SK14198A3 - Use of fluconazole for inhibiting the growth of cancers - Google Patents

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

Technical field

The present invention relates to a pharmaceutical composition useful for the treatment of cancers, leukemias and tumors of humans and warm-blooded animals. The pharmaceutical composition comprises 2- (2,4-difuophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and derivatives thereof. It can be used in combination with other chemotherapeutic agents. The same pharmaceutical composition can be used to treat viral infections.

BACKGROUND OF THE INVENTION

Cancers involving leukemia are the main causes of animal and human death. The exact cause of leukemia is unknown, but the links between certain activities such as smoking or inhalation of carcinogens and the occurrence of certain types of leukemia and tumors have been shown by many researchers.

Many types of chemotherapeutic agents have been shown to be effective against cancers, leukemias, and tumors, but not all cancer and tumor cells respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism of action of these chemotherapeutic agents is not yet known.

Despite advances in cancer and leukemia, chemotherapy and bone marrow transplantation are the main therapies of that time. Chemotherapeutic steps are particularly aggressive in the fight against cancer. Such cytocidal or cytostatic agents act best on cancers in large growth factors, i. those whose cells are rapidly dividing. Until now, the hormones mainly estrogen, progesterone and some antibiotics are produced using various alkylating agents and antimetabolites to date testosterone and microorganisms, a large number of therapies available to oncologists. However, it would be highly desirable that cytotoxic agents that have specifications for leukemia, cancer and tumor cells ideally would not be effective on normal healthy cells. To date, none has been discovered, and agents that focus primarily on rapidly dividing cells are used instead.

Of course, the development of materials that would target cells of leukemia or cancer with respect to certain unambiguous specifics would be a rapid advance for them. In a preferred embodiment, it would be desirable to invent materials that would be cytotoxic to cancer or leukemia cells while having mild effects on normal cells. It is therefore an object of the present invention to provide a pharmaceutical composition that is effective in treating leukemia with little or no effect on normal blood cells.

Even more preferably, the composition of the present invention is a pharmaceutical providing carrier and the subject matter

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivative as defined herein using a method for the treatment of cancer, leukemia and tumors

The use

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives in combination with other chemotherapeutic agents that are effective in killing is a new treatment method.

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 presence of a potentiator.

SUMMARY OF THE INVENTION

A pharmaceutical composition for the treatment of mammals, and in particular warm-blooded animals and humans suffering from leukemia, comprises a pharmaceutical carrier and an effective amount of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazole-1). -yl) propan-2-ol and its derivatives.

2- (2,4-diflurophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol has the formula:

OH

NN-CH ₂ -C-CH ₂ -NN

These compositions can be used to inhibit the growth of leukemia, tumor and cancer cells in humans or animals by administering an effective amount either orally, rectally, topically or parenterally or intravenously. These compositions do not significantly affect healthy cells.

The potentiator can 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 chemotherapeutic agents. These compositions are particularly effective against influenza viruses.

A.Definícia

As used herein, the term means that the various components may be used together in the pharmaceutical composition of the invention. Accordingly, the terms consisting essentially of and consisting of include. As used herein, the term pharmaceutically acceptable component is one that is suitable for use in humans and / or animals without undesirable adverse side effects (such as toxicity, irritation and allergic responses) that are proportional to the corresponding benefit / risk ratio.

As used herein, the term safe and effective amount with respect to a number of components sufficient to obtain the desired therapeutic response without undue adverse side effects (such as toxicity, irritation and allergic responses) that is proportional to the corresponding benefit / risk ratio when used in the method. of the invention. The specific safe and effective amount will usually vary depending on such factors as are the specific conditions used for the treatment, such as the patient's physical condition, the type of mammal being treated, the duration of treatment, the type of concurrent therapy (if any) and the specific composition used. the structure of the compounds or derivatives thereof.

The term 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol derivative as used herein includes its esters and ethers, and pharmaceutically acceptable salts thereof.

As used herein, the term pharmaceutical addition salts are salts of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol with organic or inorganic acids.

Preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malate, citrates, benzoates, salicylates, ascorbates and the like.

