JPH0331168B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cancer drug containing an organic germanium compound as a main ingredient. In recent years, organic germanium compounds have received considerable attention in terms of their pharmacological activity, and were
No. 2964, JP-A-48-61431, JP-A-46-21855
The organic germanium compounds whose manufacturing methods are disclosed in these patent publications are as follows:
It is a low molecular compound represented by (GeCH ₂ CH ₂ CO ₂ H) ₂ O ₃ . On the other hand, the present inventor focused on the pharmacological activity of organic germanium compounds, and the above formula (GeCH ₂ CH ₂
As a result of intensive research into the synthesis of organic germanium compounds other than the low-molecular-weight compound represented by −CO ₂ H) ₂ O ₃ , we discovered a new organic germanium compound, completed an organic germanium polymer, and filed a patent application for this. It was disclosed in No. 53-21992 (Special Publication No. 57-53800). Furthermore, the present inventors have discovered that this organogermanium compound exhibits particularly excellent medicinal efficacy against cancer. This organogermanium polymer has extremely low toxicity, with acute toxicity in rats after oral administration.
The LD ₅₀ is 10000 mg/Kg or more - it is physically impossible to administer a larger amount, 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. Effective doses of this polymer for adult treatment range from 10 mg to 1000 mg. Organogermanium polymers exhibiting the above-mentioned excellent effects have the general formula () or () (≡GeCH ₂ −CH ₂ −COOH) _o O _1.5o () or [In the formula, n is an integer of 3 or more. ] and has the following characteristic physical properties: (a) Infrared absorption spectrum. Band Large absorption band; 800cm ^-1 , 900cm ^-1 and
Relatively large absorption bands around 1700cm ^-1 : 560cm ^-1 , 705cm ^-1 ,
Around 760cm ^-1 , 780cm ^-1 , 1250cm ^-1 , 1350cm ^-1 and 1400cm ^-1 (however, the absorption band around 1400cm ^-1 is a doublet) (b) Raman spectrum. Band Large absorption band; 456cm ^-1 Relatively large absorption band; 382cm ^-1 , 618cm ^-1 ,
720cm ^-1 ; 901cm ^-1 , 1170cm ^-1 , 1276cm ^-1 and 1425cm ^-1 (c) Powder X-ray diffraction spectrum. Band Large diffraction peak; 6.58° Relatively large diffraction peak; 11.63°, 13.82°,
18.36°, 21.18° and 22.41°(d) Differential thermal analysis Peak start point 237°C, peak apex 256°C and peak end point 276°C; calorific value ΔH = 59.4 m cal/
(This polymer is disclosed in more detail in Japanese Patent Publication No. 57-53800 filed by the same applicant as the present invention). An example of the production of the water-soluble organic germanium polymer used according to the present invention is shown by the reaction formula as follows: GeO ₂ HX ------→ H ₃ PO ₂ or M ₂ HPO ₂ GeX ₂ HX HGeX ₃ H ⁺ +GeX ^- ₃ (1) (M is a metal or ammonium ion and X is a halogen atom) HGeX ₃ ↓↑ H ⁺ +GeX ^- ₃ +CH ₂ =CH−COOH ()→ X ₃ GeCH ₂ − CH _{2 COOH ( )} ( ₂ ) Examples of manufacturing the compounds of the present invention will be explained in detail below. Germanium dioxide is reduced with hypophosphorous acid or a salt thereof (preferably a metal salt or an ammonium salt) in hydrohalic acid, and the germanium atoms become divalent, yielding germanium dihalide. However, this material is in equilibrium with trihydrogengermanium halide, in which the germanium atom is tetravalent, in hydrohalic acid. This hydrogen trihalide germanium is also thought to be in equilibrium with the dissociated form shown at the right end of reaction formula (1) in an aqueous solution (see reaction formula (1)). By diluting this reaction solution with water, the halogermanium-phosphate complex can be isolated.
The contribution of phosphoric acid to this equilibrium system is also considered. When polarized acrylic acid CH ₂ =CH-COOH () is added to the germanium reagent thus produced, the general formula of white crystals is X ₃ GeCH ₂ -CH ₂ COOH (), where X is as described above. ) is produced in high yield (reaction formula (2)
reference). The compound of the present invention exhibits the characteristic physical properties (infrared absorption spectrum band, Raman spectrum band, powder X-ray spectrum band, and differential thermal analysis) as described above. These are as described below.
