JPS5916826A - Drug for c.r.d. complex 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 C.R.D. complexes related to mycoplasmas having very low toxicity such as acute oral toxicity >=10,000mg/kg LD50 for the oral administration to rats. 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 IIIis dissolved in acetone or another organic solvent miscible with water, e.g. ethanol, and water is then added to the resultant solution to afford the aimed compound expressed by formula I or II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides O, R
, D (0, R, D complex).

Conventionally, organic germanium compounds have recently attracted much attention in terms of pharmacological activity, and are described in Japanese Patent Publication No. 49-2964,
The organic germanium compounds disclosed in patent publications such as JP-A No. 48-61431, JP-B No. 46-21855, and JP-A-46-2498, and whose manufacturing methods are disclosed in these patent publications, are ( GθCl12CH2C02
H)20. It is a low-molecular compound represented by

On the other hand, the present inventor focused on the pharmacological activity of organic germanium compounds and developed the above formula (Gθ0H2CH2-002
H)20. As a result of intensive research into the synthesis of manium compounds other than the low-molecular-weight compounds shown in the figure, a new organic germanium compound was discovered and an organic germanium polymer was completed. It was disclosed in Japanese Patent Publication No. 57-53800).

Furthermore, the present inventors have discovered that this organic germanium compound exhibits particularly excellent medicinal efficacy against O, R, D (0, R, D complex) involved in mycoplasma diseases and the like.

This organogermanium polymer has extremely low toxicity, with an LD5o of 1 o for rats when administered orally.
, OOomy/kg or more - administering larger amounts is physically impossible, ie limited by the stomach volume of the rat.

This polymer has a therapeutic effect on chronic respiratory diseases (0,R,D), so-called OoR,D, Complex-.
(see Examples).

The compounds may be given by oral or injectable routes of administration.

Organogermanium polymers exhibiting the above-mentioned excellent effects have the general formula (III) or (tv) (miGθ0H2-a
n2-000H) nO,,5n(at) or H [wherein is an integer of ntd5 or more. ] and characteristic physical properties as below: (a) Infrared absorption spectral band Large absorption band; Relatively large absorption near each of 800 1,900 twr 21 and 1700c, yu' 560C7 /L', 705
C'nL-1,760LH".

'Do 780c*, 1250cm,
Near the valley of 1550C7IL-1 and 1400G blood-1 (however, the absorption band near 1400c, i-' is a doublet) (1)) Raman spectrum band Large absorption band i 456L"m ' Relatively large absorption r5B2L , 7rL', 618677t', 720c
nt'.

Band 90 1cnt, 1170ci, 1276
G'm' and 1425G1rL' (c) Powder xH diffraction spectrum band large diffraction peak; 6.58° relatively large diffraction i 11.63°, 13.82°,
18.36°+1-ri 21.18' and. 2.41't4) Differential thermal analysis Peak start point 237mm, peak apex 256υ and peak end point 276t: Calorific value Al-1 = 59.411oca
l/m9 (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: (M is a metal or ammonium ion and X is a halogen atom) (I) ([ I) Hereinafter, production examples of the compounds of the present invention will be explained in detail based on the above reaction formulas (1), (2), and (5).

Germanium dioxide is reduced with hypophosphorous acid or its salt (preferably a metal salt or an ammonium salt) in hydrohalic acid, and germanium atoms are reduced to 211
IIJ and produces germanium dihalide,
This is in equilibrium in hydrogen trihalide germanium, whose germanium atoms are 411[ji, and hydrogen halide +y.

It is believed that this hydrogen trihalide germanium is also in equilibrium with the dissociated form shown at the right end of reaction formula (1) in an aqueous solution (see reaction formula (1)).

Since the halogermanium-phosphoric acid complex can be isolated by diluting this reaction solution with water, the contribution of phosphoric acid to this equilibrium system is also considered.

