MXPA99006961A - Kit for inhibiting the growth of cancers, comprising a chemotherapeutic agent and a benzimidazole, and optionally a potentiator - Google Patents

Abstract

A method for inhibiting the growth of tumors and cancers in mammals comprising administering a chemotherapeutic agent to significantly reduce the tumor in mass and then administering a benzimidazole derivative. Potentiators can also be included in the benzimidazole composition.

Description

CASE TO INHIBIT THE GROWTH OF CANCERES, WHICH UNDERSTANDS A CHEMOTHERAPEUTIC AGENT AND A BENCIMIDAZOL, AND OPTIONALLY A POTENTIAL TECHNICAL FIELD The present invention relates to a method for inhibiting the growth of cancers and tumors in mammals. Particularly in humans and warm-blooded animals. The method involves the sequential administration of chemotherapeutic agents that reduce tumor size, and a benzimidazole derivative, preferably carbendazim or 2-methoxycarbonylaminobenzimidazole, in any order.

BACKGROUND OF THE INVENTION Cancers are a leading cause of death in animals and humans. The exact cause of the cancer is not known, but the relationships between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of cancers and tumors have been demonstrated by a number of researchers. It has been shown that many types of chemotherapeutic agents are effective against cancers and tumor cells, but unfortunately, many of these agents also destroy normal cells. Despite advances in the field of cancer treatment, the main therapies to date are surgery, radiation and chemotherapy. The chemotherapeutic approaches are said to fight cancers that have metastases, or some that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, ie, those whose cells are dividing rapidly. The exact mechanism for the action of these chemotherapeutic agents is not always known. On the other hand, while some chemotherapeutic agents reduce tumor mass significantly, after treatment, unfortunately they can not be administered again to the same patient when the tumor returns, as is usually the case. Some can only be administered once in the course of a life, others require a delay of several mo or years between treatments. Clearly, the development of materials targeting tumor cells due to some specificity unique to them would be an important discovery. Alternatively, materials that were cytotoxic to tumor cells while exerting mild effects on normal cells would be desirable. It has been found that benzimidazoles are especially effective in suppressing the growth of cancers and tumors. The use of these benzimidazoles in sequential combination with other chemotherapeutic agents that are effective in decreasing tumor volume is a novel treatment method. The preferred method involves first reducing the volume or reducing the tumor mass with a cytotoxic agent, and then administering the benzyl idazole. It is an object of this invention to provide an anti-cancer therapy comprising administering a chemotherapeutic agent first, to reduce the tumor mass, and then administering a benzimidazole derivative defined herein, to maintain or destroy the cancer. The agents can also be administered with the benzimidazole first and then the chemotherapeutic agent. The benzimidazole can be administered in conjunction with an enhancer.

These and other objects will become apparent from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE INVENTION The present invention describes a method for treating cancer in mammals, and in particular, warm-blooded and human animals, which comprises administering a chemotherapeutic agent that significantly reduces the mass of the tumor or cancer, and then administering a safe and effective amount of a benzimidazole selected from the group consisting of: wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms, or alkoxy of less than 7 carbon atoms; n is a positive integer less than 4; And it is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen, or an alkyl group of 1 to 8 carbon atoms, or CONHR3, and R3 is alkyl of less than 7 carbon atoms, preferably butyl or isobutyl, and R2 is 4-thiazolyl, NHCOORi, wherein Ri is an aliphatic hydrocarbon of less than 7 carbon atoms, and preferably an alkyl group of less than 7 carbon atoms. Preferably the compositions are: wherein R is hydrogen or C0NHR3, and R3 is alkyl of less than 7 carbon atoms, preferably butyl or isobutyl, or an alkyl of 1 to 8 carbon atoms, and R2 is selected from the group consisting of 4-thiazolyl, or NHCOORi, wherein Ri is methyl, ethyl or isopropyl, and the non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids. The most preferred compounds are 2- (4-thiazolyl) enimidazole, methyl- (butylcarbaoyl) -2-benzimidazolcarbamate and 2-methoxycarbonylamino-benzimidazole, and those wherein Y is chloro. These compositions can be used to inhibit the growth of cancers and other tumors in humans or animals, by the administration of an effective amount either orally, rectally, topically or parenterally, intravenously or by injection into the tumor. Enhancers with this composition can also be used.

DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS As used herein, the term "comprises" means that various components can be used together in the pharmaceutical composition of this invention. Accordingly, the terms "consists essentially of" and "consists of" are incorporated in the term comprises. As used herein, a "pharmaceutically acceptable" component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) in proportion to a benefit / benefit ratio. reasonable risk. As 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, and allergic response) in proportion to a reasonable benefit / risk ratio, when it is 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, a "pharmaceutical addition salt" is a salt of the benzimidazoles and their derivatives 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. As used herein, a "pharmaceutical carrier" is a pharmaceutically acceptable solvent, suspending agent, or vehicle, including liposomes, for delivering the anti-cancer agent to the animal or human. The carrier can be liquid or solid, and is selected with the manner of administration planned in mind.

As used herein, "cancer" refers to all types of cancers or neoplasms or malignancies found in mammals, including tumors and leukemias. As used herein, the "Benzimidazoles, and their salts" are described in detail below. Preferred materials are the products sold under the names "thiabendazole ™," "benomyl" and "carbendazim" by BASF and Hoechst, Du Pont and MSD-AgVet. As used herein, "chemotherapeutic agents" includes agents that interact with DNA, antimetabolites or agents that interact with tubulin, hormonal agents, and others, such as asparaginase or hydroxyurea. As used herein, "enhancers" are materials such as tripolidine and its cis isomer and procodazole, which are used in combination with chemotherapeutic agents and benzimidazoles. As used herein, "significantly reduces" means reducing the tumor mass by a significant amount. This will usually be less than 50% of its original mass, and preferably reduce the mass to undetectable amounts.

B. BENZMIDAZOLE COMPOUNDS Benzimidazole derivatives are known for their antifungal activity. Surprisingly it has been found that these compounds can also cause apoptosis in cancer cell lines. Apoptosis is the specific cell death that differs from necrosis. The majority of cancer cells can live indefinitely; Cancer cells are often referred to as immortalized cell lines. Therefore, the ability to induce apoptosis is very important. The compounds have the following structure: wherein X is hydrogen, halogen, alkyl of less than 7 carbon atoms, or alkoxy of less than 7 carbon atoms; n is a positive integer less than 4; And it is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen, or C0NHR3, and R3 is alkyl of less than 7 carbon atoms, preferably butyl or isobutyl, or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl, or NHCOORi, in where Ri is an aliphatic hydrocarbon of less than 7 carbon atoms, and preferably an alkyl group of less than 7 carbon atoms. Preferably the compositions are: wherein R is hydrogen or C0NHR3, and R3 is alkyl of less than 7 carbon atoms, preferably butyl or isobutyl, or an alkyl of 1 to 8 carbon atoms, and R2 is selected from the group consisting of 4-thiazolyl, or NHCOORi, wherein Ri is methyl, ethyl or isopropyl, and the non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids. The most preferred compounds are 2- (4-thiazolyl) enimidazole, methyl- (butylcarbamoyl) -2-benzimidazolcarbamate and 2-methoxycarbonylamino-benzimidazole, and the compounds wherein Y is chloro and X is hydrogen. These compounds are prepared according to the method described in U.S. No. 3, 738,995, assigned to Ada s et al., June 12, 1973. Thiazolyl derivatives are prepared according to the method described in Brown et al., J. Am. Chem. Soc, 83, 1764 (1961) and Grenda et al. J. Org. Chem. 30, 259, (1965).

C. CHEMOTHERAPEUTIC AGENTS Chemotherapeutic agents are generally grouped as agents that interact with DNA, antimetabolites, agents that interact with tubulin, hormonal agents, and others such as asparaginase or hydroxyurea. Each of the groups of chemotherapeutic agents can be further divided by the type of activity or compound. The chemotherapeutic agents used in the sequential method in combination with benzimidazoles include primarily members of the groups of agents that interact with DNA, antimetabolites, agents that interact with tubulin. For a detailed discussion of chemotherapeutic agents and their method of administration, see Dorr, et al., Cancer Chemotherapy Handboo, 2a. edition, pages 15-34, Appleton & Lange (Connecticut, 1994) incorporated herein by reference.