It has been revealed that this is a new compound that is different from the conventionally known (GeCH ₂ CH ₂ COOH) ₂ O ₃ - for example, the compound of Example 1 of Japanese Patent Publication No. 53-7960. Next, the above-mentioned pharmacological effects of the present organic germanium polymer will be specifically explained. The organic germanium polymer used for this purpose is produced by the following synthesis method. Production example of 3-oxygermylpropionic acid low-molecular polymer 252 g in 1.3 acetone, a solvent that mixes with water
(1 mol) of 3-trichlorogermylpropionic acid is dissolved and 1.3 of water is added to this solution with stirring. White hair-like crystals precipitate out, but the reaction solution is allowed to stand overnight and then absorbed to remove the crystals. The obtained crystals are thoroughly washed with acetone as a solvent and dried under reduced pressure. 144g of white needle crystal low molecular weight polymer
(85% yield) was obtained. Also, if other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, dimethyl sulfoxide, dimethylformamide, etc.) are used instead of acetone, low-molecular polymers can be produced in the same way. was obtained in high yield. Furthermore, it is also possible to obtain a low molecular weight 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 the propionic acid solution was thoroughly shaken with water, a low molecular weight polymer was precipitated. The crystals of this low-molecular polymer do not decompose or melt at temperatures below 320°C. The elemental analysis values of this product are as follows: Theoretical value (%): Carbon (C); 21.24, Hydrogen (H); 2.97 Germanium (Ge); 42.79 Measured value (%): Carbon (C); 21.10, hydrogen (H); 3.02 germanium (Ge); 42.5. The powder X-ray diffraction spectrum, infrared absorption spectrum, Raman spectrum, and differential thermal analysis of the low molecular weight polymer of the present invention produced in this manner are shown in Figures 6, 8, 11, and 13, respectively. show.
The low molecular weight polymer was relatively well soluble in water, and its solubility in water was about 1 g/100 ml (25°C). In order _to explain that low _- molecular polymers are _{structurally different} from known compounds, powder Diffraction spectrum (Figure 7), infrared absorption spectrum (Figure 9), Raman spectrum (Figure 12), differential thermal analysis (Figure 14), and difference spectrum between this known compound and the polymer of the present invention ( Figure 10) was measured, and the differences between the polymer of the present invention and known compounds were confirmed as follows: (a) Infrared absorption spectrum From the comparison between Figures 8 and 9 and Figure 10,
The structural differences between both compounds are clear. The absorption below 950 cm ^-1 is mainly due to Ge-O-Ge, and the large difference therein indicates a difference in the polymer structure. (b) Raman spectrum Comparing Figures 11 and 12, the former is
The maximum absorption peak is at 456 cm ^-1 , the latter at 449 cm ^-1
It shows that. Both are clearly structurally
They are different. (c) Powder X-ray diffraction spectra When comparing Figures 6 and 7, both spectra show peaks at different positions at different diffraction angles, indicating that they have completely different crystal structures. . (d) Differential thermal analysis Comparing Figures 13 and 14, the former shows only one endothermic peak as described later, while the latter shows two endothermic peaks, and the temperature It can be seen that the crystal structures of the two substances are different from the fact that they are also different. Since this polymer is water-soluble, it can be formulated in the usual way by using common injection solutions or excipients and/or lubricants. In the following examples, the present invention will be explained in more detail by demonstrating the pharmacological effects on antitumor effects using the organic germanium compounds obtained in the above production examples. Antitumor effect: (1) Efficacy against Ehrlichi cancer 7.5 × 10 ⁶ cells (per mouse) of Ehrlichi cancer were intravenously injected into 10 mice, and the daily dose was 100 mg/Kg for 10 days starting 72 hours later. Administered orally.
The results are shown in Table 1.

