JPS601192A - Substituted phenyl germanium compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (n is 1, or 2; X is halogen, or alkoxy; Y is cyano, carboxyl, or alkoxycarbonyl; Z is H, halogen, alkyl, alkoxy, cyano, carboxyl, alkoxycarbonyl, alkylthio, or dialkylmaino). EXAMPLE:p-(Cyano)phenyltrichloro germanium. EXAMPLE:A raw material for preparing a substituted phenyl germanium sesquioxide as a carcinostatic agent. PREPARATION:A tetrahalogeno germanium shown by the formula Ge(hal)4 (hal is halogen) is reacted with a substituted phenyl iodie compound shown by the formula II in the presence of a copper catalyst preferably in the absence of a solvent at 100-250 deg.C for several hours-100hr.

Description

DETAILED DESCRIPTION OF THE INVENTION (However, n is l or #'iz+ let halogen atom or alkoxy and ty is a cyano group, carboxyl group or alkoxycarbonyl group, and 2 is a hydrogen atom.

halogen atom, alkyl group, alkoxy group, cyano group,
An atom or group that is outside the group consisting of carbothicyl, alkoxycarbonyl, alkylthio, and dialkylamino groups. ) and a method for producing the germanium compound.

In recent years, organic germanium compounds, particularly organic germanium sessile oxide, have been found to have medicinal efficacy as anticancer agents and antihypertensive agents, and are attracting considerable attention in terms of their pharmacological activity.

The present inventors have been conducting extensive research on the synthesis and physiological activities of organometallic compounds, particularly organogermanium compounds, for many years. As a result, we succeeded in synthesizing a novel substituted phenylgermanium compound and provided the entirety of the present invention. That is,
This invention company, general formula x 3 Ge <Y (where n is l or 2.

Halogen atom, alkyl group, alkoxy group, cyano group,
It is an atom or 4 groups selected from the group consisting of carboxyl group, alkoxycarbonyl group, alkylthio group and dialkylamino group. ) is a substituted phenylgermanium compound as shown in FIG.

The substituted phenylgermanium compound of the present invention is a compound represented by the above general formula. The substituents represented by the above general formula are also as shown in mJ, but more specific examples are as follows.

Among the above-mentioned halogen original characters of General, 2nd A, X Company + QLBr + Engineering, and y, 07 and Br are particularly suitable. Moreover, the X may be an alkoxy group. The acid alkoxy group is generally a substituent represented by -OR, and the alkyl group represented by R can be used without particular limitation, but it generally has 1 to 1 carbon atoms.
6 preferably 1 to 3 lower alkyl groups, i.e. methyl IM
+, ethyl group, propyl group, butyl group, hexyl group, etc., and particularly methyl group, ethyl group, proyl group, etc. can be preferably used. Further, in the general formula M, Y is sheared. The R
There are no particular restrictions on the alkyl group, but lower alkyl groups having 1 to 6 carbon atoms are generally preferred from the viewpoint of industrial ease of availability. Therefore, the alkyl group of the alkoxycarbonyl group is generally a methyl group.

Ethyl group, propyl crystal, buty/L/ group, hentyl group.

Hexyl group and the like are most preferably used. In addition, in the general formula, 2 is as already shown above, but specific examples include a hydrogen atom and a cyan group.

In addition to (-(IN)# carboxyl group←aooH), the following are commonly used. That is, the halogen atoms include O7l, Br, engineering and! Each atom can be used, and among these, aZ and Br are particularly preferred because of their ease of availability or ease of handling. The alkyl group is not particularly limited, but is preferably a lower alkyl group having 1 to 6 carbon atoms, similar to those exemplified as the alkyl group of the 't1iJttalco1-cyclocarbonyl group because of easy availability. Further, the alkoxy group is the same as that exemplified as the alkoxy group represented by t in the general formula ``nI'', and a lower alkyl group having 9x to 6 carbon atoms is particularly preferred.

Further, the alkoxycarbonyl group used in the above general formula y may be used in the same manner as the alkoxycarbonyl group. Historically, in alkylthio groups and sial i substituents, the R(
Alkyl group) L Same as those exemplified as the alkyl group of the alkoxycarbonyl group, especially carbon atoms 1 to 6
Lower alkyls are used for tracing.

The substituted phenylgermanium compound of the present invention is a colorless and odorless transparent liquid or solid at room temperature and pressure, and can be purified by distillation or recrystallization. Regarding the boiling point, it varies depending on the type of substituent, but
As with general organic substances, it tends to increase as the molecular weight increases.

