JPS59227889A - Cermanium complex compound - Google Patents

Abstract

NEW MATERIAL:A compound of the formula [Ge(1,2-dithiolato)2], [Mn]<++> [Ge(1, 2-dithiolato)3]<--> or [Ge(R2dtc)2X2](Mn is cation; n is 1 or 2; R is alkyl, aryl or aralkyl; dtc is dithiocarbamic acid anion; X is halogen). EXAMPLE:The compound of the formula. USE:A carcinostatic agent. PREPARATION:For example, an alkali metal salt of 1,2-dithiolate is added to germanium tetrachloride at (1:2) molar ratio in an aqueous solution to give the compound of the formula [Ge(1,2-dithiolato)2], or the alkali metal salt is similarly added to the germanium tetrachloride at (1:3) molar ratio to give the compound of the formula [Mn]<++>[Ge(1,2-dithiolato)3]<-->. The germanium tetrachloride is reacted with an alkali metal dithiocarbamate at (1:2) molar ratio to afford the compou#nd of the formula [Ge(dithiocarbamato)2CL2].

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel germanium-sulfur-containing compound complex produced by adding two or three dithio compound anions serving as bidentate sites to a tetravalent germanium cation, specifically, A novel germanium complex compound (Ge
(1,2-dithiolat)z), (Mn)”
(G e (1,2-dithiola, Na, ni, Ca, etc.) or an alkali IJ metal cation such as a tetraalkylammonium ion, etc., and X is a chlorine atom, a bromine atom, etc.
Represents 10 gen atoms. ).

Here, 1,2-dithiolate is a ligand selected from the group consisting of π / \- R'OOCS-, and 1,1-dithiolate is a ligand selected from the group consisting of is the chosen ligand.

Dithiocarbamado is a ligand selected from R, d t c.

Here, R' is a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, isopropyl group, methoxy, ethoxy,
R'' represents an alkyloxy group such as a propoxy or impropoxy group or a halogen group such as a chlorine atom or a bromine atom, and R'' represents a hydrogen atom or an alkyl group such as a methyl, ethyl, propyl or isopropyl group.

In addition, R is a hydrogen atom, an alkyl group such as methyl, ethyl, propyl, isopropyl group, phenyl, tri/I/,
Halo))': represents an aryl group such as a y-phenyl group, or an aralkyl group such as benzyl, phenylethyl, methylbenzyl, or a halogenated benzyl group.

Conventionally, many drugs have been known as anticancer agents, but all of them have advantages and disadvantages.In recent years, the anticancer effects of complexes containing metals have attracted attention, and platinum complexes are a typical example. However, platinum complexes have a major obstacle because they have side effects such as nephrotoxicity.

Conventionally, organic germanium compounds have attracted considerable attention in terms of pharmacological activity (for example, Japanese Patent Publication No. 4G-2, 49
No. 8, Special Publication No. 4 B-21,855, Special Publication No. 1977
- IE30,319, Special Publication No. 54-160, 74
See No. 2 and Japanese Patent Publication No. 56-11 & 015. ).

However, all conventionally known compounds are so-called organic germanium compounds in which carbon is directly bonded to divalent germanium.

On the other hand, it is known that Korean carrots, saru no koshikake, garlic, etc. that have been used as Japanese and Chinese medicines contain large amounts of germanium, but the relationship between these pharmacological actions and germanium is not clear. It has not been.

The present inventors believe that tetravalent germanium, which is in a physicochemically more stable state, can form a stable complex compound with a compound containing germanium, and as a result of extensive research, we found that germanium We succeeded in synthesizing a large number of (IV)-containing sulfur compounds. That is, it has been found that when an alkali metal salt of a dithiol or a dithiocarbamate is added to germanium tetrachloride in an aqueous solution or an organic solvent, a dithiolate or dithiocarbamate complex is easily formed.

For example, for germanium tetrachloride, 1,
When an alkali metal salt of 2-dithiolate is added at a molar ratio of 1:2, (Ge(1,2-dithiolate)) is produced, resulting in crystals. Similarly, when added at a molar ratio of 1:3, (M n )"
(G e (1,2-dithiolate)) A compound with the formula 0e is produced. From this, it is more soluble in water than the former in an aqueous solution, so it is difficult to commercialize it as a tetraalkylammonium halide. It is understood that the addition of tetraalkylammonium salt results in a higher yield of crystals.

