SK168697A3 - A medicament for the treatment of leukemia - Google Patents

Abstract

A pharmaceutical composition for the treatment of leukemia in mammals is disclosed. The particular fungicide used is a benzimidazole derivative of formula (I), 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 of less than 4; Y is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOOR1 wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms or the pharmaceutically acceptable inorganic or acid addition salts thereof.

Description

Disclosed is a pharmaceutical composition for treating leukemia in l'udf comprising a ftingicide which is a benzimidazole derivative of formula (I) 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 of less than 4, Y is hydrogen, chloro, nitro, methyl or ethyl, and R is hydrogen or (C 1 -C 8) alkyl and R ₂ is 4-thiazoles 1 or NHCOOR 1, where R is | is an aliphatic hydrocarbon having less than 7 carbon atoms or pharmaceutically acceptable addition salts thereof with inorganic or organic acids.

(I)

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A pharmaceutical composition for the treatment of leukemia

Technical field

The invention relates to a pharmaceutical composition which is useful for the treatment of leukemia, in particular in humans and warm-blooded animals. Said composition comprises a benzimidazole derivative.

BACKGROUND OF THE INVENTION

Cancer diseases, including leukemia, are at the forefront of the causes of death in animals and humans. The exact cause of leukemia is unknown, but apparently these causes include certain activities such as smoking or exposure to carcinogens - the incidence of certain types of leukemia and tumors has been shown by many researchers.

Many types of chemotherapeutic agents have been shown to be effective against leukemia, but not all types of leukemic and tumor cells respond positively to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism of action of these chemotherapeutic agents is not yet known.

Despite advances in the treatment of cancer and leukemia, the main therapies are radiation, chemotherapy and bone marrow transplantation. Chemotherapeutic approaches have been reported for treated steroid tumors that are extremely active. Cytocidal or cytostatic agents work best on large growth factor cancer tumors, i. those whose cells divide rapidly. Hitherto, hormones, especially estrogen, progesterone and testosterone, and some antibiotics produced by various microbes, alkylating agents and antimetabolites, have been the predominant part of the therapy available to oncologists. Ideally, cytotoxic agents that are specific to leukemia, cancer and tumor cells without affecting normal cells would be extremely desirable. Unfortunately, no agents have been found, and agents that are targeted specifically at rapidly dividing cells (both diseased and normal normal cells) are being used.

It is quite clear that the development of substances that target leukemic cells would be a first-rate scientific discovery due to its unique specificity. Alternatively, substances that are cytotoxic to leukemic cells would be desirable, with only moderate effects on normal cells.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a pharmaceutical composition which is effective in the treatment of leukemia while showing little or no effect on normal cells.

More specifically, it is an object of the present invention to provide a composition comprising a pharmaceutically acceptable carrier and a benzimidazole derivative as defined herein, together with a method of treating cancer.

A pharmaceutical composition for treating mammals, particularly warm-blooded animals and humans, which is effective against leukemia comprises a pharmaceutical carrier and an effective amount of a compound selected from the group consisting of compounds of Formula I:

Y

(I), 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, Y is hydrogen, chloro, nitro, methyl or ethyl, and R is hydrogen or an alkyl group having 1 to 8 carbon atoms and R ₂ is 4-thiazolyl, NHCOOR 1, wherein R _x is an aliphatic hydrocarbon having less than 7 carbon atoms and preferably an alkyl group having less than 7 carbon atoms is claimed. Preferred compositions are compounds of formula II:

(II) wherein R is alkyl of 1 to 8 carbon atoms and R ₂ is selected from the group consisting of 4-NHCOOR where _R is methyl, ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acid addition salts, and both with organic and inorganic acids. Most preferred compounds are 2- (4-thiazolyl) -benzimidazole, methyl (butylcarbamoyl) -2-benzimidazolecarbamate and 2-methoxycarbonylaminobenzimidazole, and such compounds of this type wherein Y is chloro.

These compositions can be used to inhibit the growth of leukemic cells in humans or animals by administering an effective amount either orally, rectally, externally or parenterally, or intravenously. These compositions do not significantly affect healthy cells.

A. Definitions

As used herein, the term comprising means that various ingredients may be combined in the pharmaceutical composition of the present invention. The terms consisting essentially of and consisting of are incorporated into the term comprising.

As used herein, a pharmaceutically acceptable substance is one that is suitable for use in humans and / or animals without causing undesirable side effects (such as toxicity, irritation, and allergic reaction) comparable to a good benefit / risk ratio .

