also useful derivatives. Pharmaceutical addition salts are salts of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol with an organic or inorganic acid. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formations, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and the like. These compounds are part of a more generic class of fungicides with the formula: wherein R1 is an optionally substituted alkyl group, cycloalkyl, aryl (2,4-dichlorophenyl) or aralkyl and Y1 and Y2 are = CH- or = N-; and metal salts and complexes and ether or esters thereof. While these materials are active against fungal diseases, some have been found to be teratogenic. Therefore, those materials that exhibit this property are not useful herein. c. chemotherapeutic agents Chemotherapeutic agents are generally grouped as DNA-interactive agents, antimetabolites, Tubulin-interactive agents, hormonal agents and others such as Asparaginase or hydroxyurea. Each of these groups of chemotherapeutic agents can be further divided by the type of activity or compound. The chemotherapeutic agents used in combination with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives include the members of all These groups. For a detailed discussion of the chemotherapeutic agents and their method of administration, see Dorr, et al, Cancer Chemotherapy Handbook, 2nd Edition, pages 15-34, Appleton & Lange (Connecticut, 1994) incorporated herein by reference. Interacting agents with DNA include alkylating agents, for example, Cisplatin, Cyclophosphamide, Altretamine; the cleaving agents of the DNA strand, such as Bleomycin; inhibitors of topoisomerase II intercalation, for example, Dactinomycin and Doxorubicin); the topoisomerase II inhibitors do not interleave, such as Etoposide and Teniposide; and Plcamidine a binder of the minor DNA groove. Alkylating agents form covalent chemical adducts with DNA, RNA, and molecular proteins and with smaller amino acids, glutathione and similar chemicals. In general, these alkylating agents react with a nucleophilic atom in a general constituent, such as an amino, carboxyl, phosphate, hydrogen sulfide group, in nucleic acids, proteins, amino acids, or glutathione. The mechanism and role of these alkylating agents in cancer therapy is not well understood. Typical alkylating agents include: Nitrogen mustards, such as Chlorambucil, Cyclophosphamide, Isofamide, Meclorotamine, Melpalano, Uracila mustard; Aziridine such as Tiotepa; methanesulfonate esters such as Busulfan; Nitroso-ureas, such as Carmustine, The ustin, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive reduction agents, such as Mitomycin and Procarbazine, Dacarbazine and Altretamine; the cleaving agents of the DNA strand include Bleomycin; inhibitors of DNA topoisomerase II include the following: intercalators, such as A sacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; non-intercalary, such as Etoposido and Teniposide The binder of the minor groove of the DNA is Plicamycin Anti-metabolites interfere with the production of nucleic acids by one or the other of the P569 two main mechanisms. Some of these drugs inhibit the production of deoxyribonucleoside triphosphates, which are the immediate precursors for DNA synthesis, thereby inhibiting DNA replication. Some of the compounds are sufficiently similar to purines or pyrimidines to be able to substitute them in the routes of the anabolic nucleotides. Then, these analogs can be replaced in DNA and RNA instead of their normal counterparts. Anti-metabolites useful herein include: folate antagonists such as metrotrexate and trimetrexate, pyrimidine antagonists, such as Flurouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine and Floxuridine, purine antagonists include Mercaptopurine, 6-Thioguanine, Fludarabine , Pentostatin; Modified analogs of sugar include Cyctrabin, Fludarabine; The inhibitors of the ribonucleotide reductase include hydroxyurea. Interacting agents with tubulin act by binding to specific sites in tubulin, a protein that polymerizes to form cellular microtubules.