As used herein, the term pharmaceutical carrier is a pharmaceutically acceptable solvent that suspends an agent or vehicle to deliver an anti-leukemia agent to an animal or human. The carrier may be liquid or solid and is selected according to the mode of intended administration.

As used herein, the term cancer refers to all types of cancer or neoplasm or malignant disease that attacks normal healthy cells or bone marrow that produces mammalian blood cells.

As used herein, viruses include viruses that cause diseases in warm-blooded animals including HIV, influenza, rhinovirus, herpes, and the like.

The term 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives as used herein includes its esters and ethers as well as the pharmaceutical acceptable salts.

As used herein, potentiators are materials such as triprolidine and its cis-isomer or 1H-benzimidazole-2-propanoic acid, which are used in combination with S

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives.

Potentiators can act on the immune system or increase the effectiveness of drugs.

Chemotherapeutic agents as used herein include DNA-interactive agents, antimetabolites, tubulin-interactive agents, hormonal agents, and others, such as asparaginase or hydroxyurea.

B. 2- (2,4-Difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives have the following formula:

OH

I

NN-CH ₂ -C — CH ₂ -NN

It is prepared according to the method described in US Patent 4404216 published by Richardson (1983).

Derivatives include lower carboxylic acid esters of the propanol group e.g. acetyl, propanoyl, butyl, pentyl and hexyl esters. Especially preferred are esters of carboxylic acids having less than seven carbons and most preferred are propyl esters. Arylic carboxylic acids such as e.g. salicylic acid, benzoic acid and related acids can also be used to esterify the propanol group. Alkyl ethers having less than seven carbons may also be useful derivatives.

Pharmaceutically acceptable addition salts are the salts of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives with organic and inorganic acids. Preferred additional acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formats, tartrates, maleates, malate, citrates, benzoates, salicylates, ascorbates and the like.

These compounds are parts of several kinds of fungicide classes with the following formula:

OH

Y 1 -N-CH ₂ -C-CH ₂ -NNY ₂

M * M wherein R is preferably a substituted alkyl, cycloalkyl, aryl (2,4-dichlorophenyl) or aralkyl group and Y and Y are = CH- or = N- and salts or metal complexes and ethers or esters thereof. Although these materials are active against fungal diseases, some have been found to be teratogenic.

Thus, these materials which exhibit these properties are not used herein.

C. Chemotherapeutic agents

Chemotherapeutic agents are generally grouped as DNA-interactive agents, antimetabolites, tubulin-interactive agents, hormonal agents and others such as asparaginase and hydroxyurea. Each of the groups of chemotherapeutic agents may be further subdivided by type of activity or compound. Chemotherapeutic agents used in combination with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol) -1-yl) propan-2-ol and derivatives thereof in the present invention include members all of these groups. For a more detailed description of the chemotherapeutic agents and their mode of administration, the reference incorporated herein by Dorr et al., Cancer Chemotherapy Handbook, second edition, pages 15-34, (Appleton and Lange, Connecticut, 1994) can be compared.

DNA-interactive agents include alkylating agents such as cisplatin, cyclophosphamide, altretamine, DNA break-chain agents such as bleomycin, intercalating topoisomerase II inhibitors (such as dactinomycin and doxorubicin), non-intercalating topoisomerase II inhibitors, and tenososidase II such as etosoposidase II with internal groove binder Plcamydin.

Alkylating agents form covalent chemical adducts with cellular DNA, RNA and protein molecules, and with smaller amino acids, glutathione, and similar chemical compounds. These alkylating agents typically react with a nucleophilic atom in a cellular component such as an aminocarboxyl, phosphate, sulfhydryl 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, mechloretamine, melphalon and uracil mustard.

Aziridines such as thiotepa.

Methanesulfonate esters such as busulfan.

Nitrosureas such as carmustine, lomustine and streptozocin.

Platinum complexes such as cisplatin and carboplatin. A bioreductive alkylator such as e.g. mitomycin, procarbazine, dacarbazine, and altretamine.

DNA break-chain agents including bleomycin.

