MXPA97009712A - Use of 1,2,4-triazol derivatives for the manufacturing of a medicine for the treatment of cance - Google Patents

Abstract

A pharmaceutical composition that inhibits the growth of tumors and cancers in mammals, comprising a material, is disclosed. The particular material that is used is a derivative of 1H-1,2,4-triazole. These compositions can also be used to treat viral infections

Description

USE OF 1, 2, 4-TRIAZOL DERIVATIVES FOR THE MANUFACTURING OF A MEDICINE FOR THE TREATMENT OF CANCERS TECHNICAL FIELD This invention is a pharmaceutical composition that inhibits the growth of cancers, leukemia and tumors in mammals, in particular in humans and warm-blooded animals. The composition contains a derivative of 1H-1,2,4-triazole. The compositions can also be used to treat viral infections.

BACKGROUND OF THE INVENTION Cancers are the leading cause of death in animals and humans. The exact cause of the cancer is unknown but it is related to certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors has been shown by several 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 the advantages in the field of cancer treatment, the most modern therapies to date are surgery, radiation and chemotherapy. Chemotherapeutic approaches are said to fight cancer that is metastasized or those that are particularly aggressive. These cytocidal or cytostatic agents work well 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 bulk of the therapies available to oncologists. Ideal cytotoxic agents that have specificity for cancer and tumor cells ideally should not affect normal cells, a feature that is greatly desired. Unfortunately none of these types of agents have been found, but only agents that target especially rapidly dividing cells (both tumor and normal type) which are the ones that have been used. Obviously, the development of materials that target tumor cells, due to a specific specificity towards them, would be an unprecedented advance. Alternatively, materials that were cytotoxic to tumor cells while exerting mild effects on normal cells would also be desired. Therefore, an object of this invention is to provide a pharmaceutical composition that is effective to inhibit the growth of tumors and cancers in mammals while having mild effects or having no effect on normal cells. More specifically, it is an object of the invention to provide an anti-cancer composition comprising a pharmaceutical carrier and a 1H-1,2,4-triazole derivative, as defined herein in conjunction with a method for treating these cancers. These and other objects will be apparent from the following detailed description of this invention.

SUMMARY OF THE INVENTION A pharmaceutical composition for the treatment of mammals, and in particular warm-blooded and human animals, comprising a pharmaceutical carrier and an effective amount of an anti-cancer compound selected from the group consisting of: P551 wherein Z is an alkylene selected from the group consisting of CH2-CH2-, -CH2-CH2-CH2-, -CH (CH3) -CH (CH,) -, and -CH2-CH (alkyl), wherein the 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 from 1 to 3 independently selected substituents of the group consisting of halo, lower alkyl, lower alkyloxy, cyano and nitro. The therapeutically active acid addition salts of the following compounds (I) are also encompassed within the scope of this invention. In the sense used in the following definition of Z, the term "alkyl" includes straight or branched chain hydrocarbon radicals having from 1 to about 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1, 1-dimethylethyl, butyl, pentyl, hexyl, heptyl, octyl, decyl and the like; in the sense used herein "lower alkyl" may refer to 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 , pentyl, hexyl and similar alkyls; and the term "halo" is generic for halogen atoms of atomic weight less than 127; that is, fluorine, chlorine, bromine and iodine. These compositions can be employed to inhibit the growth of cancers and other tumors in humans and animals by administering an effective amount either orally, rectally, topically or parenterally, intravenously or by injection into the tumor. These compositions do not significantly affect healthy cells compared to adriamycin, which has a detrimental effect on healthy cells. These compositions are also used to treat viruses.