As used herein, the term safe and effective amount means an amount of a component sufficient to elicit the desired therapeutic response without causing harmful side effects (such as toxicity, irritation, or allergic reaction) appropriately with respect to an acceptable benefit to benefit ratio. risk using the method of the invention. This safe and effective amount will, of course, vary with such factors as, in particular, the condition to be treated, the physical condition of the patient, the species of mammal being treated, the course of treatment, the nature of concomitant therapy (if any) and the specific formulation and structure used. .

As used herein, the term pharmaceutical addition salts means an anti-leukemic compound with an organic or inorganic salt. These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malate, citrates, benzoates, salicylates, ascorbates and the like.

As used herein, the term pharmaceutical carrier is a pharmaceutically acceptable solvent, suspending agent, or ointment base for delivery of an anti-leukemia agent to an animal or human. The carrier may be liquid or solid and is selected according to the intended mode of administration of the composition.

As used herein, the term cancer or leukemia refers to all types of cancer or neoplasmic or malignant diseases in which healthy blood cells or bone marrow that produce blood cells found in mammals are attacked.

As used herein, the term "anti-leukemia compounds" are benzimidazoles as described in more detail below. Preferred substances are the products sold under the names "thiabendazole ^R ", "benomyl *" and "carbendazim *" by BASF and Hoechst, DuPont and MSD-AgVet.

B. Anti-Leukemia Compounds

The anti-leukemia compounds are benzimidazole derivatives which are known for their antifungal activity. They are systemic substances used to prevent and destroy mold. These compounds have the following structure - formula I:

(I) 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 of less than 4, Y is hydrogen, chloro, nitro, methyl or ethyl, and R is hydrogen or an alkyl group having 1 to carbon atoms and R _z is 4-thiazolyl, NHCOOR 1, wherein R _x is an aliphatic hydrocarbon having less than 7 carbon atoms and preferably an alkyl group having less than 7 carbon atoms. Preferred are compounds of formula II:

(II) wherein R is C 1 -C 8 alkyl and R 2 is selected from the group consisting of 4-thiazolyl, NHCOOR 1, wherein R 1 is methyl, ethyl or isopropyl, and non-toxic, pharmaceutically acceptable acid addition salts, both with organic and inorganic acids.

Most preferred compounds are 2- (4-thiazolyl) benzimidazole, methyl (butylcarbamoyl) -2-benzimidazolecarbamate and 2-methoxycarbonylaminobenzimidazole and compounds wherein Y is chloro and X is hydrogen.

These compounds are prepared as described in U.S. Pat. No. 3,738,995, issued to Adams et al. on June 12, 1973. The thiazole derivatives are prepared by the method of Brown et al., J. Am. Chem. Soc., 83, 1764 (1961) and Grenda et al., J. Org. Chem., 30, 258 (1965).

C. Dosage

Any suitable suitable dosage may be used in the method of the invention. The type of compound and the carrier and the amount of the compound and the carrier depend largely on the species of warm-blooded animal or human, body weight, and the type of leukemia being treated. In general, a suitable dose is between 2 milligrams (mg) per kilogram (kg) of body weight and 400 mg per kg of body weight. Preference is given to using 15 to 150 mg / kg of body weight. In general, the dose in humans is lower than in small warm-blooded mammals such as mice. A unit dose may contain one compound or a mixture of the compound with other compounds or other substances having leukemia inhibitory activity. The dosage unit may also contain diluents, fillers, carriers and the like. The unit dose may be in solid or gel form, such as pills, tablets, capsules, and the like, or in liquid form for oral, rectal, topical, intravenous injection or parenteral or bone marrow injection or injection. her surroundings.

D. Delivered dosage forms

The anti-leukemic compounds are typically admixed with a pharmaceutically acceptable carrier. The carrier may be a solid or a liquid and its type is generally selected according to the type of administration. The active agent may be co-delivered in the form of tablets or capsules, as an agglomerated powder or in liquid form. Suitable solid carriers include, for example, lactose, sucrose, gelatin or agar. The capsules or tablets may be readily formulated and may be rendered easy to swallow or chew; other solid forms include granules and lumps of powder. Tablets may contain binders, lubricants, diluents, disintegrants, colorants, flavors, flowability and solubility agents. 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 composed of non-effervescent granules, and effervescent formulations of sparkling granules. Such 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 flavoring agents and coloring agents. Parenteral and intravenous forms may also contain minerals and other agents which ensure compatibility with the chosen injection or dosage type.

Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms of the invention are described in U.S. Pat. no. 3, 903, 297, Robert, Ed. 02/09/1975. Methods and compositions for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chap. 9 and 10 (Banker & Rhodes, eds., 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed. (1976).

E. Method of Treatment

The method of treatment may be any suitable method that is effective in treating the particular type of leukemia to be treated. Administration of the medicament may be oral, rectal, topical, parenteral or intravenous, or by injection into the bone marrow. The method of administering an effective amount also greatly depends on the leukemia being treated.

Parenteral treatment by intravenous, subcutaneous or intramuscular administration of 1H1,2,4-triazole compounds formulated with an acceptable carrier, another leukemia inhibiting additive compound, or several such compounds or diluents to facilitate administration is likely to be preferred routes of administration for such administration. of warm-blooded animals.

The following examples are intended to illustrate the invention in more detail, but do not limit its scope or scope.

DETAILED DESCRIPTION OF THE INVENTION

The mice to be tested are selected at random and divided into treatment groups. Five groups are infected with leukemia. Sick animals are given five days of drug dose, then two days not, then another five days of drug and no three days, then doses are given for five days and no dosing is two days. This dosing in an irregular model case is not an ideal regimen, but the results show a positive effect with Carbendazim ™. One group of mice is treated with Cytoxan ™, 2- [bis (2-chloroethyl) -amino-1-oxo-2aza-5-oxosphoridine, the comparator group is treated with canola oil, and three groups are treated with Carbendazine ™ at various concentrations, methyl- ( butylcarbamoyl) -2-benzimidazole. A comparative group that is not treated is also used. Carbendazim ™ is dosed at three concentrations - 4000 mg / kg, 2500 mg / kg and 1000 mg / kg.

Cytoxan ™ is dosed at 125 mg / kg. After 8 days in the untreated group one mouse died, on day 10 eight mice died and on day 11 all mice died. Mice in the Cytoxan ™ group survived more than 21 days. In the high dose group of Carbendazim ™, one mouse died at 14 days, two mice died at 15, 16 and 17 days, and one mouse at 20, 21 and 22 days. The average number of days in this group was 17.3 days. At moderate dosing, two mice died on day 14, four mice on day 15, one mouse on day 16, two mice on day 19, and one mouse on day 21.

The average number of days in this group was 16.5 days. At the lowest dose, two mice died on day 12, 13, 14, and 15, and one died on day 16 and 17. The average number of days in this group was 14.1 days.

Industrial usability

Since the compositions of the present invention are intended for the preparation of a medicament for leukemia, they are important for the pharmaceutical industry.

Claims (6)

A pharmaceutical composition for the treatment of leukemia comprising an effective amount of a compound of formula (I): 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, Y is hydrogen, chloro, nitro, methyl or ethyl, and R is hydrogen or alkyl of 1 to 8 carbon atoms, _Ar2 is 4-thiazolyl or NHCOOR, where _R is an aliphatic hydrocarbon of less than 7 carbon atoms or a pharmaceutically acceptable acid addition salts with inorganic or organic acids. 2. A pharmaceutical composition according to claim 1 comprising a pharmaceutically acceptable carrier and a safe amount of benzimidazole selected from the group consisting of compounds of Formula II: (II) wherein R is hydrogen or C 1 -C 8 alkyl and R ₂ is selected from the group consisting of 4-thiazolyl, NHCOOR 1, wherein R 1 is methyl, ethyl or isopropyl, and pharmaceutically acceptable addition salts thereof with organic or inorganic acids . The pharmaceutical composition of claim 1, wherein the benzimidazole is selected from the group consisting of 2- (4-thiazolyl) benzimidazole, methyl (butylcarbamoyl) -2-benzimidazolecarbamate and 2-methoxycarbonylaminobenzimidazole. Pharmaceutical composition according to claims 1, 2 or 3, characterized in that the pharmaceutically acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malate, citrates, benzoates, salicylates, ascorbates and mixtures thereof. Pharmaceutical composition according to claim 3, characterized in that the benzimidazole is in liquid form, the liquid dose being selected from the group consisting of aqueous solutions, alcoholic solutions, emulsions, suspension solutions and suspensions containing non-effervescent and effervescent products. compositions in pharmaceutically acceptable fats or oils. Pharmaceutical composition according to claim 3, characterized in that the benzimidazole is in solid form, the solid form comprising a carrier selected from the group consisting of lactose, sucrose, gelatin or