JPS6158448B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an antitumor agent containing an organic germanium compound as a main ingredient. Germanium (Ge), a homolog of carbon, has been studied in the fields of physics and inorganic chemistry for many years because of its unique property of having a semiconductor effect like silicon (Si), which is also a homolog of carbon. However, in recent years, research on its organic compounds and the presentation of its results have been actively conducted, and it has come to attract attention from various fields, especially from the medical and pharmaceutical world. For example, carboxyethylgermanium sesquioxide () (hereinafter simply abbreviated as CEG) (GeCH ₂ CH ₂ COOH) ₂ O is obtained by adding trichlorogermane to an acrylic acid derivative and subjecting the resulting product to a hydrolysis reaction. ₃ () is a macromolecular compound whose constitutional unit is a 12-membered crown ether-like ring in which germanium atoms and oxygen atoms are alternately bonded. Since it became clear that while it exhibits remarkable physiological activity such as tumor activity, it has no toxicity or side effects.
It is highly anticipated from the perspective of its potential as an excellent drug. Although the mechanism of the pharmacological activity exhibited by CEG has not been clearly elucidated, the most likely theory is that it originates from the germanium-oxygen structure, which is a partial structure in CEG. , and the structure of other parts is
If it is possible to synthesize an organogermanium compound different from CEG, it is highly conceivable that this organogermanium compound will exhibit pharmacological effects different from those of CEG, or may exhibit similar pharmacological effects at lower doses. . The present invention was made against the background of the above-mentioned circumstances, and its configuration is based on the general formula (In the formula, R ₁ to R ₃ are a hydrogen atom and a lower alkyl group, respectively (excluding cases where R ₁ to R ₃ are all hydrogen atoms)) as a main ingredient. That is. Next, the antitumor agent of the present invention will be explained in detail. The organic germanium compound which is the main ingredient of the antitumor agent of the present invention is represented by the general formula (),
Similar to the above CEG, the basic structure is a germanium atom Ge bound to a propionic acid residue whose oxygen functional group is amide- _CONH2 , and the ratio of germanium atoms and oxygen atoms in this structure is 2:3. In the general formula, R ₁ to R ₃ each represent a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group; The positions of R ₁ and R ₂ are α _- position _of the germanium atom, and R ₃ is the β-position of the same atom. This is to exclude compounds that do not have groups). Therefore, the organic germanium compound that is the main ingredient of the antitumor agent of the present invention includes, for example, the following compounds. The organic germanium compound having the above structure can be synthesized by various methods. One example is the addition of trichlorogermane () to acrylamide () as shown in Reaction Formula 1 below. There is a method of hydrolyzing trichlorogermylpropionic acid amide (). reaction formula Furthermore, in general, acrylamide () in which R ₁ to R ₃ are substituted is expensive or difficult to obtain, and addition reaction between the acrylamide () and trichlorogermane () causes undesirable side reactions. Therefore, as shown in the reaction formula below, trichlorogermylpropionic acid () obtained by adding trichlorogermane () to an acrylic acid derivative (') is chlorinated to form trichlorogermylpropionic acid chloride (), and the An organic germanium compound represented by the general formula () can also be obtained by treating chloride () with ammonia. reaction formula The organic germanium compounds obtained by the above method are generally colorless and amorphous crystals, and can be prepared as solid preparations such as tablets, powders, granules, and capsules, as shown in the table below. As this type of compound has excellent water solubility, it can also be administered as aqueous solutions such as injections.

[Table] Furthermore, the above-mentioned organic germanium compounds, which are the active ingredients of the present invention, are generally highly safe, and when the LD ₅₀ value was measured on mice, all of them, including the compounds listed above, showed high safety. It was confirmed that the organic germanium compound has extremely low toxicity, showing values of 5000 mg/Kg or more for oral administration, 2500 mg/Kg or more for subcutaneous injection, and 1250 mg/Kg or more for intraperitoneal administration. The present invention relates to an antitumor agent, and since there are various problems in confirming its pharmacological effects by administering it to actual patients, it is necessary to confirm its dosage and effect through animal experiments. It was decided to. That is, the above-mentioned organic germanium compound was dissolved in water to form a liquid medicine, and this was mixed with IMC Carcinoma 1×10 ⁶
When the tumor was orally administered to mice of the CDF ₁ strain that had been subcutaneously implanted, the tumor weight was measured over a certain period of time.
The antitumor agent of the present invention has the above-mentioned IMC as shown in the table below.
Carcinoma was well suppressed, and the degree of suppression was 41% when the control CEG was administered at 100 mg/Kg/day, whereas the suppression was the same or greater than CEG when administered at 2 mg/Kg/day. This shows an excellent result of showing the ratio.

