KR19990036138A - Use of fluconazole to inhibit cancer growth - Google Patents

Abstract

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol for the treatment of cancer or tumors in mammals and Pharmaceutical compositions containing the derivatives thereof are disclosed. Chemotherapy agents are synergists with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and derivatives thereof. Can be used together. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and derivatives thereof may also be used alone or in other antiviral agents. Or in combination with synergistic factors.

Description

Use of fluconazole to inhibit cancer growth

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl, particularly useful for the treatment of cancer and tumors in humans and warm-blooded animals ) Propan-2-ol and its derivatives. It can be used in combination with other chemotherapy agents and synergists. The same composition can be used for the treatment of viral infections.

Cancer is the leading cause of death in animals and humans. The exact cause of cancer is unknown, but the association between certain actions, such as smoking or exposure to carcinogens, and the incidence of certain types of cancer and tumors has been confirmed by many researchers.

Many types of chemotherapeutic agents are known to be effective against cancer and tumor cells, but not all types of cancer and tumors respond to the chemotherapeutic agents. Unfortunately, many of these chemotherapy agents also destroy normal cells. The exact mechanism of action of these chemotherapy agents is not always known.

Despite advances in the field of cancer treatment, the main treatment methods are still surgical, radiation and chemotherapy treatments. Chemotherapy is to attack metastasized cancer, or particularly active cancer. Such cell breakers or cell proliferation inhibitors work best for cancers with huge growth factors, ie cancers in which cells divide rapidly. To date, hormones, in particular estrogens, progesterone and testosterone, and some antibiotics, alkylating agents, and metabolic antagonists made by various microorganisms form most of the treatments available for oncology. Ideally, cytotoxic agents that have specificity for leukemia, cancer, and tumor cells but do not affect normal cells are highly desirable. Unfortunately, no alternative reagents have been found, particularly for cells that divide rapidly (tumor and normal cells).

Clearly, due to some unique specificities for cancer or leukemia cells of interest, the development of materials targeting such cells has made great progress. Alternatively, a substance that is cytotoxic to tumor cells and exhibits a less irritating effect on normal cells would be desirable. Therefore, it is an object of the present invention to provide a pharmaceutical composition that is effective in treating leukemia and exhibits little or no effect on normal cells.

More specifically, an object of the present invention is 2- (2,4-difluorophenyl) -1,3- as defined herein in parallel with a pharmaceutical carrier and a method for treating cancer, leukemia, tumors. A composition containing bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives is provided.

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propane-2 in combination with other chemotherapeutic agents effective for destroying tumors The use of -ols and derivatives thereof is a novel method of treatment. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives may also be used alone or as synergists of In the presence, it can be used for the treatment of viral tolerance.

Summary of the Invention

Pharmaceutical carriers and effective amounts of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol (Fluconazole, tradename) And pharmaceutical compositions for the treatment of mammals, in particular warm-blooded animals and humans, having leukemia containing the derivatives thereof. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol has the formula:

The composition can be used to inhibit the growth of leukemia, tumors and cancer cells in humans or animals by administration of an effective amount of oral, rectal, topical or parenteral or intravenous. The composition does not have a significant effect on healthy cells.

Synergists may also, like chemotherapeutic agents, include 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and It can be used in combination with the derivative.

The composition is particularly effective against influenza viruses.

A. Definition:

As used herein, "comprising" means a number of components that can be used together in a pharmaceutical composition of the present invention. Thus, "consisting essentially of" and "consisting of" are included in "comprising of" above.

As used herein, "pharmaceutically acceptable" component means a component suitable for use in humans and / or animals, without excessive adverse side effects (eg, toxicity, irritation and allergic reactions) corresponding to a moderate profitability / risk ratio.

As used herein, "stable amount and effective amount", when used in the methods of the present invention, provides a desired therapeutic response without excessive adverse side effects (e.g. toxic, irritant and allergic reactions) corresponding to a moderate profitability / risk ratio. It means a sufficient amount of ingredients. The particular “stable amount and effective amount” clearly refers to the particular condition to be treated, the physical condition of the patient, the type of mammal to be treated, the duration of treatment, the nature of the treatment involved (if any), and the particular agent used and It will vary depending on the structure of the compound or derivative thereof.

