JPH0324094A - Organic germanium compound and production and use thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 to R4 are H, (substituted)-lower-alkyl or (substituted) phenyl; n is >=2]. EXAMPLE:2-Oxygermylethane sulfonic acid polymer. USE:An immunomodulating agent, anticancer agent, antiviral agent, remedy for liver disease and interferon production-enhancing agent. PREPARATION:A trihalogermane expressed by the formula X3GeH (X is halogen) is reacted with an ethylene sulfide derivative expressed by formula II and the resultant 2-trihalogermylethanethiol derivative expressed by formula III is oxidized to provide a 2-trihalogermylethane sulfonic acid derivative expressed by formula IV, which is then hydrolyzed and as necessary converted into salt of hydrolysate.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel organic germanium compounds and their salts, their production methods, and their use as pharmaceutical compositions. (Prior art and its problems) Organic germanium compounds have attracted considerable attention in recent years because they exhibit various pharmacological activities, and various research reports have been published. For example, the formula (where Et is ethyl group, and Me means a methyl group> (r Y-9 in this technical field)
577, known as ) has been reported to have anti-inflammatory effects (Japanese Patent Application Laid-Open No. 56-45492, 9
9418, 99491 and 10870g publications), and the compound represented by the formula (in which Et and Me have the above meanings) (referred to as "svirogermanium" in this technical field) has anticancer activity. [r Cancer Resg, Vol. 42, p. 2852 (1982)]. On the other hand, the present inventors have also been conducting research on organic germanium compounds, and have reported that 3-oxygermylbrobionic acid derivatives have excellent immunomodulatory effects (
JP-A-61-151123). As described above, although various pharmacological activities have been reported for various organogermanium compounds, it is unclear whether there is a correlation between the structure of these organogermanium compounds and their pharmacological activity, or the mechanism by which organogermanium compounds exert their pharmacological effects. The reality is that the sequence has not yet been fully elucidated.

(Purpose of the Invention) According to the above-mentioned prior art and the experience of the present inventors, it appears that when organic germanium compounds have different structures, there are significant differences in the type and degree of pharmacological activity. Paradoxically speaking, this means that if we prepare a new organogermanium compound with a different structure from conventional ones and study its pharmacological action, we will be able to understand the relationship between structure and pharmacological activity and the mechanism of action of pharmacological action. This means that it not only contributes to elucidation, but also can be expected to enhance the activity of new or well-known pharmacological effects. Therefore, the basic object of the present invention is to provide novel organogermanium compounds that exhibit various and excellent physiological activities.

