JP2767176B2 - Anticancer drug - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anticancer drug comprising a specific carbostyril derivative and 5-fluorouracil.

[0002]

2. Description of the Related Art Various methods of cancer treatment, such as chemotherapy, immunotherapy, radiation therapy, hyperthermia, and hormonal therapy, have been tried for various cancers, but the treatment is still satisfactory. A method of producing an effect has not yet been established. Among these various cancer treatment methods, a large number of cancer chemotherapeutic agents used for cancer chemotherapy have been developed so far, but few agents have been confirmed to be effective as a single agent.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a cancer chemotherapeutic agent having a higher effective rate against cancer in the above cancer chemotherapy.

An object of the present invention is to provide an anticancer agent comprising a carbostyril derivative represented by the following general formula (1) or a salt thereof and 5-fluorouracil or a salt thereof as an active ingredient, in particular, a carbostyril derivative comprising 6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.

[0005]

Embedded image

[Wherein R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. The carbon-carbon bond between the 3-position and the 4-position of the carbostyril skeleton indicates a single bond or a double bond. The carbostyril derivative represented by the general formula (1) used as one of the active ingredients in the anticancer agent of the present invention, a salt thereof, and a production method thereof are described in, for example, Japanese Patent Publication No. 43747/1989. It is also known that carbostyril derivatives are useful as cardiotonic agents. In addition, the present inventors have previously reported that the carbostyril derivative has excellent antitumor and differentiation-inducing effects when used alone (the 51st Annual Meeting of the Japanese Cancer Society, Osaka 1).
992).

The other active ingredient of the anticancer agent of the present invention, 5-fluorouracil and a salt thereof (hereinafter referred to as “5-FU”)
Is abbreviated as an anticancer agent, and its production method is described in, for example, US Pat. No. 2,802,005 and US Pat. No. 2,802,005. Said 5-
FU has been confirmed to be effective against various gastrointestinal cancers including stomach cancer, breast cancer, uterine cancer, ovarian cancer and the like, and has already been marketed for these indications.

However, as a result of intensive studies, the present inventors have surprisingly found that the combined use of the above-mentioned carbostyril derivative and 5-FU produces a synergistic effect and a very excellent anticancer effect. Are found, and the present invention has been completed here.

Each group represented by the above general formula (1) is more specifically as follows.

Examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy. it can.

The benzoyl group which may have a lower alkoxy group as a substituent on the phenyl ring includes, for example, benzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 2-ethoxybenzoyl, 3-ethoxybenzoyl , 4-ethoxybenzoyl, 3-isopropoxybenzoyl, 4-butoxybenzoyl, 2-pentyloxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl,
The phenyl ring such as 2,5-dimethoxybenzoyl, 3,4,5-trimethoxybenzoyl group may have 1 to 3 straight or branched chain alkoxy groups having 1 to 6 carbon atoms as substituents. A benzoyl group can be exemplified.

The carbostyril derivative represented by the general formula (1) or a salt thereof, which is an active ingredient of the anticancer agent of the present invention, and 5-FU are usually used in the form of general pharmaceutical preparations. Such formulations are commonly used fillers, extenders,
It is prepared using diluents or excipients such as a binder, a humectant, a disintegrant, a surfactant, and a lubricant. Various forms can be selected as the pharmaceutical preparation according to the purpose of treatment, and typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (Solutions, suspensions, etc.).

[0013] In the form of tablets, carriers conventionally known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Potassium phosphate, polyvinylpyrrolidone sugar binder, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, humectants such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, and lubricants such as purified talc, stearates, powdered boric acid, and polyethylene glycol. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the form of pills, carriers conventionally known in the art can be widely used, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, and the like.
Examples thereof include excipients such as kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar. In shaping in the form of suppositories, conventionally known carriers can be widely used, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin,
Semi-synthetic glycerides and the like can be mentioned.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When formed into these solutions, emulsions and suspensions, they are diluted. As the agent, any one commonly used in this field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose, glycerin, etc., for preparing an isotonic solution may be contained in the pharmaceutical preparation, and ordinary solubilizing agents, buffers, soothing agents, etc. are added. May be. Coloring agent if necessary,
Preservatives, flavors, flavors, sweeteners, and other pharmaceuticals may be included in the pharmaceutical formulation.

