MXPA98000944A - Use of derivatives of 1h-1,2,4-triazol to inhibit the growth of cance - Google Patents

Abstract

A pharmaceutical composition that inhibits the growth of tumors and cancers in mammals comprising a derivative of 1H-1,2,4-triazole together with a safe and effective amount of a chemotherapeutic agent. Enhancers may be used to improve the effectiveness of the drugs. Triazole compounds and enhancers can also be used to treat viral infections

Description

USE OF DERIVATIVES OF 1H-1, 2, 4-TRIAZOL TO INHIBIT THE GROWTH OF CANCERS FIELD OF THE INVENTION This invention is a pharmaceutical composition that inhibits the growth of cancers, leukemia and tumors in mammals, particularly in humans and warm-blooded animals. The composition contains a derivative of 1H-1, 2,4-triazole and a chemotherapeutic agent.

BACKGROUND OF THE INVENTION Cancers are the main cause of death in animals and humans. The exact cause of cancer is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors have been shown by a number of researchers. Many types of chemotherapeutic agents have been shown to be effective against cancers and tumor cells, but not all types of cancers and tumors respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for the action of these chemotherapeutic agents is not always known. Despite advances in the field of cancer treatment, the main therapies to date are surgery, radiation and chemotherapy. The chemotherapeutic approaches are to fight cancers that are metastized or those 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 having specificity for cancer and tumor cells would be extremely desirable, as long as they do not affect normal cells. Unfortunately, none has been found and instead agents have been used which especially targets rapidly dividing cells (both tumors and normal). Clearly, it would be an advancement in the development of materials that target tumor cells, due to some unique specificity for them. Alternatively, materials that are cytotoxic to tumor cells would be desirable, while exerting mild or moderate effects on normal cells. It is believed that 1H-1,2,4-triazole when using a binding with chemotherapeutic agents can both reduce and suppress the growth of cancers, tumors and leukemia. 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. It has been found that 1H-1,2,4-triazole derivatives are especially effective in suppressing the growth of cancer, tumor, virus or bacteria. The use of these 1H-1,2,4-triazole derivatives in combination with other chemotherapeutic agents that are effective in tumor destruction is a new method of treatment of cancers and tumors. More specifically, it is an object of this invention to provide an anti-cancer composition comprising a pharmaceutical carrier and a 1H-1,2-triazole derivative and a chemotherapeutic agent together with a method for the treatment of such cancers. The enhancers can also improve the effectiveness of this composition. This and other objects become apparent from the following detailed description of these inventions.

SUMMARY OF THE INVENTION A pharmaceutical composition for the treatment of mammals, and in particular, comprises a pharmaceutical carrier and an effective and safe amount of a chemotherapeutic agent and an affective amount of an anti-cancer compound selected from the group consisting of: wherein Z is an alkylene selected from the group consisting of: CH - CH -, - CH - CH - - CHJ -, CH (CH3) - CH (CHj) - and - CH2 - CH (alkyl) wherein alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl, wherein "substituted phenyl" has the meaning of a phenyl radical having 1 to 3 substituents therein independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, cyano, and nitro. The therapeutically activated acid addition salts of the above compound (I) are also encompassed within the scope of this invention. As used in the above definition of Z, the term "alkyl" is proposed to include straight and branched chain hydrocarbon radicals having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1,1-dimethylethyl, butyl, phenyl, hexyl, heptyl, octyl, decyl and the like; as used herein "lower alkyl" may be straight or branched chain saturated hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1- dimethylethyl, phenyl, hexyl and similar alkyls; and the term "halo" is generic to the atomic atoms of atomic weight less than 127; that is, fluorine, chlorine, bromine, and iodine. These compositions can be used to inhibit the growth of cancers and other tumors in animals or humans by administering an effective amount either orally, rectally, topically or parenterally intravenously or by injection into the tumor. The compositions do not significantly affect healthy cells as compared to adriamycin which has a detrimental effect on healthy cells. The enhancers can be included in the compositions. The 1H-1,2,4-triazole derivatives together with the potentiating compositions are also used in the treatment of viruses. The combinations with other fungicides are also effective 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, an "additive, pharmaceutical salt" is the salt of an anti-cancer compound 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-cancer agent to the animal or human. The carrier can be liquid or solid or liposome and is selected in the planned manner of administration in mind. As used herein, "cancer" refers to all types of cancers or neoplasm or malignancies and all types of cancers including leukemia that are found in mammals. As used herein, the "anti-cancer compounds" are the 1H-1,2,4-triazoles and their salts. The exact 1H-1,2,4-triazoles are described in detail below. Preferred materials are the products sold under the name "propiconazole" by Janssen Pharmaceutical NV (Belgium). As used herein, "virus" includes viruses that cause disease (viral infections) in man and other warm-blooded animals such as the HIV virus, herpes, influenza, and rhinovirus. As used herein, "chemotherapeutic agents" includes agents interactive with DNA, anti-etabolites, Interactive Agents with Tubulin, Hormonal agents and others, such as Asparaginase or hydroxyurea. As used herein, "enhancers" are materials such as triprolidine and its cis-isomer and procodazole, which are used in combination with chemotherapeutic agents and a derivative of 1H-1,2,4-triazole.

