Pharmaceutical composition for treatment of cancer and viral diseases, a method of treating cancer, the method of treatment of viral infections on the basis of

 

(57) Abstract:

The invention relates to pharmacology relates to pharmaceutical compositions for the treatment of cancer and viral diseases, treatment for cancer and treatment of viral infections based on it. The pharmaceutical composition comprises a derivative 1H-1,2,4-triazole of the formula I, where Z represents alkylene selected from the group consisting of CH2-CH2CH2-CH2-CH2-, CH(CH3)-CH(CH3)-, CH2-CH(alkyl) where the specified alkyl has from 1 to 10 carbon atoms; Ar is a representative selected from the group consisting of phenyl, substituted phenyl, teinila, halogentated, naphthyl and fluorenyl, and inhibits the growth of tumors and cancers in mammals when mild effect or no effect on normal cells. 4 C. and 7 C.p. f-crystals, 1 PL.

The invention relates to a pharmaceutical composition that inhibits the growth of cancer, leukemia and tumors in mammals, especially in humans and warm-blooded animals. The composition comprises a derivative 1H-1,2,4-triazole. The composition can also be used to treat viral infections.

The background to the invention

Zlokacestvenno a number of researchers have shown a link between certain activities, such as Smoking or exposure to exposure to carcinogens and the frequency of occurrence of certain types of cancer and tumors.

It has been shown that many types of chemotherapeutic agents effective against cancer and tumor cells, but not all types of cancer and tumors respond to treatment with these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism of action of these chemotherapeutic agents are not always known.

Despite advances in cancer treatment, leading treatments currently are surgery, radiation therapy and chemotherapy. Chemotherapeutic approaches designed to deal with malignant tumors, which metastasized or which are particularly aggressive. Such cytosine or cytostatic agents better work on cancer, with large growth factors, i.e., those whose cells are rapidly dividing. Currently in the Arsenal of drugs available to oncologists, there are hormones, in particular estrogen, progesterone and testosterone and some antibiotics, which are produced by various microorganisms, alkylating agents and antimetabolites. Ideally naifeh and tumor cells, without damaging the normal cells. Unfortunately, these agents have not been found and not replaced the agents that specifically target rapidly dividing cells (both tumor and normal).

It is obvious that the development of materials that will be targeted to tumor cells, thanks to some unique specificity in relation to them will be a breakthrough in this area. Alternatively, materials that possess cytotoxicity against tumor cells in a mild effect on normal cells, would be desirable. Thus, the aim of the present invention is to provide a pharmaceutical composition that inhibits the growth of tumors and cancers in mammals when mild effect or no effect on normal cells.

More specifically, the present invention is the provision of anti-cancer composition comprising a pharmaceutical carrier and a derivative 1H-1,2,4-triazole, as defined in the present invention, and a method of treatment of cancer.

These and other objectives will become clear from the subsequent detailed description of the present invention.

A brief statement of the substance and the different animals and humans, comprising a pharmaceutical carrier and an effective amount of anti-cancer compounds selected from the group consisting of

(I)

where Z represents alkylene selected from the group consisting of CH2-CH2-, -CH2-CH2-CH2-, -CH(CH3)-CH(CH3) and CH2- CH(alkyl) where the specified alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, teinila, halothane, naphthyl and fluorenyl, where "substituted phenyl" means a phenyl radical, having from 1 to 3 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano and nitro. Therapeutically active acid additive salts of the aforementioned compound (I) are also included in the scope of the present invention.

In the above-mentioned definition of Z, the term "alkyl" includes straight and branched 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, etc.,; the above-mentioned "lower alkyl" may be straight or branched saturated hydrocarbons having from 1 to 6 atoms ugly; the term "halogen" refers to atoms of halogen of atomic weight less than 127, i.e., by fluorine, chlorine, bromine and iodine.

Such compositions can be used to inhibit the growth of cancer tumors and other tumors in humans or animals by introducing an effective amount either orally, rectally, topically, or parenterally, intravenously, or by injection into the tumor. These compositions do not impact significantly on healthy cells than adriamycin, which has a harmful effect on healthy cells.

