JPS5916825A - Drug for cancer consisting of organogernmanium polymer as main agent - Google Patents

Abstract

NEW MATERIAL:An organogermanium polymer expressed by formula I or II(n is an integer >=3). USE:An antitumor agent, effective against cancers in the human stomach, lung, uterus, breast, prostate gland, etc., and having very low toxicity and acute toxicity such as >=10,000mg/kg LD50 for the oral administration to rats. PROCESS:Germanium dioxide is treated with hypophosphorous acid or a salt thereof in a hydrohalogenic acid to give a halogermanium-phosphoric acid complex, which is then reacted with acrylic acid to afford a compound expressed by formula III (X is halogen). The resultant compound expressed by formula IIIis then dissolved in acetone or another organic solvent miscible with water, e.g. ethanol, and water is then added to the solution to give the aimed compound expressed by formula I or II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cancer drug containing an organic germanium compound as a main ingredient.

Conventionally, organic germanium compounds have recently attracted much attention due to their pharmacological activity, and are described in Japanese Patent Publication No. 49-2964,
The organic germanium compounds disclosed in patent publications such as JP-A No. 48-61431, JP-B No. 46-21855, and JP-A-46-2498, and whose manufacturing methods are disclosed in these patent publications, are ( GeOH, OH, C!O,
H), a low-molecular compound represented by Os.

On the other hand, the present inventor focused on the pharmacological activity of organic germanium compounds, and the above formula (GeC!H20H, -〇〇,
As a result of intensive research into the synthesis of organic germanium compounds other than the low-molecular-weight compounds represented by H) and O, a new organic germanium compound was discovered and an organic germanium polymer was completed. 2199
No. 2 (Special Publication No. 57-538'OO).

Furthermore, the present inventors have discovered that this organogermanium compound exhibits particularly excellent medicinal efficacy against cancer.

This organogermanium polymer has extremely low toxicity, and the acute toxicity is LD for rats when administered orally, o is 1o,
9 or more - administering more than this amount is physically impossible, ie limited by the stomach capacity of the rat.

It was confirmed that this polymer clearly exhibits excellent antitumor effects against cancer when administered orally or by injection.

Organogermanium polymers exhibiting the above-mentioned excellent effects have the general formula (II) or (IV) (=GeOIft-O
H, -000H)nOH,5n(III) or OH (-0-GeOH, -OH,C!OOH)n(■)■ [In the formula, n is an integer of 3 or more. ] and has the following characteristic physical properties: (al infrared absorption spectrum, large absorption band; 800 cm-', 900 cm-',
M-' and 1700 (relatively large absorption near each of M-': 560r-M-', 705r-',
760cm=.

"7F"780cm-', 1250CII
+-', 1550cy' and 1400crn' (however, the absorption band around 140ocIn-' is a doublet) (BL Raman spectrum, large absorption band: 1 at 456cn Relatively large absorption; 382CIn', 518cm' ,
72ocIn-';'<7"" 901 c
m→, 1170cF', 1276 side-1 and 142
5 i, v −' (C) Powder X-ray diffraction spectrum, band large diffraction peak; 6.58° Relatively large diffraction: 11.63°, 13.82°,
18.36°.

Peaks 21.18' and 22.41・(
(Differential thermal analysis peak start point 237 O, peak apex 256 °C and peak end point 276'O; heat quantity ΔH = 59.4 rn
It is made of a water-soluble polymer that exhibits a
7-53800).

An example of the production of the water-soluble organic germanium polymer used in accordance with the present invention is shown by a reaction formula as shown below: M, H1l'O.

(M is a metal or an ammonium ion and/or a halogen atom) Examples of producing the compound of the present invention will be explained below in detail based on the above reaction formulas (2) and (3).

Germanium dioxide is prepared as follows in 1J
When reduced with lj 17-phosphoric acid or its salt (preferably a metal salt or asimonium salt), the germanium atom becomes divalent and yields germanium dino-10genide, which is It is in equilibrium with trinohydrogermanium, which is tetravalent, in hydrohalic acid.

It is also believed that germanium trihalogen trihalide is in equilibrium with the dissociated form shown at the right end of reaction formula (1) in an aqueous solution (see reaction composition).

By diluting this reaction solution with water, the nologermanium-phosphoric acid complex can be isolated, so it is possible that phosphoric acid contributes to this equilibrium system.

The germanium reagent thus produced is polarized with Cu acrylate, ==a H-C! Addition of OOH(1) produces white crystals of the compound represented by the general formula % Formula % (1) (or as described above) in high yield (Scheme 1 Formula %) Compounds of the Invention shows the characteristic physical properties (infrared absorption spectral band, Raman spectral band, powder X, 11 spectral band and differential thermal analysis) as mentioned above. As described later, these are conventionally known (GeOH
,OH,C00H)20. -For example, special public service in 1984-79
It has been revealed that this compound is a new compound different from the compound of Example 1 of No. 60.