To reduce the mass of the tumor or stop the growth of the cancer cells, the chemotherapeutic agent must prevent the cells from replicating, and must also interfere with the ability of the cells to maintain themselves. The agents that do this are primarily the agents that interact with DNA, such as Cisplatin, and the agents that interact with tubulin. Agents that interact with DNA include alkylating agents, for example Cisplatin, Cyclophosphamide, Altretamine; the breaking agents of the DNA strand, such as Bleomycin; inhibitors that are intercalated with topoisomerase II, for example Dactinomycin and Doxorubicin); inhibitors that do not intercalate from topoisomerase II such as Etoposide and Teniposide; and the binder of the minor groove of the Plcamidin DNA. Alkylating agents form covalent chemical adducts with cellular DNA and RNA, and with smaller protein and amino acid molecules, glutathione and similar chemical compounds. Generally, these alkylating agents react with a nucleophilic atom in a cellular constituent, such as an amino, carboxyl, phosphate, sulfhydryl group in nucleic acids, proteins, amino acids, or glutathione. The mechanism and role of these alkylating agents in cancer therapy are not very well understood. Typical alkylating agents include: Nitrogenated mustards, such as Chlora bucil, Cyclophosphamide, Isofamide, Mechlorethamine, Melphalan, Uracil mustard; aziridines such as Tiotepa; phonate metansul esters such as Busulfan; nitrous ureas, such as Carmustine, Lomustine, Streptozocin; platinum complexes, such as Cisplatin, Carboplatin; biorreductive alkylating agents, such as Mitomycin, and Procarbazine, Dacarbazine and Altretamine; DNA strand break agents that include Bleomycin; inhibitors of DNA topoisomerase II including the following: Intercalators, such as Amsacrine, Dactinomycin, Daunorubicin, Doxorubicin, Idarubicin and Mitoxantrone; Non-intercalary, such as Etoposide and Teniposide. The binder of the minor groove of DNA is Plicamycin. Antimetabolites interfere with the production of nucleic acids by one or the other of two main mechanisms. Some of the 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 anabolic pathways of the nucleotide. These analogs can then be replaced within the DNA and RNA instead of their normal counterparts. Antimetabolites useful herein include: folate antagonists such as methotrexate and trimetrexate, pyrimidine antagonists, such as Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, and Floxuridine. purine antagonists including mercaptopurine, 6-thioguanine, fludarabine, and pentostatin; modified sugar analogues, which include cyctrabin, fludarabine; inhibitors of ribonucleotide reductase including hydroxyurea. The agents that interact with tubulin act by binding to specific sites on tubulin, a protein that polymerizes to form cellular microtubules. Microtubules are critical units of the cellular structure. When interactive agents bind on the protein, the cell can not form microtubules. Agents that interact with tubulin include vincristine and vinblastine, both alkaloids, and paclitaxel. Adrenal cortical 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 divisions and interrupt DNA synthesis. These compounds include prednisone, dexamethasone, methylprednisolone, and prednisolone. Hydroxyurea appears to act primarily through the inhibition of the enzyme ribonucleotide reductase.

Asparaginase is an enzyme that converts asparagine into non-functional aspartic acid and thus blocks the synthesis of proteins in the tumor. Hormone agents and luteinizing hormones are not usually used to substantially reduce the mass of the tumor. However, they can be used in conjunction with chemotherapeutic agents or benzimidazoles. Hormone blocking agents are also useful in the treatment of cancers and tumors.

They are used in hormonally susceptible tumors, and are usually derived from natural sources. These include: estrogens, conjugated estrogens and ethinyl estradiol and diethylstilbestrol, chlorotrianiseno and idenestrol; progestins such as hydroxyprogesterone caproate, medroxyprogesterone, and mage trol; androgens such as testosterone, testosterone propionate; fluoximestrone, methyl tert-butyl; Hormone agents that release luteinizing hormone or hormone antagonists that release gonadotropin 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 Tamosifen, antiandrogen agents such as flutamide; and anti-adrenal agents such as mitotane and aminoglutethimide.

D. POTENTIATORS "Enhancers" can be any material that improves or increases the efficacy of the pharmaceutical composition and / or acts on the immune system. One enhancer is triprolidine and its cis isomer, which are used in combination with chemotherapeutic agents and benzimidazole. Triprolidine is described in US No. 5,114,951 (1992). Another enhancer is procodazole, 1H-benzimidazole-2-propanoic acid; [β- (2-benzimidazole) propionic acid; and 2- (2-carboxyethyl) -benzimidazole; propazole]. Procodazole is a non-specific active immunoprotective agent against viral and bacterial infections, and may be used with the compositions claimed herein. The enhancers can improve the efficacy of the benzimidazole compounds, and can be used in a safe and effective amount. These combinations can be administered to the patient or animal by oral, rectal, topical or parenteral administration. Antioxidant vitamins such as ascorbic acid, beta-carotene, vitamin A and vitamin E can be administered with the compositions of this invention.

E. DOSAGE Any suitable dosage can be given in the method of the invention. The type of compounds and carriers and the amount will vary widely, depending on the species of the warm-blooded or human animal, body weight, and cancer, or tumor being treated. The range and relationship of the chemotherapeutic agent and the benzimidazoles and their derivatives used will depend on the type of chemotherapeutic agent and the cancer being treated. Generally, for benzimidazoles a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight and about 4000 mg per kg of body weight is adequate. Higher dosages, up to 6000 mg / kg, can also be used. Preferably, from 15 mg to about 3000 mg / kg of body weight is used for the benzimidazoles. For chemotherapeutic agents, a lower dosage may be appropriate, that is, from about 0.01 mg / kg of body weight to about 400 mg / kg of body weight, although amounts of up to 1500 mg / kg of body weight may be used. . Generally, the dosage in man is lower than for small warm-blooded mammals, such as mice. A dosage unit may comprise a single compound or mixtures thereof with other compounds or other compounds that inhibit cancer. 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, capsules, liposomes and the like, or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration, or injection into or around the tumor.

F. DOSAGE SUPPLY FORMS Benzimidazoles and their derivatives, and chemotherapeutic agents are typically mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or a liquid, or a liposome, and the type is generally selected based on the type of administration being used. The active agent can be co-administered in the form of a tablet or capsule, liposome, or as an agglomerated powder, or in liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be formulated easily, and can be easily made to swallow or chew; other solid forms include granules, and loose 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 water, pharmaceutically acceptable oils and fats, 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. Such liquid dosage forms may contain, for example, solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and suitable melting agents. Oral dosage forms optionally contain flavors and coloring agents. Parenteral and intravenous forms would also include minerals and other materials to make them compatible with the type of injection or delivery system selected. Specific examples of acceptable pharmaceutical carriers and excipients that can be used to formulate the oral dosage forms of the present invention are described in US Patent No. 3,903,297 issued to Robert, published September 2, 1975. The techniques and compositions to make 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 Phar aceutical Dosage Forms 2nd Edition (1976).

G. METHOD OF TREATMENT The method of treatment can be any suitable method that is effective in the treatment of the cancer type or particular tumor that is being treated. The treatment may be oral, rectal, topical, parenteral or intravenous administration, or by injection into the tumor and the like. The method of applying an effective amount also varies, depending on the tumor that is being treated. It is believed that parenteral treatment by intravenous, subcutaneous or intramuscular application of the benzimidazole compounds, formulated with an appropriate carrier, an additional compound or compounds that inhibit cancer, or diluent to facilitate the application will be the preferred method of administering the compounds to warm-blooded animals. Preferably, the chemotherapeutic agent is administered first, to reduce the size of the cancer or the mass of the tumor significantly. Usually this will take from 3 to about 14 days. The reduction in the tumor or concentration of cancer cells will be less than 50% of the original concentration. Radiation therapy can be used in conjunction with the. chemotherapeutic treatment. Once the tumor has been reduced, benzimidazole is administered. Due to the relative safety of this material, it can be administered for 14 days to 365 days, when needed, to maintain its effectiveness in reducing the resurgence of cancer. The following example is illustrative, and is not intended to be limiting of the invention.