These compositions are also used for the treatment of viral diseases.

Detailed description of the invention

A. Definitions:

Used in the present description, the term "comprising" means that the pharmaceutical compositions of the present invention can be used in conjunction the various components. Accordingly, the terms "consisting essentially of" and "consisting of" are included in the term "comprising".

Used in the present description, the term "pharmaceutically acceptable" component is a component that is suitable for use in humans and/or animals without undue adverse side effects (such deystviya and risk.

Used in the present description, the term "safe and effective amount" refers to that amount of a component that is sufficient to obtain the desired therapeutic response without undue adverse side effects (such as toxicity, irritation or allergic response), commensurate with an acceptable ratio of favorable actions and risk, provided the application in accordance with the present invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal that is being treated, duration of treatment, the nature of concurrent therapy (if there is one) and the specific formulations employed and the structure of the compounds or their derivatives.

Used in the description, the term "pharmaceutical salts accession" is a salt of anticancer compounds with an organic or inorganic acid. These preferred acid additive salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, t the th in the description, the term "pharmaceutical carrier" is a pharmaceutical acceptable solvent, suspendisse agent or carrier for delivery of anticancer agent to the animal or person. The carrier may be liquid or solid and is selected with the planned manner of administration.

Used in the present description, the term "cancer" refers to all types of cancer or neoplasm or malignant tumors, including leukemia, which detect in mammals.

Used in the present description, the term "cancer connection" represents 1H-1,2,4-triazole and their salts. Specific 1H-1,2,4-triazole described in detail below. Preferred substances are the products sold by Janssen Pharmaceutica NV (Belgium) under the trade names "propiconazole(propiconazole).

Used in the present description, the term "virus" includes viruses that cause disease (viral infection) in humans and other warm-blooded animals, such as HIV, herpes viruses, influenza and rhinoviruses.

Century Anticancer compounds

Anti-cancer compounds are derivatives of 1H-1,2,4-triazole, which are known for their antifungal activities. They are the substances that are used to prevented the last of the group, consisting of CH2-CH2-, -CH2-CH2-CH2-, -CH (CH3)-CH(CH3) and CH2-CH(alkyl) where the specified alkyl has from 1 to about 10 carbon atoms; and Ar is a member selected from the group consisting of phenyl, substituted phenyl, teinila, halothane, naphthyl and fluorenyl, where "substituted phenyl" means a phenyl radical, having from 1 to 3 substituents independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, cyano and nitro. Therapeutically active acid additive salts of the aforementioned compound (I) are also included in the scope of the present invention.

In the above-mentioned definition of Z, the term "alkyl" includes straight and branched 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, etc.,; the above-mentioned "lower alkyl" may be straight or branched 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 the like alkali; and the term "halogen" refers to atoms of halogen of atomic weight less than 127, i.e., by fluorine, x the content of inorganic fillers, and inorganic acids.

Preferred derivatives include

1-[2-(2,4-dichlorophenyl)-1,3-dioxolane-2-ylmethyl]-1H-1,2,4-triazole;

1-[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole;

1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane-2-ylmethyl]-1H-1,2,4-triazole;

1-[2-(2,4-dichlorophenyl) -4-propyl-1,3-dioxolane-2-ylmethyl]-1H-1,2,4-triazole;

1-[2-(2,4-dichlorophenyl)-4-pentyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole and their therapeutically active acid additive salt.

These compounds are prepared in accordance with the method described in U.S. patent N 4079062, issued March 14, 1978 Van Reet et al.

It is believed that these specific substances have the ability to reduce tumor or significantly reduce their growth, due to its ability to inhibit the synthesis of sterols.

C. Dosage

In the method of the present invention can be any suitable dosage. The type of disease (cancer, leukemia or virus), the connection carrier and the amount will vary widely depending on the species of warm-blooded animal or human body weight and tumor being treated. Usually are appropriate dose of between about 2 milligrams (mg) per kilogram (kg) of body weight and priblem, doses for humans are lower than for a small warm-blooded mammals, such as mice. The standard form can be a single compound or mixtures thereof with other compounds or other compounds, any abscopal cancer. A standard form may also include diluents, fillers, carriers, etc., This unit may be in solid form or in gel form, such as pills, tablets, capsules, etc., or in liquid form suitable for oral, rectal, local, intravenous injection or parenteral administration or for injection into the tumor or the surrounding tumor tissue.

