JPS6328070B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel method for producing organic germanium and an external preparation for skin containing the same. In recent years, it has become known that organic germanium has various pharmacological effects. In other words, Tokkosho
46-2964, bis-β-ethylcarboxylic acid germanium sesquioxide or bis-β-ethylcarboxylic acid amide germanium sesquioxide is said to have the effect of suppressing the proliferation of Ehrlitsu ascites cancer cells, and in JP-A-52-51327, 3-
Salts of trihydroxygermylpropionic acid have been disclosed to have a wide range of medicinal effects. Although the usefulness of organic germanium has been shown to be clear in this way, all of these substances use trihalogenated germane, particularly trichlorogermane, as a starting material. This starting material is not currently widely used industrially, so obtaining it requires passing hydrogen chloride through metal germanium under a copper catalyst at high temperatures and various other complicated methods. This leads to the high price of the organic germanium obtained, which has an undesirable effect on practical aspects. Moreover, in the case of the above patent, when reacting trichlorogermane and acrylic acid, an ethyl ether solution, which is often dangerous, is used.
It is difficult to call it industrial as it needs to be carried out at a low temperature of 30°C. Furthermore, the production method disclosed in Japanese Patent Publication No. 46-2964 has a low yield and is not economical as the production process is relatively long. Furthermore, most of the organic germaniums that have been discovered so far and are used in the medical field are water-soluble compounds, and it can be said that there is no oil-soluble organic germanium that is effective and safe for living organisms. . As a result of intensive research, the present inventors have finally completed the desired invention. One of the objects of the present invention is to provide an organic germanium compound, particularly an oil-soluble organic germanium compound, which can be put to practical use. Another object of the present invention is to provide a simple and high-yield method for producing organic germanium compounds. A further object of the present invention is to provide an external skin preparation containing the above-mentioned organic germanium compound and effective for skin beauty. The organogermanium compound according to the present invention is produced by reacting tetrahalogenated germanium and trihalogenated silane in the presence of an organic base to form an organic salt of trihalogenated germane, and then α,β-
The formula obtained by reacting an unsaturated acid ester or an α,β-unsaturated acid amide derivative and then hydrolyzing it. (In the formula, X represents OR ₁ or NHR ₁ , R ₁ , R ₂ ,
When R ₃ are all hydrogen atoms and R ₁ in OR ₁
When X is OR ₁ , except when is a saturated linear alcohol residue having 1 to 12 carbon atoms.
R ₁ is selected from saturated straight chain, saturated branched, unsaturated straight chain, unsaturated branched or cyclic alcohol residue;
When X is NHR ₁ , R ₁ is selected from a hydrogen atom or a saturated straight chain, saturated branched, unsaturated straight chain, unsaturated branched or cyclic amine residue, common to
R ₂ and R ₃ represent a hydrogen atom or an alkyl group. ) is an organic germanium compound represented by When obtaining the above-mentioned organic germanium compound, the halogen of the starting materials tetrahalogenated germanium and trihalogenated silane may be fluorine, chlorine, bromine, iodine, etc., but is preferably chlorine, and other halogens in the reaction. Regarding the substances used, the organic bases include primary to tertiary organic bases, preferably tertiary organic bases,
α,β-Unsaturated acid esters include saturated linear alcohols (excluding those with alcohol residues having 1 to 12 carbon atoms), saturated branched alcohols, unsaturated linear alcohols, unsaturated branched alcohols, Cyclic alcohol and α, β of acrylic acid, methacrylic acid, crotonic acid, 2,3-dimethylacrylic acid, etc.
- ester with unsaturated acid, preferably carbon number
It has 14 to 32 alcohol residues. Further, α,β-unsaturated acid amide derivatives include saturated linear amines, saturated branched amines, unsaturated linear amines, amides of unsaturated branched amines or cyclic amines with the above α,β-unsaturated acids. and preferably has an amine residue having 1 to 32 carbon atoms. Next, the method for producing the organic germanium compound of the present invention will be described in detail. (Production method) Tetrahalogenated germanium such as tetrachlorogermanium and trihalogenated silane such as trichlorosilane are mixed with benzene and
Organic bases such as triethylamine, pyridine, picoline, dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, propylamine, etc. are particularly preferably added while mixing and stirring with or without an inert solvent such as toluene or xylene. Triethylamine is added dropwise to cause a reaction, and then it is distilled at room temperature to dropwise temperature to remove unreacted trihalogenated silane and by-products to obtain an organic salt of trihalogenated germane as a residue. α,β-unsaturated acid esters, preferably acrylic acid alkyl esters or α,β-unsaturated acids, including acrylic esters, in the presence of a suitable anhydrous solvent such as dioxane, dimethylsulfoxide, dimethylfuran, tetrahydrofuran, etc. Amide derivative If necessary, add an appropriately selected organic acid such as formic acid, acetic acid, propionic acid, etc., stir at room temperature or heat under reflux to react, and then distill off the solvent (if necessary).