When an alkali metal salt of 1,1-dithiolate is added to germanium tetrachloride at a molar ratio of 1:2, as in the case of 1,2-dithiolate salt, (Ge(1,1-dithiolate)
] crystals are formed.

In the case of alkali metal dithiocarbamates, unlike dithiolates, which are divalent anions, they become monovalent anions, so they react with germanium tetrachloride at a molar ratio of 1:2 (Ge (dithiocarbamado)). C1] is generated.

These compounds are stable because they have a structure in which four or six sulfur atoms are coordinated around a tetravalent germanium ion, and the structure can be easily estimated by elemental analysis or infrared analysis.

Furthermore, these germanium (IV)-sulfur-containing compound complexes are expected to have physiological activity, and when we actually investigated their physiological activity against Ehrlich ascites tumors in mice, it was revealed that they have extremely strong antitumor effects. Became.

Hereinafter, the present invention will be explained in detail with reference to Examples.

Example 1 1.373 g (5 mmol) was dissolved in 10 ml of water, and while stirring, 0.536 g (2,
5m mol), a yellow precipitate was immediately formed,
If you continue stirring, it will turn brown. The crystals were collected by suction filtration using a glass filter, washed with water, and dried under reduced pressure in a calcium chloride desiccator overnight to obtain the desired compound as brown crystals (0,997 g, yield 85.7%).

　　　.

Elemental analysis: (G e (CJS5)2 ) ・2 H
xOtoL Teno calculated value C, 14,37%; H, 0,8
1%; S, 63.95% actual value C, 14,04%; I
(,0,10%; S, 63.75% Infrared absorption spectrum: Viax (cm-'): 421,465,51
1.1058 Example'l (Ge (E t2.d
t c) Production of 2C12) Germanium tetrachloride 0.53
Dissolve 6 g (Z5m mo 1 ) in methylene chloride,
Furthermore, 0.856 g (5 m mo
When 1) is added, the solution gradually becomes colored. After heating under reflux for 5 hours, the generated common salt and unreacted E t, d t c
The Na crystals are filtered off using a glass filter, the crystals are further washed with 60 ml of methylene chloride, and the filtrate and washing liquid are combined and concentrated under reduced pressure using a rotary evaporator to a volume of about 20 ml. 30 ml of n-hebutane was added thereto, and the precipitated yellow crystals were collected by suction filtration using a glass filter and dried under reduced pressure at 80°C overnight to obtain 0.906 g of the title compound (yield 8z).
4%).

Elemental analysis: [Ge((C2H5)2NC82)2C12
] Calculated values as; C, 27,29%; H, 4,59%; N, 6
．． 37%; S, 29.14%; C1, 16, 11% actual value; C, 28, 28%; II, 4.90%, N, 8.
72%; S, 27.22%; C117, 11% Infrared absorption spectrum: Vw+ax (cm-'): 570,996,1204
, 1279.1531 toreene-3,4-dithiol 0.71H4g (5 intestines of) was dissolved in 50ml of 0.2N sodium hydroxide aqueous solution, and GeC1+0.
538 g C, 1.5 mmol> was added. Immediately, the solution turned yellow and a white precipitation of 1 was generated. After stirring for a while, the mixture was collected by suction filtration using a G-4 glass filter and washed with a small amount of water. The obtained white crystals were dried under reduced pressure over CaClz overnight to obtain 0.6735 g of bis()/l/xy-3,4ythiolate)germanium (■).

Elemental analysis: Calculated value C, 44, 12%; Fl, 3.18%; S, 3
3.65% actual value C, 44,69%; H, 3,04%
;S, 32.76% Infrared absorption spectrum: Vlax (cm): 4B1,807,1118.14
80 toluene-3,4-dithiol 1.1720 g (7
, 51101) in a 0.2N aqueous sodium hydroxide solution 85
GeC1,0,536g (2,
5 mmol 1) was added. The reaction solution immediately turned yellow, and at the same time a small amount of white crystals precipitated. The crystals were filtered off and the filtrate was dissolved in 5 ml of water [(
C, l(?), N] Br1.6122g (5m mo
l) was added. The reaction solution became a pale yellow emulsion, but 2
An orange oil formed after ~3 minutes. The supernatant was removed and the oil was washed with water. Dry under reduced pressure at 40-50℃ overnight,
226 g of crystals were obtained.