The fact that the germanium compound has the chemical structure represented by the above general formula is generally determined by the following means [0) to [
Ship identification-r is possible.

By measuring the infrared absorption spectrum (IR), it is possible to confirm the characteristic chemical bonds and the '9N functional groups present in the germanium compound molecule. For example, the germanium compound is %30003
Absorption based on protons of phenyl group in the vicinity e Z 6
00 C11l -” +1500cm-”, B O
It shows characteristic absorption based on phenyl group near Ocm-'. Furthermore, when the substituent (Y and 2) in the germanium compound is a cyano group, it shows a sharp absorption around 22303-'', and when it is a carboxyl group, it shows a sharp absorption at 3400d1.
In the case of an alkoxycarbonyl group, there is an absorption based on 10H and a strong absorption based on a C=0 bond near 1700 cm-JJ. I'm in charge.

(b) Separation spectrum (m8) All measured, each peak observed (general vch ion molecule in! charge 'Ij h:
By calculating the compositional formula t corresponding to t*m'th> represented by m/e, which is expressed by e, it is possible to estimate the bonding mode of the sample with Lξ, and ultimately its molecular weight. can. That is, the sample subjected to measurement has a general formula (where n is l or 2. An atom or group selected from the group consisting of an alkyl group, an alkoxy group, a carbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group, and a sialkylamino group. Peak ('') *B corresponds to the mass of M@-1 with X desorbed from the molecular ion peak. Furthermore, in addition to these peaks, many peaks appear, indicating that germanium-containing compounds with many isotopes [characteristic It has a similar appearance.

(c) By measuring the 1H-Nuclear Mountain Resonance Svector ("H-nmr), it is possible to know all the numbers and types of protons present in the compound subjected to measurement. For example, p-
(cyano)phenyltric tetrarogermanium “H-n”
Chemical shift value of each peak (
The analysis results for δ+ppm) are as follows.

/ ＼ 7.46 (d) 7.66 (gradient) Determine the weight of each element, hydrogen, nitrogen, halogen, and germanium, h1%'t-, by the element 'Of', and further the weight of each recognized element. By subtracting the % chord from 100, the oxygen concentration % can be calculated, and therefore the compositional formula of the compound subjected to measurement can be determined.

The method for producing the substituted phenylgermanium compound of the present invention is not particularly limited, and any method may be used. As a typical production method that is generally suitably adopted, tetrahalogenogermanium, substituted phenyl iodo compound and t
- A method of reacting under a copper catalyst is proposed. The reaction formula for this counterfeiting method is as shown below.

(However, in the formula, hal represents a halogen atom, and the other symbols have the same meanings as above.) Requirements for the reaction t'i are not particularly limited, but are suitable depending on the type of raw materials, etc. It is preferable to select and implement certain conditions. Generally, it is preferable to conduct the reaction without a solvent, the reaction temperature is in the range of 100°C to 250°C, and the reaction time is r.
It is sufficient to make it in the range of several hours to 100 hours.

In addition, tetrahalogenogermanium and substituted phenyl B-
The molar ratio of the charged compound to the F compound may be appropriately determined and used as required, but it is common to use them in an equimolar ratio.

Also, another lIi! ! As a production method, substituted phenyltrialkoxygermanium can be produced by reacting f[I> phenyltrihalogenogermanium and alcohol-' or metal alkoxide as shown in the reaction formula below (However, (In the formula, hal represents all heshigene atoms, Xa represents an alkoxy group, and other symbols have the same meanings as above.) This reaction can be carried out without a solvent. , is generally carried out in the presence of a solvent. As the solvent, any solvent that does not react with the raw material acid ψ and the product can be used without particular limitation, and in general, hydrocarbon solvents such as dibenzene and hexane are preferably used. Also,
Alcohols used in the reaction are generally indicated by WOH,
In particular, an alkyl group such as the W company hydrocarbon residue can be preferably used. More preferred are alcohols composed of lower alkyl groups such as methyl, ethyl, and propyl groups having 1 to 3 FA atoms in view of ease of purification of the product. The metal alkoxide is not particularly limited and any known metal alkoxide can be used, particularly alkali metal alkoxides such as sodium alkoxide, potassium alkoxide, and calcium alkoxide.

Alkaline earth metal alkoxides and the like can be suitably used.

The reaction conditions used in the above-mentioned reaction curve are not particularly limited, and may be carried out in advance at a suitable distance depending on the raw materials, etc. Generally reaction temperature is 120℃~120℃
It is sufficient to carry out two reactions simultaneously in the range Fl from 10 minutes to 100 hours.