D. forms of delivery dose

Anti-cancer compounds are usually mixed with a pharmaceutically acceptable carrier. This carrier can be solid or liquid, and its type is usually chosen depending on the method of introduction. The active agent may be administered together in the form of tablets or capsules, in the form of agglomerated powder or in liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily manufactured and thus, making them easy to swallow or chew; other solid forms include granules and nerazpakovanno the interacting agents, colouring agents, flavouring agents, agents that cause flowability, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions, again composed of nishiuchi granules and effervescent preparations, again composed of effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspendresume agents, diluents, sweeteners, thickening agents, and melting agents. Oral dosage forms optionally contain flavoring agents and dyes. Parenteral and intravenous forms will include inorganic substances and other materials that make them compatible with the selected type of injection or delivery system.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used to create oral dosage forms of the present invention described in U.S. patent N 3903297 issued by Robert September 2, 1975, Technology and composers is 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).

E. treatment

The treatment can be any suitable method which is effective for treating a particular type of cancer or virus that may need treatment. Treatment can be an oral, rectal, local, parenteral or intravenous injection, or by injection into the tumor, etc., a Method using an effective amount also varies depending on the tumor that is being treated. Believe that the preferred method of administration of the compounds of warm-blooded animals will parenteral treatment by intravenous, subcutaneous or intramuscular injection of compounds 1H-1,2,4 - triazole, made with an appropriate carrier, additional cancer by inhibiting compound or compounds or diluent to facilitate the use of.

A method of treating viral infections can also be oral, rectal, local, parenteral or intravenous administration.

Studies in vitro.

The following examples are illustrative and do not constitute limitations of the present invention.

Tumor cells of the colon (NT from the American type culture collection (ATSS) and breast cancer (MG of cell lines from ATSS) were cultured in minimum essential medium Needle (Eagle) with 10% serum fetal cows. Tumor cells of the lung (from A549 cell lines ATCC) were cultured in medium Ham F12 (ham F12) with 10% serum fetal cows.

Tumor cells were passively and seeded in culture flasks at desired densities of cells. Culture medium decantation and cell layers washed twice with saline phosphate buffer (FSE). The cells were trypsinization and was ground into powder before planting the bulb. Unless otherwise specified, the cultures were incubated at 371oC in humidified atmosphere containing 51% of the carbon dioxide in the air. Cultures were incubated until then, until he reached 50-80% of confluently.

Cells were perseval, when the layer in the vial stanovilsya solution was added trypsin, to cover the cell layer. The trypsin solution was removed after 30-60 minutes and the flask incubated at room temperature for two to six minutes. When 90% of the cells became displaced, was added to the growth medium. The cells were removed by rubbing and transferred to a sterile centrifuge tube. Determined the concentration of cells in suspension and properly it was diluted to obtain a density of 5 000 cells/ml Cells were perseval inscribed in the wells of 96-well plates for biological research (200 microliters cell suspension per well). All remaining wells were added to the FSE to maintain humidity. The tablets are then incubated overnight before processing the test connection.

Each dose of the test compounds was investigated by processing a quadruple holes culture 100 Microlitre each dilution. Wells, designated as controls solvent, received an additional 100 microlitres control of methanol; the negative control wells received an additional 100 microlitres manufacturing environment. The remaining holes that were not processed the test compound or the environment, was added to the FSE. The tablets are then incubated for about 5 days.

the processing environment was diluted MTT 0.5 mg/ml of this dilution was filtered through a filter of 0.45 μm to remove nerastvorim crystals. Wednesday decantation of the holes tablets for biological research. Immediately after that, all experimental wells, with the exception of two raw empty holes, added 2 000 microlitres filtered solution of MTT. The two blank wells were added 200 microliters manufacturing environment. The tablets were returned to the incubator for about 3 hours. After incubation, the medium containing MTT, decantation. To each well was added an excess of the environment, and tablets shaking at room temperature for approximately 2 hours.