A further object of the present invention is to provide a method for producing such organogermanium compounds. (Means and effects for achieving the purpose) As a result of intensive studies to develop a novel organic germanium compound exhibiting excellent physiological activity, the present inventors discovered that the compound has a sulfonic acid residue in its molecule. The present invention was completed by discovering that organic germanium compounds are preferable. This organic germanium compound is a compound of the formula (where R1. group, and n means an integer of 2 or more〉 and its salts.With regard to the above compounds, specific examples of lower alkyl groups that can have substituents include: is a linear or branched saturated hydrocarbon residue having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl, t-butyl, bentyl, hexyl group, fluoromethyl, Halogens such as chloromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, chloroethyl, promoethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, fluorobrovir, chloroprovil, difluorobrovir, trifluoroprovir groups, etc. Alkyl group, benzyl group, 0-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, P-nitrobenzyl,
Examples include substituted benzyl groups such as p-methoxybenzyl group. On the other hand, specific examples of phenyl groups that can have substituents include phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-promophenyl, 3-promophenyl, 4-promophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2.5-dichlorophenyl, 2.6 -dichlorophenyl, 3,4-dichlorophenyl, 3.5-dichlorophenyl, 2.3-difluorophenyl, 2.4-difluorophenyl, 2.5-difluorophenyl, 2,6-difluorophenyl, 3.4
-difluorophenyl, 3,5-difluorophenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4
-Hydroxyphenyl, 2.3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2.5-dihydroxyphenyl, 2.6-dihydroxyphenyl, 3.4-
Dihydroxyphenyl, 3.5-dihydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-
Mel xyphenyl, 2,3-dimethoxyphenyl, 2
, 4-dimethoxyphenyl, 2.5-dimethoxyphenyl, 2.6-dimethoxyphenyl, 3,←dimethoxyphenyl, 3.5-dimethoxyphenyl, etc., a halogen atom or hydroxyl group as a substituent on the phenyl ring, An example is a phenyl group having 1-3 alkoxy groups. Salts of the above organic germanium compounds include sodium, potassium, canolecium, magnesium, iron, zinc,
Salts with metals such as copper and silver, salts with ammonia, salts with organic bases such as methylamine, dimethylamine, ethanolamine, ethylenediamine, meglumine, dicyclohexylamine, penzylamine, lysine, arginine, ornithine, histidine, tryptophan, oxylysine,
Examples include salts with basic amino acids such as oxyarginine and homoarginine. According to the method of the present invention,
The above organic germanium compounds and salts thereof are trihalogermanes represented by the formula X, GeH (wherein, A 2-trihalogenylethanethiol derivative represented by the following formula (wherein R1, R2, R,, R4 and X have the above-mentioned meanings) obtained by reacting with a sulfurized ethylene derivative represented by and the resulting formula (where R,, R2, Rs and U R4 and XliT
It can be produced by hydrolyzing the 2-trihalogenmylethanesulfonic acid derivative shown in the following formula and then converting it into a salt as necessary. In this production method, the reaction between the trihalogermane and the sulfurized ethylene derivative can be carried out by stirring at O-80°C, preferably at room temperature, in the presence or absence of a solvent. In this case, there is no need to isolate the 2-trihalogermylethanethiol, which is to be taken into consideration, and the next step, oxidation treatment, can be carried out immediately, thereby converting it into a 2-trihalogermylethanesulfonic acid derivative. be able to. The oxidation treatment in this case can be carried out using conventional oxidizing agents such as hydrogen peroxide, organic peracids, peroxosulfuric acid, potassium permanganate, chromic acid, nitric acid, hydrogen bromide, hypochlorites, hypobromites, This can be easily carried out using nitrogen peroxide, potassium superoxide, dimethyl sulfoxide, etc. It is particularly preferred to use hydrogen peroxide as the oxidizing agent, in which case the reaction can be carried out under any conditions, neutral, acidic or alkaline, and in this case acetic acid, formic acid,
