JPS5827773B2 - Cancer metastasis inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cancer metastasis phase trapping agent 1 characterized in that it contains 7-diethylamino-5-methyl-S triazolo-[1,5-a]-pyrimidine. .

Surgical therapy, radiotherapy, and chemotherapy have been mainly attempted for the treatment of cancer, but none of these treatments have shown satisfactory therapeutic effects in terms of cancer recurrence and survival prolongation.

One of the reasons for this is that even though these treatments can reduce or remove the primary cancer tumor, the cancer can spread to other parts of the body, especially major organs such as the brain, lungs, or liver. This is because it will lead to fatal consequences.

Therefore, in addition to treatments that reduce the size of the primary cancer tumor or surgically remove the cancer, it is extremely important to prevent cancer metastasis in order to completely cure cancer.

From this point of view, the present inventors conducted research on numerous chemical substances and found that 7-diethylamino-5-methyl-8-triazolo-[1,5a]-pyrimidine (generic name: trapidil) has been shown to be effective in cancer metastasis. The present invention has been developed based on the discovery that it strongly suppresses

Trapidil is a known compound having the structure represented by the following formula (I): It is easily soluble in water and organic solvents, is a white to pale yellow crystalline powder with a bitter taste, and has a crown dilating effect (Hashimoto Toroku et al., Applied Pharmacology, 8.33-43 (1974)).

Next, the cancer metastasis suppressing effect and toxicity of trapidil will be explained in detail.

Experimental Example 1 Effects of Trapidil on L 1210 Leukemia Lung Metastasis Model experiment of cancer cell blood circulation metastasis by Amaba et al.
(2013)].

104 I, 1.210 leukemia cells were intravenously transplanted into 6 BDF mice per group, and 7 days later, the lungs were removed, fixed with a fan, and the number of metastatic nodules was measured.

Trapidil was orally administered twice a day for 7 days, including the day of cancer cell transplantation.

The results are shown in Table 1.

Lung metastasis was significantly suppressed by oral administration of trapidil.

Experimental example 2 Effect of I.rapidil on lung metastasis of Lewis lung cancer Group 1 6
1X106 Lewis lung cancer cells were implanted subcutaneously in the left hind limb of two BDF1 mice.

Nine days after transplantation, the lower leg containing the primary tumor was amputated, and 20 days later, the lungs were removed and the number of metastatic nodes was measured.

Trapidil was orally administered twice a day for 9 days starting the day after cancer cell transplantation.

The results are shown in Table 2.

Lung metastasis was clearly inhibited by trapidil administration.

Experimental Example 3 Acute Toxicity Trapidil was administered orally, subcutaneously and intravenously to 10 ddY mice or Wistar rats per group, and acute toxicity was investigated.

The LD5o value was calculated from the mortality rate 7 days after administration in the case of oral administration, and from the mortality rate 3 days after administration in the case of subcutaneous and intravenous administration, respectively.
d) Determined by law.

The results are shown in Table 3.

As shown in the above experimental examples, trapidil markedly suppresses the metastasis of subcutaneously and intravenously transplanted tumor cells to the lungs, and the dose that produces these pharmacological effects is 50 minutes below the LD5o value. 1 or less, making it an extremely safe drug.

Generally, drugs used as chemotherapy agents for cancer have strong side effects or toxicity, and even if they suppress cancer growth, they may cause physical damage to the patient.
It cannot be used safely because it causes mental breakdown.

On the other hand, the acute toxicity of trapidil in animals is low as shown in the experimental example, and it has been confirmed that the toxicity is sufficiently low when trapidil is administered daily to animals for a long period of time (Chihiro Ito et al., Pharmaceutical Research, 7(2), 170178
(1976), Chihiro Ito et al., Pharmaceutical Research, 7(2), 1
79-186 (1976)) Furthermore, no abnormalities were observed in the fetuses even if lotrapidil was administered every 14 days during the organ formation period of pregnant rabbits (Chihiro Ito et al., Pharmaceutical Research, 7(2),
195-199 (1976)) Therefore, trapidil is expected to be an ideal cancer metastasis inhibitor that is highly safe even in long-term use.

When Trapidil is administered to humans, the daily dose is usually 10
0~! The dose is 500my administered orally, but the dose may be increased or decreased as appropriate depending on the medical condition.

The dosage form is preferably tablets or capsules according to conventional methods.

That is, using excipients such as lactose, starch, manilla I, etc., disintegrants such as carboxymethylcellulose and potato starch, binders such as potato starch and gum arabic, and lubricants such as magnesium stearate, talc, and silica. Tablets or capsules can be manufactured.

Furthermore, the tablets may be coated with sugar if necessary.

The formulations are shown below as examples, It is not limited to only.

Example 1 The tablet formulation is as follows: (1) Trapidil 50g (11) Lactose appropriate amount (Ill) Crystalline cellulose 60g 0V) Japanese yam starch 54P (V)
) Magnesium stearate 21 Among the above, (1) to 6V) were mixed and separated in advance (iV
) is added as 10% glue to make granules and dried.

Next, add (v) to this and mix to make 200 tablets per tablet.
Let it be a tablet of mσ.

The tablets may be coated with sugar by a conventional method, if necessary.

Example 2 Capsule (1) Trapidil 50g (Ii)
Calcium hydrogen phosphate 50P (111)
Aluminum silicate appropriate amount (iV)
Crystalline cellulose 60L? (V) Magnesium stearate 2g (I) - (■
), and after passing through a sieve and mixing thoroughly, capsules with a size of 200 m9 per unit are made according to a conventional method.

Example 3 100P of crystals of injection TR were dissolved in 24 grams of distilled water for injection, and then 1007 grams per ampoule was prepared using a conventional method.
ry/2 ml injection.

Claims (1)

[Claims] 17-diethylamino-5-methyl-8-triazolo-
A cancer metastasis inhibitor characterized by containing C1.5-a]-pi1 nomidine.