[0016] The anticancer agent of the present invention may be prepared so that at least one of the carbostyril derivative and a salt thereof and 5-FU are contained in a single preparation. Can also be used. In any case, the combination ratio (mixing ratio) of the two can be appropriately selected from a wide range. For example, when the clinical use of the present invention anticancer, 5-FU as an active ingredient, usually about one day to about 0.1 to 50 mg / kg is selected is <br/> is from the amount to be administered, in combination therewith The carbostyril derivative (and its salt) of the general formula (1) is usually used in an amount of about 3 to 1 per day per adult.
About 800 mg / body weight, preferably about 10 to 300 mg
The amount is preferably selected from the range of about / weight.

As described above, the 5-FU described above is commonly used in the art because the compound of the general formula (1) is generally employed in this field in order to enhance the inhibitory effect on tumor cell growth with the compound of the general formula (1). When used at a certain clinical dose, the commonly used clinical dose of 5-FU is 1 / 100-fold to 9/1.
It can be reduced to about 0 times. In addition, 5-FU is
From the viewpoint of avoiding the side effects, it is preferable to administer the drug in the lowest possible dose within the above-mentioned effective dose range.

The compound of the general formula (1) of the present invention and 5-FU
The administration ratio of the compound of the general formula (1) and 5-FU in the anticancer agent containing as active ingredients is not particularly limited as long as both are used within the respective ranges of the active ingredients, and may be appropriately selected from a wide range. In general, the amount of the compound (mg / body) / 5-FU (mg / body) of the general formula (1) should be 0.
It is desirable to set it to about 1 to 1000, preferably about 1 to 100, and more preferably about 10.

The anticancer agent of the present invention is used in various dosage forms commonly used in this field, depending on the purpose of use.
For example, when prepared as an injection, the solutions, emulsions, and suspensions are preferably sterilized and isotonic with blood.

The amounts of the compound of general formula (1) and 5-FU contained as active ingredients in the anticancer agent of the present invention are not particularly limited, and may be appropriately selected from a wide range. The total amount is suitably in the range of about 1 to 70% by weight, preferably about 1 to 30% by weight.

The anticancer agent of the present invention can be the same as that of a general pharmaceutical composition of this kind, and may optionally contain other pharmacologically active ingredients and conventional ingredients in pharmaceutical preparations.

5-FU as an active ingredient of the anticancer agent of the present invention
And a pharmaceutical preparation comprising a carbostyril derivative represented by the general formula (1) or a salt thereof, which can be administered separately in the form of two agents containing each active ingredient as a single component, or both May be combined in the same formulation and administered as a single agent. In addition, the carbostyril derivative represented by the general formula (1) or a salt thereof, which is one of the active ingredients of the present invention, can be administered, for example, orally or parenterally by any of the conventionally known administration routes. it can. At present, oral administration is preferable, and the production of the oral and parenteral pharmaceutical preparations can be carried out with reference to the description of Japanese Patent Publication No. 1-41282.

The method of administration of the pharmaceutical preparation thus obtained is not particularly limited, and is determined according to various preparation forms, the age and sex of the patient, other conditions, and the degree of the disease.

A suitable administration route according to the form of the pharmaceutical composition, for example, a pharmaceutical preparation in the form of an injection is administered by intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal administration, etc. Pharmaceutical formulations can be administered orally or enterally. The administration method includes, for example, orally administering a carbostyril derivative represented by the general formula (1) or a salt thereof, which is one of the active ingredients of the present invention, or intravenously administering a pharmaceutical preparation in the form of an injection.
Intramuscular, subcutaneous, intradermal, intraperitoneal administration, etc.
Iv containing the pharmaceutical preparation in the form of an injection containing FU,
It can also be administered by intramuscular, subcutaneous, intradermal, intraperitoneal administration and the like. In addition, both the carbostyril derivative represented by the general formula (1) or a salt thereof, which is an active ingredient of the anticancer agent of the present invention, and 5-FU can be blended in the same preparation and administered orally as a single agent. . The administration may be performed once a day or three to four times a day, and the pharmaceutical preparations containing the active ingredients may be administered simultaneously or separately at different times. The combination of the active ingredient of the present invention can be administered once a day or divided into three to four times a day.