The reaction can be significantly accelerated by coexisting an acid catalyst such as methanesulfonic acid or a metal catalyst such as tungsten, molybdenum, titanium, osmium, or chromium. The 2-trihalogermylethanesulfonic acid derivative can be isolated by treating the reaction mixture in a conventional manner, and the 2-trihalogermylethanesulfonic acid derivative can also be treated with an ion exchange resin by taking advantage of the presence of sulfonic acid residues in the natural compound. If you do 2.
- A trihalogenmylethanesulfonic acid derivative can be obtained. The final step of the method of the present invention, which is the step of hydrolyzing the 2-trihalogenmylethanesulfonic acid derivative, can be easily carried out using water, a basic aqueous solution, or a mixture of these and an organic solvent. The desired substance, 2-oxygelmylethanesulfonic acid derivative, can also be isolated by conventional methods. The step of converting this derivative into a salt can also be carried out in a conventional manner, for example by simply mixing the derivative with the desired base, by lyophilization or in a suitable solvent such as acetone, methanol, ethanol, dioxane, etc. The desired salt can be obtained in the form of crystals or crystalline powder. Incidentally, if the above hydrolysis step is carried out in an aqueous solution containing a desired base, the salt of the 2-oxygermylethanesulfonic acid derivative can be directly obtained. (Examples, etc.) Next, the present invention will be explained in more detail and specifically in relation to production examples and medicinal efficacy test examples. Germanium hydroxide (
6.40 g) of 1.80 M HCI in ether solution 100
ml and stirred at room temperature. Next, 5.41 g of ethylene sulfide was added dropwise while cooling with water, and the mixture was stirred at room temperature for 70 hours. After filtering off insoluble materials and condensing the filtrate under reduced pressure, 6.0 ml of water and methanesulfone PR 576B were added, heated to 100°C, and mixed with 50 ml of 31% hydrogen peroxide solution while stirring.
ml was added dropwise over 2 hours and then heated for an additional 30 minutes. After cooling, it was treated with Diaion IJA-21 and
, eluted with 5N ammonia water and concentrated under reduced pressure,
The crystals were suspended in methanol and collected by filtration. This crystal was dissolved in water and treated with Diaion PK-216,
The effluent was concentrated under reduced pressure to yield the desired polymer as a colorless glass (7.41 g). 'H-NMR spectrum (D20) δppm: 1.6
−2.0 (2H, m, −GeCi
ilCH2S-)2.9-3.3 (2H, m,
-GeCH2CH. S->IR spectrum (L"+
'a'x) CIO-' :1150. 1030
(SO2). 820 (Ge-0-) To germanium hydroxide (3.20 g) was added 50 ml of 1.80 M HCI ether solution and stirred at room temperature. Next, 2.71 g of ethylene sulfide was added dropwise under water cooling, and the mixture was stirred at room temperature. The mixture was stirred for 70 hours. After filtering off insoluble materials and concentrating the filtrate under reduced pressure, 3
．． 0! Add II+ and 288+ ur of methanesulfonic acid, warm to 100°C, and add 288+ ur of 31% hydrogen peroxide while stirring.
5l1 was added dropwise over 2 hours and then heated for an additional 30 minutes. After cooling, it was treated with Diaion IIA-21 and
．． Elute with 5N ammonia water and under reduced pressure? Shrink it,
The crystals were suspended in methanol and collected by filtration. The desired polymer was obtained by recrystallizing the crystals from water-methanol (3.50 g). Melting point: > 300°C 'H-NMR spectrum (D20) δppm: 1.6
- 2.0 (2H, m, -GeCHCH2S-)
2.9 - 3.3 (2H, m, -GeCH2CH
S-) IR spectrum (ν envelope) am-': 340
0 - 2800 (NH4 >, 1400 (N}
! 4), 1185.1040 (SO■), 79
0 (Ge-0-) 2-triclogelmylethanesulfonic acid Add 25ml of a 1.80M MCI-ether solution to 2.23g of the ammonium 2-oxygelmylethanesulfonate polymer obtained in Production Example 2. After the addition, 50 ml of acetone was added, the precipitated crystals were filtered off, and the filtrate was concentrated under reduced pressure to obtain the desired compound as a colorless oil.
(2.85 g), '+4-NMR spectrum (acetone-d6) δ ppm: 2.2 - 2.6 (2H,
l, -GeCHCH2S-)3.0 - 3.4 (
2t{, m, -GeCH2CiilS-) Production Example 1
2-oxygelmylethanesulfonic acid polymer (2.06 g) obtained by was dissolved in 30+ sl of water, 1.OO
The desired polymer was obtained (2.28 g) by adding 10.0 ml of N Nail{ followed by lyophilization.
.