Next, the pharmacological effects of this organic germanium polymer, such as water bending, will be explained in detail. The organic germanium polymer used for this purpose is produced by the following synthesis method.

Example of manufacturing 252f (
1 mol) of 3-trichlorogermylpropionic acid is dissolved, and 1.3 t of water is added to this solution with stirring. White hair-like crystals precipitate, but after the reaction solution has been left alone for a day and night,
Aspirate and collect the crystals. The obtained crystals are thoroughly washed with acetone as a solvent and dried under reduced pressure. A low molecular weight polymer with white needle-like crystals was obtained as 144F (85% yield).

Father, other water-miscible solvents instead of acetone (e.g.
Similarly, low-molecular polymers have been obtained in high yields using ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, digly, dimethyl sulfoxide, dimethylformamide, etc.). Furthermore, it is also possible to obtain a low-molecular polymer by using a solvent that is immiscible with water (for example, chloroform, methylene chloride, carbon tetrachloride, benzene, ether, etc.); in this case, 3-trichlorogermyl When a solution of propionic acid was thoroughly mixed with water, a low molecular weight polymer was precipitated. The crystal of this Sakai molecule ■ combination is 520
It neither decomposes nor melts under 0 seeds.

Low molecular weight polymer powder X of the present invention produced in this way
Line diffraction spectra, infrared absorption spectra, Raman spectra, and differential thermal analysis are shown in Figures 6, 8, and 11, respectively.
and FIG. 13. Low-molecular polymers are relatively well soluble in water, and the solubility in water is approximately 1 f/100g1
! , (25゛0).

In order to explain that low molecular weight polymers are different from known compounds, powder X-ray analysis of the known compound 03 (GeOH, C! Diffraction spectrum (Figure 7), infrared absorption spectrum (Figure 9), difference spectrum with Raman body (1st
0), and the following differences between the polymer of the present invention and known compounds were confirmed: (a) From the comparison of the infrared absorption spectra of Figures 8 and 9 and Figure 10, The structural differences of the solidified compounds are obvious.

The absorption below 950 cm-1 is mainly based on Ge-0-Ge, and the large difference therein indicates the yellowing of the polymer structure.

(b) Comparing the Raman spectra in Figures 11 and 12, the former is 456 (:
It shows the maximum absorption peak at In-', the latter at 449 cm-
' shows it. The two are clearly structurally different.

(c) Comparing the powder X-ray diffraction spectra in FIGS. 6 and 7, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures.

(2) Differential thermal analysis When comparing Figures 16 and 14, the former shows only one endothermic peak, while the latter shows two.
It can be seen that the crystal structures of the two substances are different from the fact that they exhibit two endothermic peaks and their temperatures are also different.

Since this polymer is water-soluble, formulation can be carried out in the usual way by using common injection solutions or excipients and/or lubricants.

In the following examples, the organic germanium compounds obtained in the above production examples will be used to demonstrate the pharmacological effects on antitumor effects, and the present invention will be explained in more detail.

(1) Medicinal efficacy for Ehrlich carcinoma 7.5×10′ cells (per mouse) of Ehrlich carcinoma were intravenously injected into 10 mice, and 72 hours later, 100 m9/kg per day was orally administered for 10 days. did. The results are shown in Table 1.

As can be seen from Table 1, the administration of the organogermanium polymer clearly increased the number of days the mice survived, the length of time they slept, and the number of mice that survived.

(2) Effect of Lewis lung cancer on lung cancer 1 x 103 Lewis lung cancer cells per mouse were subcutaneously inoculated, and from the next day onwards, once a day for 5 days, organic germanium polymer (obtained in the production example) was applied. was administered orally. Then, the amount of decrease in 1i4i tumor weight was measured. The results are shown in Table 2.

Table 2 (3) Effect on rat ascites hepatoma AH66 strain, AH-44 strain Sutake AH-410 strain Ascites hepatoma AH66 strain, Al-44 in Ton-Liu rats
107 cells (per rat) of A. or AH-410 strain were inoculated intravenously, and from the 3rd day onwards, 100~/ky of the organic germanium low molecular weight polymer of Production Example was orally administered once a day for 10 days.

As a result, as shown in FIG. 1, FIG. 2, and FIG. 3, respectively, the extension of survival days and the increase in the number of surviving rats were halted.