Elemental analysis: Calculated value C, 62,38%; H, 8,91%; N, 2.7
5%; S, 18.85% actual value C, C30, 73%;)
1, 8.16%; N, 2. (31%; S, 18.15%
Infrared absorption spectrum: Vlax (cs-'): 624,807,97t! ,
1114,1453.29804.5-dimercapto-
1,3 dithiol-2-thione potassium salt 2.0590
G e C10,536 g (25 m mol) was dissolved in 15 ml of water with stirring.
) was added, a yellow precipitate was immediately deposited. As the stirring continued, the mixture became blackish. After stirring for a while, perform centrifugation.
The upper layer was removed by decantation. Water was added, stirred, and centrifuged again, and the supernatant was removed. The obtained crystals were converted into CaC1
The mixture was dried under reduced pressure overnight to obtain 1.2644 g of dark brown crystals.

Elemental analysis: Calculated value C, 14,81%: H, 0,00%; S, 85
．． 01% actual value C, 14, 38%; l(, 0, 22%
; S, 59.77%, (2.5 mmol) was added, and a yellow precipitate was immediately deposited. Shibara (after stirring G4
The crystals were collected by suction filtration through a glass filter, and the crystals were washed with cold water.

When dried under reduced pressure overnight on Ca C12, yellow crystals with 0. [10
24g was obtained.

Elemental analysis: Calculated value C, 27, 22%; o, o, oo%; N, 15.
88%; S, 36.33% actual measurement m C, 25.63%;
l(,1,16%; N, 14.32%; S, 28.
GeC191,
When 0.07 g (5.0 mm o 1 ) was added, a yellow precipitate was instantaneously generated. The precipitate was collected by suction filtration through a 64 glass filter and dried under reduced pressure overnight to obtain 1.47 g of crystals.

Elemental analysis: Calculated value C, 32, 24%; l(, 2, 25%; N, 6.
27%; S, 2B, 69% actual value C, 27, 81%; l
(,2,03%; N, 5.54%; S, 21.84% Infrared absorption spectrum: Vax (ell-'): 493,732.1
140.1655.2175 Examples & Antitumor Activity Test +1) Test Animals ICR/CRJ strain female mice, 5 mice per group, 8 weeks old were used.

(b) Test method (in vitro) The survival rate was examined on day 0, which was the day when 10 Ehrlich ascites cancer cells were intraperitoneally transplanted into the mouse.

On the other hand, taking into account the possibility of various germanium compounds and interferon-induced effects, the administration route was determined to be 7 days after administration.2) The solution was prepared with physiological saline. Let it be day 0, (-7~-
3, ÷ 1~+5) is +11 from the -7th day to the 13th day.
Administer on day +55.

The drug was administered ip for a total of 10 times, once on day 3 and once on day 1 to day 5, and physiological saline was used as a control.

The results are shown in Table 1.

As is clear from the above results, the germanium complex compound of the present invention exhibits antitumor properties.

Patent applicant: Ajinomoto Co., Inc.

Claims (1)

[Claims] 1. A germanium compound represented by any of the following formulas. (Ge(1,2-dithiolat)2]. (Mn)” (Ge(1,2-dithiolat)3) (
Ge(1,1-dithiolat)2], and (Ge (
R2d t c )2 X2) where Mn is a cation, n is 1 or 2, R is an alkyl, aryl or aralkyl group, dtc is a dithiocarbamate anion,
X represents halogen. 21.2-dithiolate is a ligand selected from the group consisting of ( I /\- R'00CS and 1,1-dithiolate is a ligand selected from the group consisting of A compound according to Item 1 of the scope.In the formula, R/ represents a hydrogen atom, an alkyl group, an alkyloxy group, or a halogen, and R" represents an alkyl group. & At least one germanium complex compound represented by any of the following formulas. Prevention of cancer contained as a child active ingredient,
therapeutic agent. (Ge (1,2-dithiolat)2]. (M n )” (G e (1,2-dithiolat>
, ]ee. (Ge(1,1-dithiolat)2 ], and (Ge
(R2d t c)2X2) In the formula, Mn represents a cation, n represents 1 or 2, R represents an alkyl, aryl or aralkyl group, dtc represents a dithiocarbamate anion, and X represents a halogen.