DETAILED DESCRIPTION OF THE INVENTION Aj. Definitions: In the sense in which the term "comprising" is used herein, it means that several components can be used together in the pharmaceutical composition of this invention. Accordingly, the terms "consisting essentially of" and "consisting of" are encompassed by the term comprising. In the sense used here a component "Pharmaceutically acceptable" is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation and allergic responses) commensurate with a reasonable benefit / risk ratio. In the sense used herein, the term "safe and effective amount" refers to the amount of a component that is sufficient to provide a desired therapeutic response without undue adverse side effects (such as toxicity, irritation or allergic responses) commensurate with a relationship reasonable between benefit / risk, 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 applicable) and the specific formulations used and the structure of the compounds or their derivatives. As used herein a "pharmaceutical addition salt" is a salt of the anticancer compound 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. In the sense used herein a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, a suspending agent or vehicle for administering the anti-cancer agent to the animal or human. The carrier can be liquid or solid and is selected from the planned administration form. As used herein the term "cancer" refers to all types of cancers or neoplasms or malignancies, including leukemia, which are found in mammals. In the sense used here, the term "Anticancer compounds" are 1H-1, 2,4-triazoles and their salts. The exact 1H-1,2,4-triazoles are described in detail below. The preferred materials are the products sold under the trade names "propiconazole®" from Janssen Pharmaceutica NV (Belgium). In the sense used here, "virus" includes viruses that cause diseases (viral infections) in humans and other warm-blooded animals such as HIV, herpes, influenza and rhinovirus.

ANTI-CANCER COMPOUNDS Anticancer compounds are 1H-1, 2,4-triazole derivatives that are known for their antifungal activity. They are systemic materials that are used to prevent and eradicate fungi. The compounds have the following P5S1 structure: wherein Z is an alkylene selected from the group consisting of CH2-CH2-, -CH2-CH2-CH2-, -CH (CH,) -CH (CH,) -, and -CH2-CH (alkyl), wherein the 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 from 1 to 3 independently selected substituents of the group consisting of halo, lower alkyl, lower alkyloxy, cyano and nitro. The therapeutically active acid addition salts of the following compounds (I) are also encompassed within the scope of this invention. In the sense used in the following definition of Z, the term "alkyl" includes straight or branched chain hydrocarbon radicals having from 1 to about 10 carbon atoms, such as, for example, methyl, ethyl, 1-methylethyl, propyl, 1, l-dimethylethyl, P551 butyl, pentyl, hexyl, heptyl, octyl, decyl and the like; in the sense used herein "lower alkyl" may refer to 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 , pentyl, hexyl and similar alkyls; and the term "halo" is generic for halogen atoms of atomic weight less than 127; that is, fluorine, chlorine, bromine and iodine. Their pharmaceutically acceptable acid addition salts can also be employed with both organic and inorganic acids. Preferred derivatives include: 1- [2- (2,4-dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole; 1- [2- (2,4-dichlorophenyl) -4-methyl-1,3-dioxolan-2-ylmethyl] -1H-1,2, -triazole; 1- [2- (2,4-dichlorophenyl) -4-ethyl-l, 3-dioxolan-2-ylmethyl] -1H- 1,2,4-triazole; 1- [2- (2,4-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 .

P551 These compounds are prepared according to the method described in United States Patent 4,079,062 issued to Van Reet, et al, on March 14, 1978. It is believed that these particular materials have the ability to reduce tumors or decrease their growth significantly, due to its ability to inhibit the synthesis of sterols.

DOSAGE Any suitable dose can be administered 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-blooded or human animals, the body weight and the tumor being treated. In general, a dose of between about 2 milligrams (mg) per kilogram (kg) of body weight and about 400 mg per kg of body weight is suitable. Preferably between 15 mg and 150 mg / kg of body weight, approximately, is what is used. In general, the dose in man is lower than that used in small warm-blooded mammals such as mice. A dosage unit may comprise a single compound or mixture thereof with other compounds or other cancer inhibitors. The dose unit may also comprise diluents, extenders, carriers and P55Í similar. The unit may also be in the form of a solid or gel, for example in the form of pills, tablets, capsules and the like or in a liquid form suitable for oral, rectal, topical administration, intravenous injection or parenteral administration or injection into the tumor or near it.

