JPH05238982A - Antitumor agent - Google Patents

Abstract

PURPOSE:To obtain a new antitumor agent showing higher medicinal effects on cancerous cells, comprising a specific compound as a metabolite of a bacterium belonging to the genus Streptomyces. CONSTITUTION:An antitumor agent comprising a compound of the formula [R is COCH2CH2CH3 or COCH2CH2CH(CH3)2], namely SF2,418 substance (R= COCH2CH2CH3], piloquinone [R=COCH2CH2CH(CH3)2] or its salt as active ingredient. A daily dose of the compound of the formula is preferably 10-500mg/kg in the case of oral administration and 2-200mg/kg in the case of parenteral administration. In the case of injection, 5-50wt.% of the compound of the formula is contained in injection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an antitumor agent.

[0002]

2. Description of the Related Art In recent years,
New cancer drugs are being developed one after another, but no drug capable of completely curing or preventing cancer has been found until now. It is an object of the present invention to provide an antitumor agent showing a more useful drug effect on cancer cells.

[0003]

The present invention provides the following formula (I):

[0004]

[Chemical 2]

(Wherein R represents COCH ₂ CH ₂ CH ₃ or COCH ₂ CH ₂ CH (CH ₃ ) ₂ ), and an antitumor agent containing a pharmacologically acceptable salt thereof as an active ingredient. Regarding agents.

SF24 which is a compound represented by the formula (I)
18 substances (R = COCH₂CH₂CH ₃) And Pyroquino
(R = COCH₂CH₂CH (CH₃)₂) Is strep
Isolated and structurally determined as a metabolite of Tomyces sp.
Are known compounds [JP-A-62-30735, Na
true 199, 285-286 (1963)]. now
Once, the present inventors newly found that the compound of formula (I) has an antitumor effect.
That is, the present invention has been completed. In the present invention
The daily dose of the compound of formula (I) is about 2 mg
500 mg / kg is suitable, and about 10 mg to 5 for oral administration
00mg / kg / day, about 2mg-200mg / kg for parenteral
/ Day is preferred.

The pharmacologically acceptable salts of the compound (I) of the present invention include alkali metal salts (eg sodium salt,
Potassium salts, etc., alkaline earth metal salts (eg calcium salts, magnesium salts etc.), salts with inorganic bases such as ammonium salts, salts with organic bases (eg triethylamine salts, pyridine salts, picoline salts etc.) ..

When the active ingredient of the present invention is orally administered, there are various forms, for example, tablets, granules, fine granules, powders, syrups, elixirs and the like can be used. Particularly, the granules and powders are capsules if necessary. Can be enclosed in a unit dose form. Of these orally administered agents, solid agents are commonly used excipients such as silicic acid anhydride, metasilicic acid, aluminate, magnesium, synthetic aluminum silicate, lactose,
Sugar, corn starch, microcrystalline, cellulose, hydroxypropyl starch or glycine; binders such as gum arabic, gelatin, tragacanth, hydroxypropylcellulose or polyvinylpyrrolidone; lubricants,
It may contain, for example, talc or magnesium stearate; disintegrants such as calcium carboxymethyl cellulose or potato starch; wetting agents such as sodium lauryl sulfate, polyethylene glycol, sorbitan monooleate.

The liquid preparation for oral administration may be an aqueous or oily emulsion, a syrup, or the like, or may be a dry product which can be redissolved in an appropriate vehicle before use. Such liquid preparations are commonly used additives such as emulsification aids sorbit syrup, methyl cellulose, gelatin, hydroxyethyl cellulose and the like;
Also emulsifiers such as lecithin sorbitan monooleate,
Polyoxyethylene hydrogenated castor oil; non-aqueous vehicles such as almond oil, peanut oil; preservatives such as sorbic acid, methyl P-hydroxybenzoate, propyl P-hydroxybenzoate and the like may be added. Furthermore, these orally administered agents may contain stabilizers, preservatives, etc., if necessary.

When the active ingredient of the present invention is to be injectable, it may be in the form of an aqueous solution, an oil solution or an emulsion, and these liquids include an emulsifier, a stabilizer and the like which are usually used. May be included. These drugs may contain 1% by weight or more, preferably 5 to 50% by weight, of the active ingredient depending on the administration method. In addition, the active ingredient of the present invention can be made into a suppository by a conventional method.

[0011]

EXAMPLES Examples will be shown below, but these are merely examples and do not limit the present invention. Of course, it is possible to have many modified or modified means not exemplified here.

[0012]

Example 1 A uniform solution was prepared by mixing 15 g of the compound of formula (I) and 120 g of polyethylene glycol (Macrogol 400). Separately, 85 g of gelatin and 25 of glycerin
g, D-sorbitol 10 g, ethyl paraoxybenzoate 0.4 g, propyl paraoxybenzoate 0.2 g and titanium oxide 0.3 g to prepare a gelatin solution,
Using this as a capsule film agent, a soft capsule containing 180 mg of the content was manufactured by a manual flat plate punching method.

[0013]

Example 2 1 g of the compound of formula (I), an appropriate amount of peanut oil and 1 g of benzyl alcohol were mixed, and peanut oil was used to make the total amount 100 ml. 1 ml of this solution was poured into ampoules by aseptic operation and melted.

[0014]

[Test example]Effectiveness The P388 leukemia cell line contains 10% FCS, 10 μM 2-
Hydroxyethyl disulfide added RPMI 1640 culture
MethA fibrosarcoma, Lewis lung cancer, B16 melanoma
Is 10% FCS, DMEM medium, 5% CO₂ Three
The culture was performed under the condition of 7 ° C. Cytotoxicity in the growth medium
Compound (I) (R is COCH₂CH₂CH ₃Or COC
H₂CH₂CH (CH₃)₂) Was added, and after culturing for 72 hours
The survival rate was examined by the MTT method. The results are shown in Table 1.

[0015]

[Table 1] Table 1 SF2418 substance Pyroquinone Cell line IC ₅₀ (μg / ml) IC ₅₀ (μg / ml) P388 0.23 2.3 MethA fibrosarcoma 1.0-Lewis lung cancer 0.6- B16 melanoma 0.9-

Toxicity In three male ICR mice, 300 mg / kg of compound (I) (R is COCH ₂ CH ₂ CH ₃ or COCH ₂
After oral administration of CH ₂ CH (CH ₃ ) ₂ ) and observation for 1 week, all the cases survived and no toxicity was observed.

[0017]

Since the SF2418 substance and pyroquinone have antitumor activity against various tumor cells, their use as antitumor agents is expected.

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[Procedure amendment]

[Submission date] March 15, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0015

[Correction method] Change

[Correction content]

[0015]

[Table 1] Table 1 SF2418 substance Pyroquinone Cell line IC ₅₀ (μg / ml) IC ₅₀ (μg / ml) P388 0.23 2.3 MethA fibrosarcoma 0.82 11.0 Lewis lung cancer 0.59 5.9 B16 melanoma 0.99 1.8

Continuation of the front page (72) Inventor Harumi Fuyasu, 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. inside the Pharmaceutical Research Institute (72) Mieko Nagasawa 760, Shimo-oka, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Confectionery (72) Inventor Masayuki Takagi Meiji Confectionery Co., Ltd., Meiji Seika Co., Ltd.

Claims (1)

[Claims] 1. The following formula: (In the formula, R is COCH ₂ CH ₂ CH ₃ or COCH ₂ CH
₂ Indicates CH (CH ₃ ) ₂ . ) An antitumor agent comprising a compound represented by the formula (4) or a pharmaceutically acceptable salt thereof as an active ingredient.