B. ANTI-CANCER COMPOUNDS Anti-cancer compounds are 1H-1,2,4-triazole derivatives that are known for their antifungal activities. They are systemic materials used to prevent and eradicate fungi. The compounds have the following structure: wherein Z is an alkylene selected from the group consisting of: CH; -CH-, - CH2-CH2-CH2-, CH (CH3) -CH (CH3) - and -CH2-CH (alkyl) wherein alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl, wherein "substituted phenyl" has the meaning of a phenyl radical having 1 to 3 substituents therein independently selected from the group consisting of halo, lower alkyl, lower alkyloxy, cyano and nitro. The therapeutically activated acid addition salts of the above compound (I) are also encompassed within the scope of this invention. As used in the above definition of Z, the term "alkyl" is proposed to include straight and branched chain hydrocarbon radicals having from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1,1-dimethylethyl, butyl, phenyl, hexyl, heptyl, octyl, decyl and the like; as used herein "lower alkyl" may be straight or branched chain saturated hydrocarbons having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1- dimethylethyl, phenyl, hexyl and similar alkyls; and the term "halo" is generic to the atomic atoms of atomic weight less than 127; that is, fluorine, chlorine, bromine, and iodine. Their pharmaceutically acceptable acid addition salts with both organic and inorganic acids can also be used herein. Preferred derivatives include: l - [- [2- (2,4-dichlorophenyl) -l, 3-dioxolan-2-yl] methyl] -1H-1,2, -triazole (propiconazole); 1- [2- (2, -dichlorophenyl) -4-methyl-1,3-dioxolan-2-ylmethyl] -1H- 1, 2,4-triazole, 1- [2- (2,4-dichlorophenyl) - 4-ethyl-l, 3-dioxolan-2-ylmethyl] -1H- 1, 2,4-triazole, 1- [2- (2, -dichlorophenyl) -4-propyl-l, 3-dioxolan-2-ylmethyl ] - 1H-1,2, 4-triazole, 1- [2- (2, -dichlorophenyl) -4-pentyl-1,3-dioxolan-2-ylmethyl] -1H-1,2, -triazole, and the Therapeutically active acid addition salts thereof. These compounds are prepared according to the method described in U.S. Patent No. 4,079,062 issued to Van Reet, et al., March 14, 1978. It is believed that these particular materials in combination with chemotherapeutic agents and optionally enhancers, have the ability to of reducing tumors or decreasing their growth significantly due to their ability to inhibit the synthesis of sterols.

