JPS5916824A - Drug for cataract consisting of organogermanium polymer as main agent - Google Patents

Abstract

NEW MATERIAL:An organogermanium polymer expressed by formula I or II (n is an integer >=3). USE:A drug for cataract, having very low toxicity such as acute toxicity >=10,000 mg/kg LD50 for the oral administration to rats, and usable as injections or eye drops. 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 III is then dissolved in acetone or another organic solvent miscible with water, e.g. ethanol, and water is then added to the resultant solution to give the aimed compound expressed by formula II or III.

Description

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

Conventionally, organic germanium compounds have recently attracted much attention in terms of pharmacological activity, and have been disclosed in Japanese Patent Publication No. 49-2964, Japanese Patent Publication No. 48-61431, and Japanese Patent Publication No. 46-21955.
The organic germanium compounds whose manufacturing methods are disclosed in these patent publications are (GeOH2CH2CO2).
H) It is a low molecular compound represented by 203.

On the other hand, the present inventor focused on the pharmacological activity of organic germanium compounds, and the above formula (G e OH20H2-a
As a result of intensive research into the synthesis of organic germanium compounds other than the low-molecular compounds represented by O,,H)203, a new organic germanium compound was discovered and an organic germanium polymer was completed. -219
No. 92 (Special Publication No. 57-53800).

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 an acute toxicity of LD5o for rats of 1 when administered orally.
0.000 my/Ky or more - administering larger amounts is physically impossible, ie limited by the stomach volume of the rat. This polymer is administered orally.
It has also been confirmed that it has excellent therapeutic effects on human cataracts by injection or as eye drops.

Organogermanium polymers exhibiting the above-mentioned excellent effects have the general formula ([1+) or (IV) (=aθaH, -c
a2-coon) no, 5o(III) or? (-o-OeCH2-OH2-Coo:H)n(fV)
■ [In the formula, n is an integer of 3 or more. ] and the following characteristic physical properties = (a) Infrared absorption spectrum band Large absorption band: 800cnT', 900cm
Relatively large absorption near ' and 1700 crn': 560 cm ', 705 m ', 7
60 pad --・, 780 (771-'
, 1250--.

Around 1350 crn' and 1400 low 1 (however 1
2. The absorption band around 1400cy' is a doublet) (b) Raman spectrum band Large absorption band; 456ci' Relatively large absorption; 382crn-', 618Cr
n', 720'''do --・2. . 1--・
, 1170 cm-'.

1276c7n' and 1425cn-' (C) Powder X
Line diffraction spectrum band Large diffraction peak; 658° Relatively large diffraction: 11.63°, 1582°, 181
6°.

Toku 21.18・and 2゜41・(a
) Differential thermal analysis peak start point 237°C, peak apex 256°C and peak end point 276°C; calorific value, ΔH-59, 4meal/+
y (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 in accordance with the present invention is shown below using a reaction formula.

2HPO2 (M is a metal or ammonium ion and X is a halogen atom) (1) (It) Production of the compound of the present invention based on the following reaction formulas (1), (2) and (3) Let's elaborate on an example.

Germanium dioxide is...reduced with hypophosphorous acid or its salt (preferably a metal salt or ammonium salt) in hydrologonic acid, and germanium atoms become divalent and become dino-logogenated. This produces germanium, which is in equilibrium with trinohydrogengermanium, in which the germanium atom is tetravalent, in hydrohalic acid. It is thought to be in equilibrium with the dissociated form shown at the right end of 1) (see reaction formula (1)).

By diluting this reaction solution with water, the no-rokermanium-phosphoric acid complex can be isolated, so it is possible that phosphoric acid contributes to this equilibrium system.

When polarized acrylic acid aH2-aH-cooH (1) is added to the germanium reagent thus produced, a compound of the general formula %() (or as described above) is formed in the form of white crystals. is produced in high yield (reaction formula % formula %).
Convergence hector bands, Raman spectral bands, powder Xi spectral bands and differential thermal analysis).

As described later, these are conventionally known (GeCH2C
H2C00H) 203-For example, Special Publication No. 53-7960
It has been clarified that this compound is a new compound different from the compound of Example 1 of No.

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.