Melting point: > 300°C H-NMR spectrum (D20) δppm: 1-6
- 2.0 (2}{, l, -GeCH1CH2S
-) 2.9 - 3.3 (28, m, -GeCH
2C! liLS-)! R spectrum (νC!go) c+
a-': 1190. 1045 (SO2), 79
0 (Ge-0-) 2-oxygelmylethanesnorefonic acid polymer (1.03 g) obtained in Production Example 1 was added to 10 ml of water.
Let me understand, 1. OON NaOH 5. The desired polymer was obtained by adding Oml and concentrating under pressure, followed by recrystallization from water-methanol (1.0
8g>.

The physicochemical properties of this polymer matched those in Preparation Example 4.

Dissolve the 2-oxygelmylethanesulfonic acid polymer (1.03 g) obtained in Production Example 1 in 20 ml of water,
．． The desired polymer was obtained by adding 5.0 ml of 00N ammonia water and freeze-drying it (1.11 g
>. The physicochemical properties of this polymer matched those in Preparation Example 2.

1 (Effect on antibody production) a) Objective To examine the effect of the compound according to the present invention on antibody production using tumor-bearing mice as animals with reduced immune response.

b) Operation: 2 x 10 mouse tumor cells (Sarcoma 180) were subcutaneously transplanted into the back of male ICR mice (6 weeks old) to induce solid tumors, thereby making them tumor-bearing mice. The compound according to Production Example 4 was adopted as a compound according to the present invention, dissolved in 4x bovine serum albumin, and administered to tumor-bearing mice at 0.1% from day 9 after transplantation of Sarcoma 180 cells.
, 1.0 and 10. It was orally administered for 5 days at a dose of Orag/kg/day. Sarcoma 180! On the 14th day after transplantation of f[l cells,
2 x 10' sheep red blood cells (SPBC) were injected into the tail vein of a tumor-bearing mouse to sensitize it, and on the fourth day after sensitization, the spleen was removed and the number of PFCs in 10 tile cells was measured. This was used as an indicator of antibody production. C) Results and Discussion The results are as shown in Table 1 below, and the antibody production ability, which decreased due to tumor bearing, was recovered by administering the compound according to the present invention, and the degree of recovery was in accordance with the dose administered. It has been found. Lyu#: Standard error of the mean (n 7) *: Significant difference for bile cancer mice (p <0.05> ** Book: Significant difference for bile cancer mice (p < 0.
001> Effects on antibody production a) Objective: New Zealand patients who develop autoimmune diseases due to voriclonal activation of B cells due to decreased function of sublessor T cells.
B/WF. Examining the effect of the compound according to the present invention on antibody production using strain mice 6 b) Operation NZB/WFI male mice (11 weeks old) were used in groups of 5, and sheep red blood cells (SPBC) 2 x 10? Each group of mice was sensitized by intravenous injection into the tail vein of each group, and the compound according to Production Example 4 was selected as the compound according to the present invention three times on the day before, immediately after, and one day after sensitization for the test group. 1.0 and 10.Ora dissolved in bovine serum albumin
The spleen was orally administered at a dose of 100 g/kg/day, and the spleen was removed on the 4th day from the start of the sensitization described above, and the number of PFCs in 10' tile cells was measured and used as an index of antibody production. C) Results and Discussion The results are shown in Table 2 below. In the control group to which no drug was administered, the number of PFCs increased abnormally, but in the test group, it was significantly suppressed. Considering this result and the result shown in Example 1 of the drug efficacy test, that is, the recovery of the antibody production ability suppressed by tumor bearing, it can be concluded that the compound according to the present invention has an immunomodulatory effect. It turns out. Toyu wood: Standard error of the mean (n・5): Significantly different from the control group (p < 0.05) 0
: Significant difference compared to control group (p <0.01>