The microtubules are units of critical cellular structure. When the interactive agents join the P569 protein, the cell can not form microtubules. Interacting agents with tubulin include vincristine and vinblastine, both alkaloids and Paclitaxel. Hormonal agents are also useful in the treatment of cancers and tumors. They are used in highly susceptible tumors and are usually derived from natural sources. These include: estrogens, conjugated estrogens and Etinil Estradiol and Diethylstilbesterol, Clortrianisen and Idenestrol; progestins such as caproate Hydroxyprogesterone, Medroxyprogesterone and Megestro; androgen such, testosterone, testosterone propionate; fluoxi esterone, methyltestosterone; Adrenal corticosteroids are derived from natural adrenal cortisol or hydrocortisone. They are used because of their anti-inflammatory benefits as well as the ability of some to inhibit mitotic and halt conversions of DNA synthesis. These compounds include Prednisone, Dexamethasone, Methylprednisolone and Prednisolone. Leutinizing hormone releasing hormone agents or gonadotropin-releasing hormone antagonists are used primarily for the treatment of prostate cancer. These include leuprolide acetate and goserelin acetate. They prevent the P569 biosynthesis of steroids in the testicles. Antihormonal antigens include: antiestrogenic agents such as Tamosifene. antidrogenic agents such as Flutamide; and antiadrenales agents such as Mitotano and Aminoglutethimide. Hydroxyurea appears to act primarily through the inhibition of the ribonucleotide reductase enzyme. Asparaginase is an enzyme that converts asparagine to non-functional aspartic acid and thus blocks the synthesis of the protein in the tumor. Taxol is the preferred chemotherapeutic agent. d. enhancers "Enhancers" can be any material that improves or increases the efficiency of the pharmaceutical composition or acts as an immunosuppressant. One such enhancer is triprolidine and its cis-isomer which are used in combination with the chemotherapeutic agents and 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazole-1). -il) propan-2-ol and its derivatives. Triprolidine is described in U.S. Patent 5,114,951 (1992). Another potentiator is procodazole, lH-benzyl idazole- P569 2-Propanoic; [ß- (2-benzimidazole) propionic acid; and 2- (2-carboxyethyl) benzimidazole; propazole] procodazole is an immunoprotective, active, non-specific agent against viral and bacterial infections and can be used with the compositions claimed herein. It is effective with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives alone in the treatment of cancers, tumors, leukemia and viral infections or in combination with chemotherapeutic agents. Propionic acid and its salts and esters can also be used in composition with those claimed herein. Antioxidant vitamins such as vitamins A, C and E and beta-carotene can be added to these compositions. and. Dosage Any suitable dosage can be given in the method of the invention. The type of compound and the carrier and the amount will vary widely depending on the species of warm or human blood animal, body weight and the type of tumor cancer or viral infection being treated. In general, it is suitable for either 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives or the chemotherapeutic agent a PF > 69 dosage of between about 1 milligrams (mg) per kilogram (kg) of body weight and about 8000 mg per kg of body weight. Preferably from 15 mg to about 5000 mg / kg of body weight is used. In general, the dose in man is lower than for small warm-blooded animals such as mice. A dosage unit may comprise a single compound or mixtures thereof with other compounds or other individual cancer compounds. The dosage unit may also comprise diluents, extenders, carriers, liposomes and the like, The unit may be in solid or gel form such as pills, tablets or capsules and the like or in a liquid form suitable for oral, rectal, topical administration , intravenous or parenteral injection or injection in or around the bone marrow. The range and the ratio of 2- (2,4-difluorophenyl) -1,3-bis (1H-1, 2,4-triazol-1-yl) propan-2-ol and its derivatives to the chemotherapeutic agent will depend on the type of cancer or tumor in question and the particular chemotherapeutic agent.

F. Dosage distribution forms The chemotherapeutic agents, 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives and, optionally, the enhancers are typically mixed with a pharmaceutically carrier P569 acceptable. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration used. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily formulated and can be easily processed for swallowing or chewing; other solid forms include granules, and bulk powders. The tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in pharmaceutically acceptable water, fat and oils, alcohols and other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, dispersing agents, diluents, sweeteners, thickeners and melting agents. The oral dosage forms contain P569 optionally flavors and coloring agents. Parenteral and intravenous forms will also include minerals and other materials to make them compatible with the type of injection system or distribution chosen. Specific examples of the pharmaceutically acceptable carriers and excipients that can be used to formulate the oral dosage forms for the present invention are described in the North American Patent No. 3, 903,297 of Robert, issued September 2, 1975. The techniques and compositions for making the dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker &; Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosacre Forms 2nd Edition (1976). q. Treatment method The method of treatment can be any suitable method that is effective in the treatment of the particular type of cancer or tumor being treated. The treatment can be oral, rectal, topical, parenteral or intravenous administration or by injection into the tumor or cancer. The method to apply an effective amount also varies depending on the leukemia, cancer tumor or virus that is P569 try. It is believed that parenteral treatment by intravenous, subcutaneous or intramuscular application of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives, formulated with an appropriate carrier, additional cancer inhibitor compound or compounds or diluents to facilitate application will be the preferred method of administration of the compounds to warm-blooded animals. In addition to the use of the chemotherapeutic agents and the enhancers, 2- (2,4-difluorophenyl) -1,3-bis (1H-1, 2,4-triazol-1-yl) propan-2-ol and its derivatives are It can combine with fungicides, herbicides or other antiviral agents. Preferred herbicides and fungicides include carbendazim, fluoconazole, benoyl, glyphosate and propicodazole. When the pharmaceutical compositions are used for the treatment of viral infection, they can be combined with other antiviral agents. antiviral evaluation with human influenza virus CD (Charles Riber Breeding mice are used Labotatories, Portage, MI) females 5 to 7 years old at the time of reception. The mice are approximately 6 to 9 weeks old and weigh approximately 20 to 28 grams at the time of onset of P569 the test. All the mice used in the study did not vary in age for more than 10 days. The mice are housed 6 per cage with straw bed. The mice are fed at will with a diet of rodents 5002 (PMI, St. Louis Missouri). Fresh water is supplied to the mice at will. The AT2 / Taiwan / l / 64 strain of human influenza virus is used to stimulate the mice. The organism is stored at approximately -70 ° C. Before the infectious stimulation, thaw and dilute a concentrated, frozen dilution bottle, at the appropriate concentration in buffered saline. The mice are anesthetized with Halothane and the dose of virus stimulation is administered intranasally in a volume of 50 microliters. The test materials are administered at the concentration and volume as provided below. On days 1 to 14, 10 mice per group received the test items by oral wash. Control animals with saline (10) received a comparable volume of saline compared to mice dosed with the test article. The dosing of the test article is achieved at approximately 24 hour intervals. On day 0 approximately 4 hours after the second dosage P569 of the test articles or saline, all mice are stimulated intranasally with an ineffective dose of virus calculated to produce approximately 90% lethality. It is observed in the animals daily for 21 days after the infectious stimulation for mortality or moribund state.