Example of manufacturing 3-oxygermylpropionic acid low-molecular combination: zs2r (
1 mol) (7) 5-) IJ Dissolve chlorogermylpropionic acid, and add 1.5 t of water to this solution while stirring. White hair-like crystals precipitate out, but the reaction solution is allowed to stand overnight, and then the crystals are removed by suction. The obtained crystals are thoroughly washed with acetone as a solvent and dried under reduced pressure. 144 tons (85 percent yield) of a low-molecular polymer with white needle-like crystals were obtained.Also, other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane) were used instead of acetone. , diglyme, dimethyl sulfoxide, and dimethyl formamide), low-molecular-weight polymers have been similarly obtained in high yields. Historically, low-molecular polymers can also be obtained using solvents that are immiscible with water (e.g., chloroform, methylene chloride, carbon tetrachloride, benzene, ether, etc.); in this case, 5-trichloro When a solution of germyl propionic acid was thoroughly shaken with water, a low molecular weight polymer was precipitated. The crystals of this low molecular weight polymer are 320
Powder X-ray diffraction spectrum of the low-molecular-weight polymer of the present invention, which does not decompose, decompose, or melt at temperatures below ℃,
The infrared absorption spectrum, Raman spectrum, and differential thermal analysis are shown in FIGS. 1, 3, 6, and 8, respectively. Low-molecular polymers are relatively well soluble in water, and their solubility in water is approximately 1? /100rn1. (25°C).

In order to explain that low-molecular polymers are structurally different from known compounds, the powder X-ray diffraction spectrum of a known compound (GeCH2CH2C00H)2o3 (Fig. ), infrared absorption spectrum (Figure 4), Raman spectrum (Nr, Figure 7) and differential thermal analysis (Figure 9) - as well as the difference spectrum between this known compound and the polymer of the present invention (Figure 5). The differences between the polymer of the present invention and known compounds were confirmed as follows.

(a) From the comparison of the infrared absorption spectra of FIG. 6 and FIG. 4 and from the 51st flash, structural differences between the solid compounds are clear.

Absorption below 950 cm-' is mainly due to Ge-0-Ge.
The large difference in absorption indicates the difference in polymer structure.

1) Comparing the Raman spectra in Figure 6 and Figure 7, the former is 456 cm
' and the latter shows it at 449 c1n'. The two are clearly structurally different.

(c) Comparing the powder X-ray diffraction spectra in FIG. 1 and FIG. 2, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures.

(b) Differential thermal analysis When comparing Figures 8 and 9, the former shows only one endothermic peak, as described below, while the latter shows two endothermic peaks, and this temperature also varies. It can be seen that the crystal structures of both substances are different from each other.

Since this 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 detail by demonstrating various pharmacological effects 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 organic germanium polymer (A) according to the present invention is also effective for this disease.

Politz solution ([12% boric acid solution 10-÷005chi Borax solution 9O
-1pH911) and 1% organic germanium low molecular weight polymer.
An ophthalmic solution with a pH of 7.2 was prepared by dissolving it in H. 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
~1.2 mA, energizing time is 5 to 6 minutes, energizing is carried out 10 times every other day, and then 10 times to make one course. Also, organic germanium low molecular weight polymer, daily dose 10v9-150m
9/If continued oral administration for adults (weight around 50), it will take more days than electrification therapy, but it will have almost the same effect.

The results obtained by the electrical therapy are shown in Table 1 as follows.

Table 1

[Brief explanation of the drawing]

Figure 1 shows a water-soluble low molecular weight polymer (
This shows the powder X-ray diffraction spectrum of A). Figure 2 shows the (GeO
2 shows a powder X-ray diffraction spectrum of H20H2COOH)203 (hereinafter abbreviated as a known compound). FIG. 3 shows an infrared absorption spectrum of a water-based 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 the water-soluble low molecular weight polymer which is the compound of the present invention. FIG. 9 shows a differential thermal analysis chart of a known compound. ;゛1〕 Agent Hikaru Esaki 1. ．． , :J, λ110' 1 figure

Claims (1)

[Claims] A germanium phosphate complex obtained by treating germanium dioxide with hypophosphorous acid or its salt in hydrohalic acid is reacted with acrylic acid, and the general formula (
II) X30eOH2-OH2000H (II) [wherein, X is a halogen atom. ] Compound (n) is obtained, and compound (It) is obtained.
is prepared by dissolving it 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: (a) Infrared absorption spectrum band Large absorption band: 800
Relatively large absorption near 900 cm-' and 1700 cr++': 560 cTnt, 705 tyn-'
, 760 band --to 780cyn
t, 1250 (Ml'. Around 1550 cm-'' and 1400 tv-'' (however, the absorption band around 1400 cm-' is a doublet), (b) Raman spectrum band Large absorption band: 456 ctn'', Relatively large absorption: 382>-', 618 cyn-', 720'''
Do-11. 901cvy+', 1
170cm'. 1276crn-凰 and 1425c! n″-11(C
) Powder X-ray diffraction spectrum band large diffraction peak;
650° relatively large diffraction: 11.63°, 1! L82°, 1a
36°. 1-ri 21.18・and 22.41・
(d) A drug for cataracts containing a water-soluble organic germanium polymer as a main ingredient and exhibiting differential thermal analysis peak start point of 237°C, peak apex of 256°C and peak end point of 276°C; calorific value ΔH-59.4meal/q.