Awakin 1144 艷肚'' 1 (Influence on M-prolonged hypersensitivity) a) Purpose Experiment using tumor-bearing mice as animals with reduced immune response and delayed-type hypersensitivity (DT) as an indicator of cell-mediated immunity. Using this system, the effect of the compound according to the present invention on the DTH response, which is decreased due to tumor bearing, is investigated. b) Inject mouse tumor i into the peritoneal cavity of a manipulated ICR male mouse (8 weeks old).
10' cells (Sarcoma 180) were transplanted, and about 3 hours later, 10' sheep red blood cells (SRBC) were injected into the tail vein for sensitization, and 4 days after the sensitization, SRBC 2 x
Inject 10' into the right hind foot and do DT}! A reaction was induced, and 24 hours after SRBC injection, the thickness of the foot was measured using a stereomicroscope. In addition, the test group was given a compound according to the present invention as a compound according to Production Example 4 dissolved in 4% bovine serum albumin, and 4 days before SRBC sensitization, 0.1,
It was administered orally at doses of 1.0, 10, and 0 mg/kg. C) Results and Discussion The results are shown in Table 3 below, and it was found that the DTH response, which had decreased due to bile cancer, was restored to a normal level by administration of the compound according to the present invention. This indicates that the compound according to the present invention has a 4fIl immunostimulatory effect. Spring Σ Effect on type hypersensitivity) a) Objective: To investigate the effect of the compound of the present invention on delayed type hypersensitivity reaction in normal mice. b) Manipulation Inject sheep red blood cells (SRBC) into male ICR mice (8 weeks old).
Four days after the sensitization, the test group was injected with 10' of the compound according to the present invention, prepared by Preparation Example 4, dissolved in 4x bovine serum albumin. Immediately after this administration, 2 x 10' SRBC were injected into the right hind paw to elicit a DTH response.
24 hours after C injection, the thickness of the foot was measured using a stereomicroscope. C> Results and Discussion The results are shown in Table 4 below, and it was found that administration of the compound according to the present invention significantly suppressed the DT}I response in normal mice. This result and the results shown by Pharmacology Test Example 3,
That is, considering that the DTH reaction suppressed by bile cancer was recovered by administration of the compound according to the present invention, it is clear that this compound has an immunomodulatory effect.
Furthermore, taking into account the results shown in Pharmacology Test Examples 1 and 2, that is, that this compound modulates antibody production ability, the compound according to the present invention modulates not only the humoral immune response but also the cellular immune response. 6 East 1 #: Standard error of the mean (x O.01mm, n = 10>*: Significant difference compared to the control group (p < 0.05) *Umbrella: Compared to the control group Significant difference (ρ < 0.01) Ne**: Significant difference compared to control group (ρ < 0.001) Drug Pharmacology Example 5 (Effect on interferon production) a) Target Effect on interferon production The effects of the compounds according to the invention are investigated. b) Operation: A group of 5 male BALB/c mice were used as experimental animals, and influenza virus (A/PR/8 strain) was infected at 9.0%.
Intratracheal infection was carried out at an infectious dose of PFυ/mouse, and the test group was immediately given 0.1 and 1.0 doses of the compound according to the present invention, the compound according to Production Example 4 dissolved in Shingyu serum albumin.
, administered orally at a dose of 10.0 mg/kg. Three days after infection, the lungs were removed and homogenized to 2000
Centrifugation supernatant at 0 x g was obtained, and the interferon activity of this supernatant was determined by L92 induced by vesicular stomatitis virus (VSV).
9 cell degeneration inhibitory effect. C) Results and Discussion The results are shown in Table 5 below, and the compound according to the present invention increased interferon production by about 2.5 and 2.8 times at doses of 1.0 and 10.0 mg/kg, respectively. It was found that it improved. This indicates that the compound according to the present invention has the ability to enhance interferon production.