[Table] As can be seen from Table 1, administration of the organogermanium polymer clearly prolonged the survival period and increased the number of surviving mice. (2) Effect of Lewis on lung cancer Lewis lung cancer cells were administered 1x per mouse.
10 ⁵ cells were subcutaneously inoculated, and from the next day, the organic germanium polymer (obtained in the production example) was orally administered once a day for 5 days. Then, the amount of reduction in tumor weight was measured. The results are shown in Table 2.

[Table] (3) Rat ascites liver cancer AH66 strain, AH-44 strain or
Effect on AH-41C strain Don Liurat's ascites liver cancer AH66 strain,
10 ⁷ cells (per rat) of AH-44 strain or AH-41 strain were inoculated intravenously, and from the 3rd day, 100 mg/Kg of the organic germanium low molecular weight polymer prepared in the production example was administered.
was orally administered once a day for 10 days. As a result, as shown in Figures 1, 2, and 3, it was observed that survival days were prolonged and the number of surviving rats increased. (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. (A) Treatment of lung adenocarcinoma A 71-year-old woman with lung adenocarcinoma in the right upper lobe was given 1
The drug was administered at a daily dose of 30 mg for 3 months. As shown in FIG. 4, most of the cancerous lesions disappeared. In the figure, (a) shows the lung with cancer focus (c) before administration, and (b) shows the lung with cancer focus (c) before administration.
FIG. 2 is a schematic diagram showing the lungs after administration for several months. (B) Treatment of pulmonary metastasis from skin cancer A 69-year-old man with cervical skin cancer that had metastasized to the lungs.
The drug was administered at a daily dose of 90 mg for 2 months. As shown in Figure 5, most of the cases were cured. In the figure, (a) is a schematic diagram showing a liver with skin cancer metastasized to the lungs (c) before administration, and (b) is a diagram showing a liver after two months of administration. (5) Medicinal effect on Sarcomer 180 2 × 10 ⁴ Sarcomer 180 cells (per mouse) were transplanted into the abdominal cavity of mice, and 24 hours later, 5
The organic germanium low-molecular-weight polymer of the production example was orally administered in a mixed feeding method for days. The results are shown in Table 3 below.

[Table] Administration of the organogermanium polymer resulted in a marked extension of survival days and an increase in the number of surviving mice.

[Brief explanation of the drawing]

Figures 1, 2, and 3 show the effect of suppressing death in Donriyu rats caused by liver cancer strains AH-66, AH44, and AH41C, respectively, when the compound of the present invention was used. be. FIG. 4 is a schematic diagram showing the lungs of a lung adenocarcinoma patient before and after administration of this drug. FIG. 5 is a schematic diagram showing the liver of a hepatocutaneous carcinoma patient before and after administration of this drug. Figure 6 shows
1 shows a powder X-ray diffraction spectrum of a water-soluble low-molecular-weight polymer that is a compound of the present invention. FIG. 7 shows a powder X-ray diffraction spectrum of (GeCH ₂ CH ₂ COOH) ₂ O ₃ (hereinafter abbreviated as known compound) of Example 1 of Japanese Patent Publication No. 53-7960. FIG. 8 shows an infrared absorption spectrum of a water-soluble low molecular weight polymer 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. FIG. 12 shows a Raman spectrum of a known compound. FIG. 13 shows a differential thermal analysis chart of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 14 shows a differential thermal analysis chart of a known compound.

Claims (1)

[Claims] 1. A halogermanium phosphate complex obtained by treating germanium dioxide with hypophosphorous acid or its salt in hydrohalic acid is reacted with acrylic acid to form a compound of the general formula ( ₎ GeCH ₂ -CH ₂ COOH () [In the formula, X is a halogen atom. ] A compound of the general formula (≡GeCH ₂ −CH ₂ −COOH) _o O _1.5o () or [In the formula, n is an integer of 3 or more. ] and have the following characteristic physical properties: (a) Infrared absorption spectral bands Large absorption bands; 800 cm ^-1 , 900 cm ^-1 and
Relatively large absorption bands around 1700cm ^-1 ; 560cm ^-1 , 705cm ^-1 ,
around 760cm ^-1 , 780cm ^-1 , 1250cm ^-1 , 1350cm ^-1 and 1400cm ^-1 (however, the absorption band around 1400cm ^-1 is a doublet), (b) Raman spectrum band Large absorption band; 456cm ^-1 , relatively large absorption band; 382cm ^-1 , 618cm ^-1 ,
720cm ^-1 , 901cm ^-1 , 1170cm ^-1 , 1276cm ^-1 and 1425cm ^-1 , (c) Powder X-ray diffraction spectrum band Large diffraction peak; 650° Relatively large diffraction peak; 11.63°, 13.82° ，
18.36°, 21.18° and 22.41°(d) Differential thermal analysis value Peak start point 237°C, peak apex 256°C and peak end point 276°C; heat amount ΔH = 59.4 m cal/
A cancer drug whose main ingredient is a water-soluble organic germanium polymer.