(4) Effect on human cancer The organogermanium polymer according to the present invention is effective against various human cancers such as stomach cancer, lung cancer, uterine cancer, breast cancer, and prostate cancer. This figure shows the treatment results for liver metastasis of cancer.

(Treatment of Al lung adenocarcinoma) A 71-year-old father with lung adenocarcinoma in the right upper lobe was given 50
mQ was administered for 3 months.

As shown in Figure 4, most of the vomiting caused by treatment disappeared. In the figure, (
al is the lung with treatment % (rl) before administration, and (
b) Schematic diagram showing the lungs after 5 months of administration.

(Bl skin) Treatment of liver metastasis of cancer A 69-year-old man with cervical skin cancer that had metastasized to the liver was given a daily dose of 9.
0 mq was administered for 2 months.

As shown in Figure 5, the wound was almost completely cured. In the figure, (al is
The liver with skin) 8 (C) that had metastasized to the liver before administration was
(bl is a schematic diagram showing the liver after administration for 2 months.

(5) Medicinal efficacy against Sarcoma-180 2x10'l Sarcoma-180 cells (per animal)
was implanted into the abdominal cavity of a mouse, and 24 hours later, the organic germanium low molecular weight polymer of the production example was orally administered in a mixed feeding method for 5 days. The results are shown in Table 3 below.

Table 6 By administering the organogermanium polymer, a marked prolongation of survival days and an increase in the number of surviving mice were observed.

[Brief Description of the Drawings] Figures 1, 2, and 3 show liver cancer strains AH-66, A) 144, and A) when the compound of the present invention was used.
+(410 strains) to suppress death in Donriyu rats. Figure 4 is a schematic diagram showing the lungs of a lung adenocarcinoma patient before and after administration of this drug. Figure 5 is a diagram showing the lungs of a lung adenocarcinoma patient before and after administration of this drug. 1 is a schematic diagram showing the liver of a skin cancer patient before and after administration of this drug. FIG. 6 shows a powder X-ray diffraction spectrum of a water-soluble low molecular weight polymer made from the compound of the present invention. Figure 7 shows Example 1 (7) of Japanese Patent Publication No. 53-7960 (
This figure shows a powder X-ray diffraction spectrum of Ge (!H, OH, 0OOH), 03 (hereinafter abbreviated as a known compound). FIG. 8 shows an infrared absorption spectrum of water-soluble low molecule 1, which is a compound of the present invention. FIG. 9 shows infrared absorption spectra of known compounds. FIG. 10 shows a difference spectrum between the infrared absorption spectra of FIGS. 8 and 9. FIG. FIG. 11 shows a Raman spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. Figure 12 is from a book showing Raman spectra of known compounds. FIG. 13 shows a differential thermal phase separation chart of the water-soluble low molecular weight polymer which is the compound of the present invention. FIG. 14 shows a differential thermal analysis chart of a known compound. Agent Mitsuyoshi Esaki ・1゛1 Agent Mitsufumi Esaki 1” 'l □,, -1 Figure 1 Japanese Autumn Figure 2 20 40 60 Number of days Figure 6 20 40 60 Number of days Figure 4 (0 ) ] Leaf Fig. 5 (a) (C) (b) Fig. 7 90 - 0 0 vo 0

Claims (1)

[Claims] A halogermanium phosphate complex obtained by treating germanium dioxide with hypophosphorous acid or its salt in a hydrogen halide solution is reacted with acrylic acid to form a compound of the general formula (Ill XGθOH- A compound (n) represented by OH0OOH(It) [in the formula or a halogen atom] was obtained, and the compound (Ill
It can also be prepared by dissolving % in acetone or other organic solvent that is mixed with water and adding water to this solution according to the general formula %() (), where n is an integer of 3 or more. ] and has the following characteristic physical properties: (al infrared absorption spectrum band: large absorption band; around 800c+++, 900cmb and 1700cm', relatively large absorption; 560cm-', 705c)
m-', 760 cU'. Band 780crn→, 1250cm",
Around 1550α-1 and 1400Crn' (however, the absorption band around 1400cm-' is a doublet), (BL Raman spectrum band large absorption band; 456c1n=. Relatively large absorption: 582cm-', 618cy')
, 72ocm-'. Band 90 yr', 1170 CU',
1276α-1 and 142-5 cm-', (Q) Powder X-ray diffraction spectrum band Large diffraction peak; 650° Relatively large diffraction: 11.63°, 13.82°,
18.36°. Peak 2L1B° and 22.41° (+
11 Differential thermal analysis value Peak start point 237° 0, peak apex 256°C, and peak end point 276'O: amount of heat ΔH = 59.4 m (!
A cancer drug whose main ingredient is a water-soluble organic germanium polymer exhibiting a 17 m9.