As used herein, “2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol derivative” is an ester thereof Ethers thereof and pharmaceutically acceptable salts thereof.

"Pharmaceutical addition salt" as used herein refers to 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol And salts of inorganic or organic acids. Preferred acid addition salts are chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, malate, citrate, benzoate, salicylate, ascorbate and the like.

As used herein, “pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or excipient that delivers an anticancer agent to an animal or human. The carrier may be liquid or solid and is selected according to the intended mode of administration.

As used herein, "cancer" or "leukemia" refers to any type of cancer, including all types of cancer or tumors, or malignancies that harm normal healthy blood cells and cancers that produce blood cells found in mammals.

As used herein, "viruses" are viruses that cause diseases of other warm blooded animals (viral infections), such as the HIV virus, herpes, influenza and rhinoviruses.

As used herein, "2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and derivatives thereof" is an acid Addition salts as well as esters and ethers.

As used herein, an "elevating factor" is 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its Substances such as triprolidine and its cis isomers or 1H-benzimidazole-2-propanoic acid used in combination with derivatives. Synergists can affect the immune system or enhance the effects of drugs.

As used herein, "chemotherapeutic agent" includes DNA interactions, anti-metabolic agents, tubulin-interacting agents, hormones and other asparaginases or hydroxyureas.

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 formula:

It is prepared according to the method described in US 4,404,216 issued to Richardson (1983).

Derivatives include lower carboxylic acid esters of propanol groups such as acetyl, propanoyl, butyl, pentyl and hexyl esters. Especially preferred are esters of carboxylic acids having up to 7 carbons, most preferably propyl esters. Aryl carboxylic acids such as salicylic acid, benzoic acid and related acids can also be used by esterifying propanol groups. Alkyl ethers having up to 7 carbons are also useful derivatives.

Pharmaceutical addition salts are salts of organic or inorganic acids with 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol to be. Preferred acid addition salts are chloride, bromide, sulfate, nitrate, phosphate, sulfonate, formate, tartrate, maleate, malate, citrate, benzoate, salicylate, ascorbate and the like.

The compound is part of a more comprehensive class of fungicides of the general formula:

Wherein R ¹ is an optionally substituted alkyl, cycloalkyl, aryl (2,4-dichlorophenyl) or aralkyl group, Y ¹ and Y ² are = CH or = N-; And salts or metal complexes and ethers or esters thereof. While these substances are active against fungal diseases, some are teratogenic. Thus, materials exhibiting these properties are not useful here.

C. Chemotherapy

Chemotherapy agents are generally classified as DNA-interacting agents, anti-metabolic agents, tubulin-interacting agents, hormones and other asparaginases or hydroxyureas. Each group of chemotherapeutic agents can be further classified by activity or type of compound. Chemotherapy agents used in combination with the 1H-1,2,4-triazole derivatives of the invention include all members of the group. For a detailed discussion of chemotherapeutic agents and methods of their administration, see Cancer Chemotherapy Handbook, 24th Edition, p15-34, Appleton & Lange (Connecticut, 1994), incorporated herein by reference.

DNA-interacting agents include alkylating agents such as cisplatin, cyclophosphamide, altretamine; DNA chain breakers such as bleomycin; Intercalated topoisomerase II inhibitors such as dactinomycin and doxorubicin; Non-inserted topoisomerase II inhibitors such as etoposide and teniposide; DNA minority sphere binding flicamidine.

Alkylating agents form covalent chemical adducts with cellular DNA, RNA and protein molecules and with small amino acids, glutathione and similar chemicals. Generally, such alkylating agents react with nucleophilic atoms in cell constructs such as amino, carboxyl, phosphate, sulfhydryl groups in nucleic acids, proteins, amino acids or glutathione. The role of the alkylating agent in the mechanism and cancer treatment is not known. Typical alkylating agents include nitrogen mustards such as chlorambucil, cyclophosphamide, isopamide, mechloretamine, melphalan, uracil mustard; Aziridine such as thiotepa; Methanesulfonate esters such as busulfan; Nitroso ureas such as carmustine, lomustine, streptozosin; Platinum complexes such as cisplatin, carboplatin; Mitomycin and bioreductive alkylating agents such as procarbazine, dacarbazine and altretamine; DNA chain breakers include bleomycin; DNA topoisomerase II inhibitors include inserts such as amsacrine, dactinomycin, daunorubicin, doxorubicin, idarubicin and mitoxantrone; Non-inserts such as epoxide and teniposide.