DNA topoisomerase inhibitors including the following:

Intercalators such as amsacrine, dactinomycin, doxorubicin, idarubicin and mitoxantrone. Non-intercalators such as etoposide and teniposide. DNA with internal groove binder Plcamydin.

Antimetabolites interfere with the production of nucleic acids by one or the other of the two main mechanisms. Some drugs inhibit the production of deoxyribonucleoside triphosphates, which are direct precursors for DNA synthesis and thereby inhibit DNA replication. Some of the compounds are sufficiently capable of being substituted by anabolic nucleotide pathways such as purines and pyrimidines. These analogs can then be substituted for DNA and RNA instead of their normal purlins. Useful antimetabolites include:

Folate antagonists such as e.g. methotrexate and trimetrexate. Pyrimidine antagonists such as fluorouracil, fluorodeoxyuridine, CB3717, azacitidine, cytarabine and floxuridine. Purine antagonists include mercaptopurine, 6-thioguanine, fludarabine and pentostatin. Modified sugar analogs include cytrabin and fludarabine. Ribonucleotide reductase inhibitors include hydroxyurea. Tubulin interactive agents react by binding to specific sites of tubulin of a protein that polymerizes and forms cellular microtubules. Microtubules are critical units of cellular structures. When interactive agents bind to a protein, the cell cannot form microtubules. Tubulin interactive agents include both the alkaloids vinblastine and vincristine and paclitaxel. Hormonal agents are also useful in the treatment of cancers and tumors. They are used in hormone-susceptible tumors and are usually derived from natural sources. These hormonal agents include: estrogens, conjugated estrogens and ethynyl estradiol and diethylstilbesterol, chlorotranisene and idenestrol. Progestins such as hydroxyprogesterone capronate, medroxyprogesterone and megestrol. Androgens such as e.g. testosterone, testosterone propionate, fluoxymesterone and methyltestosterone.

Adrenal corticosteroids are derived from natural cortisol and / or hydrocortisone. They are used because of their anti-inflammatory ability and also the ability of some of them to inhibit mitotic division and to stop DNA synthesis. These compounds include prednisone, dexamethasone, methylprednisolone and prednisolone. Leutinizing hormones that release hormone agents or gonadotropin triggering hormone antagonists are preferably used in the treatment of prostate cancer. These include leuprolide acetates and goserelin acetates. These prevent steroid biosynthesis in tests.

Antihormonal agents include: antiestrogenic agents such as e.g. tamosifen, antiandrogenic agents such as e.g. flutamide and antiadrenal agents such as e.g. mitotane and aminoglutethimide. The hydroxyurea appears to act preferentially by inhibiting the enzyme ribonucleotide reductase.

Asparaginase is an enzyme that converts asparagine to aspartic acid and thus blocks protein synthesis in the tumor.

Taxol is a preferred chemotherapeutic agent.

D. Potentiators

The potentiators can be any material that improves or increases the effectiveness of the pharmaceutical composition. They include immunosuppressors or materials that act on the immune system. One such potentiator is triprolidine and its cis-isomer, which is used in combination with chemotherapeutic agents and

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives. Triprolidine is described in US 5114951, 1992.

Another potentiator is procadozal, 1H-benzimidazole-2-propanoic acid (beta- (2-benzimidazole) propionic acid and

2- (2-carboxyethyl) benzimidazole, propazole). Procodazole is a non-specific active immunoprotective 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 either alone in the treatment of cancers, tumors, leukemia and viral infections or together with chemotherapeutic agents.

Propionic acid and salts and esters thereof may also be used in combination with the pharmaceutical compositions claimed herein.

Antioxidant vitamins such as vitamins A, C and E and beta-carotene may be added to these compositions.

