JPS6158449B2 - - 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 type of metal, has been the subject of research from this aspect for many years because it has a semiconductor effect similar to silicon (Si), which is a homolog of carbon. However, in recent years, as research into organic compounds has progressed and the results have been actively published, they have come to attract attention from various quarters, especially from pharmaceutical societies. For example, the compound carboxyethylgermanium sesquioxide, which is represented by the formula (GeCH ₂ CH ₂ COOH) ₂ O ₃ , exhibits extremely strong physiological activities such as hypotensive and antitumor effects, but has no toxicity or side effects. It is becoming a well-known fact in the medical academic society that this is not the case. On the other hand, research is being actively conducted on analogue compounds of sesquioxide type compounds represented by the above-mentioned compounds. A sesquisulfide type compound (Ge-C-C-CO-) ₂ S ₃ with a structure in which sulfur atom having similar bonding properties is substituted for is synthesized by one of the inventors of the present invention, and a patent application has already been filed along with its manufacturing method. (Unexamined Japanese Patent Publication No. 57-203090)
However, although the physiological activity of the sesquioxide-type compounds has not yet been clearly elucidated, the prevailing theory is that they originate from the germanium-oxygen bond in their structure. It is fully expected that sesquisulfide type compounds in which the oxygen atom of is replaced with its homologue sulfur will also exhibit excellent physiological activity. Against the background of the above-mentioned circumstances, the inventors of the present invention have energetically conducted various experiments, and as a result have learned that certain sesquisulfide-type organic germanium compounds exhibit extremely strong antitumor properties, and have developed the present invention. The antitumor agent of the present invention has been completed and has the general formula (In the formula, A represents a hydrogen atom, a lower alkyl group, or a phenyl group, B represents a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively.) It is something. Next, the antitumor agent of the present invention will be explained in detail. As mentioned above, the antitumor agent of the present invention has an organic germanium compound represented by the general formula () as its main ingredient.
A molecular compound whose basic structure is a germylpropionic acid derivative to which propionic acid residues having -Z are bonded, and in which the germylpropionic acid and sulfur atoms are bonded alternately in a ratio of 2:3, and its general structure is Substituent A in the formula is a hydrogen atom or a so-called lower alkyl group such as a methyl group, ethyl group, propyl group or isopropyl group, or a substituted or unsubstituted phenyl group, and substituent B is a hydrogen atom or They are similar lower alkyl groups, and their bonding positions are such that substituent A is at the α-position of the germanium atom, and substituent B is at the β-position of the germanium atom. On the other hand, since the substituent Z related to the oxygen functional group represents either a hydroxyl group -OH or an amino group -NH ₂ , the organic germanium compound which is the main ingredient of the antitumor agent of the present invention has, for example, the following: Contains things. Any of the organic germanium compounds having the above structure can be synthesized by various methods, but one example is the method shown in the reaction formula below, which is based on the method disclosed in JP-A No. 57-203090. Trichlorogermylpropionic acid derivative () obtained by adding trichlorogermane HGeCl ₃ to acrylic acid derivative () is reacted with hydrogen sulfide in an anhydrous state and in the presence of a base to obtain trimercapto derivative (). ), and the trimercapto compound ( ) is desulfurized between molecules. (A, B and Z are the same as those mentioned above) In addition, substituted acrylic acid amides [(where Z=NH ₂ ]) are not only expensive or difficult to obtain, but also Since the substituted acrylic acid amide is accompanied by an unfavorable side reaction in the addition reaction with trichlorogermane, especially those in which the substituent Z is NH ₂ , as shown in the reaction formula below, substituted or unsubstituted acrylic acid is used as the starting material. In some cases, it may be better to use this method. In addition, in any of the above methods, the trimercapto compound () produced by the action of hydrogen sulfide
may or may not be isolated. Including compounds (1) to (7) obtained by the above method,
The organic germanium compound represented by the general formula () is generally a colorless and transparent crystal, and the antitumor agent of the present invention can be prepared into tablets, powders, granules, etc. using the organic germanium compound as a main ingredient by conventionally known methods.
It is formulated into an appropriate dosage form such as a capsule. The present invention relates to an antitumor agent having the above structure, which is administered to patients suffering from various tumors in order to suppress or eliminate their growth. Since there are various problems in administering and confirming the antitumor agent of the present invention, we decided to confirm the dosage and effect through animal experiments. That is, when the above-mentioned organic germanium compound was suspended in water and administered orally for a certain period of time to mice in which 1×10 ⁶ IMC Carcinoma cells were subcutaneously implanted, the antitumor agent of the present invention showed the results shown in Table (1) below. Like IMC
The growth of Carcinoma was well suppressed.

