JPS60228490A - Organogermanium compound - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R is alkyl; n is a positive integer; A is H or alkyl; X, Y and Z are H, halogen or alkyl, etc.). EXAMPLE:N-(p-Bromophenylmethylidene)-gamma-aminopropyltriethylgermanium. USE:A carcinostatic agent. PREPARATION:For example, an amino alkyl(trialkyl)germanium compound of formula II, e.g. gamma-aminopropyltriethylgermanium, is condensed with a substituted benzaldehyde of formula III, e.g. p-bromobenzaldehyde, in a solvent, e.g. benzene, through dehydration.

Description

Detailed Description of the Invention The present invention is based on the general formula (wherein R is an alkyl group; n is a positive integer; A is a hydrogen atom or an alkyl group Hz; x and 2 are the same or different hydrogen atoms, halogen atoms, respectively; , alkyl group, alkoxy group, hydroxy group, cyano group, nitro group, alkylthio group, alkoxycarbonyl group, carboxyl group and its salt type group, sulfonic acid group and its salt type group, di(alkyl)amino group, or di( ) \roalkyl) amino group,! The present invention provides an anticancer agent containing an organic germanium compound in which and Y is substituted with an adjacent carbon atom, and a cough gel mononium compound as active ingredients.

In recent years, the pharmacological activities of organic germanium compounds, particularly their antitumor properties, immunostimulatory effects, antihypertensive effects, and anti-inflammatory effects, have attracted much attention.

The present inventors have been conducting intensive research on the synthesis and physiological activities of organometallic compounds, particularly organogermanium compounds, for many years. As a result, the following general (where R is an alkyl group; n
is a positive integer; A is a hydrogen atom or an alkyl group: X,! and 2 are hydrogen atoms of the same or different types, respectively.) Rogge/atom, alkyl group, alkoxy group, hydroxy group, cyano group, nitro group, alkylthio group, alkoxycarbonyl group, carboxyl group and its salt type group, sulfonic acid group and its salt type group, di(alkyl)amino group, or di(haloalkyl)amino group,! as well as! may be a group represented by substituted with adjacent carbon atoms. ) has been established, and the organic germanium compound has excellent physiological activity,
They have found that it has particularly anticancer activity, and have completed and proposed the present invention.

That is, the present invention is based on the general formula (where R is an alkyl group; n is a positive integer; M is a hydrogen atom or an alkyl group; Alkoxy group, hydroxy group, cyano group, nido tetragroup, alkylthio group, alkoxycarbonyl group, carboxyl group and its salt type group, sulfonic acid group and its salt type group, di(alkyl)amine group, or di(/10 alkyl ) In the amino group, X and ! may be a group represented by ○ substituted with adjacent carbon atoms. It is.

The organic germanium compound of the present invention is a compound represented by the above general formula. In the general formula, R is not particularly limited as long as it is an alkyl group, but generally has 1 to 1 carbon atoms.
The linear or branched lower alkyl group of No. 4 is preferably used because of its industrial ease of availability. Isomorphically, methyl group, ethyl group, n-propyl group, lll0-globyl group,
-+CH27] n is not particularly limited as long as it is a positive integer, but n is
is preferably 1 to 12, preferably 1 to 6. Specific examples of particularly preferably used alkylene groups include -aw@-, -0111011101!
l-1-QiIlolllORlcal-1-OH@O
TE, OH@OH snow OH snow-, -011 Goose QTI@CJ
H@CJH@OK snow C3H heat-1fOIhi etc. In addition, the alkyl group represented by the general formula is not particularly limited, but lower alkyl groups such as methyl and ethyl groups are generally preferably used from the viewpoint of easy availability of raw materials. In the substituents X, Y, and ZK in the general formula, if X, Y, and Z are all hydrogen atoms, it is an unsubstituted product, a substituent in a -substituted product, and a disubstituted product! If the substituent is I, !, and the trisubstituted case is x, y, z, then
Examples include halogen atoms, alkyl groups, alkoxy groups,
Hydroxy group, cyano group, nitro group, alkylthio group, alkoxycarbonyl group, carboxyl group and its salt type group, sulfo/acid group and its salt type group, di(alkyl)amino group, di(haloalkyl)amino group, etc. suitable.