Although the reaction process continues even in the absence of a base, the presence of a base significantly increases the reaction porosity. The bases to be allowed to coexist are not particularly limited;
It is preferable to select a suitable one according to the type and the like. Generally ammonia, pyridine 1. Triethylamine is preferably used. In the above reaction formula, in the presence of a base, when y and z are carboxyl groups, the compound directly obtained by the reaction is a salt with the coexisting base, and this is The target product t- can be obtained by performing the treatment.

In addition, as a method for producing substituted phenylgermanium compounds, a method of reacting an ffl&'l phenyllithium compound with tetrahalogenogermanium or tetraalcothogenium at a low temperature may also be used. For example, -10
When p-(cyano)phenyllithium synthesized at 0°C is reacted with tetrachlorogermanium, p-(cyano)
PhenyltricotI germanium easily? I can connect with you.

The substituted phenylgermanium compound of the present invention 19 can be easily converted into ground phenylgermanium heptaskioxide represented by the following general formula by subjecting the compound fx' to a hydrostatic force t.

(However, n is l or 2: Y/ri cyano group, carbo 1-
Cyrus (or alkoxycarbonyl group; zFi) selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, an alkoxy thread, a cyano group, a carboxyl group, an alkoxycarbonyl/L/ group, an alkylthio group, and a sialkylamino group. ) The substituted phenylgermanium sesquioxide that is released by the hydrolysis exhibits excellent physiological activity, as is clear from the application examples described below.
In particular, it exhibits full anticancer effect when applied to cancer cells such as Ehrlich's carcinoma in mice and 9 Ocher 256 carcinoma in rats.As described above, the 16-methyl-benzenyl germanium compound of the present invention has various uses. This is an extremely useful new compound that can be used for.

In order to explain the present invention more specifically, the following examples and application examples will be given and explained, but the present invention is not limited to these examples and application examples.

Implementation fAJ+ (Synthesis of p-(cyano)phenyltrichlorogermanium) In a three-loaf flask equipped with temperature iml', am/5a2 sp-, p-bromobenzonitrile (10,71,9
), anhydrous tetrahedral 07 run (1oo-) and anhydrous hexane (3011t) were added. The mixture was cooled to −100° C. in an ether/liquid nitrogen bath, and a hexane solution (28, 80, 9) of n-butyllithium was gradually added from the dropping funnel while stirring for 2 m under an argon stream. After dropping, approx. 1
At 111 hours, the solution was cooled with liquid nitrogen and added dropwise to tetrachlorogermanium (16001
9) Anhydrous hexane (zom) solution quickly added 0
Thereafter, the mixture was gradually returned to the vortex and stirred overnight. After gradually removing the solvent, the resulting pale yellow liquid was distilled under reduced pressure to a boiling point of 77'.
C10,1 Hg colorless 6-light liquid (3,20i>t-
Obtained.

When the infrared absorption spectrum of the compound was measured, it was found that there was an an bond v at 2230cff'' shown in Figure 1.
Strong absorption based on c, 3100-3000i'', 149
Absorption based on phenyl group was observed at 0d" radiation 820c+ff'. When the quality m spectrum was measured, m
/・In addition to the molecular ion peak (Mo) at 281,
Eight characteristic peaks were shown at m/e 246e 179t137 and 102.

At the same time, it also showed a characteristic peak as a germanium-containing compound with many isotopes. Elemental analysis was conducted for Tojiro, 030.30%, Hl, 53%.

4.86%, Oj! 37.50%, Ge26.01% 1fft-' Compositional formula 〇, H4tJJ3Gall
As (281' 06) (Th with iHH+6 0
29.91%, Hl, 44%, M4.98%, 0J37
．． 84% and Ge25.83%.

When the IH-nuclear magnetic resonance spectrum (δ+ppm: tetramethylsilane standard) was run, the results were as follows.

7.4'6 (dJ \7.66 (dJ) From the above results, it was confirmed that the product was p-(cyano)phenyltrichloride.

Example 2 (Synthesis of p-(ethoxycarbonyl)phenyltrichlorogermanium) Tetrachlor on germanium (22,39JI), ethyl p-iodobenzoate (18,90Ii) and copper powder (
12, 20p) Place in a T-glass sealant and place in an oil bath (2
After opening the tube, benzene-soluble components were extracted from the reaction mixture.

The extract was then distilled at a boiling point of 91-92°C, 70°C, and 1°C.
mtlg f) Colorless and transparent ff (9,60!I) was obtained. The compound solidified after a while. When the external absorption spectrum of the compound was measured, as shown in the attached figure σU second plane, 0 = Og of the ester at 1720 B-''.
Combined K a ”j < strong 1/' fl yield, 1390G+
! -'* Absorption associated with the benzene ring was observed at 12800I-1.