【table】

[Table] Although (GeCH ₂ CH ₂ COOH) ₂ O ₃ , which was listed as a representative sesquioxide type compound, was not listed, the tumor weight when administered at 100 mg/Kg/day to 10 mice was However, in this case, the amount ratio (dose/formula amount) is as large as approximately 0.3215, and when considered in this way, it is clear how strongly the antitumor agent of the present invention suppresses the growth of IMC Carcinoma. Become. On the other hand, the physiology of tumors in the human body is extremely complex due to various factors, but if the results in Table (1) above are applied as is, the antitumor agent of the present invention, which has compound (7) as its main ingredient, will be effective against the human body. It is expected that administration of 1mg/Kg/day (50mg per day for a human weighing 50Kg) will show the same inhibition rate as in mice, and the drug is currently undergoing repeated clinical trials as an antitumor agent. Although the dosage of sesquioxide-type compounds is approximately 500 to 2000 mg/day, and the LD50 value of compound (7) is 560 mg/Kg, although it varies depending on the organic germanium compound, the upper limit of the dosage is Due to this considerable margin, together with the fact that it can be administered orally, the antitumor agent of the present invention can be applied to tumors in the human body. Next, examples of the present invention will be described. Experimental example 1 Synthesis of organic germanium compound Synthesis of compound (1) 2-carboxyethyltrichlorogermane
Dissolve 25.2 g (0.1 mol) of Cl ₃ GeCH ₂ CH ₂ COOH in 200 ml of anhydrous benzene and 24 g of anhydrous pyridine.
(0.1 mol) was added and stirred, and then dry hydrogen sulfide gas was passed through the mixture for 60 minutes. Benzene was removed while being careful of the oily substance formed, and the oily substance was dissolved in methanol 100%.
ml, this was added to 300 ml of purified water, and the precipitated crystals were recrystallized from methanol.
16.8 g of colorless plate-like crystals of 2-carboxyethylgermanium sesquisulfide (2) (GeCH ₂ CH ₂ COOH) ₂ S ₃ were obtained. The yield was 86.7%. Melting point 200℃ (value calculated by DTA spectrum) Solubility Easily soluble in DMSO, dioxane, THF, acetone, etc. Elemental analysis Ge ₂ C ₆ H ₁₀ O ₄ S ₃ as Ge C H S Calculated value 37.44 18.61 2.62 24.83 Analysis value 37.21 18.69 2.68 24.89 IR (KBr, cm ^-1 ), 3420, 1707, 425 NMR (dioxane-d ₈ , δ) 1.97, 2.57 Synthesis of compounds (2) to (7) These compounds can also be synthesized according to the above method. Among the obtained compounds, (2) to (5) are shown in Table (2).
In addition, (6) and (7) exhibited physical properties as listed in Table (3).

【table】

【table】

【table】

[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 1 mg to
The drug was administered orally for 5 days at a dose of 100 mg/Kg/day, followed by 1 day off, three times. Two days after the final administration, the animals were dissected and tumor weights were measured, and the results shown in Table (1) above were obtained.

Claims (1)

[Claims] 1. General formula (In the formula, A represents a hydrogen atom, a lower alkyl group, or a phenyl group, B represents a hydrogen atom or a lower alkyl group, and Z represents a hydroxyl group or an amino group, respectively.) Antitumor agent.