C. CHEMOTHERAPEUTIC AGENTS The chemotherapeutic agents are generally grouped as DNA-interactive agents, antimetabolites, tubulin-interacting 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 a 1H-1,2,4-triazole derivative of this invention 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, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; bioreductive reducing agents, such as Mitomycin and Procarbazine, Dacarbazine and Altretamine; agents of rupture of the DNA strand include Bleomycin; inhibitors of DNA topoisomerase II include the following: intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin, and Mitoxantrone; non-intercalary, such as Etoposido and Teniposido. The binder of the minor groove of DNA is Plicamycin. Anti-metabolites interfere with the production of nucleic acids by one or the other of the 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 bind to the 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 hydroxyprogesterone caproate, Medroxyprogesterone and Megestro; androgen such, testosterone, testosterone propionate; fluoxymesterone, 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 biosynthesis of steroids in the testicles. Antihormonal antigens include: antiestrogenic agents such as Tamosifene. 'antidrogenic agents such as Flutamide; and anti-adrenal agents such as Mitotane 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.

D. POTENTIATORS "Enhancers" can be any material that improves or increases the efficiency of the pharmaceutical composition. They include immunosuppressants or materials that act as an immune system. One such enhancer is triprolidine and its cis-isomer which are used in combination with chemotherapeutic agents and a derivative of 1H-1,2,4-triazole. Triprolidine is described in U.S. Patent 5,114,951 (1992). Another enhancer is procodazole, 1H-benzimidazole-2-propanoic acid; [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 1H-1,2,4-triazoles only 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.

E. DOSAGE Any suitable dosage can be given in 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 or human blood animal, body weight, and that of the tumor being treated. In general, a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight and about 400 mg per kg of suitable body weight is adequate. Preferably from 15 mg to about 150 mg / kg of body weight is used. For chemotherapeutic agents a lower dose may be adequate, for example 0.5 mg / kg of body weight to 400 mg / kg of body weight. 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 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, injection administration intravenous or parenteral or injection into or around the tumor. The range and ratio of the chemotherapeutic agent to the anti-cancer compound will depend on the type of chemotherapeutic agent and the cancer being treated.

F. FORMS OF DISTRIBUTION OF DOSAGE Anti-cancer compounds and chemotherapeutic agents are typically mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type is generally chosen based on the type of administration used. Liposomes can also be used to deliverate the composition. The active agent can be co-administered in the form of a tablet or capsule, 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 can contain, for example, suitable solvents, preservatives, emulsifying agents, dispersing agents, diluents, sweeteners, thickeners and melting agents. The oral dosage forms optionally contain 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 pharmaceutically acceptable carriers and excipients that can be used to formulate the oral dosage forms for the present invention are described in Robert's North American Patent No. 3,903,297, issued September 2, 1975.

The techniques and compositions for making 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 Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

G. TREATMENT METHOD The treatment method 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 and the like. The method to apply an effective amount also varies depending on the tumor being treated. It is believed that parenteral treatment by the intravenous, subcutaneous or intramuscular application of the compounds 1H-1,2,4-triazole, formulated with an appropriate carrier, additional compound cancer inhibitor or compounds or diluents to facilitate the application will be the preferred method of administration of the compounds to warm-blooded animals. The method for treating viral infections can also be by oral, rectal, topical, parenteral, or intravenous administration. A preferred method of treating viral infection is the administration of procodazole and propiconazole. The 1H-1,2-triazole derivatives can also be administered with other fungicides such as benzimidazole derivatives, for example, thiabendazole, benomyl, carbendazim; N-phosphonoglycines, for example, glyphosate and herbicides such as N-chlorophenyl and N-chloro-thiocarbamates, for example, chloroprofan. They can also be used with griseofulvin ANTIVIRAL EVALUATION WITH HUMAN INFLUENZA VIRUS CD (Charles Riber Breeding Labotatories mice, Portage, MI) females 5 to 7 years of age are used at reception. The mice are approximately 6 to 9 weeks old and weigh approximately 20 to 28 grams at the time of the start of 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 / Tai an / 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 items 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 dosing 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 moribundity. The test animals were observed twice after dosing on day 1, three times on day 0 and twice daily thereafter. The mice that stained in the test were discarded without necroscopy. At a dose of 175 mg / kg propiconazole, 40% of the mice survived compared to a control with saline in which mice did not survive. At a dose of 350 mg / kg, 57% of the mice survived.