D. Dosage Management Forms Anticancer compounds are typically mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid and the type is selected in general based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, as an agglomerated powder or as a liquid. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily formulated and can be easily processed to be swallowed or chewed; other solid forms include granules and bulk powders. The tablets may contain binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow inducing agents and suitable melting agents. Examples of suitable liquid dosage forms include solutions or suspensions • in pharmaceutically acceptable water, oils and fats, P551 alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms can contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners and melting agents. Oral dosage forms optionally contain flavors and coloring agents. The parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or system of administration chosen. Specific examples of pharmaceutically acceptable carriers and excipients that can be employed to formulate the oral doses of the present invention are described in United States Patent No. 3,903,297 to 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 & amp;; Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms; Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

P551 E. Treatment Method The treatment method may be an appropriate method that is effective in the treatment of particular cancers or of particular tumors or viruses being treated. The treatment can be oral, rectal, topical, parenteral or by intravenous administration or by injection into the tumor, and the like. The method of applying an effective amount also varies depending on the tumor being treated. It is believed that parenteral treatment by intravenous, subcutaneous or intramuscular administration of the 1H-1, 2,4-triazole compounds, formulated with an appropriate carrier, with additional cancer inhibitor compounds or with compounds or diluents to facilitate the application, will constitute the preferred method of administration of the compound in warm-blooded animals. The method of treating viral infections can also be by oral, rectal, topical, parenteral or intravenous administration.

In Vitro Data The following examples are illustrative and are not intended to limit the invention.

P5S1 Tumor Cell Test in Colon, Breast and Lung The following cell culture tests were performed to test the toxicity of n-phosphonoglycine compounds in human colon, breast and lung tumor cells. The viability of the cells was tested by reviewing in MTT the bromide reduction of (3 - [4,5-dimethylthiazol-2-yl] -2,5-diphenyltetrazolium). The MTT assay is a well-known measure of the viability of cells. Colon tumor cells (HT29 from the American Type Culture Collection (ATCC)) and breast cells (MXI from the ATCC cell line) were cultured in an Eagle Minimum Essential Medium with 10% fetal bovine serum. Lung tumor cells (A549 from ATCC cell lines) were cultured in Ham's F12 medium with 10% fetal bovine serum). The tumor cells are subcultured and seeded in culture flasks at the desired cell densities. The culture medium was decanted and the cell lamellae were washed twice with phosphate buffered saline (PBS). The cells were trypsinized and ground before the flasks were seeded. Unless otherwise indicated, the cultures were incubated at 37 ± 1 ° C in a humidified atmosphere of 5 ± 1% carbon dioxide in air. The cultures were incubated until they were 50 to 80% confluent.

P551 The cells were subcultured when the flasks were subconfluent. The medium was aspirated from the flasks and the cell lamellae were washed twice with PBS. Then, the Trypsin Solution was added to each flask to cover the cell lamellae. The Trypsin Solution was removed after 30 to 60 seconds and the flasks were incubated at room temperature for 2 to 6 minutes. When 90% of the cells were dislodged, the growth medium was added. The cells were removed by trituration and transferred to a sterile centrifuge tube. The concentration of the cells in the suspension was determined and a suitable dilution was made to obtain a density of 5000 cells / ml. The cells were eubcultivated in designated cavidadee from 96-well bioassay plates (200 microliters of cell suspension per well). PBS was added to all reetantee cavities to maintain moisture. The plaques were incubated overnight before the treatment of the test article. Each dose of the test article was tested by treating the culture wells in quadruplicate with 100 microliters of each dilution. Those cavities were designated as solvent controls receiving an additional 100 microliters of methanol as control; the negative control cavities received another 100 microliters of medium P551 of treatment. The PBS was added to the remaining cavities not treated with the article or test medium. The plates were then incubated for approximately 5 days. At the end of the fifth day of incubation, each dose group was examined microscopically to determine toxicity. A 0.5 mg / ml dilution of MTT was made in the treatment medium and the dilution was filtered through a 0.45 micron filter to remove the insoluble crystals. The medium was decanted from the cavities of the bioassay plates. In a subsequent way, 2000 microliters of the filtered MTT solution were added to all the test cavities except for the two blank test cavities that did not receive treatment. The two white cavities received 200 microliters of the treatment medium. The plates were returned to the incubator for approximately 3 hours. After incubation, the medium containing MTT was decanted. Excess medium was added to each well and the plates were shaken at room temperature for about 2 hours. The absorbance at 550 nm (OD550) of each well was measured with a Vmax plate reader from Molecular Devices (Menlo Park, CA). The average DO550 of the solvent control cavidade and each of the dilutions of the article of P551 test, and from each of the white and positive control cavities, were calculated. The mean DO550 of the white cavities was subtracted from the mean of the solvent control cavities, and the cavities of the test article, respectively to give the corresponding average DO550. % deCant? nL = p? mqrtia (neqfa efe la Dünci? i cfeL Article (te Pcu ± a "m The dose response curves were prepared as semi-logarithmic graphs with% control in the ordinate (linear) and concentration of the test article in the abscissa (logarithmic scale). The ECrl0 was interpolated from the graphs of each test item. For the test articles administered in methanol, separate responses were prepared to correct the methanol data. Adriamycin was used as a positive control. In all cases, it was more toxic than either of the test materials by one or two logarithmic units. Adriamycin is one of the most potent agents currently used and has considerable lateral effects. The peak plasma concentration of fairly effective chemotherapeutic agents may be 10 to 50 times higher than that of Adriamycin. The EC-50 is the concentration at which P551 kill half of the cells.