When polarized acrylic acid 01(2,=OH-000H(I) is added to the germanium reagent thus produced, white crystals are formed with the general formula % %() (X is as described above). The compound of the present invention is produced in high yield (reaction formula 1 formula %).
J absorption spectral bands, Raman spectral bands, powder X-ray spectral bands and differential thermal analysis). As described later, these are conventionally known (Ge O
H2CH2000H) 20s -ν Lieba, Special Public Service 1977
It has been revealed that this compound is a new compound different from Compound-1 of Example 1 of No.-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 6-oxygermylpropionic acid low molecular weight polymer Acetone, a solvent that mixes with water, 1.31 to 252.9
(1 mol) of 5-t')chlorogermylgropionic acid is dissolved and 1.61 mol 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 the crystals are removed by suction. The obtained crystals are thoroughly washed with acetone solvent and dried under reduced pressure F. 144.9 (85% yield) of a low molecular weight polymer with white needle-like crystals was obtained. or,
Similarly, high yields of low-molecular polymers can be obtained by using other water-miscible solvents (e.g., ethanol, methanol, cellosolve, acetonitrile, tetrahydrofuran, dioxane, dimethquinethane, diglyme, dimethyl sulfoxide, dimethylformamide, etc.) instead of acetone. obtained at a high rate. In addition, water-immiscible solvents (e.g., chloroform, methylene chloride, carbon tetrachloride, benzene,
It is also possible to obtain a low-molecular polymer by using a solvent such as ether) as a solvent; in this case, when a solution of 6-dochlorogermylpropionic acid is thoroughly shaken with water, the low-molecular polymer precipitates out. The crystals of this low molecular weight polymer are 3207:F
It will not decompose or melt.

Low molecular weight polymer powder X of the present invention produced in this way
The line diffraction spectrum, infrared absorption spectrum, Raman spectrum, and differential thermal analysis are shown in FIG. 1, FIG. 1, FIG. 6, and FIG. 8, respectively. Low-molecular polymers are relatively well soluble in water, with a solubility of approximately 1. T'/100
mR'(25t'').

In order to explain that the low-molecular polymer is structurally different from known compounds, the powder X-ray diffraction spectrum (Fig. ), 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) were measured. , and 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 Figures 5 and 4 and from Figure 5, the structural differences of the solid compound were confirmed. The difference is obvious.

The absorption of 950 (rough-1 and below) is mainly based on Gθ-〇-Ge, and the large difference therein indicates the difference in the nail base structure.

Comparing the (L+) Raman spectra in Figures 6 and 7, r? ij person is 4566
The maximum absorption peak r is shown at 1rt', and the latter shows it at the foot of 449G-1. There are clearly 10 structural differences between the two names.

(・→A comparison of the powder X-ray diffraction spectra in Figures 1 and 2 reveals that both spectra have peaks at different diffraction angles, indicating that they have completely different crystal structures.

Comparing differential thermal analysis Figures 8 and 9, the former shows only one endothermic peak as described below, while the latter shows two endothermic peaks. It can be seen that the crystal structures of the two substances are different from the fact that the temperatures 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 pharmacological effects will be demonstrated using the organic germanium compounds obtained in the above production examples, and the present invention will be explained in detail in detail.

0, R-D (C, R, D complex (Comp
lex)) A method for reliably treating 0, R, D or (3, R1D complexes has not yet been established.) The inventors have demonstrated that organic germanium low molecular weight polymers are significantly effective against the above diseases discovered.

(A) O,R,D (0,f(,D complex)
Confirmation test (■): Table 1 shows the results of oral administration of 100,211 kg/ky of Germanium low-molecular-weight polymer to Tonryu rats, which naturally have O, R, and D complexes, for 8 days. .

Table 1 Mycoglazma (M, pulmonio, M,
arthritis) was isolated using a nasal wash, and the medium used was that of ChaOck et al.

Its components are shown below.

-... Bacteria-free +... Bacterial count of 10 or more... 〃11-50+...〃51-100 Bacteria...Channock et al.'s culture medium has 100 or more bacteria. 0.5% glucose and 0.002% phenol red were added to the mixture.