When the placement spectrum AI was measured, there was a molecular ion at m/5a2s (in addition to the peak corresponding to M town, m/e 28
3, a peak corresponding to M@-EtoK was observed. Many peaks associated with isotopes characteristic of germanium-containing compounds were also observed. In addition, elemental analysis revealed that 0 32.91LH2, 67L OJ 32.40%
, Ge22.21%, and the composition formula OqHgO1
Ill' calculated value as 3Ge02 (328,12) is 032.94%, H' 2.70%.

0J 32.42% and Go 22.12%. 1
H-Nuclear Magnetic Resonance Spectrum (δs Pp'''tetramethylsilanestandard)' t-Set measurement was carried out, and the results were as follows.

From the above results, the product is p-(ethoxycarbonyl)
It turned out to be phenyltrichlorogermanium.

Example 6 (Synthesis of p-(carboxy)phenyltrichlorogermanium) Tetractetragermanium (11,241), P-
Ethyl iodobenzoate (9,47&) and copper powder (7
, 3ON) Insert into Tt glass tube, in oil bath (200
℃) for 50 hours. After opening.

The entire hexane soluble fraction was extracted from the reaction mixture.

Then, the extract was magnetically concentrated and the boiling point was 110°C, 10.2 liters
(I's thermoelectric solids (2, 14, 9) were proposed.

When the infrared absorption spectrum of the compound was measured, it was found that 1'
A strong absorption based on the C-0 bond of carbonic acid was observed at 700 cm-1, and a wide absorption based on the O-H bond of carbonic acid was observed at 3400 cm-1. i quantity spectrum kkili
1+, a molecular ion (Ml
) In addition to the peak corresponding to Ml-OH at m/e283
The peaks corresponding to , etc. are shown.

Further, elemental analysis revealed that it was 02B, 10%.

H1,65%10/35.50%1G824.15% tiI'l t-, compositional formula a□H5a13Geo
□(300,07) as ljl”4-7.The value is 0 28.02%, H168, OA! 35.45
A result of 0 or more consistent with %IG@24.19% revealed that the product was p-(carboxy)phenyltrictetragermanium.

Example 4 (Synthesis of p-(ethoxycarbonyl)phenyltriethoxygermanium) Synthesized in Example 2, rt, p-(ethoxycarbonyl)phenyltrichlorogermanium (10,50,9), anhydrous ethanol (30,9) and anhydrous Hensen (100I
Ammonia gas was gradually vented into the flask at room temperature. After a while, heat was generated and the solution became cloudy. After bubbling the ammonia scum for a total of about 2 hours, the solution I was stirred overnight in an argon atmosphere. After filtering the white substance produced, the solvent was removed and evaporation was carried out to obtain a colorless transparent liquid with a boiling point of 115-116°C and 10.2% Hg (8,
589) was obtained.

The infrared absorption spectrum of the compound was determined by 1720 filtration. A strong absorption based on the C=0 bond of the ester was observed. When the entire spectrum was selected to J, m
In addition to the -f peak corresponding to the molecular ion (Ml) at /e a 5s, a peak corresponding to M'-JCto at m/e 313, a peak corresponding to Ml2 (ICto) at m/e = 268, etc. were observed. It was done. In addition, elemental analysis revealed 050.45%, H669, Go 20.52
%, and the compositional formula 015”24Geo5 (35
693) is 050.47%, H6
78%l G6 matched 20.34%.

Example 5 (Preparation of p-(ethoxycarbonyl)phenyltrimethoxygermanium, ) l■l°, stirrer and dropping funnel) Into a third flask containing 1 ml, add methyl p-bromobenzoate (9,40Ii) and into ether (10011t)'. The flask was cooled in a dry ice/methanol bath, and a hexane solution (19.65F) of n-butyllithium was gradually added from the dropping funnel while stirring under an argon stream. After cooling the solution for 1 hour at 11 °C, the ether (2) of tetramethoxygermanium (9,51) was added dropwise.
0 mL) solution was quickly <JJ:+. After the addition, the mixture was gradually warmed to room temperature (1C) without stirring, and nasal spraying was performed overnight at room temperature.

After distilling off the solvent, the resulting liquid was distilled under reduced pressure to obtain a colorless transparent liquid (4,02I) with a boiling point of 103° C./0.2 ysmH9f).