[Table] On the other hand, since the physiology of tumors in the human body is extremely complex due to various factors,
Kg/day, i.e. per day for a person weighing 50Kg.
Although it cannot be stated for certain that administration of 100mg will show the same inhibition rate as when administered to mice, the dosage of CEG, which is currently undergoing repeated clinical trials as an antitumor agent, is approximately 500mg to 2000mg/day. Therefore, the anti-tumor agent of the present invention is approximately 10 mg to 40 mg as described above.
Since it is expected to exhibit pharmacological effects equivalent to CEG, it is clear that the antitumor agent of the present invention can also be useful against tumors in the human body, coupled with the fact that it can be administered orally. . Next, an experimental example of the present invention will be described. Experimental example 1 Synthesis of organic germanium compound (1) 36 g (0.2 mol) of trichlorogermane was dissolved in 100 ml of concentrated hydrochloric acid, and 17.2 g (0.2 mol) of crotonic acid was dissolved under ice cooling.
mol) and stirred for 2 hours to precipitate trichlorogermylpropionic acid [Cl ₃ GeCH (CH ₃ )].
CH ₂ COOH, elemental analysis (calculated/experimental values) Ge:
27.28/27.31, C: 18.06/18.18, H: 2.65/
2.68, Cl: 39.98/39.96, IR1690 (C=O) 1260
(C-O) 420, 400 (Ge-Cl)], and then 20.9 g of this trichlorogermylpropionic acid.
After adding excess thionyl chloride SOCl ₂ to (0.2 mol) and heating under reflux for 2 hours, unreacted thionyl chloride was distilled off, and the residue was subjected to vacuum distillation to obtain trichlorogermylpropionic acid chloride [Cl ₃ GeCH ( CH ₃ ) CH ₂ COCl, elemental analysis values (calculated values/experimental values) Ge: 25.52/25.36, C: 16.89/
16.61, H2.12/2.21, Cl49.65/49.69, IR1790
(C=O)590(Ge-C)430,400(Ge-Cl)] are obtained. Finally, add 5.70 g (0.02 mol) of this trichlorogermylpropionic acid chloride to anhydrous benzene.
After introducing dry NH ₃ under ice cooling for 1 hour, 500 ml of water was added and stirred to separate the aqueous layer. This aqueous layer was gel-filtered and evaporated to dryness to obtain compound (1). 2.63g of colorless amorphous crystals were obtained (yield:
72.4%). In addition, compounds (2) and (3) and other organic germanium compounds represented by the general formula () could be synthesized by almost the same method as described above. According to the above experimental example, trichlorogermylpropionic acid amide () was isolated and the organic germanium compound, which is the main ingredient of the present invention, could be synthesized either by hydrolyzing it or by following the reaction formula. Examples of the physical properties of the obtained organic germanium compound are shown in the table below.

[Table] Experimental Example 2 Tumor suppressive effect of the antitumor agent of the present invention CDF ₁ strain mice, 9-week-old female mice were included in each group with 10 mice, and only the control group had 20 mice.
1×10 ⁶ Carcinoma tumor cells were subcutaneously transplanted, and from the next day, the antitumor agent of the present invention containing an organic germanium compound represented by the general formula () was administered.
The dose of the organogermanium compound is 2 mg, 10
The drug was administered orally for 5 days at a dose of 50 mg/Kg/day, followed by 1 day off, three times. When dissected and measured tumor weight two days after the final administration, as shown in the table above, CEG administered in the same manner had an inhibition rate of 41% at 100 mg/Kg/day, whereas the present invention The antitumor agent showed the same inhibition rate at 2 mg/Kg/day.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ to R ₃ represent a hydrogen atom and a lower alkyl group, respectively [except when R ₁ to R ₃ are all hydrogen atoms]) An anti-tumor agent.