JPH06179621A - Anticancer agent - Google Patents

Abstract

PURPOSE:To provide the anticancer agent containing a specific carbostyril derivative and 5-fluorouracil as active ingredients exhibiting a synergistic effect, and expressing a highly excellent anticancer effect. CONSTITUTION:The anticancer agent is characterized by containing (A) a compound of the formula (R is benzoyl which may have a lower alkoxy group on its phenyl ring; the carbon-carbon bond between the 3 and 4 positions of the carbostyril skeleton is single bond or double bond) or its salt, e.g. 6-[4-(3,4- dimethoxybenzoyl)-1-piperazinyl)-3,4-dihydroxycarbostyril, and (B) 5-fluorouracil or its salt as active ingredients. Both the ingredients may be prepared so as to be contained in a single preparation or separately prepared so as to simultaneously use both the formed preparations, and on the clinical utilization of the ingredients, the ingredient A is used at a dose of 3-1800mg/kg body weight, preferably 10-300mg/kg body weight, a day for an adult, and the ingredient B is also desirably used at a dose of 0.1-50mg/kg body weight.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anticancer agent containing a specific carbostyril derivative and 5-fluorouracil.

[0002]

2. Description of the Related Art Various methods such as chemotherapy, immunotherapy, radiation therapy, hyperthermia therapy, and hormone therapy have been attempted for various cancers as cancer treatments, but they are still sufficiently satisfactory. The method of producing the effect has not been established. In addition, among the various cancer treatment methods, many cancer chemotherapeutic agents used for cancer chemotherapy have been developed up to now, but the effectiveness of a single agent has not been confirmed.

[0003]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a cancer chemotherapeutic agent having a higher efficacy rate against cancer in the above-mentioned cancer chemotherapy.

The above-mentioned object is an anticancer agent containing a carbostyril derivative represented by the following general formula (1) or a salt thereof and 5-fluorouracil or a salt thereof as active ingredients, especially a carbostyril derivative containing 6- [4- It is achieved by the above anticancer agent which is (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril.

[0005]

[Chemical 2]

[In the formula, 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 4-position of the carbostyril skeleton represents a single bond or a double bond. In the anticancer agent of the present invention, the carbostyril derivative represented by the general formula (1) and its salt, which are used as one of the active ingredients, and the production method thereof are described in, for example, Japanese Patent Publication No. 1-34747. It is also known that carbostyril derivatives are useful as cardiotonics. The present inventors have previously reported that the carbostyril derivative as a single agent has excellent antitumor activity and differentiation induction activity (The 51st Annual Meeting of the Japanese Cancer Society, Osaka 1
992).

5-Fluorouracil and its salt (hereinafter referred to as "5-FU") as the other active ingredient in the anticancer agent of the present invention.
Is widely known as an anticancer agent, and its manufacturing method is described in, for example, US Pat. No. 2802005, US Pat. No. 2802005, and the like. The 5-
FU has been confirmed to be effective against various gastrointestinal cancers such as gastric cancer, breast cancer, uterine cancer, and ovarian cancer, and has already been marketed for these indications.

However, as a result of earnest studies, the present inventors have found that, when the above-mentioned carbostyril derivative is used in combination with 5-FU, a surprisingly synergistic effect is exhibited and a very excellent anti-cancer effect. Was found to be expressed, and the present invention has been completed here.

More specifically, each group represented by the above general formula (1) is as follows.

Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups. 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 and 3-ethoxybenzoyl. , 4-ethoxybenzoyl, 3-isopropoxybenzoyl, 4-butoxybenzoyl, 2-pentyloxybenzoyl, 3-hexyloxybenzoyl, 3,4-dimethoxybenzoyl,
It may have 1 to 3 linear or branched alkoxy groups having 1 to 6 carbon atoms as a substituent on the phenyl ring such as 2,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzoyl groups. A benzoyl group can be illustrated.

The carbostyril derivative represented by the general formula (1) or a salt thereof and 5-FU, which are the active ingredients of the anticancer agent of the present invention, are usually used in the form of a general pharmaceutical preparation. Such formulations include commonly used fillers, fillers,
It is prepared using a diluent or excipient such as a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections. (Solutions, suspensions, etc.) can be exemplified.

In the case of molding in the form of tablets, those conventionally known in this field can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid. Excipients such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,
Potassium phosphate, polyvinylpyrrolidone sugar binder, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multilayer tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil,
Examples include excipients such as kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrating agents such as laminaranthantene. In the case of molding into a suppository, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin,
Semi-synthetic glyceride etc. can be mentioned.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into a solution, emulsion and suspension, they are diluted. As the agent, all agents 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 or the like for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent, etc. are added. You may. If necessary, colorant,
Preservatives, flavors, flavors, sweeteners and other pharmaceuticals may be included in the pharmaceutical preparation.

The anticancer agent of the present invention may be prepared such that at least one of carbostyril derivative and its salt and 5-FU are contained in a single preparation. Can also be used. In any case, the combined ratio (mixing ratio) of both can be appropriately selected from a wide range. For example, in clinical use of the anticancer agent of the present invention, 5-FU, which is an active ingredient, is usually about 0.
1 to 50 mg / kg can be selected from the administered dose,
The carbostyril derivative of the general formula (1) (and its salt) used in combination therewith is usually about 3 to 180 per day for an adult.
The amount should be selected from the range of about 0 mg / body weight, preferably about 10 to 300 mg / body weight.

