JPH0288524A - Antineoplastic agent - Google Patents

Abstract

PURPOSE:To provide an antineoplastic agent consisting of a salt of a hiteropolyacid containing elements selected from Mo, W, Nb and V, having a high effect for inhibition of prolification of tumor while side effects are very low. CONSTITUTION:An antineoplast agent containing a compound of the formula [A is alkali metal, ammonium, alkylammonium, H or mixture thereof; M and M' are Mo, W, Nb and V (Provided that valences of the below-mentioned respective Mo are mutually different in case both are Mo. In case they are not Mo, M and M' are not the same element); m is 1-16; X is 1-5] as the active component. The compound of the formula is preferably an oxo acid ionic poly-nuclear complex which is a cluster compound consisting of a kind of isopolyacid, having such a base unit that Mo and/or W atom, etc., is 4- or 6-coordinated with O atom and having such a structure that the respective base units are mutually bonded through arrises or apexes thereof. The above-mentioned antineoplastic agent shows a remarkable effect for solid tumors such as mammary cancer, lung cancer and sarcoma.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an antitumor agent. More specifically, the present invention relates to an antitumor agent consisting of a heteropolyacid salt containing an element selected from molybdenum, tungsten, niobium, or vanadium, and particularly to an antitumor agent that is highly effective against solid tumors.

(Conventional technology) Currently, the treatments for malignant tumors include surgery, chemotherapy,
There are immunotherapy, radiotherapy, etc., but among these, surgery and radiotherapy have the most radical meaning. However, surgery and radiation therapy are both local treatments, so they are useful as long as the tumor remains within the local area, but if the tumor has spread beyond the local area, There are major limitations for progressive or systematic diseases.

On the other hand, chemotherapy and immunotherapy have the characteristic of being systemic treatments, and although they are both relatively new treatments, they are fields in which progress has been remarkable and future development is strongly expected.

Surgery, radiation therapy, and chemotherapy are treatments based on different principles, and their efficacy and limitations are also different. Therefore, the appropriate combination of these various treatments will work synergistically with each other or compensate for each other's deficiencies, helping to enhance the therapeutic effect.
Improvements in malignant tumor treatment can only be brought about by such multifaceted treatment methods and combined treatment methods. Among these complex treatment methods, chemotherapy is steadily gaining its practical significance.

However, although multi-drug combination therapy including adriamycin has been developed for chemotherapy, its strong side effects still limit chemotherapy to limited adjunctive therapy, and its usage is also limited due to side effects. Due to this, the quantity is very limited, and the treatment results are not satisfactory.

As described above, a number of antitumor agents have been developed and put into practical use, but each of these antitumor agents has advantages and disadvantages in terms of antitumor effects and toxicity (side effects), and it is necessary to meet the necessary conditions. At present, there is no fully satisfactory antitumor agent, and the emergence of a new type of antitumor agent is desperately desired.

As such an antitumor agent, the present inventors have proposed an antitumor agent containing a heteropolyacid salt as an active ingredient. Japanese Patent Application No. 189762/1989 discloses an antitumor agent containing an alkali metal salt of polymolybdate as an active ingredient.
No. 4316 discloses an antitumor agent containing a polymolybdate as an active ingredient, and Japanese Patent Application No. 74464/1987 discloses an antitumor agent containing a heteropolyarate of molybdenum and tungsten as an active ingredient.

Furthermore, the present inventors focused on those containing two types of elements selected from molybdenum, tungsten, niobium, or vanadium among a large number of heteropolyacid salts, and as a result of intensive research, the present invention was developed. It was completed.

(Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide a novel antitumor agent. Another object of the present invention is to provide an antitumor agent that has a high tumor growth inhibiting effect and has very low side effects.

(Means for Solving the Problems) The following general formula ■ [A] [MxM-011(I) m 6-x 19 [However, in the formula, A is an alkali metal atom or an ammonium group] , an alkylammonium group (however, the number of carbon atoms in the alkyl group is an integer of 1 to 5), a hydrogen atom or a mixture thereof, M is molybdenum, tungsten, niobium or vanadium, M' is molybdenum, tungsten, niobium or vanadium (However, if M and M' are molybdenum, the valences of molybdenum are different, and M and M'
is other than molybdenum, except when M and M' are the same element. ), m is an integer from 1 to 16, and X is 1 to 5
is an integer. This can be achieved by using an antitumor agent containing a heteropolyacid salt represented by the following as an active ingredient.

Further, the present invention is an antitumor agent in which the heteropolyacid salt is in the form of an aqueous solution. Furthermore, the present invention provides that the aqueous solution has a pH of 5 to
It is an antitumor agent that is stable within the range of 8.

(Effect) The heteropolyacid salt used in the antitumor agent of the present invention is a compound represented by the general formula I [A] [MxM6-xO19] (I). In General 2), A is an alkali metal atom, an ammonium group, an alkylammonium group (however, the number of carbon atoms in the alkyl group is an integer of 1 to 5), a hydrogen atom, or a mixture thereof, preferably an alkali metal atom. M is molybdenum, tungsten, niobium or vanadium, M' is molybdenum, tungsten niobium or vanadium (however, when M and M- are molybdenum, the valences of molybdenum are different, for example [Mo
vMo■5o19], when M and M' are other than molybdenum, except when M and M'' are the same element), m is 1 to
16 is an integer and X is an integer from 1 to 5.

The heteropolyacid salt used in the present invention may be any heteropolyacid salt containing two types of elements selected from molybdenum, tungsten, niobium, and vanadium, but in particular, it is a type of isopolyacid that is a cluster compound. Oxoacid ion polynuclear complexes are preferred, which have a structure in which the basic unit is a structure in which oxygen atoms are usually 4 or 6 coordinated to molybdenum and/or tungsten atoms, etc., and these are bonded via ridges or vertices. The general characteristics of such isopolyate ions are as follows.

