JPS58206520A - Agent for suppressing metastasis of malignant tumor - Google Patents

Abstract

PURPOSE:To provide the titled suppressing agent having low toxicity and exhibiting strong effect to inhibit the formation of metastatic nest, by using a specific dibenzooxazepine derivative. CONSTITUTION:The agent contains the compound of formula (R1 and R2 are H or lower alkyl) having excellent lipid metabolizing activity, e.g. ethyl 10,11- dihydro-4-methoxydibenzo[b,f][1,4]oxazepine-8-carboxylate as an active component. The compound of formula has extremely low toxicity (the LD50 of the exemplified compound is >=45g/kg for mouse), and can be orally administered to a cancered patient for a long period. It can be effectively applied for the prevention of the metastasis of cancer before or after a surgical operation. Dose: ordinary 0.1-10g, preferably 0.3-3g daily for adult by oral or parenteral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a malignant compound containing a compound represented by the following general formula (wherein R1 and FL2 are the same or different and represent a hydrogen atom or a lower alkyl radical) as an active ingredient. The present invention relates to the metastasis inhibitor of No. 8.

The biggest obstacle in cancer treatment is that cancer cells can break away from the primary tumor and easily form distant metastases. The formation of distant metastases involves a complex process in which cancer cells are released from the primary tumor, travel in the bloodstream, are spread throughout the body, adhere to the vascular intima, and begin to grow. Most cancer cells that emerge into the bloodstream away from the primary tumor die. However, cancer cells in the primary tumor are not uniform in nature;
Among them may be cancer cells that have the ability to form distant metastases. The key factor for cancer cells to form distant metastases is thought to be that they interact with and adhere to host platelets, clogging the microcirculation and adhering to the intima of blood vessels at the site. . Once attached, the cancer cells form a protective clot made of platelets that surrounds them, are pulled out of the blood vessel, and begin to proliferate. Anticoagulants such as aspirin, dipyridamole, heparin and warfarin have been used for many years to prevent cancer metastasis, but without satisfactory results.

Today, thanks to advancements in surgical techniques, it is not uncommon for cases in which the primary tumor of cancer can be completely removed. However, even if one is lucky enough to have the primary tumor completely excised, the patient still has to fear the risk of recurrence due to the proliferation of metastatic lesions. The organs or tissues that are susceptible to distant metastasis depend on the type of cancer. For example, breast cancer tends to metastasize to the bones, lung cancer to the brain, and stomach cancer to the liver. It is also known that there are cancers such as malignant melanoma that do not involve specific organs but instead form metastatic foci throughout the body.

Therefore, if distant metastasis of cancer can be suppressed by some means, it would be possible to bring about revolutionary progress in cancer treatment.

The present inventors conducted research focusing on these points, and found that the above general formula (D It has been found that the expressed compound has a strong inhibitory effect on the formation of metastatic foci when administered orally to experimental animals.

The present invention was completed after further study based on this new knowledge.

The compound of the present invention is, for example, an extremely low toxicity substance produced by the method described in JP-A-55-76869 (for example, the LD5 value of compound-1 described below is 4.5 in mice).
f/9 or more).

The compound of the present invention is usually administered in an amount of 0.1 t per day for adults.
-10f, preferably 0.31-3t, administered orally or parenterally.

For administration, the active ingredient may be used alone, but it is usually mixed with common excipients or other adjuvants to formulate a dosage form suitable for parenteral and preferably oral administration. Preferred preparations include, for example, powders, granules, sugar-coated tablets, pills, capsules, and suppositories. These preparations can be manufactured using conventional methods, for example, using the excipients or adjuvants described below. lactose,
sucrose.

・Various starches, glucose, cellulose, methylcell
[Loose, carboxymethyl cellulose, hydroxypropyl cellulose, magnesium stearate, lauryl sulfate, talc, vegetable oil 1 various polysorbates,
Polyethylene glycol, mixtures of two or more of these, and preparations for oral administration preferably contain active ingredients in an amount of 10 to 55% F/acid, and crude drugs preferably contain 1 to 50 wk%.

Next, an example will be shown. The B-16 melanoma used as an experiment in the example was a 4-passage transplant of a 057 BL strain mouse, which is frequently used for experimental evaluation of cancer metastasis inhibitors. has been done. When Rho-16 melanoma cells are intravenously transplanted into syngeneic mice, they invade any organ and begin to proliferate, but there are many rumors about their proliferation. Therefore, the effectiveness of suppressing metastasis is evaluated by counting the number of lesions that have developed after a certain period of time.

Practice 911゜4] Oxazepine-8-carboxylate (Compound 1)
It was suspended in t2X gum arabic solution and administered orally by force once a day. To the control group, gum arabic solution was administered orally by force in the same manner. Four days later, after the final administration was completed, 3 x 10 6 B-16 melanoma cells were injected through the kite vein and transplanted. Mice were then kept for aiN and then sacrificed to remove B-16 from the lungs.
The number of melanoma metastatic growth foci was calculated.

Next season P<0.01 1) Mean±8D (Number of mice used; 8 each) Actual example 2 lltt% teacher transfer rate when each compound was administered at 100 μ/ky in the same manner as in Example 1 The formation inhibitory effect is shown in the table.

Minemai P<0.01 1) Mean+8D (number of mice;
(8 animals in each group) 'Thus, the medicament of the present invention can be effectively used to prevent distant metastasis of malignant asthma in humans and animals, and is extremely safe. Therefore, it is not only possible to administer the drug to patients with cancer over a long period of time, but it can also be used effectively to prevent cancer metastasis before and after surgery for patients with cancer. can.

Next, a formulation example of Compound 4 shown in Example 2 will be shown.

Practical row 3゜ Well-ground compound 4.100t, lactose 210r, result!
Cellulose 721. ) Corn starch 14f? Add 4ff of magnesium stearate to the mixture, mix well, and use a tablet machine to press into tablets with a diameter of 8 m and a weight of 200 m~.

Applicant: Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Scope of Claims] An agent for suppressing the metastasis of malignant sites, which contains a compound represented by the general formula (in the table, R1 and R2 are the same or different and mean a hydrogen atom or a lower alkyl group) as an active ingredient.