JPS62106017A - Anti-tumor agent - Google Patents

Abstract

PURPOSE:To provide an anti-tumor agent containing 5,7-dihydroxy-4'-substituted- isoflavone-2-carboxylic acid or its ethyl ester as an active component and having strong oncogene-originated tyrosine-specific phosphorylase-inhibiting activity. CONSTITUTION:The 5,7-dihydroxy-4'-substituted-isoflavone-2-carboxylic acid of formula (R<1> is OH or methoxy; R<2> is carboxyl or ethoxycarbonyl) or its ethyl ester is used as an anti-tumor agent. The compound of formula I e.g. 5,7-dihydroxy-4'-methoxyisoflavone-2-carboxylic acid. The compound of formula strongly inhibits oncogene-originated tyrosine-specific phosphorylase which is suspected to participate in then canceration of normal cell and the proliferation of cancer cell. Accordingly, the agent is useful for the prevention of carcinogenesis and remedy of cancer.

Description

[Detailed description of the invention] (Industrial application field) The present invention is based on the general formula (In the formula, R1 is a hydroxyl group or a methoxy7 group.

R2 means a carboxy group or an ethoxycarbonyl group. ) The present invention relates to an antitumor agent containing 5,7-cyhydroquine-11'-substituted-isoflavone-2-carboxylic acid or its ethyl ester as an active ingredient.

(Prior Art) Compounds represented by the above general formula, except for compounds in which R1 is a methoxy group and R2 is an ethoxycarbonyl group, are listed in the Journal of the Chemical Society (J
internal of the chemical 5o
1852 ++1859 pages, 1.9
It is a known compound described in 1953. The same document is
Since we have reported a new method for synthesizing inflavone compounds, we have not reported any pharmacological effects, especially antitumor effects, of inflavone compounds.

(Operations and Effects of the Invention) The present inventors have discovered that the compound represented by the above general formula has five strong
Oncogenes that have been found to have an inhibitory effect on tyrosine-specific kinases derived from oncogenes and are considered to be useful in the present invention include the following virus-derived oncogenes.

sarcoma virus (fgr) + feline Snyder-Tylen sarcoma virus (fes), chicken primitive sarcoma virus ('p
s)-chicken erythroblastosis virus (erbff), 7
Abelson's leukemia virus (ab) has been reported to be expressed in many cancers in mice (
For example, Science, vol. 224.

256 pages, 1984).

Since it is thought to be involved in the proliferation of 9, compounds that can specifically block its enzymatic activity would be useful in the prevention of carcinogenesis and cancer treatment.

The inhibitory effect and toxicity of cancer gene-derived tyrosine-specific kinase of the compounds of the present invention will be explained below.

■Method for measuring oncogene-derived tyrosine-specific kinase blocking effect: Human epithelial cancer cell growth factor receptor (EGF receptor,
A431 cells) Method for measuring tyrosine-specific kinase activity (Nis-Koraen.

C. Carventer, Elle King; Journal of Biological Chemistry Volume 255, 483
4-4842, 1980) human epithelial cancer cells (A4
Cell membranes prepared from 31 cells) were used as an enzyme source.

In 50μL, 20mM Pipes-NaOHpH
7,2,10mM MgCI2゜3mMnC12,1m
MDTT, 10−/+M[r”P] ATP(Qm
Ci/mmol), A431 cell membrane (protein amount 10 μg), and a reaction solution containing the above compound (I) were reacted for 5 minutes, then 9 reactions were stopped, and 9 reaction solutions were subjected to 8% polyacrylamide gel electrophoresis-autoradiography. Analyze the following to determine the presence or absence of phosphorylation of the EGF receptor, which has a molecular weight of 2, 170,000. Furthermore, we cut out the EGF receptor.

The degree of phosphorylation was quantified by measuring radioactivity with a dispersion/antirayon counter.

Note that cell membrane preparation from A431 cells was performed as follows.