After that, various aqueous solutions such as water, alcohol aqueous solution, alkaline aqueous solution, etc. are added for hydrolysis, preferably 70% alcohol aqueous solution, and then neutralized with an alkali such as sodium hydrogen carbonate, caustic soda, potassium carbonate, etc., solvent extraction is performed, and washing is performed with water. , the solvent is distilled off and, if necessary, dried to obtain the desired organic germanium compound. An example of the above production method is summarized as follows using a reaction formula. *R in the above reaction formula represents a saturated linear chain, saturated branched chain, unsaturated linear chain, unsaturated branched chain, or cyclic alcohol residue. Specific examples of organic germanium obtained by the production method of the present invention include bis-β-propionic acid 2
-Octyldodecylgermanium sesquioxide (colorless viscous liquid), bis-β-propionate isolaxerylgermanium sesquioxide (same as above), bis-β-propionate oleylgermanium sesquioxide (white solid, mp300℃ or higher), bis- β-propionic acid 2-hesisal 2-
Tetradeceryl germanium sesquioxide (colorless viscous liquid), bis-β-propionate cholesteryl germanium sesquioxide (white solid, mp300℃ or higher), bis-β-(3-methyl)
2-Octyldodecylgermanium sesquioxide propionate (colorless viscous liquid), bis-β-
(2,3-methyl)propionate oleylgermanium sesquioxide (white solid, mp300℃
above), bis-β-(2-methyl)propionic acid 2
-ethyl 2-butenyl germanium sesquioxide (same as above), bis-β-(2-methyl)propionate cholesteryl germanium sesquioxide (same as above), bis-β-(N-stearyl)propionamide germanium sesquioxide (same as above),
Bis-β-(N-2-hexyldecyl)propionamide germanium sesquioxide (colorless viscous liquid) and the like. The obtained organic germanium compound is based on literature reports on conventionally known compounds (JACS, 98
8287 (1976)), it is considered to be a sheet-like compound in which a germylpropionic acid derivative and an oxygen atom are bonded in a ratio of 2:3. The organic germanium obtained as described above has conventionally known pharmacological effects, such as improvement of various intractable diseases such as visceral cancer, leukemia, liver dysfunction, hypertension, and menopausal disorders, psoriasis vulgaris, and psoriasis vulgaris.
Not only can it be used to treat skin diseases such as acne and hyperpigmentation, to prevent and improve skin tone and fine lines, and to have a whitening effect, but it also has anti-inflammatory and skin irritation-inhibiting effects. It can be used even if it is exposed. Other uses include various health foods, feeds, plant growth promoters, herbicides, toothpastes to prevent cavities, oral preparations, and many others. In addition, the organic germanium of the present invention is widely used as a starting material, such as tetrachlorogermanium, in the production of high-purity germanium, which is widely used as rectifiers and detectors using its semiconductor properties, and is therefore easily available. It can be used effectively. Moreover, the organic germanium obtained by the production method of the present invention has a yield of almost 80%.
As described above, this product has significantly improved quality characteristics. Furthermore, the production method of the present invention does not use ethyl ether and can be produced at around 0°C or at room temperature, resulting in markedly improved industrial efficiency. Furthermore, the organic germanium of the present invention is bis-
β-propionic acid 2-hexyldecyl germanium sesquioxide, bis-β-propionic acid 2
-heptyl undecyl germanium sesquioxide, bis-β-propionic acid 2-octyldodecyl germanium sesquioxide, bis-β-
2-hexyl propionate 2-tetradeceryl germanium sesquioxide, bis-β-(N-
If it is oil-soluble, such as 2-hexyldecyl) propionamide germanium sesquioxide, it goes without saying that it is compatible with various oils in any ratio, and oil-based products that have traditionally been difficult to blend effectively. It can be used for In particular, when the organic germanium of the present invention has a branched chain in its structure, the oil solubility increases as the number of carbon atoms increases. (Conspicuous when the number of carbon atoms is 14 or more) Next, Table 1 shows the solubility test results that demonstrated that the organic germanium of the present invention dissolves easily in various oils. The test method involved placing approximately 2 g of water and an oil such as liquid paraffin, olive oil, squalane, IPM (isopropyl myristate), or MOD (2-octyldodecyl myristate) in six stoppered test tubes. Conventional water-soluble organic germanium bis-β-propionate germanium sesquioxide (a) and β-trihydroxygermylpropionate sodium salt
(b) Approximately 2 g of samples of organic germanium (c) to (k) obtained in the present invention were individually added in small portions with stirring, and the solubility was observed with the naked eye after 1, 3, and 7 days. Summer. ◎Easily soluble 〇Dissolved △Partially dissolved ×Insoluble

