JPH0124767B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a drug for hypertensive cardiovascular diseases 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 . 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 organogermanium compound exhibits particularly excellent medicinal efficacy against hypertensive cardiovascular diseases. That is, this organogermanium polymer has extremely low toxicity (acute toxicity: LD ₅₀ for rats when administered orally is 10,000 mg/Kg or more - administering a larger amount is physically difficult, i.e., due to the gastric volume of the rat). Oral administration (or injection) to spontaneously hypertensive rats (SHR) (see Examples, Table 1 and Figure 1) and human hypertension (see Figure 2) ), it has the effect of lowering blood pressure, but it also has the characteristic that it does not drop below normal levels. It also shows the effect of curing cardiovascular disorders including arrhythmia (see Figure 3), angina pectoris (see Figure 4), myocardial infarction, encephalomalacia, and stroke in humans. Organic germanium polymers exhibiting the above excellent effects have the general formula () or () (≡GeCH ₂ −CH ₂ −COOH) _o O _1.5o () and [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 bands Large diffraction peak; 658° Relatively large diffraction peak; 11.63°,
13.82゜18.36゜, 21.18゜and 22.41゜(d) Differential thermal analysis Peak start point 237℃, peak peak 256℃ and peak end point 276℃; It is a water-soluble polymer showing a calorific value ΔH = 59.4mcal/mg ( 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 following 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.
It is possible that phosphoric acid contributes to this equilibrium system. When polarized acrylic acid CH ₂ =CH-COOH () is added to the germium 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
(See (2)). 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 (85g) of white needle-like low molecular weight polymer
% yield) was obtained. Also, low-molecular polymers can be produced in the same way by using other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, dimethyl sulfoxide, dimethylformamide, etc.) instead of setone. was obtained in high yield. 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-trichlorogermylpropion When the 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 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 5, 7, 10, and 12, respectively. .
The low molecular weight polymer was relatively well soluble in water, and its solubility in water was approximately 1 g/100 ml (25°C). In order _to explain that low _- molecular polymers are _{structurally different} from known compounds, powder Diffraction spectrum (Figure 6), infrared absorption spectrum (Figure 8), Raman spectrum (Figure 11), differential thermal analysis (Figure 13), and difference spectrum (Figure 1) between this known compound and the polymer of the present invention. Figure 9) 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 7 and 8 and Figure 9,
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 spectra Comparing Figures 10 and 11, the former is
The maximum absorption peak is at 456 cm ^-1 , the latter at 449 cm
^-1 shows it. The two are clearly structurally different. (c) Powder X-ray diffraction spectra Comparing Figures 5 and 6, both spectra show peaks at different diffraction angles, indicating that they have completely different crystal structures. (d) Differential thermal analysis Comparing Figures 12 and 13, 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 this polymer is water-soluble, it can be formulated in a conventional manner 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 using the organic germanium compounds obtained in the above production examples. Example 1 Effect on spontaneously hypertensive rats 100mg/day for 4 months in spontaneously hypertensive rats
Kg was orally administered, blood pressure was measured after 7 months, and the animals were sacrificed and heart weights were measured. Clear results were obtained as shown in Table 1 and Figure 1.

[Table] However, Figure 1 shows the relationship between blood pressure and heart weight in spontaneously hypertensive rats. The following can be seen from Table 1 and Figure 1. (1) There was no difference in blood pressure between the control group and the experimental group before the start of the experiment. (2) Looking at the blood pressure after 126 days of administration, it was clearly lower in the experimental group than in the control group. Moreover, the blood pressure does not fall below normal blood pressure. (3) Comparing the heart weight on day 126, it was clearly lower in the experimental group than in the control group. Example 2 Example of human application of medicinal effects on the heart and vascular system A hypotensive effect on hypertension was observed at a daily dose of 10 mg to 90 mg/adult (body weight 50 kg) or at a higher dose depending on the symptoms. A specific example is shown in Figure 2. This figure shows a 52-year-old man with hypertension having 40
This figure shows the improvement process in systolic blood pressure when administered for 40 days at a dose of mg/adult (body weight 50 kg). Clear improvement was also observed in electrocardiogram findings for angina pectoris, heart failure, and arrhythmia at a daily dose of 10 mg to 90 mg/adult (body weight 50 kg) or at a higher dose depending on the symptoms. . Specific findings for arrhythmia are shown in Figure 3, and for angina pectoris in Figure 4. Figure 3 shows the dose before administration (a) and 30 mg/day for an adult (weight 50 kg) in a 60-year-old man with arrhythmia.
The electrocardiogram findings shown in (b) after administration for 10 days are shown. As can be seen from this figure, improvement in arrhythmia was clearly achieved. Figure 4 shows before administration (a) and 40 mg/day for an adult (body weight 50 mg/day) in a 63-year-old woman with angina pectoris.
(b) ST wave findings 15 minutes after administration (Kg), showing normalization of the number of pulses. Anti-bleeding effect, promotion effect on blood circulation, improvement of neurocirculatory weakness, and improvement of pulmonary edema also occur in one day.
The shortest term was 1 month and the longest was over 6 months, in doses of 10 mg to 90 mg/adult (50 kg body weight) or higher depending on symptoms.

[Brief explanation of drawings]

FIG. 1 illustrates the relationship between blood pressure and heart weight of spontaneously hypertensive rats and administration of the drug of the present invention. FIG. 2 shows the time course of blood pressure reduction in hypertensive patients by administration of this drug. Figure 3 shows the electrocardiogram of an arrhythmia patient before and after administration of this drug. FIG. 4 shows the electrocardiogram of a patient with angina before and after administration of this drug. FIG. 4 shows the effects of the compounds of the present invention on spontaneously hypertensive rats. FIG. 5 shows a powder X-ray diffraction spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. Figure 6 is the special public service issued in 1973.
7960 shows the powder X-ray diffraction spectrum of (GeCH ₂ CH ₂ COOH) ₂ O ₃ (hereinafter abbreviated as known compound) of Example 1. FIG. 7 shows an infrared absorption spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 8 shows infrared absorption spectra of known compounds. Figure 9 shows
This shows a difference spectrum between the infrared absorption spectra of FIG. 7 and FIG. 8. FIG. 10 shows a Raman spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. FIG. 11 shows a Raman spectrum of a known compound. FIG. 12 shows a differential thermal analysis chart of the water-soluble low molecular weight polymer which is the compound of the present invention. FIG. 13 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 () [wherein, X is a halogen atom]. ] and further prepared by dissolving the compound () in acetone or other organic solvent mixed with water and adding water to this solution, and having the general formula (≡GeCH ₂ − CH ₂ −COOH) _o O _1.5o () and [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 1700 cm ^-1 ; 560 cm ^-1 , 705 cm ^-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; 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; 11.63°, 13.82°, 18.36°,
21.18° and 22.41°(d) Differential thermal analysis values Peak start point 237°C, peak apex 256°C and peak end point 276°C; hypertensive heart based on water-soluble organic germanium polymer showing calorific value ΔH = 59.4 mcal/mg Drugs for vascular diseases.