(1) Ion size from 6 to 25 and from 1,000 to
It shows a molecular weight of 10.000.

(2) Many of them are obtained as crystals and have high solubility in water and polar solvents.

(3) The number of hydrated molecules is large.

(4) It is a strong oxidizing agent (works as a multi-electron pooling agent)
.

Heteropolyacid ions have the property of carrying out pre-oxidation-interactive reactions in solids and solutions, and are beginning to hold great promise industrially for applications such as display functional devices. On the other hand, the high reactivity of these compounds is expected to have physiologically active effects, and various studies have shown that heteropolyacids containing two elements selected from molybdenum, tungsten, niobium, and vanadium are highly reactive. They found that it has a remarkable antitumor effect. In particular, breast cancer, lung cancer, and sarcoma (sarcoma) will become the biggest problems in the future.
It was found to have a dramatic effect on solid tumors such as oma), and to have significantly lower toxicity than the currently widely used aminonitrosourea (ACNU). Examples of such heteropolyacid salts include the following compounds.

K4 [V2W40□9] (Compound A) [NH4] 4
[V2 H4019] [NH3C3H7(is
o) ] 4 [V2 H4019] (Tatashi, is
o indicates an isomer of the compound. )H4[V2 H40
5 [Nb3W3019] (Compound B) [NH4] 5 [Nb3H301
9 [NH3C3H7(i s o) ] 5 [N
b3 H3019] H5[Nb3 H3019] K6 [V2W40□9] (Compound C) [NH4] 5
[V2 H4019] [NH3Cal H7(i
s o)] [V2 H4019] Ha [V2
H4019] VI K 3 [M o M o 5, OL9]
(However, ■ represents pentavalent and ■ represents hexavalent.) (Compound D) ■ ■ ENH4] 3 [Mo Mo 5019] VI [NH3C3H7] 3 [Mo Mo 501
g]V ■ H3[MOM O5019 4 [Nb2 H4019] (Compound E) [NH4] 4 [Nb2 H4019] [NH
3C3H7(i s o) ko 4 [Nb2
H4019] H4[Nb2W4019] Although not shown as an example, the cation moiety may be a mixture of each.

The antitumor agent according to the invention 1 usually contains at least one of the above compounds having the general formula (2) in a solid or liquid carrier, especially a liquid carrier. The compounds according to the invention can also be used in combination with known active substances.

According to the invention, the antitumor dosage form may be of any suitable and/or conventional type. When the compound is administered parenterally, subcutaneously, intravenously and intraperitoneally, the carrier is a sterile pharmaceutically acceptable liquid such as water, vegetable oils and the like, especially water. Generally, the water loss body of the aqueous solution for injection contains 0.1 to 50% by weight of active substance, preferably 1 to 20% by weight. The compounds according to the invention can also be administered by the oral route, and are also suitable for the treatment of lung cancer and the like using vapor or spray forms for the nose and throat. The most preferred oral dosage forms are tablets, capsules, powders, solutions, suspensions, and the like. In these dosage forms, the amount of the compound according to the invention is at least 1% by weight, preferably from 5 to 20% by weight, based on the total weight of the composition.

The dosage of said compound is usually 50 to 4 per day for adults.
00 mg, preferably 100-200 mg.

(Example) Next, the present invention will be described in further detail by giving examples.

Examples 1 to 10 and Comparative Examples 1 and 2 (Evaluation based on inhibition of tumor metastasis) 10 mg of each of the heteropolyacid salts (compounds A, BSC, D and E) were dissolved in 0.85% NaCl solution.
/ml solution was obtained. This solution was administered to female BDF1 mice transplanted with Lewis lung cancer, and the tumor metastasis suppressive activity of the compound was measured.

That is, I x 105 cells of Lewis lung cancer per mouse were subcutaneously transplanted into the right ear and excised on 14 days. The drug solution (25 mg or 50 mg/k of the compound
The tumor weight and number of metastases were measured after 14 and 21 days. The results obtained are shown in Table 1. In addition, for comparison, measurements were also performed on non-administered samples and 5-FU administered samples, and the results are shown in Table 1.

Acute toxicity test Compound A was administered to BDF17 mice at 2000 mg/kg i.
No toxicity was observed even after administration of p.

Medicinal Efficacy It has been revealed that the heteropolyacid salt of the present invention inhibits the metastasis of Lewis lung cancer and exhibits a remarkable effect on inhibiting cancer metastasis.

(Effects of the Invention) As described above, the present invention is an antitumor agent containing a heteropolyacid salt represented by the general formula I as an active ingredient, which has high tumor suppressive activity, and particularly suppresses lung metastasis. shows a remarkable effect. Furthermore, compared to 5-FU, which has been widely used in the past, it not only shows the same inhibitory activity but also has significantly improved toxicity and low toxicity. Furthermore, since it can be made into an aqueous solution, it is very easy to handle and the formulation is stable.

Claims (1)

[Claims] (1) The following general formula I [A]_m[MxM'_6_-_xO_1_9] ( I
) [wherein A is an alkali metal atom, an ammonium group, an alkylammonium group (however, the number of carbon atoms in the alkyl group is an integer of 1 to 5), a hydrogen atom or a mixture thereof, M is molybdenum, Tungsten, niobium or vanadium, M' is molybdenum, tungsten, niobium or vanadium (However, when M and M' are molybdenum, the valences of molybdenum are different, and M and M'
is other than molybdenum, except when M and M' are the same element. ), m is an integer from 1 to 16, and X is 1 to 5
is an integer. ] An antitumor agent containing a heteropolyacid salt represented by the following as an active ingredient.