I is a halogen atom, an alkyl group, and x1Y and 2 in the above general formula are the same or different hydrogen atoms, halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, cyan groups, nitro groups, alkylthio groups, Alkoxycarbonyl group, carboxyl group and its salt type group,
The group may be a sulfonic acid group or its salt type group, a cy(alkyl)amino group, or a di(haloalkyl)amino group, in which X and Y are substituted on adjacent carbon atoms. When all of the above X, Y and 2 are hydrogen atoms, it is an unsubstituted product, but in other cases it can take the form of a monosubstituted, disubstituted or trisubstituted product. The substituents include the various groups mentioned above.
However, in general, as the number of substituents increases, the production becomes more complicated.

Generally, industrially, mono-substituted substituents selected from the above substituents are most widely used, but di-substituted ones are particularly suitable for one type of substituents selected from the above-mentioned substituents and di-substituents. Halogen atoms, alkyl groups, alkoxy groups, hydroxy groups, etc. are industrially suitable, and substituents as trisubstitutes include halogen atoms, alkyl groups, alkoxy Bases and the like are preferred from the viewpoint of easy availability of raw materials.

The halogen atoms represented by X, Y, and Z in the general formula are:
Although F, O2, Br, and I can be used without particular limitation, F, OL, and Br are particularly preferred. In addition, the aliphatic saturated hydrocarbon residues of the alkyl groups and alkoxy groups represented by X, Y, and Z in the general formula are not particularly limited, but can be used,
Generally, those having 1 to 4 carbon atoms, ie, methyl group, ethyl group, propyl group, butyl group, methoxy group, ethoxy group, propoxy group, and butoxy group, are preferably used. In addition, the aliphatic saturated hydrocarbon residue represented by Preferably. That is, methylthio group, ethylthio group, propylthio group, butylthio group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, di(methyl)amine group, di(ethyl)amino group, di(propyl)amino group , di(butyl)amine group, etc. are preferably used.

Furthermore, the carboxyl group salt type group and the sulfonic acid group salt type group represented by X in the general formula are generally -aooeMe
Although there are no particular limitations on the content, it is generally ammonium (NH).
4e); Alkali metals such as sodium (Nae), potassium (KO), lithium (Lte); magnesium (1
Alkaline earth metals such as calcium (1/2 Mg") and calcium (1/2 ca'e) are most preferably used.

Furthermore, bis(haloalkyl) represented by X in the above general formula
The amino group is generally represented by (X'(Oa2))zN, and the halogen atom represented by x' is chlorine, bromine, iodine,
and fluorine atoms are used without particular limitation, and m is most preferably an integer of 1 to 4.

The organic germanium compound represented by the above general formula is generally a colorless transparent, pale yellow, yellow, or brown liquid or solid at normal temperature and pressure, and can be purified using distillation or column chromatography. Furthermore, the organic germanium compound is generally sparingly soluble in water, but hexane and benzene are soluble in almost all organic solvents. In addition, in acidic or alkaline aqueous solutions, the stability varies depending on the concentration and temperature, but in general, the carbon-nitrogen double bond undergoes hydrolysis, and aminoalkyl (trialkyl) germanium and the corresponding carbonyl compound (such as substituted benzaldehyde or Substituted acetaldehydes, etc.) tend to undergo K decomposition.

The fact that the organic germanium compound has the chemical structure represented by the above general formula can generally be confirmed and identified by the following methods (a) to (b).

(a) By measuring the infrared absorption spectrum (1r), it is possible to confirm the characteristic chemical bonds and functional groups present in the molecule of the organic germanium compound.

For example, the organic germanium compound exhibits a characteristic absorption based on the 1-O=N- bond in the vicinity of 1/4Q ◎←) Mass spectrum <ms> is measured, and each peak observed (Generally, the quality of the ion, 11m, is divided by the number of charges, m
/e) By calculating the corresponding compositional formula, it is possible to estimate the binding mode and ultimately the molecular weight of the sample subjected to measurement. That is, when a sample subjected to measurement is expressed by a general formula, it is generally difficult to observe a molecular ion peak (Mo) corresponding to the molecular weight, but from the molecular ion peak R
A peak corresponding to Mo-R desorbed from O, a peak corresponding to R3Go, R2Go, 'fC, etc. appear.