In each well was measured by the absorption at 550 nm (OD550with the help of the apparatus for reading tablets Mach company Molecular Devices (Menio Park, CA).

Expected average OD550for holes and control of the solvent and for each dilution of the test compounds, as well as for each of the empty holes and positive control. The average OD550for the empty holes subtracted from the average value for the holes of the control solvent and holes of the test compounds, respectively receiving the corresponding average OD550.

% of control = [(adjusted average OD550dilution of the test compound): (adjusted is as a semi-log graphs with % control on the y axis (linear) and the concentration of the test compounds on the x-axis (logarithmic). EU50was interpolable from the graphs for each of the test compounds.

For each of the test compounds, which was introduced in methanol, received individual responses for data correction methanol.

As a positive control was used adriamycin. In all cases it appeared to be more toxic than any of the tested substances on one or two logarithm. Adriamycin is one of the most potent agents that are currently in use, and has significant side effects. Peak plasma concentrations of other, quite effective chemotherapeutic agents, can be 10-50 times higher than the concentration of adriamycin. EU50represents the concentration that will kill 50% of cells.

These experiments showed that these compositions effectively kill tumor cells without affecting significantly on healthy cells. They are more secure than adriamycin.

1. Pharmaceutical composition having antitumor and antiviral activity, for the treatment of cancer or viral infection, characterized in that it includes a safe and effective amount of

< / BR>
where Z represents alkylene,>)-, CH2-CH(alkyl) where the specified alkyl has from 1 to 10 carbon atoms;

Ar is a representative selected from the group consisting of phenyl, substituted phenyl, teinila, halogentated, naphthyl and fluorenyl,

and pharmaceutically acceptable carrier.

2. The pharmaceutical composition according to p. 1, wherein said 1H-1,2,4-triazole selected from the group consisting of:

1-[2-(2,4-dichlorophenyl)-1,3-dioxolane-2-ylmethyl]-1H-1,2,4-triazole,

1-[2-(2,4-dichlorophenyl)-4-methyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole,

1-[2-(2,4-dichlorophenyl)-4-ethyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole,

1-[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole,

1-[2-(2,4-dichlorophenyl)-4-pentyl-1,3-dioxolane-2-ylmethyl] -1H-1,2,4-triazole,

and their pharmaceutically acceptable salts accession acids.

3. The pharmaceutical composition according to p. 2, characterized in that the specified pharmaceutically acceptable salts accession acids are salts of joining pharmaceutically acceptable acids and their salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, tartratami, malatov, malatov, citrates, benzoates, salicylates, ascorbates and mixtures thereof.

5. The method according to p. 4, characterized in that the specified 1H-1,2,4-triazole is administered orally, enterline, intravenous, peritoneal, parenterally or by injection into the tumor.

6. The method according to p. 4, characterized in that the specified 1H-1,2,4-triazole is administered in solid form, where this solid form includes a carrier selected from the group consisting of lactose, sucrose, gelatin and agar.

7. The method according to p. 4, characterized in that the specified 1H-1,2,4-triazole is administered in liquid form, with specified liquid dosage form selected from the group consisting of aqueous solutions, alcohol solutions, emulsions, suspensions, suspensions recovered from nishiuchi or effervescent preparations and suspensions in pharmaceutically acceptable fats or oils.

8. The composition in the form of a standard form with antitumor and antiviral activity, for the treatment of cancer and viral infections in animals or humans, containing a safe and effective amount of 1H-1,2,4-triazole under item 1 or 2.

9. A method of treating viral infections in warm-blooded mammals, characterized in that VK is different, however, what malignant tumor is breast cancer, colon cancer or lung cancer.

11. The method according to p. 9, wherein the viral infection is influenza or rhinoviral infection.

 

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R3- R5-R4, -R6-R4or-R7-R4< / BR>
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< / BR>
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