As described above, the 5-FU and the compound of the general formula (1) mutually enhance the tumor cell growth inhibitory action, so that the compound of the general formula (1) is usually employed in this field. When used at a clinical dose of 5-FU, the usual clinical dose of 5-FU is 1/100 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 dose as low as possible within the above 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 an active ingredient is not particularly limited as long as both are used within the above respective active ingredient amount ranges, and may be appropriately selected from a wide range. However, in general, the compound (mg / body) / 5-FU (mg / body) of the general formula (1) is 0.
It is desirable that the amount is 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 solution, emulsion and suspension are preferably sterilized and isotonic with blood.

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

The anticancer agent of the present invention may be the same as a usual pharmaceutical composition of this kind, and may optionally contain other pharmacologically active ingredients, conventional ingredients for formulation and the like.

5-FU as an active ingredient of the anticancer agent of the present invention
And a carbostyril derivative represented by the general formula (1) or a salt thereof, the pharmaceutical preparations may be separately administered in the form of two agents containing each active ingredient as a single ingredient, or both May be mixed in the same preparation and administered as a single agent. The carbostyril derivative represented by the general formula (1) or a salt thereof, which is one of the active ingredients of the present invention, may be administered by any of the conventionally known administration routes, for example, orally or parenterally. it can. Oral administration is currently preferred, and the production of the above-mentioned oral and parenteral pharmaceutical preparations can be carried out with reference to the description in JP-B-1-41128.

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

An appropriate administration route depending on 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. The pharmaceutical preparation may be administered orally or enterally. The administration method includes, for example, orally administering a carbostyril derivative represented by the general formula (1), which is one of the active ingredients of the present invention, or a salt thereof, or administering a pharmaceutical preparation in the form of an injection intravenously,
Intramuscular, subcutaneous, intradermal, intraperitoneal administration, etc.
-Injecting a pharmaceutical preparation of the above injection form containing FU intravenously,
It can also be administered by intramuscular, subcutaneous, intradermal or intraperitoneal administration. Further, both the carbostyril derivative represented by the general formula (1) or its salt, which is the active ingredient of the anticancer agent of the present invention, and 5-FU can be mixed in the same preparation and orally administered as one agent. . The administration can be performed once a day or divided into 3 to 4 times a day, and a pharmaceutical preparation containing the active ingredient can be administered simultaneously or separately at different times. Further, the active ingredient compounding agent of the present invention can be administered once a day or divided into 3 to 4 times a day.

[0025]

[Examples] Formulation examples and pharmacological test examples are given 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 in 1 tablet , Tablets of the above composition were prepared.

[0027]

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

[0028]

[Pharmacological Test Example 1] First, 5-fluorouracil (5-Fluoro
uaracil: manufactured by Kyowa Hakko Kogyo Co., Ltd.) with a final concentration of 0.
Eagle MEM (Eagle ') containing 10% neonatal calf serum (NBCS, manufactured by Gibco) so as to have 625 μg / ml.
s MEM, manufactured by Nissui Pharmaceutical Co., Ltd.). next,
6- [4- (3,4-dimethoxybenzoyl) -1-piperazinyl] -3,4-dihydrocarbostyril (hereinafter referred to as compound I) as a test compound was dissolved in 1N hydrochloric acid, and then dissolved with 1N NaOH. The mixture was diluted and diluted with Eagle's MEM medium containing 10% NBCS to prepare a 30 μg / ml solution.

A 96-well microplate (manufactured by Corning) was divided into 4 sections, and only 50 μl of the 5-fluorouracil solution was added to each section (0.625 μg / m 2).
l), only 50 μl of the compound I solution was added (30 μg / m
l), 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 (5-fluorouracil and compound I non-added section).

Next, HSG-AZ was added to the wells of the above-mentioned sections.
A3 human salivary adenocarcinoma cell [HSG-AZA3 cell line is a cell line obtained by treating human salivary adenocarcinoma cell line HSG with 5-azacytidine, and exhibits acinar cell morphology. The cells were provided by Professor 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 (manufactured by Nissui Pharmaceutical Co., containing 10% NBCS) containing 1 × 10 ⁴ cells was added, and the mixture was kept at 37 ° C. under 5% CO ₂ conditions.
The cells were cultured for one day in a CO ₂ incubator (Napco). After culturing, MTT [DOTITE MTT (3- (4,5-dimethyl-2-thiazole) -2,5-diphenyl-2H
-Tetrazolium; manufactured by Wako Pure Chemical Industries, Ltd.) 10 μl of PBS (-) solution (manufactured by Nissui Pharmaceutical Co., Ltd.) containing 2.5 mg / ml was added to each well, and after incubation for 3 hours under the same conditions,
0.01N hydrochloric acid containing 10% SDS (manufactured by Wako Pure Chemical Industries) 1
00 μl was added and further incubated overnight under the same conditions. After completion of the incubation, the absorbance at a wavelength of 580 nm was measured using Titer Tech Multiscan (manufactured by Flow Laboratories), and the relative value of the measured value of each of the other sections was determined with the measured value of the solvent-added section being 100%. The cell growth rate (%) was used.

The results are shown in Table 1.

[0032]

[Table 1]

From the table, the HSG of 5-fluorouracil
-It was confirmed that the growth inhibitory action on AZA3 cells was synergistically enhanced by the combined use of Compound 1.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shoichi Adachi 9349-3, Ishihara-cho, Takasaki-shi Gunma 9 (72) Inventor Hiroyuki Ichikawa 3-11 Nakadori-cho, Tokushima-shi, Tokushima (72) Inventor Seiji Akamatsu 223-1 Kawasaki, Omamachi, Naruto City, Tokushima Prefecture (72) Inventor Shiro Saito 2294-80 Yamanamachi, Takasaki City, Gunma Prefecture

Claims (2)

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