Furthermore, the peak containing one germanium atom exhibits a characteristic feature of a compound containing a germanium atom with many isotopes.

(c) +3□-nuclear magnetic resonance spectrum (180-nmr
), it is possible to know the number of carbon atoms, the arrangement of carbon chains, and the bonding mode of carbon atoms in the organic germanium compound.

As a representative example, in the above general formula, R is an ethyl group, A is a hydrogen atom, n is 3, and X is a bromine atom. and the chemical shift value of the peak appearing in O-nmr of a germanium compound in which 2 is a hydrogen atom (tetramethylsilane standard, δ, ppm
) The analysis results are as follows.

) Carbon, hydrogen, nitrogen, sulfur atoms, by elemental analysis
The weight percent of oxygen can be calculated by adding the weight percent of halogen atoms and germanium, and subtracting the sum of the weight percent of each recognized element from 100, and therefore the weight percent of the organogermanium compound subjected to measurement. The compositional formula can be determined.

The method for producing the organic germanium compound of the present invention is not particularly limited, and any method may be used. Typical manufacturing methods that are generally suitably used are shown below. That is,
An aminoalkyl (trialkyl) germanium compound represented by the general formula % formula % (wherein R is an alkyl group and n is a positive integer) and a general formula (wherein A is a hydrogen atom or an alkyl group, 1% "N2 is a hydrogen atom, an alkyl group, an alkoxy group, a hydroxy group, a cyan group, a nitro group, an alkylthio group, an alkoxycarbonyl group, a carboxyl group and its salt type group, a sulfonic acid group and its salt type group, di(alkyl)amino or a di(haloalkyl)amine group, in which X and I are substituted on adjacent carbon atoms and may be a single group represented by C.) By doing this, the desired organic germanium compound of the present invention can be obtained in high yield.

The molar ratio of charges in the above reaction is not particularly limited, but it is usually desirable to carry out the molar ratio. In addition, it is preferable to use a reaction solvent in the above reaction, such as benzene,
Solvents that are azeotropic with water, such as toluene, ethanol, and chloroform, are preferably used. The reaction temperature is, for example, -20℃~
Although it can be carried out at 150°C, it is preferably carried out within a suitable temperature range. Although the reaction time varies depending on the reaction temperature, it can generally be selected from several minutes to several days.

In order to promote the dehydration condensation reaction of the above reaction, a means of adding an acid such as acetic acid, formic acid, or BF3.r;t2o to the reaction system is often suitably used. In addition, adding calcium chloride, molecular sheep, etc. as a dehydrating agent into the reaction system is also an effective method.◎ The organic germanium compound of the present invention is a new compound,
When the present inventors conducted a physiological activity test on the compound, it was confirmed that it has a particularly remarkable anticancer effect. That is,
As shown in the examples below, the germanium compound is
It exhibits excellent anticancer effects against Ehrlich ascites carcinoma in mice.

That is, the organic germanium compound of the present invention is an extremely useful compound that can be used as an anticancer agent for the prevention, treatment, or treatment of various cancers.

When the organic germanium compound of the present invention is used as an anticancer agent, it can be administered to a patient either orally, parenterally (for example, intraperitoneally or rectally), or locally. The effective dose varies depending on the age, weight, severity of symptoms, type of cancer, etc. of the patient to whom it is administered, but generally it is 800 to 800 o,
o 02 my/Ky/day, preferably 500-0°0
It can be 111g/Kp 7 days. The daily dose can be administered only once a day or divided into several times (3 to 5 times) a day. It goes without saying that the above-mentioned dosage is merely a guideline, and it is possible to administer doses exceeding the above-mentioned range at the discretion of the treating physician.

When administering the above-mentioned active ingredient, the above-mentioned organic germanium compound should be administered according to the desired administration method (oral, parenteral or topical).
Depending on the K, various dosage forms can be formulated.

For example, for oral administration, it can be formulated into syrups, capsules, etc., for parenteral administration, it can be formulated into suspensions, crude drugs, etc., and for topical administration, it can be formulated into dosage forms such as suspensions and crude drugs. can be formulated into dosage forms such as ointments, plasters, and creams.

The concentration of the active ingredient in these preparations is not particularly limited and can vary widely depending on the dosage form, but is generally 0.05 to 90% by weight, preferably 1 to 6% by weight.
The concentration can be about 0% by weight.