Table 5 #: Standard error of the mean (HJ/B protein, n = 5) **: Significant difference compared to control group (p < 0.01) a) Objective: To investigate the anticancer effect of the compound according to the present invention on Lewis lung cancer. b〉 Operation One group of 10 C57BL/6 male mice were used as experimental animals, and 1 x 10' of Lewis pneumonocytes were subcutaneously inoculated. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4x bovine serum albumin, and 0.1, 1.
The mice were orally administered at doses of 0 and 10.0 mg/kg/day for 5 days starting the day after vaccination. Solid tumors formed by inoculation of cancer cells were excised after 14 days and their weight was measured.
The tumor inhibition rate was calculated from the weight loss of M tumor). C) Results and Discussion The results are shown in Table 6 below, and it was revealed that the compound according to the present invention exhibits an inhibitory effect on Lewis lung cancer. Ryo Ichigo #: Standard error of the mean (n = 10) Umbrella: Significantly different from the control group (p < 0.05) l So l4 Strictly 艷燵yu (anticancer effect) a) Purpose Sarcoma 180 cancer The anticancer effect of the compound according to the present invention on cells is investigated. b) Operation One group of 10 male ICR mice were used as experimental animals, and 2 x 10' Sarcoma 180 cancer cells were inoculated subcutaneously.
For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4% bovine serum albumin, and 0.1,
The mice were orally administered at doses of 1, 0, and 10.0 mg/kg/day for 10 days starting the day after vaccination. Solid tumors formed by inoculation of cancer cells were excised after 20 days and their weight was measured.
The tumor inhibition rate was calculated from the decrease in tumor f1.