E. Dosage

Any suitable dosage may be introduced by the method of the invention. The type of disease (cancer, leukemia or virus), the compound, the carrier and the amount will vary widely depending on the species of warm-blooded animal or human, their body weight and the type of tumor being treated. The dosage is usually between about 1 milligram (mg) per kilogram (kg) body weight and about 1000 mg per kg body weight, suitable for either 2- (2,4-difluorophenyl) -1,3-bis (1H-1). (2,4-triazol-1-yl) propan-2-ol and its derivatives or chemotherapeutic agents. A dosage range of about 15 mg to about 800 mg / kg body weight is predominantly used. The dosage in humans is generally lower than in small warm-blooded mammals such as e.g. in mice. The dosage unit may also comprise the individual components or mixtures thereof with other cancer inhibiting compounds or compounds. The dosage unit may also contain diluents, fillers, carriers, liposomes, and the like. The unit may be in solid or gel form such as in pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, introvenous injection or parenteral administration or injection into or around the bone marrow. The extent and ratio of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) ropan-2-ol and its derivative to the chemotherapeutic agent will depend on the type of cancer or tumors that are treated on a single chemotherapeutic agent.

F. Delivery forms

The chemotherapeutic agents of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives and preferably potentiators are admixed with a pharmaceutically suitable carrier. The carrier may be solid or liquid and its type is usually selected based on the type of administration application being used. The active agent may be co-administered in the form of a tablet or capsule, liposome as an agglomerated powder, or in liquid form. Examples of suitable solid carriers are lactose, sucrose, gelatin and agar. Capsules or tablets can be readily formed and can be made to be swallowed or chewed. Other solid forms include granules and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, coloring agents, fragrances, flow-inducing agents, and emollients. Examples of suitable dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols, or other organic solvents that include esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from sparkling granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners and emollients. Oral dosage forms preferably contain fragrance agents and coloring agents. Parenteral and intravenous forms could also include minerals and other materials that render them compatible with the type of injection or selected delivery system. Specific examples of pharmaceutically acceptable carriers and excipients that could be used to form oral dosage forms for oral dosage in accordance with the present invention are described in U.S. Pat. 3903297 by Robert issued September 2, 1975. Techniques and compositions for making dosage forms used in accordance with this invention are described in the following references: 7 Modern Pharmaceutics, Chapter 9 and 10 (Banker and Rhodes, Editors, 1979), Lieberman et al., (Pharmaceutical Dosage Forms, 1981) and Ansel , (Introduction to Pharmaceutical Dosage Forms 2nd Edition, 1976).

G. Method of treatment

The method of treatment may be any suitable method that is effective for treating the particular types of cancer or tumors being treated. The treatment may be oral, rectal, topical, parenteral or intravenous, or by injection into a tumor or cancer. The mode of administration of the effective amount also varies depending on the tumor being treated. It is known that parenteral treatment by intravenous, subcutaneous or intramuscular administration of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives which are formed with a suitable carrier, an additive compound or compounds inhibiting cancer, or a diluent to facilitate administration will be the preferred method of administering the compounds to warm-blooded animals.

A preferred method of treating a viral infection is to administer procadazole or propiconazole.

In addition to the use of chemotherapeutic agents and potentiators, 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives may be combined with fungicides , herbicides or other antiviral agents. Preferred fungicides and herbicides include carbendazim, fluoconazole, glyphosate, benomyl, glyphose and propicodazole.

When pharmaceutical compositions are used to treat viral infections, they may be combined with other antiviral agents.

DETAILED DESCRIPTION OF THE INVENTION

1. anti-viral evaluations using human influenza virus.

Female CDs (Charles River Breeding Laboratories, Portage, MI) mice 5 to 7 weeks of age at the time of intake are used. Mice are approximately 6 to 9 weeks old and weigh 20 to 28 g at the start of the test. All mice used in the study do not differ by more than 10 days of age. Mice are housed six per cage with bedding. Mice are fed ad libitum with rodent diet 5002 (PMI, St. Louis Missouri). Fresh water is also supplied to mice at will.

Human influenza virus, strain AT2 / Taiwan / 1/64 is used to elicit a response in mice. The organism is stored at a temperature of about minus 70 ° C. Prior to the infection-induced reaction, the frozen ampoule is thawed and diluted to a preferred concentration in buffered saline. Mice are anesthetized with Halothane and the viral challenge is administered intravenously in a volume of 50 microliters.