As excipients that can be used in the above preparations, any excipient commonly used in the field can be used; for liquid preparations, for example, physiological saline, surfactant solution, glucose solution, alcohol , esters, etc.

Specific examples of such formulations are as follows.

Production Example 1: Capsule Add 4.5 parts by weight of lactose to 0.6 parts by weight of magnesium stearate, stir and mix to make the mixture more uniform, then add 5 parts by weight of lactose and 10 parts by weight of crystalline cellulose and mix. . Add 20 parts by weight of an organic germanium compound to this mixture and mix again to obtain a prepared liquid. Capsules may be prepared by filling this liquid into gelatin capsules.

Production example 2: Softener stearyl alcohol 10 parts by weight, liquid paraffin 20 parts by weight
After heating and dissolving 160 parts by weight of vaseline at 80°C, Cholesteel O-Q was obtained.

5 parts by weight and 10 parts by weight of the organic germanium compound are added with thorough stirring, and after further stirring, the mixture is allowed to stand at room temperature to obtain an appropriate hardness to obtain a softener.

EXAMPLES In order to explain the present invention more specifically, examples will be described below, but the present invention is not limited to these examples.

Example 1゜r-aminopropyltriethylgermanium (3,78
JF), p-bromobenzaldehyde (3,40t),
Azeotropic dehydration was performed by heating and refluxing a mixture of benzene and benzene (30st/) for 2 hours on an oil bath. After removing the low-boiling components, the residue is vacuum distilled to a boiling point of 15'O
℃/0.15ff17iHg pale yellow transparent liquid (/
i, 22JF) was obtained.

When the infrared absorption spectrum of the compound was measured, as shown in Figure 1 of the attached drawings, it was 2950-2800 crn-
Absorption based on the a-i bond in ', 1640 儂-'Kcn=
Absorption based on a bond, and 1590cWL-”, 14
80 cIIL-'K-based absorption was observed.

When the mass spectrum was measured, I! Peak corresponding to I/e 356-0@H5, m/e 161K (0
1Ej)3Ge''K-corresponding peaks were observed.

A 1m()-nuclear magnetic resonance spectrum (tetramethylsilane standard, δppm) was measured, and the chemical shift values of each peak in the obtained spectrum were analyzed, and the results were as follows.

(129,9) (152,03 Elemental analysis revealed 049.87%, H6,8
9%, N3.79%, Br20.50%, Ge18.9
It shows a value of 6% and the composition formula Of, 8 TIHN nr G
o49,92 which is the calculated value as e(384,91)
%, 116.82%, MS, 64%, Br2Q, 76%
, Ge18.86%.

From the above results, the product is a-(
It was revealed that the product was p-bromophenylmethylidene)-aminoptetrapyrutriethylgermanium.

Example λ δ-aminobutyltriethylgermanium (1,21t
), 2.4-ciprolopenzaldehyde (o, 91
#) and chloroform (20 sl) was heated under reflux on an oil bath for 3 hours to perform azeotropic dehydration from K.

After removing low boiling point components, the residue is vacuum distilled to reduce the boiling point to 1.
60℃10.1WLWL Ilg colorless transparent liquid (1,
44#) was obtained.

When the infrared absorption spectrum of the compound was measured, it was found that 29
Absorption based on O-H bond at 50-2800 CII-', absorption based on 1650 cm+-11c ca=y bond, and 1580.146011! Absorption based on the benzene ring was observed at III=1.

When the mass spectrum was measured, m/*3? OK
Molecular ion (Me) K corresponding peak, m/e360
- Peaks corresponding to t4H6 were observed.

1m (3-nuclear magnetic resonance spectrum (tetramethylsilane standard, δ, ppff') was measured, and the chemical shift values of each peak in the obtained spectrum were analyzed, and the results were as follows.

t a (13Z4), b (135,6), c (1
29,6) a (136,7), e (127,5)
, r (129,6) elemental analysis revealed that 0
52.47%, H7″: 7%, N3.54%, 0t18
．． 01%, G519.10%, and the compositional formula % formula % From the above results, the product is shown by the following structural formula.
It became clear that it was (2,4-dichlorophenylmethyliso/)-δ-aminobutyltriethylgermanium.