【table】

[Animal test]

One shaved white Angora rabbit, male and female.
Six rabbits were divided into four groups, and one side of the rabbit's back skin was treated as damaged skin and the other as normal skin, and 0.1 g of the above specimen was administered for 3 days. From the first day after administration, observation of erythema and edema was started. It lasted until the fourth day.
The total score for each stimulus item was calculated. The results are shown in Table-2. [Human body patch test] Nitto Denko's characteristic patch test bandage containing 0.05g of the above sample was applied in a sealed manner to the backs of 52 healthy subjects. After 24 hours, the bandage was replaced. After 48 hours, the bandage was removed, and after 30 minutes, the bandage was applied to the skin. The reaction was observed. Judgment = Positive person/Executive person Judgment results are shown in Table 3.

[Table] 〓
〓 〃 2~5; Moderate irritation

[Table] From Tables 2 and 3, compounds [B] to [E] were found to have an irritation-suppressing effect, and the degree of irritation was found to be [B] to [E].
It is clear that very little is observed between the compounds [E]. The acute toxicity of various organic germanium compounds such as bis-β-propionate germanium sesquioxide and other organic germanium compounds used in the external skin preparation of the present invention is 10 g/Kg or more in both sexes, and oral toxicity for 6 months. In chronic toxicity tests, the dosage is 50mg/Kg per day.
No abnormalities were observed in general conditions, body weight changes, blood, organ weights, or various functional tests within the 1000 mg/Kg range, and all test animals survived during the experiment period. In addition, when the local irritation potential of these compounds was investigated using the Draize method using rabbits, it was found that the local irritation potential ranged from 0.1 to
No skin irritation such as erythema, edema, or hyperemia was observed in the 10% range, and no local irritation was confirmed in human patch tests at concentrations below 10%. In addition, a total of 50 people including 45 general women and 5 professional panelists were tested using external skin preparations (cosmetic creams) containing various organic germaniums according to the present invention and conventional skin preparations (cosmetic creams) that did not contain any organic germanium. Table 4 shows the results of a 30-day usage test. The evaluation items were A: Improvement of pigmentation (spots), B: Color gloss, and C: Prevention of fine lines.

[Table] Z: Average From the above evaluation results, it can be said that the skin external preparation (cosmetic cream) of the present invention is significantly superior to conventional products in all evaluation items A, B, and C. Examples of the skin external preparation of the present invention are shown below. The content ratio is in weight percent. Example 5 Skin cream (for acne) (A) Squalane 10.0 Bis-β-propionic acid 2-octyldodecylgermanium sesquioxide 1.0 Vaseline 9.0 Beeswax 3.0 Microwax 9.0 spermaceti wax 3.0 IPM 12.0 Polyoxyethylene monostearate 4.6 Sorbitan monostearate 5.0 (B) Propylene glycol 10.0 Distilled water 33.4 (C) Fragrance/preservative Appropriate amount Production method: Heat emulsify oil layer A and water layer B to 80℃, add C during cooling and mix 30 Cool to ℃ and use as a product. Example 6 Scalp treatment lotion (A) Liquid paraffin 40.8 Bis-β-propionic acid 2-hexyldecyl germanium sesquioxide 0.5 Dehydrated lanolin 0.5 Sorbitan monooleate 5.0 (B) Salicylic acid 0.1 Propylene glycol 2.0 Distilled water 51.0 (C) L-menthol 0.1 Fragrance Appropriate amount Manufacturing method: Product made in the same manner as Example 7 Example 7 Oil-in-water emulsion (A) spermaceti 2.0 Vaseline 2.5 Bis-β-propionate 2-ethylhexyl germanium sesquioxide 0.5 Setanol 1.0 Squalane 9.5 Polyoxyethylene monostearate 2.6 Sorbitan monooleate 1.4 (B) Propylene glycol 3.0 1% Carbopol 934 10.0 1% triethanolamine 2.5 Water 65.0 (C) Fragrance/preservative appropriate amount Production method: Same as Example 5 Example as a product 8 Foundation (A) Stearic acid 3.0 Setanol 1.0 Bis-β-propionate 2-ethylhexylgermanium sesquioxide 0.01 Squalane 9.5 Polyoxyethylene stearate 3.0 Glyceryl monostearate 3.0 Pigment 10.0 (B) Propylene glycol 10.0 Triethanolamine 0.4 Distilled water 60.0 (C) Fragrance/preservative Appropriate amount Manufacturing method: Example 9 Product made in the same manner as Example 5 9 Face powder kaolin 6.0 Magnesium carbonate 4.0 Zinc stearate 3.0 Talc 85.0 Myristyl myristate 1.0 Bis- β-propionic acid 2-octyldodecylgermanium sesquioxide 1.0 Fragrance/pigment Appropriate amount Production method: Examples of mixing and pulverizing each component to make a product 10 Lipstick Carnauba wax 8.0 Parafine wax 7.0 Ozokerite 7.0 Lanolin 5.5 Bis-β- Cetyl germanium propionate sesquioxide 0.5 Castor oil 30.0 Squalane 35.0 Pigment 7.0 Fragrance/preservative Appropriate amount Manufacturing method: Add each ingredient, heat to 80-85℃, mix with stirring, and mold with a lipstick molder to form the product. do.