DNA minority binding agent is plicamycin.

Antimetabolic agents interfere with the production of nucleic acids by one or more major mechanisms. Some of the drugs inhibit DNA replication by inhibiting the production of deoxyribonucleoside triphosphate, a DNA synthesis intermediate precursor. Some of the compounds are like furin or pyrimidine, which can be fully substituted for them in the assimilation nucleotide pathway. The analog may then be substituted with DNA and RNA in place of its general counterpart. Useful anti-metabolic agents here include folic acid antagonists such as totrexate and trimetrexate, fluorouracil, fluorodeoxyuridine, CB3717, azacytidine, pyrimidine antagonists such as cytarabine and phloxuridine, mercapto Pyrimidine antagonists including furin, 6-thioguanine, fludarabine, pentosatin; Sugar modified analogs including cycltravin, fludarabine; Ribonucleotide reduction inhibitors including hydroxyurea.

Tubulin interactions act by binding proteins that polymerize to form cellular microtubules to specific sites on the tubulin. When the interacting agent binds on the protein, the cells cannot form microtubules. Tubulin interactions include both vincristine and vinblastine, alkaloids, and placitaxel.

Hormones are also useful for the treatment of cancer and tumors. They are hormonally sensitive to tumors and are generally derived from natural sources. These include estrogens, conjugated estrogens and ethynyl estradiol and diethylstilbestol, chlortriacene and edestrol; Progestins such as hydroxyprogestrone caproate, hydroxyprogesterone and mezestrol; Androgens such as testosterone, testosterone propionate, fluoxymesterone, methyltestosterone.

Adrenal corticosteroids are derived from natural adrenal cortisol and hydrocortisone. They are used because of their anti-inflammatory benefits, as well as some ability to inhibit mitosis and stop DNA synthesis. Such compounds include prednisone, dexamethasone, methylprednisolone, and prednisolone.

Routine releasing hormone or gonadotropin releasing hormone antagonist is mainly used for the treatment of prostate cancer. This includes leuprolide acetate and goserelin acetate. This inhibits the biosynthesis of steroids in the test.

Antihormonal antigens include antiestrogens such as tamoshifen, antiandrogens such as flutamine, and antiandronal agents such as mitotans and aminoglutetimides.

Hydroxyurea appears to play a major role in the overall inhibition of enzyme ribonucleotide reducing agents.

Asparaginase is an enzyme that inhibits protein synthesis in tumors by converting asparagine into nonfunctional aspartic acid.

Taxol is a preferred chemotherapy agent.

D. Rising Factor

"Elevation factor" may be a substance that improves or increases the efficacy of a pharmaceutical composition or acts on the immune system. One such synergistic factor is chemotherapy and 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propane-2 Triproridine and its cis-isomers used in combination with -ols and derivatives thereof. Triproridine is described in US Pat. No. 5,114,951 (1992). Other synergistic factors include procodazole, 1H-benzimidazole-2-propanoic acid; [β- (2-benzimidazole) propionic acid; 2- (2-carboxyethyl) benzimadazole; Propazol]. Procodazole is an active immunoprotectant that is nonspecific against viral and bacterial infections and can be used with the compositions claimed herein. The compounds are effective in treating cancer, tumors, leukemias and viral infections with 1H-1,2,4-triazole alone or in combination with chemotherapy.

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 can be added to these compositions.