Example 1 In a mouse model for breast cancer, cytoxan was administered to the animals to significantly reduce the tumor mass. Carbendazim was administered to the mice at 4,000, 5,000 and 6,000 mg / kg of body weight in a separate leg. The tumor continued to decrease in size, and its resurgence was limited even after 180 days, with the treatment of carbendazim. The growth was dependent on the dose. The control treated with cytoxan had a resurgence of the tumor after 100 days; and when stimulated with estrogen on day 115, it had a rapid resurgence. Even with estrogen stimulation, animals treated with carbendazim did not have a significant change in tumor mass. After 130 days, carbendazim was administered to the mice (at 4,000, 5,000 and 6,000 mg / kg body weight) who had been treated with cytoxan. The tumor continued to decrease in size, and resurgence was limited even after 180 days.

Claims (10)

1. RE IV INDICATIONS 1. A medicine package for treating cancer, characterized in that it comprises combining two drugs in a kit form, the first drug is a safe and effective amount of a chemotherapeutic agent, which is in such a dosage that it is first administered for reducing cancer significantly, and wherein the second medicament is a safe and effective amount of a second pharmaceutical composition used to continue treating the cancer, comprising a benzimidazole selected from the group consisting of: "£ where * X is hydrogen, halogen, alkyl of less than 7 carbon atoms, or alkoxy of less than 7 carbon atoms, n is a positive integer less than 4, and is hydrogen, chlorine, nitro, methyl or ethyl, and R is hydrogen, or CONHR3, wherein R3 is alkyl of less than 7 carbon atoms, or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOORx, wherein Rx is an aliphatic hydrocarbon of less than 7 carbon atoms, or the pharmaceutically acceptable inorganic or inorganic acid addition salts.
2. 2. A kit according to claim 1, characterized in that the kit contains from about 0.5 mg / kg of body weight to about 400 mg / kg of body weight of the chemotherapeutic agent drug, and from about 2 mg / kg of weight body weight to about 400 mg / kg body weight of the benzimidazole medication.
3. 3. A kit according to claim 1 or 2, characterized in that the benzimidazole medicament is selected from the group consisting of those having the formula: wherein R is hydrogen, and R2 is selected from the group consisting of NHCOORi, wherein Ra is methyl, ethyl or isopropyl, and pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
4. 4. A kit according to claim 1, 2 or 3, characterized in that the chemotherapeutic agent medicament is selected from the group consisting of Agents that interact with DNA, Antimetabolites or Agents that interact with Tubulin.
5. 5. A kit according to claim 4, characterized in that the chemotherapeutic agent medicament is selected from the group consisting of Asparaginase, Hydroxyurea, Cisplatin, Cyclophosphamide, Altretamine; Bleomycin, Dactinomycin, Doxorubicin, Etoposide, Teniposide, and Plcamidine.
6. 6. A kit according to claim 4, characterized in that the drug of chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridine, CB3717, Azacitidine, Cytarabine, Floxuridine, Mercaptopurine, 6-Thioguanine, Fludarabine, Pentostatin, Cytarabine, and Fludarabine
7. 7. A kit according to claim 4, 5 or 6, characterized in that the chemotherapeutic agent medicament is in the form of a liposome.
8. 8. A kit according to claim 7, characterized in that the benzimidazole medicament is in a liquid form selected from the group consisting of aqueous solutions, alcohol solutions, emulsions, suspensions, and reconstituted suspensions from non-effervescent and effervescent preparations, and suspensions. in pharmaceutically acceptable fats or oils.
9. 9. A kit according to claim 7, characterized in that the chemotherapeutic agent medicament is selected from Taxol or Cisplatin, and wherein the second medicament is a pharmaceutical composition comprising 2-methoxycarbonylaminobenzimidazole or the pharmaceutically acceptable organic or inorganic acid addition salts. acceptable therefrom, and wherein the kit is for treating breast cancer in warm-blooded mammals.
10. 10. A kit according to claim 9, characterized in that the chemotherapeutic agent medicament is in a dosage form for a treatment from 3 to 14 days, and wherein the 2-methoxycarbonylaminobenzimidazole is in a dosage for about 3 days to about 365 days .