L Example Penta-aminoptetrapyrutriethylgermanium (3,06
Add KBIF, -etherate (3 drops), a mixture of p-chloroacetophenone (2°02t), and benzene (5 [1mg)], and heat under reflux on an oil bath for 6 hours to perform azeotropic dehydration. Ta. After removing low boiling point components,
Vacuum distillation of the residual liquid yields a boiling point of 144°C/0.05 WL
A pale yellow viscous liquid (3,09#) of m Hg was obtained.

When the infrared absorption spectrum of the compound was measured, it was found that 29
Absorption based on 0-H bond at 50-2800m-8, 16
Absorption based on 0H=N bond was observed in 30 CIL-'.

When the mass spectrum was measured, a peak corresponding to -OlH5ic at m/@526, m/e 268K M
The 0+AC-nuclear magnetic resonance vector (tetramethylsilane standard) δ5P1)II) in which peaks corresponding to ``-(Ox Hlt)s were observed was measured, and the chemical shift value of each peak in the obtained spectrum was calculated. The analysis revealed the following.

Elemental analysis revealed o57.23%, H7.8
5X, N 5.95%, 0t10.5596', G.

It shows a value of 20.75% and the composition formula C! 17 H2B k
0 which is the calculated value as l OtG@(354,45)
57.59X, 17.98%, N5.95%, 0L10
．． 00%, Go 20.48 XK matched.

From the above results, the product is N-(
It became clear that it was 1-(1)-chlorophenylethylidene)]-]r-aminopropyltriethylgermanium.

B3 Example 4 Various organic germanium compounds were synthesized in the same manner as in Examples 1 to 3. Types of substituents R1A, X, Y, Z and n in the structural formula of the product represented by the following formula
value, as well as the aspect of the nuclear compound, the characteristic absorption value in the infrared absorption spectrum, the chemical shift value in the 11□-nuclear magnetic resonance spectrum (however, the value of the methylene group is omitted because it shows almost the same value), and Elemental analysis values are listed in Table 1.

Example 5 The organogermanium compound synthesized in Example 1 was tested for anticancer activity against Ehrlich's ascites carcinoma in mice.

A sample solution was prepared by suspending a specified amount of the germanium compound in physiological saline (o, as#) containing surfactant Tween 80 to which a small amount of dimethyl sulfoxide was added. The sample solution was intraperitoneally administered into 6 O D Fl mice (female) containing 1×10' Ehrlich cancer cells.
Administered by continuous injection for 9 days. From the results of the 60-day survival effect test, the mean survival days (MST) was determined and T/C+ (%) was calculated by comparing it with the mean survival days of the control group (30 animals). The results are listed in Table 2.

Example 6 Using the organic germanium compounds synthesized in Examples 2.3 and 4, the anticancer activity against Ehrlich's ascites carcinoma in mice was tested in the same manner as in Example 5. The results are listed in Table 3.

':j T'', Mortar Table 3 Example 1 Various organic germanium compounds were synthesized in the same manner as described in Examples 1 to 3, and the results were shown to be effective against Ehrlich ascites carcinoma in mice in the same manner as in Example 5. The anticancer activity was tested. The structural formula, elemental analysis values, and anticancer activity results of the core compound are listed in Table 4.

X1゛・桿1)

[Brief explanation of the drawing]

FIG. 1 of the accompanying drawings is a chart of the infrared absorption spectrum of N-(p-bromophenylmethylidene)-γ-aminopropyltriethylgermanium obtained in Example 1. Patent applicant Tokuyama Soda Co., Ltd.

Claims (1)

[Claims] is a hydrogen atom or an alkyl group: X,! and 2 are the same or different hydrogen atoms, hydrogen atoms, alkyl groups,
Alkoxy group, human tetraxy group, cyano group, 2) a group,
An alkylthio group, an alkoxycarbonyl group, a carboxyl group and its salt type group, a sulfonic acid group and its salt type group, a di(alkyl)amino group, or a di()-roalkyl)amine group, where X and I also include adjacent carbon atoms. good. ) An organic germanium compound represented by (However, R is an alkyl group; n is a positive integer; A is a hydrogen atom or an alkyl group; z, , x and 2 are the same or different hydrogen atoms, ha, a rogen atom, an alkyl group, an alkoxy group, a human X and An anticancer agent containing an organic germanium compound as an active ingredient.