[Brief explanation of the drawing]

FIGS. 1 and 2 are infrared absorption charts of the organic germanium compounds of the present invention, bis-β-propionate 2-octyldodecylgermanium sesquioxide and bis-β-propionate isolaxeryl germanium sesquioxide, respectively.

Claims (1)

[Claims] 1 formula (In the formula, X represents OR ₁ or NHR ₁ , R ₁ , R ₂ ,
When R ₃ are all hydrogen atoms and R ₁ in OR ₁
X is a saturated straight chain alcohol residue having 1 to 12 carbon atoms and a saturated branched alcohol residue having 3 or less carbon atoms.
When OR ₁ , R ₁ is selected from saturated straight chain, saturated branched, unsaturated straight chain, unsaturated branched or cyclic alcohol residue, and when X is NHR ₁ , R ₁ is a hydrogen atom or saturated straight chain, saturated branched, selected from unsaturated straight chain, unsaturated branched or cyclic amine residues, and R ₂ and R ₃ each represent a hydrogen atom or an alkyl group. ) An organic germanium compound represented by 2. Tetrahalogenated germanium and trihalogenated silane are reacted in the presence of an organic base to form an organic salt of trihalogenated germane, and then α,β-unsaturated acid ester or α,β-unsaturated acid amide derivative is reacted. A formula characterized by reacting and then hydrolyzing it (In the formula, X represents OR ₁ or NHR ₁ , R ₁ , R ₂ ,
When R ₃ are all hydrogen atoms and R ₁ in OR ₁
X is a saturated straight chain alcohol residue having 1 to 12 carbon atoms and a saturated branched alcohol residue having 3 or less carbon atoms.
When OR ₁ , R ₁ is selected from saturated straight chain, saturated branched, unsaturated straight chain, unsaturated branched or cyclic alcohol residue, and when X is NHR ₁ , R ₁ is a hydrogen atom or saturated straight chain, saturated branched, selected from unsaturated straight chain, unsaturated branched or cyclic amine residues, and R ₂ and R ₃ each represent a hydrogen atom or an alkyl group. ) A method for producing an organic germanium compound. 3 formulas (In the formula, X represents OR ₁ or NHR ₁ , R ₁ , R ₂ ,
When R ₃ are all hydrogen atoms and R ₁ in OR ₁
X is a saturated straight chain alcohol residue having 1 to 12 carbon atoms and a saturated branched alcohol residue having 3 or less carbon atoms.
When OR ₁ , R ₁ is selected from saturated straight chain, saturated branched, unsaturated straight chain, unsaturated branched or cyclic alcohol residue, and when X is NHR ₁ , R ₁ is a hydrogen atom or saturated straight chain, saturated branched, selected from unsaturated straight chain, unsaturated branched or cyclic amine residues, and R ₂ and R ₃ each represent a hydrogen atom or an alkyl group. ) An external preparation for skin, characterized by containing an organic germanium compound represented by: