MXPA97009530A - Use of bis-1,2,4-triazoles for the manufacture of a medicinal product for the treatment of cance - Google Patents

Abstract

A pharmaceutical composition that inhibits the growth of tumors and cancers in mammals, comprising fungicide, is set forth. The particular fungicide is used as a derivative of 1,3-bis-triazolyl-2-propanol. These compositions are also effective against viral infections

Description

USE OF BI8-1.2.4-TRIAZOLES FOR MANUFACTURING A MEDICINE FOR THE TREATMENT OF CANCERS TECHNICAL FIELD The present invention relates to a pharmaceutical composition that inhibits the growth of cancers and tumors in mammals, in particular in humans and in warm-blooded animals. The composition contains a 1,3-bis-triazolyl-2-propanol derivative.

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 EWI 7 Modern 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-etabolites form the bulk of 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. For the P5? therefore, it is an object of this invention 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, an object of the invention is to provide an anti-cancer composition comprising a pharmaceutical carrier and a 1,3-bis-triazolyl-2-propanol 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 anti-cancer amount, of a compound selected from the group consisting of: wherein R ^ is an alkyl, cycloalkyl (for example cyclopentyl or cyclohexyl), aryl or haloaryl (for example phenyl or 2,4-dichlorophenyl) or aralkyl (for example benzyl) optionally substituted; and metal salts and complexes and ethers or esters thereof, and the pharmaceutically acceptable and non-toxic acid addition salts, both with organic and inorganic acids. Specifically, these bis-triazole derivatives, such as 2- (2,4-dichlorophenyl) -1,3-bis (1H-1, 2, -triazol-1-yl) propan-2-ol and their corresponding analogs thereof - and 4-chlorophenyl and the analogues 2, 4-difluorophenyl, are those that are claimed. These compositions can be used to inhibit the growth of cancers, leukemias and other tumors in humans or animals by administering an effective amount, either orally, rectally, topically or parenterally, intravenously or by injection, to 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 effective against viruses. Therefore, an object of the invention is to provide an effective composition as against HIV, herpes, influenza, rhinovirus and the like.

DETAILED DESCRIPTION OF THE INVENTION A. Definitions: In the sense in which the term is used here r, r. p "comprising" means that various 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 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 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 herein, the term "anticancer compounds" is the 1,3-bis-triazolyl-2-propanols and their salts. The exact 1, 3-bis-triazolyl-2-propanols are described in detail below. Preferred materials are the products sold under the tradenames "fluconazole®" by Pfizer. In the sense used here, "virus" includes F "> ^ I viruses that cause diseases (viral infections) in humans and other warm-blooded animals such as HIV, herpes, influenza and rhinovirus.

B_ ?. Anticancer Compounds Anticancer compounds are derivatives of 1,3-bis-triazolyl-2-propanol which are known for their antifungal activity. They are systemic fungicides that are used to prevent and root fungi. The compounds have the following structure: wherein R 1 is an optionally substituted alkyl, cycloalkyl (for example cyclopentyl or cyclohexyl), aryl or haloaryl (for example phenyl or 2,4-dichlorophenyl) or aralkyl (for example benzyl); and metal salts and complexes and ethers or esters thereof, and pharmaceutically acceptable and non-toxic acid addition salts with both organic and inorganic acids. Specifically, these bis-triazole derivatives such as 2- (2,4-dichlorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and their corresponding analogues of 2- and 4-chlorophenyl and 2,4-difluorophenyl analogues are useful herein. Preferably the composition is 2- (2,4-difluorophenyl) -1, 3- 1", < 17 bis (lH-1, 2,4-triazol-1-yl) propan-2-ol and its pharmaceutically acceptable acid addition salts with both organic and inorganic acids. These compounds are prepared according to the method described in U.S. Patent No. 4, 404,216 issued to Richardson, on September 13, 1983 and British Patent Application No. 2,078,719A published on January 13, 1982 and European Patent Application No. 44,605 published on January 27, 1982 (both assigned to Imperial Chemical Industries Ltd). It is believed that these particular fungicides have the ability to reduce tumors or decrease their growth significantly, due to their ability to inhibit the synthesis of sterols.