Table 1 Test Material Results EC-50 (ppml) HT29 MX1 A549 Adriamycin 0.00639 0.00078 0.00373 Propiconazole 0.0331 0.0284 0.113 These experiments show that these compositions are effective in killing tumor cells without considerably affecting the eanae cells. They are safer than adriamycin.

P551

Claims (2)

CLAIMS;

1. A pharmaceutical composition for treating cancers and viruses, comprising a safe and effective amount of: wherein Z is an alkylene selected from the group consisting of CH2-CH2-, -CH2-CH2-CH2-, -CH (CH3) -CH (CH) -, and -CH2-CH (alkyl), wherein the alkyl has from 1 to 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, thienyl, halothienyl, naphthyl and fluorenyl. 2. A pharmaceutical composition according to claim 1, comprising a pharmaceutically acceptable carrier and a safe and effective amount of a 1H-1,2,4-triazole selected from the group consisting of: 1- [2- (2, 4- dichlorophenyl) -1,3-dioxolan-2-ylmethyl] -1H-1,2,4-triazole; 1- [2- (2,4-dichlorophenyl) -4-methyl-1,3-dioxolan-2-ylmethyl] -1H- 1,2,4-triazole; PS51 1- [2- (2,4-Dichlorophenyl) -4-ethyl-1,3-dioxolan-2-ylmethyl] -1H- 1,2,4-triazole; 1- [2- (2,4-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. A pharmaceutical composition according to Claims 1 or 2, wherein the pharmaceutically acceptable acid addition eleates are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates, citrates, benzoates, salicylates, ascorbates and mixtures thereof. 4. A method of treating cancer in warm-blooded mammals, comprising administering 2 mg / kg of body weight to 400 mg / kg of a 1H-1,2,4-triazole derivative according to claims 1 or 2. 5 A method according to claim 4, wherein the 1H-1,2,4-triazole is administered orally or enterically, intraveny, peritoneally, parenterally or by injection into the tumor. 6. A method according to claim 4, wherein the 1H-1,2,4-triazole is administered in a form Solid P551, wherein the solid form includes a carrier selected from the group consisting of lactose, sucrose, gelatin and agar. A method according to claim 4, wherein the 1H-1,2,4-triazole is administered in a liquid form, wherein the liquid dose is solved from the group consisting of aquesolution, alcohol solution, emulsions, suspensions, and reconstituted suspensions from effervescent and non-effervescent preparations, and suspensions in pharmaceutically acceptable oils or fats. 8. A unit dose composition for treating cancer and viral infections in animals and humans comprising a 1H-1,2,4-triazole according to claims 1 or 2. 9. A method for treating viral infections in warm-blooded mammals , which comprises administering from 2 mg / kg to 400 mg / kg of body weight of a derivative of a 1H-1,2,4-triazole, according to claims 1 or

2. P551