C) Results and Discussion The results are shown in Table 6 below, and it was revealed that the compound according to the tree invention also exhibited an inhibitory effect on Sarcoma 180 cancer cells.

Shishiichi #; Standard error of the mean (n 10) *: Significantly different from control group (p < 0.05) ・Reason; 8 (Antiviral action) a) Objective The present invention against vaccinia virus Investigate the effects of compounds by b) Operation A group of 10 male ddY mice were used as experimental animals and infected with vaccinia virus (DI strain) by inoculation into the tail vein at an infectious titer of 5 x 10'PFU/mouse. Immediately after inoculation, the test group was given a compound according to Production Example 4 dissolved in 4% bovine serum albumin as a compound according to the present invention.
1.0 and IO. It was administered orally at a dose of Omg/kg. Seven days after virus infection, the number of bocks formed on the tail was counted, and the inhibition rate was calculated from the decrease in the number of bocks, which was used as an index of antiviral activity. C) Results and Discussion The results are shown in Table 8 below, and it was found that the compound according to the present invention exhibits an inhibitory effect on vaccinia virus.

Laoichi Master #: Standard error of the mean <n・10> Book: Significantly different from the control group (p < 0.001) Yingxun I'4 Ri4 Shark' - (Antiviral effect) a> Purpose The antiviral effects of the compounds of the present invention are investigated using an influenza virus infection model. b) Operation: One group of 10 BALB/c male mice were used as experimental animals.
Influenza virus (A/PR/8 strain) 9. O
Intratracheal infection was performed at an infectious dose of PFU/mouse. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4x bovine serum albumin, and 0.1, 1, O,
at a dose of 10.0 mg/kg/day and immediately after infection treatment.
It was orally administered six times on days 1, 2, 3, 4, and 5 after infection. The survival of the mice was checked for 20 days after virus infection. C> Results and discussion The results are shown in Table 9 below, and in the control group to which no compound was administered, death cases began to appear on the 8th day after infection.
All died by the 10th day. On the contrary,
In the test group, which is the administration group of the compound according to the present invention,
In particular, in the 1.0 mg/kg administration group, there were cases of infection and death from day 10, but even at the end of the test 20 days later, there were still 4 cases of infection.
Regarding the average survival time, there was a significant difference in both test groups when compared with the control group. - There was a significant difference compared to the control group (p < 0.05) * *: Significant difference compared to the control group (p < O.Oi) 0*: Significant difference compared to the control group (p < 0.001) Drugs / Effects on acute liver injury) a) Purpose The effects of the compounds of the present invention on galactosamine-induced acute liver injury, which is an experimental model of liver injury, will be investigated using serum transaminase as an indicator. b) Operation A group of 10 Wista male rats were used as experimental animals, and acute liver damage was induced by intraperitoneally administering galactosamine at a dose of 400 mg/kg twice at 6-hour intervals. The test group received Production Example 4 as a compound according to the present invention.
The compound was dissolved in 4x bovine serum albumin and diluted with 0.
It was orally administered at doses of 1, 1.0, and 10.0 mg/kg/day for 5 days starting 3 days before galactosamine administration. Blood was collected 48 hours after the first administration of galactosamine, and serum GOT and GPT values were measured. C
) Results and Discussion The results are shown in Table 1O below, and the compound according to the present invention shows that the GO
Table 10 N: Standard error of the mean <n=10>: Significantly different from the control group (p < 0.05): Significantly different from the control group (p <0.01> Ne0: Significant difference from control group (p < 0.001) ・ ・ = 11 (Effect on chronic liver damage) a) Carbon tetrachloride-induced chronic liver disease, which is an experimental model of objective liver damage The effect of the compound according to the present invention on liver damage is investigated using serum transaminase as an indicator. b) Operation A group of 10 Wistar male rats were used as experimental animals, and chronic liver damage was induced by intraperitoneal administration of carbon tetrachloride at a dose of 480 mg/kg twice a week for 10 weeks. For the test group, as a compound according to the present invention, the compound according to Production Example 4 was dissolved in 4% bovine serum albumin, and 0%
．． 1, 1.0, 10. It was orally administered at a dose of Otag/kg/day every other day for 10 weeks from the start of the study. Two days after the final administration of carbon tetrachloride, blood was collected and serum GOT and GPT values were measured. C) Results and Discussion The results are shown in Table 11 below, and the compound according to the present invention suppresses the increase in GOT and GPT values associated with liver damage induced by the administration of carbon tetrachloride at a dose of 1. Omg
It was found that it was significantly reduced by 1 kg. #: Standard error of the mean (n・10〉*: Significantly different from the control group (p <0.05>) Umbrella * Umbrella: Significantly different from the control group (p < 0.
0Or) Pharmacology: 12 (Acute Toxicity) Acute toxicity tests were conducted using ICR mice and SD rats as experimental animals, and the compound according to the present invention showed LD, when administered orally. The value was 2 g/kg or more, and it was therefore found that the toxicity was low and the safety of use was excellent. (Effects of the Invention) As shown in the medicinal efficacy test examples, the compound according to the present invention has various bioimbalance activities, namely, immunomodulatory action, interferon production enhancement action, anticancer action, antiviral action, and hepatoprotective action. etc. Therefore, the compound according to the present invention is expected to be used as an active ingredient in therapeutic agents for various diseases, such as various immunological diseases of the immunostimulatory system and immunosuppressive system, various viral diseases, cancer or tumor diseases, liver diseases, etc. be done.

In recent years, the spread of acquired immunodeficiency syndrome (AIDS) has become a social problem, and the virus that causes AIDS is human immunodeficiency syndrome.
irus (HIV). Currently, nucleic acid synthesis inhibitors are mainly used for the treatment of AIDS.
Although this class of drugs has virucidal effects, they have strong side effects and also tend to destroy normal tissue, so there is an urgent need to develop safe drugs to replace them. by the way,
As mentioned above, the compound according to the present invention has an effect of regulating immunity including activation in vivo, and a strong anti-11V
Since it also has the effect of enhancing the production of interferon, which has already been proven as a substance, it has an extremely high possibility of being used as a new drug for the treatment of AIDS. Procedural amendment (voluntary) August 17, 2016

Claims (4)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. (n is an integer of 2 or more) and salts thereof. (2) Trihalogermane represented by the formula X_3GeH (in the formula, atom, a lower alkyl group which may have a substituent, or a phenyl group which may have a substituent), and the resulting formula ▲ formula, There are chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, R_3, R_4 and , tables, etc. ▼ (In the formula, R_1, R_2, R_3, R_4 and There are formulas ▲mathematical formulas, chemical formulas, tables, etc., which are characterized by changing to A method for producing an organic germanium compound and its salt shown in (3) Formulas ▲ Numerical formulas, chemical formulas, tables, etc. a phenyl group that can contain a phenyl group, and n means an integer of 2 or more). (4) The pharmaceutical composition according to claim (1), which is an immunomodulator, an anticancer agent, an antiviral agent, a liver disease treatment agent, and an interferon production enhancer.