JPS6362495B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a drug for viral 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 . 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 organic germanium compound exhibits particularly excellent medicinal efficacy against viral diseases. 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. The polymers can be applied in application formats such as ointments by oral administration or injection or, in the case of viral skin diseases, using a variety of common bases. Effective doses of this polymer for adult treatment range from 10 mg to 1000 mg/day. Since this polymer is water-soluble, formulation into injection solutions and tablets can be carried out in a conventional manner by using common injection solutions or excipients and/or lubricants. This polymer is therapeutically effective in various viral diseases including viral skin diseases (see Examples). 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; 382cm ^-1 , 618cm ^-1 ,
720cm ^-1 , 901cm ^-1 , 1170cm ^-1 , 1276cm ^-1 and 1425cm ^-1 (c) Powder X-ray diffraction spectrum bands 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℃; It is a water-soluble polymer showing a calorific value △H = 59.4 mcal/mg ( This polymer is disclosed in 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 synthetic 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. (A) is 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 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 this temperature also It can be seen that the crystal structures of both substances are different from each other. In the following Examples, the present invention will be explained in more detail by demonstrating the pharmacological effects against viral diseases using the organic germanium compounds obtained in the above production examples. Effects on viral diseases: (1) Effects on DNA-type viruses: Experimental group A: It was confirmed that the organic germanium low molecular weight polymer obtained in the production example is effective against viral skin diseases. The dosage is as follows: Infants: 10mg divided twice a day School children and older: 20mg divided twice a day Adults: 30mg divided three times a day Effects on various viral skin diseases used are shown in Tables 1, 2 and 3 below.

【table】

[Table] In 6 effective cases, some of the warts disappeared, but due to discontinuation, it was not possible to observe the warts until they were completely healed.

[Table] Effective cases were those who stopped taking the drug for 21 days but showed some disappearance. Experimental group B: In a facility different from experimental group A, the organic germanium low molecular weight polymer based on the above manufacturing example was found to have DNA type. It has been confirmed that it is highly effective against viruses. The dose was the same as in experimental group A, and the administration effect was determined after 3 months (however, after 4 months)
(Some were administered for months). Patients were selected as cases of relapse (meaning cases that were treated with the use of "Bleomycin" or cryotherapy but were not completely cured or relapsed).

【table】

[Table] No side effects
(2) Effect on RNA-type viruses Next, we investigated the effect of organic germanium low-molecular-weight polymers on influenza disease in mice, which is an RNA virus. The virus used was influenza A ₂ /
ddY mice weighing 10-12 g were intranasally infected with the Adachi strain. The dose of this virus is
The amount is 10 x LD ₅₀ . 100% of organogermanium low molecular weight polymer 24 hours after virus inoculation.
Oral administration of mg/Kg and 300 mg/Kg was started and continued for 5 days. Twenty-five mice were used in one group of experiments. Necropsy was performed on the 14th day to measure (1) mortality, (2) gross lung lesions, and (3) the amount of virus in the lungs.
Lung lesions were indicated by scoring. That is, 0 means no lesions at all, 1 means lesions are seen in 1/4 of the lungs, and 2.
3 shows lesions in about 1/2 of the lungs, 3 shows lesions in 2/3 of the lungs
Level 4 indicates that changes are observed in the entire lung area, and the sum of lesions in each mouse was divided by 20. Those who died within 14 days and had clearly congested lungs were given a score of 4. The next lung viral load is 25
Five of the chickens were randomly taken out, homogenized, and inoculated into a Petri strain containing a monolayer of chicken fibroblasts, and cultured at 37°C. After 3 days, the lesions that appeared in the neutral funnel (neutral red) were collected, counted and thereby determined for virus content. The results of the experiment are shown in Table 4.

[Table] From the results, it can be seen that the organic germanium low molecular weight polymer is effective against influenza symptoms.

[Brief explanation of drawings]

FIG. 1 shows a powder X-ray diffraction spectrum of a water-soluble low molecular weight polymer which is a 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 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 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 viruses.