As shown in Table 1, despite the administration of Myoiso Germanium Low Molecular Polymer, some of the mycoglazma bacteria remained alive, but those without lung lesions were in the non-administered group. It has increased compared to

(B) Confirmation test for the effect on O, R, D (0, R, D complex) (11): Using 6-week-old 20 male rats and 40 male rats, they were divided into two groups and the experiment was conducted. The experiments were carried out at room temperature (22 tl" ± 3 υ) in a normal breeding environment. Organogermanium low-molecular polypolymer (from the ring-forming example) and tylosin were administered, and the animals were dissolved in paper water and taken freely. Ta.

The effectiveness was determined at 60 days of age, during which time all conditions such as piloerection and 3V1 were observed, and autopsies were conducted across the country to observe O and R0D lesions in the lungs. There were no cases of death en route.

Experimental situation: Tylosin 100 my/Icy 5-day administration 5-day administration 6-week administration Table 2 Notes = (Blanks indicate that the general condition is good or that there are no changes in the lungs.

(2) Organogermanium low molecular weight polymer administration group ♀Chizu 8 was in good general condition, but he was giggling, so when he was dissected at 60 days old, -5 (++++i) × 3 lung sounds
There was a measurement of (my).

(6) Degree of pneumonia: ÷...Metricization over one lobe or more of the lung → Dou...Metricization, but limited to less than one lobe of the lung+...Slight change in part of one lobe of the lung In other words, there were several petechial hemorrhages in the lungs.
D-5 is effective against C, R, D complex, but it is also effective against O, R, D (C, R
, D complex) and human pneumonia.

[Brief explanation of the drawing]

FIG. 1 shows a powder X-ray 1gI analysis spectrum of a water-soluble low molecular weight polymer which is a compound of the present invention. Figure 2 shows Example 1 (GeO
This figure shows a powder xH diffraction spectrum of H20H2000H) 203 (hereinafter abbreviated as a known compound). FIG. 5 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 FIG. 6 and FIG. 4. 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 hydrothermal analysis chart of the water-soluble low molecular weight polymer which is the compound of the present invention. FIG. 9 shows a hydrothermal analysis chart of a known compound. ,-!゛Consideration: 1 Agent Hikaru Esaki Yoshi Ii・- 011 1 diagram

Claims (1)

[Scope of Claims] A halogermanium phosphate complex obtained by treating germanium dioxide with the following triphosphoric acid or its salt in hydrohalic acid is reacted with acrylic acid to form a compound of the general formula (n) X, GθC ! H2-CH2COOH(u) [wherein, X is a halogen atom]. ] Obtain a compound (II) of the general formula %, which is further prepared by dissolving the compound in acetone or other organic solvent mixed with water and adding water to this solution. %() () [In the formula, n is the number of fireflies greater than or equal to 5.] It is expressed as %() () [where n is the number of fireflies of 5 or more] and has the following characteristics: (a) Infrared absorption spectrum band Large absorption band; 900 and 1700
Relatively large absorption near α-1; 560 cm', 705 ci
', 760c, 77L-'. Band 7801', 1250c77L',
1350'cwt' and 1400Cyt',
6 (however, the absorption band near 1400t and u' is a doublet), (1)) Raman spectrum band Large absorption band; 456 儂, relatively large absorption; 582 t, ', 618 cm-'
, 720 is -1°p7d 901r;m',
11701-, 1276Cban-1 and 1425-
1, (C) Powder X-ray diffraction spectrum band large diffraction peak; 650° relatively large diffraction; 11.63°, 13.82°, 1
8.36°, 21-18° peak and □, 41・(a) Differential thermal analysis value Peak start point 257 r, peak apex 256'c, and peak end point 2.76 υ; amount of heat Δ) f=59. 411n
O whose main ingredient is a water-soluble organic germanium polymer exhibiting Ca1/2,
drug for fl, D (0, R, D complex).