The test products are administered in concentration and volume as shown below. On days 1 to 14, a group of ten mice receives the test articles by oral irrigation. A salt control group of animals (ten mice) received a comparable volume of saline to be compared to a group of mice that were tested with dosed products. The dosage of the test products is stable at approximately 24 hours. intervals. At day 0 approximately 4 hours after the second dosing of test products or saline, all mice are examined for response intravenously with an injectable dose of virus, which is expected to produce approximately 90% mortality. The animals are observed daily for 21 days after inducing an infectious reaction to mortality or dying.

Tested material

Dose (mg / kg)

Mortality Percentage (%)

fluconazole

fluconazole

Saline

amantadine

350

700

100

2. Human in vitro tumor colony forming the test units

Patient solid tumors are chopped into 2-5 mm fragments and immediately placed in McCoys Medium 5A together with 10% hot inactivated penicillin / streptomycin. mechanically divided calf serum along with 1%. Within 4 hours, these solid tumors are scissors pushed through No. 100 stainless steel mesh using calibrated needles and then washed with McCoy's medium as described above. Abdominal, pleural, pericardial and bone marrow are obtained by standard techniques. The liquids and bone marrow are placed in a sterile container containing ten units of preservative, heparin-free, per ml of malignant fluid or bone marrow. After centrifugation at 150 rpm for 10 minutes, the cells obtained are washed with McCoy's medium together with 10% hot inactivated calf serum. The viability of the cell suspensions is determined on a trypan blue hemocytometer.

Cells to be cloned are suspended in 0.3% CMRL-enriched agar supplemented with 15% hot inactivated calf serum, penicillin (100 units / ml), streptomycin (2mg / ml), glutamine (2mM), insulin (3 units / ml). ml), asparagine (0.6 mg / ml) and HEPES (2 mM). For a continuous exposure test, each compound is delivered to the above mixture. Cells are plated in 35 mm Petri dishes in the upper agar layer below the surface to prevent fibroblast growth. Three Petri dishes are ready for every aspect of the data. The plates are placed in an incubator at 35 ° C and selected for 14 days to calculate the number of colonies in each plate. The number of colonies (defined as 50 cells) settled in three compound treated dishes is compared to the number of colonies settled in three control dishes, and the percentage of colonies that survive at compound concentration can be determined. Three positive control plates are used to determine the survival rate. As a positive control, 200 µg / ml orthosodium vanadium is used. If more than 30% of the positive control columns are present compared to the untreated control, the test is evaluated.

At concentrations of 0.5 and 5.0 µg / ml in a single test dose of flucanozole, they were not effective (0/3 and 0/13, respectively) against tumors in this assay. At a concentration of 50 µg / ml in continuous challenge, flucanosole was effective against cancers of the lung melanoma (non-small cell) and especially the ovaries. Of the total 4/13, more than 50% survived.

Claims (5)

PATENT What is claimed is: 1. A pharmaceutical and viral composition for the treatment of cancer and tumors of infections, comprising: a 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. A pharmaceutical composition characterized in that. according to claim 1, further comprising a safe and effective amount of a chemotherapeutic agent. according to claim 1 or 2, characterized in that the chemotherapeutic agents containing DNA-interactive tubulin-interactive agents, 3. The pharmaceutical composition of the agent is selected from the group of agents, antimetabolites. hormonal agents, asparaginase or hydroxyurea. Pharmaceutical composition according to claims 1, 2 or 3, characterized in that the chemotherapeutic agent is selected from the group consisting of asparaginase, hydroxyurea, cisplatin, cyclophosphamide, altretamine, bleomycin, dactinomycin, doxorubicin, etoposide, teniposide and the composition according to claims 1, 2 , 3 or 4, characterized in that the chemotherapeutic agent is selected from the group consisting of taxol, fluorouraci I, fluorodeoxyuridine, CB3717, azacitidine, cytarabine, fluorodine, not tophrin, 6-thioguanine, fludarabine , pcntostatin, cyctrabine and fludarabine. Pharmaceutical composition according to claims 1, 2, 3, 4 or 5, characterized in that it comprises a potentiator. plcamyd í n. 5. The pharmaceutical agent is me tot rexate,