When the infrared absorption spectrum of the compound was measured, 171
Strong absorption based on the a=O bond of the ester was observed at 5 cm-1. When the shell spectra were measured, m/e
A peak corresponding to the molecular ion (M@) at 302 and a characteristic peak at m/e 271 + 240 etc. were observed. In addition, elemental analysis revealed that 0 43
．． 86%, H5, 29%, Go 24.10%, Si1 formula 01□H1, Ge05 (300,83
) is the calculated value as −〇43.92%, H5,3
6% and Ge24.13%.

Example 6 Various substituted phenylgermanium compounds were totally synthesized in the same manner as described in Examples 1 to 5. The structural formula 1 compositional formula and elemental analysis value t of the product are listed in Table 1.

Application example 1 p-(ethoxycarbonyl)phenyltrichlorogermanium (5,80,9) f 1ia obtained in Example 2
In addition to 2003 aqueous solution (50 m), 4 h (
h Stirred. The generated isomer was separated and dried, and p-(ethoxycarbonyl) phenylgermanium sesquioxide was obtained as a white solid (4,01) (4J).The infrared absorption spectrum was measured, and a strong ethoxycarbonyl was observed at 1720 cm-'. Suction Q, 850-820 cm-”V
The strong characteristic absorption of cGe-0 was fully exhibited. Elemental analysis revealed 04401%, H3, 65%, Ge29.
All values of 48% are shown, composition formula 〇, H0GeO,, (24
5,75) if' n value as C343,98
%, H3, 69%, G.

The agreement was 29.54%.

The surfactant Tween 8 was prepared by adding a small amount of dimethyl sulfoxide to the p-(eth4-dicarbonyl)phenylgermanium sesquioxide obtained above.
A total sample solution was prepared by suspending it in physiological saline (0.85 J/3) containing 0.0%.This sample solution 't, *Number of Walker Cardiosarcoma 256 cancer cells in the cavity I
Sprague-Dawley sutures (1) 64 were given intraperitoneal injections for 5 consecutive days, and a life-prolonging sound effect was given for 1+ months. The mean survival days (M 8 T) was calculated from the obtained results and compared with the mean survival days of the control group (24 animals) to calculate T70%.

That is, the average survival days were calculated for the test subject ('I) and control subject (0) using T10 x 100 (%). As a result, when the administration force was t't-100m1A9, 6 out of 6 rats died, and their MST was 30.0 days or more. On the other hand, vs. Jj+:j l! MS of #
The T10 at a dose of 100/kll of P-(ethoxycarbonyl)phenylgermanium sesquioxide was calculated as 361 or more, which is a significant cancer suppressant for Walker ships. It became clear that it showed activity.

Application Example 2 Using each of the V-converted phenol germanium sesquioside shown in Table 2, the anticancer activity (Yc) against Ehrlitzhil J hydrosis in mice was tested. An injection prepared by the method described in Application Example 1 above was added to the germanium heptaoxidase in 4 Ehrlich cancer cells (5 x 10). Continuous injections were administered for 9 days. Based on the results of the 60-day 111-day survival test, the average survival days (T/Q (support)) were calculated by comparing with the average survival days of the control group (30 animals).

[Brief explanation of the drawing]

Figure 1 is a chart of infrared absorption spectra of substituted phenylgermanium compounds obtained in Actual Spinning Example 1 and Figure 2 is Example 2, respectively.

Claims (3)

[Claims] (1) General formula (where n is l or 2. A substituted phenylgermanium compound represented by: an atom or group selected from the group consisting of a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylthio group, and a dialkylamino group. (2) General formula oe (hayo) 4 (however, ha
(wherein, in formula A, n is l or 2, Y is a cyano group,
Carboxyl group
It is an atom or an it group selected from the group consisting of cyano, carboxyl, alkoxycarbonyl, alkylthio, and dialkylamino groups. ) with a substituted phenyl iodo compound represented by n, hal, Y and z in the presence of a copper catalyst.
Fi Same as above. ) A method for producing a substituted phenylgermanium compound shown in (3) General formula (wherein, n is l or 2, hal is a halogen atom, Y is a cyano group, a carboxyl group or a alkoxycarbonyl group, and ezFi is a hydrogen atom, a halogen atom, an alkyl group, An atom or group selected from the group consisting of an alkoxy group, a cyanocrystal, a carboxy/I/ group, an alkoxycarbonyl group, an alkylthio group, and a dialkylamide 7 group) and an alcohol. The general formula is a koxy group, and n, Y and 2 are the same as above. ) A method for producing an N-substituted phenylgermanium compound.