JPS6362492B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cataract 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-46-21955
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 . In response, the present inventor focused on the pharmacological activity of organic germanium compounds and conducted intensive research into the synthesis of organic germanium compounds other than the low-molecular compound represented by the above formula (GeCH ₂ CH ₂ CO ₂ H) ₂ O ₃ . As a result of repeated efforts, a new organic germanium compound was discovered and an organic germanium polymer was completed.
No. 53800). Furthermore, the present inventors have discovered that this organic germanium compound exhibits particularly excellent medicinal efficacy against cataracts. 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 has been confirmed that this polymer has an excellent therapeutic effect on human cataracts when administered orally or by injection, or as an eye drop. When this polymer is used for adult treatment, the effective dose is 10 mg to 1000 mg/day, and it is used as a 1% solution (Poriz solution) in the current eye method. 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 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 bands; 382 cm ^-1 , 618 cm ^-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; It is a water-soluble polymer with a calorific value △H = 59.4 mcal/mg (this The 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 below using a reaction formula: (M is a metal or ammonium ion and X is a halogen atom) Production examples of the compounds of the present invention will be explained in detail below based on the above reaction formulas (1), (2), and (3). 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 compounds of the present invention exhibit characteristic physical properties (infrared absorption spectral bands, Raman spectral bands, powder X-ray spectral bands and differential thermal analysis) as described above. These are as described below.
It has been revealed that this is a new compound 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 for a day and night, and then the crystals are removed by suction. 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, a low molecular weight polymer can be obtained by using a water-immiscible solvent (for example, chloroform, methylene chloride, carbon tetrachloride, benzene, ether, etc.) as a solvent; 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 way are shown in Figures 1, 3, 6, and 8, 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 2), infrared absorption spectrum (Figure 4), Raman spectrum (Figure 7), differential thermal analysis (Figure 9), and difference spectrum between this known compound and the polymer of the present invention ( Figure 5) 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 3 and 4 and Figure 5,
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 Figure 6 and Figure 7, the former is 456
It shows the maximum absorption peak at cm ^-1 , the latter at 449 cm ^-1
It shows that. The two are clearly structurally different. (c) Powder X-ray diffraction spectra Comparing Figures 1 and 2, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures. . (d) Differential thermal analysis Comparing Figures 8 and 9, the former shows only one endothermic peak as described below, 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 the polymer is water-soluble, formulation can be carried out in the usual manner by using common eye drops, injection solutions, or excipients and/or lubricants. In the following Examples, the present invention will be explained in more detail by demonstrating each pharmacological effect on cataract diseases using the organic germanium compounds obtained in the above production examples. Effect on cataract: Cataract is one of the most difficult-to-cure ophthalmic diseases, and it has been found that the organogermanium polymer (A) according to the present invention is also effective for this disease. Politz solution (0.2% boric acid solution 10ml ÷ 0.05% borax solution 90ml
An eye drop with a pH of 7.2 was prepared by dissolving a 1% organic germanium low-molecular-weight polymer in 1% of the organic germanium low-molecular-weight polymer. Using this, a cup filled with a medicinal solution is applied to the eye using an Ito-style iontophoresis device, and electricity is applied. The strength of the current is 1.0 to 1.2 mA, and the energizing time is 5 to 6 minutes.
The current is applied 10 times every other day, and then 10 times more to make one course. If the organogermanium low molecular weight polymer is continued to be taken orally at a daily dose of 10 mg to 150 mg/adult (body weight 50 kg), it will take more days than the electrification cancer method, but will have almost the same effect. The results obtained by the electrical therapy are shown in Table 1 as follows. 【table】

[Brief explanation of drawings]

FIG. 1 shows the powder X-ray diffraction spectrum of the water-soluble low molecular weight polymer (A) which is the compound of the present invention. FIG. 2 shows the 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. 3 shows an infrared absorption spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 4 shows infrared absorption spectra of known compounds. FIG. 5 shows a difference spectrum between the infrared absorption spectra of FIGS. 3 and 4. FIG. FIG. 6 shows a Raman spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 7 shows a Raman spectrum of a known compound. FIG. 8 shows a differential thermal analysis chart of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 9 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 values Peak start point 237℃, peak peak 256℃ and peak end point 276℃; Main ingredient is water-soluble organic germanium polymer showing calorific value △H = 59.4mcal/mg A drug for cataracts.