ANTIVIRAL EVALUATION WITH RINOVIRUS. In an in vitro selection for Rhinovirus, type A-1, the WI-38 cell line, propiconazole was effective at 32 μg / ml. The positive control was A-36683 from Abbot Company, (S, S) -1,2-bis- (5-methoxy-2-benzimidazolyl) -1,2-ethanediol. He A-36683 has therapeutic index of 1000-3200. Propiconazole has a therapeutic index of 1-3. (See Schleicher et al, Applied Microbiology, 23, No. 1, 113-116 (1972).

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. Ascitic, plural, pericardial, and bone marrow fluids are obtained by normal techniques. The fluid or marrow is placed in sterile containers containing 10 units of preservative-free heparin per ml. 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 cell suspensions is determined in a hemocytomer with trypan blue. 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 on 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 3 plates treated with the compound compares the number of colonies formed in the 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 are 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, propiconazole was not effective (0/1) against the tumors in this test. At a concentration of 50.0 μm / ml in a continuous exposure experiment, propiconazole was effective against cancers of the colon, lung, (non-small cell) melanoma and ovary. In all, 4/13 had less or equal 50% survival. More than 6 of the 8 had < 50% survival

Claims (8)

1. CLAIMS; A pharmaceutical composition comprising a pharmaceutically acceptable carrier and from 0.5 mg / kg to up to about 400 mg / kg of body weight and a chemotherapeutic agent from about 2 mg / kg to about 400 mg / kg of body weight of a triazole of the formula: wherein Z is an alkylene selected from the group consisting of: CH2-CH2 -, - CH2-CH2-CH2-, CH (CH3) -CH (CH3) - and -CH2-CH (alkyl) wherein alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl.
2. 2. A pharmaceutical composition according to claim 1, wherein the 1H-1,2,4-triazole is selected from the group consisting of: 1- [2- (2,4-dichlorophenyl) -1,3-dioxolan -2-yl] methyl] -1H-1,2,4-triazole (propiconazole); 1- [2- (2, -dichlorophenyl) -4-methy1-1, 3-dioxolan-2-ylmethyl] -1H-1,2, -triazole, 1- [2- (2, -dichlorophenyl) -4- ethyl-l, 3-dioxolan-2-ylmethyl] -1H-1, 2,4-triazole, 1- [2- (2, -dichlorophenyl) -4-propyl-l, 3-dioxolan-2-ylmethyl] - 1H-1,2, 4-triazole, 1- [2- (2,4-dichlorophenyl) -4-pentyl-1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole, and the Therapeutically active acid addition salts thereof.
3. 3. A pharmaceutical composition according to claim 1 or 2, for inhibiting the growth of tumors.
4. 4. A pharmaceutical composition according to claim 1, 2 or 3, wherein the pharmaceutically acceptable addition salts are selected from the group consisting of chloride, bromides, sulfates, nitrides, phosphates, sulfonates, formates, tartrates, maleates, alates , citrates, benzoates, salicylates, ascorbates and mixtures thereof.
5. 5. A pharmaceutical composition according to claim 1, 2, 3 or 4, wherein the chemotherapeutic agent is selected from the group consisting of agents interactive with DNA, anti-metabolites, agents interactive with tubulin, hormonal agents, asparaginase or hydroxyurea.
6. 6. A pharmaceutical composition according to claim 1, 2, 3, 4 or 5, wherein the chemotherapeutic agent is selected from the group consisting of Asparaginase, hydroxyurea, Cisplatin, Cyclophosphamide, altetramida, bleomycin, dactinomycin, doxorubicin, etoposide, Tenipóxido and Plcamidina.
7. 7. A pharmaceutical composition according to claim 1, 2, 3, 4 or 5, wherein the chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, fluorodeoxyuridine, CB3717, -azacitidina, cytarabine, floxuridine, mercaptopurine, 6 -thioguanine, fludarabine, pentostatin, cictrabine, and fludarabine. 8. A pharmaceutical composition according to claim 1, 2, 3, 4, 5, 6, or 7, further comprising an enhancer. A method for treating cancer, comprising administering a safe and effective amount of the composition of claims 1, 2, 3, 4, 5, 6, 7 or 8. 10. A method of treating viral infection comprising administering a composition according to claims 1, 2, 3, 4, 5, 6, 7 or
8. 8.