E. Dosage

Appropriate dosages may be given in the methods of the invention. The types and amounts of compounds and carriers vary depending on the type, weight of the warm-blooded animal or human, and the type of cancer or tumor or viral infection to be treated. Generally, a dosage of about 1 mg to about 1000 mg per kg of body weight is 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) It is suitable for propan-2-ol and its derivatives or chemotherapeutic agents. Preferably from 15 mg to 800 mg per kg of body weight is used. In humans the dosage is generally lower than for small warm blooded animals such as rats. Dosage units may comprise a single compound or mixtures thereof and other compounds or other cancer inhibiting compounds. Dosage units may also include diluents, extenders, carriers, liposomes, and the like. The unit may be in solid or gel form, such as pills, tablets, capsules, or the like, or liquids suitable for oral, rectal, topical, intravenous or parenteral administration or intramedullary or peripheral injection. Ranges for 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and derivatives thereof for chemotherapeutic agents and The rate depends on the type of cancer or tumor to be treated and the type of specific chemotherapeutic agent.

F. Dosage Form

Chemotherapeutic agents, 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and its derivatives and optional synergists Typically mixed with a pharmaceutically acceptable carrier. Such carriers may be solid or liquid, the type of which is generally selected according to the dosage form employed. The active agent may be administered together in the form of tablets or capsules, such as aggregated powders, in the form of liposomes or in liquids. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily formulated and made easy to swallow or chew. Other solid forms include granules and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colorants, flavors, flow agents, melts. Examples of suitable liquid dosage forms include solutions reconstituted from water, pharmaceutically acceptable fats and solutions, or suspensions, emulsions, syrups or elixirs, suspensions, non-bubble granules in other organic solvents including oils, alcohols or esters. And / or foam preparations reconstituted from suspensions and foam granules. Such liquid dosage forms may, for example, contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweetening agents, thickening agents and melting agents. Oral dosage forms optionally contain flavoring and coloring agents. Parenteral and intravenous forms will also contain minerals and other materials that make them suitable for the type of injection or delivery system selected.

Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in US Pat. No. 3,903,297 to Robert, issued September 2, 1975. Techniques and compositions for preparing dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editor 1979); Lieberman and co-authors, Pharmaceutical Dosage Forms: Tablets (1981); And Ansel, Introduction to Pharmceutical Dosage Forms 2nd Edition (1976).

G. Treatment Methods

The method of treatment can be any method effective for the treatment of the particular cancer type or tumor being treated. The method of treatment can be oral, rectal, topical, parenteral or intravenous administration or injection into a tumor or cancer. Methods of administering an effective amount also depend on the leukemia, tumor or cancer or virus being treated. 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazole- formulated with a suitable carrier, additional cancer suppressing compound, or compound or excipient to facilitate administration Parenteral treatment by intravenous, subcutaneous or intramuscular injection of 1-yl) propan-2-ol and its derivatives may be the preferred method of administration to warm-blooded animals.

In addition to the use of chemotherapeutic agents and synergists, 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 herbicides and fungicides include carbendazim, fluconazole, benoyl, glyphosate and propicodazole.

When the pharmaceutical composition is used for the treatment of a viral infection, it can be combined with other antiviral agents.

Antiviral Evaluation Method by Human Influenza Virus

When arrived, 5 to 7 week old female CDs (mouse, Charles River Breeding Laboratory, Potato, MI) were used. At the initial test mice were approximately 6-9 weeks old and weighed approximately 20-28 g. All mice used in the study did not differ by age more than 10 days. Mice were placed in 6 cages with one bottom and fed with tongue food 5002 (PMI, St. Louis Missouri). Fresh water was provided to the mice from time to time.

Human influenza virus, strain AT2 / Taiwan / 1/64, was used for antigen administration of mice. The virus is stored at about −70 ° C. and thawed frozen storage vials prior to challenge challenge and diluted to appropriate concentration in saline buffer solution. Mice were anesthetized with haloethane and viral antigen doses were administered through the nose in a volume of 50 μl.

Test drugs were administered at the concentrations and volumes provided below. For 1 to 14 days, 10 mice per group were administered test drug by oral wash. As a comparison to the test drug administration mice group, the saline control group 10 was dosed with equal amounts of saline. Test drug administration was performed at about 24 hour intervals. Viral infection doses were antigenically administered to all mice via the nose, calculated to show about 90% mortality about 4 hours after 0 second administration of the test drug or saline. Test animals were observed daily for 21 days after the administration of an infectious antigen that could cause a fatal or fatal condition.