C. Dosage Any suitable dose can be administered in the method of the invention. The type of compound and the carrier and the amount will vary widely depending on the species of warm-blooded or human animals, the body weight and the type of tumor, cancer virus or disease 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 adequate. Preferably between 15 mg and approximately 150 mg / kg of body weight is what is used. In general, the dose in man is lower than that used in small warm-blooded mammals such as mice. The dose unit may comprise a single compound or mixtures thereof with other compounds or with other cancer inhibiting compounds. The dosage unit may also comprise diluents, extenders, carriers and the like. The unit may be in the form of solid or gel such as for example pills, tablets, capsules and the like or in liquid form, suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection into or near the tumor itself .

D_i_ 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; Fr > 47 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 water, pharmaceutically acceptable oils and fats, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and / or suspensions reconstituted from granules. non-effervescent and effervescent preparations reconstituted from effervescent granules. These liquid dosage forms may 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. 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, F'Fi? 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 Dosacre Forms 2nd Edition (1976).

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 1,3-bis-triazolyl-2-propanol 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. l'bA 'l

Claims (2)

CLAIMS: 1. A pharmaceutical composition for treating cancers, tumors, and viruses comprising a safe and effective amount of: wherein R 1 is an optionally substituted alkyl, cycloalkyl (for example cyclopentyl or cyclohexyl), aryl or haloaryl (for example phenyl or 2,4-dichlorophenyl) or aralkyl (for example benzyl); and metal salts and complexes and ethers or esters thereof, and pharmaceutically acceptable and non-toxic acid addition salts with both organic and inorganic acids. 2. A pharmaceutical composition according to claim 1, comprising a pharmaceutically acceptable carrier and a safe and effective amount of 1,3-bis-triazolyl-2-propanol selected from the group consisting of: 2- (2,4-dichlorophenyl) -1, 3-bis (1H-1, 2,4-triazol-1-yl) propan-2-ol and its corresponding analog of 2- and 4-chlorophenyl and 2,4-difluorophenyl analogues, and 2- ( 2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol and the pharmaceutically acceptable acid addition salts with both organic and inorganic acids. 3. A pharmaceutical composition according to l'M I claims 1 or 2 to inhibit the growth of tumors and to treat leukemia. 4. A pharmaceutical composition according to claims 1, 2 or 3, wherein the pharmaceutically acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, maleates , citrates, benzoates, salicylates, ascorbates and mixtures thereof. 5. A method for treating cancer and viral infections in warm-blooded animals, comprising administering 2 mg / kg of body weight to 400 mg / kg of a 1,3-bis-triazolyl-2-propanol according to claims 1, 2 or 4. The method according to claim 5, wherein the 1,3-bis-triazolyl-2-propanol is administered orally or enterically, intravenously, parenterally, or by injection into the tumor. A method according to claim 6, wherein the 1,3-bis-triazolyl-2-propanol is administered in a solid form, wherein the solid form includes a carrier selected from the group consisting of lactose, sucrose, gelatin and agar 8. A method according to claim 6, wherein the 1,3-bis-triazolyl-2-propanol is administered in a
1. P ') 41 liquid form, wherein the liquid dose is selected from the group consisting of aqueous solutions, alcohol solutions, emulsions, suspensions and suspensions reconstituted from non-effervescent preparations and effervescent preparations, and suspensions in pharmaceutically acceptable oils or fats. 9. A method according to claims 6, 7 or 8, wherein the pharmaceutically acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, alloys, alatos, citrates, benzoates, salicylates, ascorbates and mixtures thereof. 10. A unit dose composition for treating viral infections and cancer in animals or humans, comprising a 1,3-bis-triazolyl-2-propanol according to claims 1 or
2. 2. P547