TEST MATERIAL DOSAGE PERCENT OF (mg / kg) MORTALITY Fluconazole 350 0 Floconazole 700 30% Saline Solution - 100% Amantadine 75 0% PROOF OF THE TRAINING UNITS OF COLUMNS OF HUMAN TUMORS, IN VITRO. Solid tumors removed from patients were excised in fragments of 2 to 5 mm and were immediately placed in the medium of McCoy 5A plus 10% calf serum nionate, inactivated with heat, plus 1% penicillin / streptomycin. In the space of 4 hours, these solid tumors were mechanically dissociated with scissors, forced through a No. 100 stainless steel mesh, through 25 gauge needles, and then washed with McCoy's medium as described previously. The fluids P569 ascitic, plural, pericardial, and the bone marrow are obtained by normal techniques. The fluid or marrow is placed in sterile containers containing 10 units of preservative-free heparin per me. of fluid or malignant marrow. After centrifugation of 150 x g for 10 minutes, the cells are harvested and washed by McCoy's medium plus 10% calf serum, inactivated with heat. The viability of the cell suspensions in a hemocytomer with trypan blue is determined. The cells to be cloned are dispersed on 0.3% agar in enriched CMRL 1066, supplemented with 15% horse serum, inactivated with heat, penicillin (100 units / ml), streptomycin (2mg / ml), glutamine (2mM) ), insulin (3 units / ml) asparagine (0.6 mg / ml), and HEPES buffer (2mM). For the continuous exposure test, each compound is added to the previous mixture. The cells are placed in 35 mm petri dishes in an upper agar layer on an upper agar layer on an underlying agar layer to prevent the growth of the fibroblasts. Three plates are prepared for each data point. Plates are placed in an incubator at 37 ° C and removed at day 14 for counting the number of colonies on each plate. The number of colonies (defined as 50 cells) formed in the three plates treated with the compound compares the number of colonies formed in the P569 3 control plates, and the percent of colonies that survive the concentration of the compound can be estimated. 3 positive control plates are used to determine the survival rate. Orthodium vanadate at 200 μg / ml is used as the positive control. If there is less than 30% of colonies in the positive control, when compared to the untreated control, the test is evaluated. At the concentration of 0.5 and 5.0 μl / ml in a single dose experiment, Fluconazole was not effective (0/1) against the tumors in this test. At a concentration of 50.0 μm / ml in a continuous exposure experiment, Fluconazole was effective against cancers of the colon, lung, non-small areas and ovary. In all, 4/13 had less or equal 50% survival.

P569

Claims (9)

1. CLAIMS I 1. A pharmaceutical composition for treating cancer and tumors, and viral infections, comprising a pharmaceutical carrier and from 1 mg / kg to approximately 800 mg / kg per body weight of a member selected from the group consisting of 2- ( 2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives and mixtures thereof and a pharmaceutically acceptable carrier.
2. 2. A pharmaceutical composition according to claim 1 further comprising a safe and effective amount and a chemotherapeutic agent.
3. 3. A pharmaceutical composition according to claim 1 or 2, wherein the chemotherapeutic agent is selected from the group consisting of DNA-interactive agents, Anti-metabolites, Interactive agents with Tubulin, Hormone Agents, Asparaginase or hydroxyurea.
4. 4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the chemotherapeutic agent is selected from the group consisting of Asparaginase, Hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine, Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide and Plcamidine.
5. 5. A pharmaceutical composition according to claim 1, 2 or 3, wherein the agent P569 chemotherapeutic is selected from the group consisting of Taxol, Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cictrabine, and Fludarabine. 6. A pharmaceutical composition according to claim 1, 2, 3, 4 or 5, further comprising an enhancer. 7. A method for treating cancer or tumors in warm-blooded animals, comprising administering a safe and effective amount of a composition according to claims 1, 2, 3, 4, 5 or 6. 8. A method for treating viral infections in warm-blooded animals comprising administering a composition according to claims 1, 2, 3, 4, 5 or
6. 6. The method according to claim 7 or 8, wherein the 2- (2,4-difluorophenyl) -1, 3-bis (lH-1,2,4-triazol-1-yl) propan-2-ol and its derivatives are administered orally or enterically, intravenously, peritoneally or by injection into the tumor. P569