[0025]

EXAMPLES Examples of preparations and pharmacological tests are described below.

Formulation Example 1 6- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril 5 mg 5-Fluorouracil 40 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 240 mg One tablet A tablet of the above composition was produced.

[0027]

[Pharmacological test] The following test compounds were used for the following pharmacological tests.

[0028]

[Pharmacological test example 1] First, 5-Fluorouracil (5-Fluorouracil)
uaracil: manufactured by Kyowa Hakko Kogyo Co., Ltd.)
Eagle MEM (Eagle's) containing 10% newborn calf serum (NBCS, manufactured by Gibco) so that the concentration becomes 625 μg / ml.
s MEM (manufactured by Nissui Pharmaceutical Co., Ltd.) medium. next,
6- [4- (3,4-Dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril (hereinafter referred to as compound I) as a test compound is dissolved in 1N hydrochloric acid, and then dissolved in 1N NaOH. And diluted with Eagle's MEM medium containing 10% NBCS to prepare a 30 μg / ml solution.

A 96-well microplate (manufactured by Corning Incorporated) was divided into four sections, and only 50 μl of the above-mentioned 5-fluorouracil solution was added to each section (0.625 μg / m2).
l), only 50 μl of the compound I solution was added (30 μg / m
l), both 50 μl of the 5-fluorouracil solution and 50 μl of the compound I solution were added, or only 50 μl of the solvent was added (the section where 5-fluorouracil and compound I were not added).

Next, HSG-AZ was added to the wells in each section.
A3 human salivary gland carcinoma cells [HSG-AZA3 cell line is a cell line obtained by treating human salivary gland carcinoma cell line HSG with 5-azacytidine and shows the morphology of acinar cells. The cells were provided by Prof. Mitsunobu Sato, Faculty of Dentistry, Tokushima University. For the characteristics of the cells, see Cancer Res., 47 , 4
453-4459 (1987). 100 μl of Eagle MEM (10% NBCS, manufactured by Nissui Pharmaceutical Co., Ltd.) containing 1 × 10 ⁴ cells was added, and the mixture was added at 37 ° C. under 5% CO ₂ conditions.
The cells were cultured in a CO ₂ incubator (Napco) for one day. After the culture, MTT [DOTITE MTT (3- (4,5-dimethyl-2-thiazole) -2,5-diphenyl-2H
-Tetazolium; 10 μl of a PBS (-) solution (manufactured by Nissui Pharmaceutical) containing 2.5 mg / ml of 2.5 mg / ml was added to each well, and incubated for 3 hours under the same conditions.
0.01N hydrochloric acid 1 containing 10% SDS (Wako Pure Chemical Industries, Ltd.)
After adding 00 μl, the mixture was further incubated overnight under the same conditions. After completion of the incubation, the absorbance at a wavelength of 580 nm was measured using Titertec Multiscan (manufactured by Flow Laboratories), and the relative value of the measured value in each of the other sections was determined, taking the measured value in the solvent-added section as 100%. The cell growth rate (%) was used.

The results are shown in Table 1.

[0032]

[Table 1]

From the table, it can be seen that the HSG of 5-fluorouracil is
-It was confirmed that the growth inhibitory effect on AZA3 cells was synergistically enhanced by the combined use of Compound 1.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Hiroyuki Ichikawa 3--11 Nakadori-cho, Tokushima City, Tokushima Prefecture (72) Inventor Seiji Akamatsu 223-1 Kawasaki, Omamachi, Naruto City, Tokushima Prefecture (72) Inventor Shiro Saito Gunma 2294-80 Yamana-cho, Takasaki-shi, Japan (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 31/495 ADU A61K 31/505 AGA CA (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [In the formula, R represents a benzoyl group which may have a lower alkoxy group on the phenyl ring. Carbostyril skeleton 3
The carbon-carbon bond between the 4-position and the 4-position indicates a single bond or a double bond. ] The carbostyril derivative represented by these, or its salt, and 5-fluorouracil or its salt as an active ingredient. 2. The method of claim 1, wherein the carbostyril derivative is 6- [4-
(3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.
3. The anticancer agent according to item 1.