Dulbetsko's M containing 7% tallow serum (manufactured by Gibco)
A431 cells cultured in EM (manufactured by Nippon Suisan ■) medium were collected and used according to the method of Cohen et al. (Stanley Cohen, Hiron e Ushiro).

Krista Stoschenok, Michael Chinkers - Journal of Biological Chemists, Volume 25, 1
523-1531, 11982).

Measurement results: Inhibitory effect of compound (I) on tyrosine-specific kinase A I 0.
0B 2
．． OC2,0 (Note) Compound A: 5,7-dihydroxy-4'-methoxyisoflavone-2-carboxylic acid (a compound in which R1 is a methoxy group and R2 is a carboxy group in the general formula) Compound B: 5,7.4' -trihydroxyinflapon-2-carboxylic acid (general formula.

Compounds in which R1 is a hydroxyl group and R2 is a carboxyl group) Compound C: Ethyl ethyl 5.7,4'-trihydroxyisoflavone-2-carboxylate (in the general formula, R1 is a hydroxyl group).

Compounds in which R2 is an ethoxycarbonyl group) ■ Toxicity Using ddY mice, Compound A was injected intraperitoneally at 251 kg/day for 4 days, Compound B was injected subcutaneously at 25 mg/kg/day for 18 days, and Compound C was injected at 500 mg/kg/day subcutaneously. A single dose of mg/kg was administered intraperitoneally, but there were no deaths.

For the prevention of cancer in humans and animals, the treatment of diseases associated with cancer metastasis, and the prevention of recurrence, usually per day for adults,
The dosage is 200 to 1,000 square meters, which is divided into 1 to 4 doses. The dosage is adjusted as appropriate depending on the individual patient's condition, age, etc.

Compound (I) can be used alone for treatment.

Used in combination with other chemotherapeutic agents or immunotherapeutic agents. Chemotherapy agents used in combination include cyclophosphamide, vinblastine, vincristine, adriamycin, 6
-Mercabutofurin, 5-fluorouracil, mitomycin C, pleomycin, aclacinomycin, neocarzinostatin, cytosine arapinoside, cisplatin, actenomycin D, nitrosourea drugs, and the like.

In addition, examples of immunotherapeutic agents include crestin,
BCG, watermelon, lentinan.

Examples include interferon and interleukin.

When used in combination with these drugs, the dosage is compound (■) 1
On the other hand, it is appropriate for the concomitant drug to be about 0.001 to 10.

Compound (I) is administered in the form of oral preparations (tablets, capsules, liquid preparations) or parenteral preparations (rectal preparations, injections, pellets). These formulations are prepared as compositions incorporating any conventional pharmaceutical carriers or excipients by conventional methods. The carrier and excipient used in this case may be those commonly used, for example in the case of two tablets.

Water, glucose, lactose, gum arabic, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, gelatin, colloidal silica, potato starch, urea, etc. can be used. Also, the liquid medicine.

Aqueous or oily suspensions, solutions, syrups.

It may also be an elixir and these are prepared in a conventional manner. For rectal administration.

It is provided as a composition for suppositories, and as a base.

Commonly used materials such as polyethylene glycol, lanolin, cacao butter, Witep Sol (Dynamite Nobel), etc. can be used.

Claims (1)

[Claims] 1. General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 means a hydroxyl group or a methoxy group, and R^2 means a carboxyl group or an ethoxycarbonyl group.) An antitumor agent containing 5,7-dihydroxy-4'-substituted-isoflavone-2-carboxylic acid or its ethyl ester as an active ingredient shown in 2,5,7-dihydroxy-4'-methoxyisoflavone-2-carboxylic acid Antitumor agent 3,5,7,4'-trihydroxyisoflavone-2- according to claim 1 as an active ingredient
Antitumor agent 4,5,7,4'-trihydroxyisoflavone-2- according to claim 1, which contains carboxylic acid as an active ingredient.
The antitumor agent according to claim 1, which contains an ethyl ester of carboxylic acid as an active ingredient.