Test substance Dose (mg / kg) Lethality Fluconazole 350 0 Fluconazole 700 30% Brine - 100% Amantadine 75 0 %

Human Tumor Colony Forming Unit Test In Vitro

Solid tumors removed from patients are chopped into 2-5 mm fragments and immediately placed in fresh calf serum + 1% penicillin / streptomycin inactivated in McCoy's medium 5A + 10% heat. Within 4 hours these solid tumors are mechanically separated with scissors, passed through a stainless steel mesh 100 and a 25 gauge needle and washed with McCoy medium as described above. Ascites, pleura, pericardial fluid and bone marrow are obtained by standard techniques. The fluid or bone marrow is placed in a sterile container containing heparin free of 10 units of preservative per ml of malignant fluid or bone marrow. After centrifugation for 10 min at 150 x g, cells are incubated and washed with calf serum inactivated in McCoy medium + 10% heat. The viability of the cell suspension was measured by a hemocytometer by trypan blue.

The cells to be replicated were inactivated horse serum, penicillin (100 units / ml), steeptomycin (2 mg / ml), glutamine (2 mM), insulin (3 units / ml), asparagine (0.6 mg) in 15% heat. / ml) and suspended in 0.3% agar in incubated CMRL 1066 supplemented with HEPES buffer (2 mM). For continuous exposure testing, each compound was added to the compound. Cells were placed in a 35 mm Petri dish in the agar of the upper layer on the agar of the lower layer to inhibit the growth of fibroblasts. Three plates were made to find each data point. Each plate was placed in a 37 ° C. incubate and removed on day 14 to calculate the number of colonies in each plate. The number of colonies formed on plates treated with 3 compounds (defined as 50 cells) was compared to the number of colonies formed on three control plates and the percentage of colonies surviving at the concentration of compound was calculated. Three positive controls were used to calculate survival. 200 μg / ml of orthosodium vanadate was used in the positive control. The test was evaluated when the colonies were less than 30% in the positive control compared to the untreated control.

Fluconazole at concentrations of 0.5 and 5.0 μg / ml in single dose experiments was not effective against tumors in this experiment (0/3 and 0 / l3, respectively). Fluconazole was particularly effective against colony, lung (small cell) melanoma and ovarian cancer at concentrations of 50.0 μg / ml in subsequent exposure tests. 4/13 had a survival rate of 50% or more.

Claims (9)

About 1 mg to about 800 mg of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2- per kg body weight A pharmaceutical composition for treating cancer, tumors, and viral infections, which comprises a raw and pharmaceutically acceptable carrier selected from the group consisting of ol and derivatives thereof and mixtures thereof. The composition of claim 1, wherein the composition additionally contains a chemotherapeutic agent in a safe amount and an effective amount. The composition of claim 1 or 2, wherein the chemotherapeutic agent is selected from the group consisting of DNA interacting agents, antimetabolizing agents, tubulin-interacting agents, hormones, asparaginase or hydroxyurea. The method of claim 1, wherein the chemotherapeutic agent is asparaginase, hydroxyurea, cisplatin, cyclophosphamide, altretamine, bleomycin, dactinomycin, doxorubicin, etoposide, tenni. A composition selected from the group consisting of forside and flamidine. The method of claim 1, wherein the chemotherapeutic agent is taxol, methotrexate, fluorouracil, fluorodeoxyuridine, CB3717, azacytidine, cytarabine, phloxuridine, mercaptopurine, A composition selected from the group consisting of 6-thioguanine, fludarabine, pentostatin, cycltrabin, and fludarabine. The composition according to any one of claims 1 to 5, further comprising a synergistic factor. A method of treating cancer or tumors in a warm blooded mammal comprising administering a safe amount and an effective amount of the composition according to any one of claims 1 to 6. A method of treating viral infection in a warm blooded mammal comprising administering a safe amount and an effective amount of the composition according to any one of claims 1 to 6. The method of claim 7 or 8, wherein the 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol Or a derivative thereof is administered orally or by injection into the small intestine, intravenous, intraperitoneal or tumor.