JPH0130827B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new and useful oxazolium compound and a cosmetic containing the compound. In this family of compounds, 2-anilinovinyl-
3,4-Dimethyloxazolium iodide has excellent effects such as enhancing skin function, improving light keratosis skin diseases, and nourishing hair. This is a compound listed on page 25 of the Cosmetic Raw Materials Standards 1st Edition (Yakuji Nipposha, 1962). The present inventors previously synthesized a 2-(2-alkyl anion) vinyl-3,4-dimethyloxazolium compound as an improved compound of this compound (Japanese Patent No. 903362). This product had biological effects equivalent to those of Photosensor No. 401, and had favorable physical properties, particularly excellent stability. However, it was pointed out that it was inferior in safety to Kosenshi No. 401, and after that, we continued to synthesize compounds of this type with various substituents, and as a result of various studies, we decided to add an alkoxycarbonyl group to the para position of the phenyl group. The present invention was completed based on the discovery that the new compound has low toxicity, excellent stability, and is an excellent skin physiologically active substance. Compound (1) of the present invention is a new substance that has not been described in any literature and is represented by the following general formula. In the above formula, R ₁ and R ₂ represent the same or different lower alkyl groups, R ₃ represents an alkyl group having 1 to 4 carbon atoms, and X represents an anion. Examples of the novel oxazolium compounds of the present invention include the following. Compound (A) 2-[N-methyl-4-ethoxycarbonylanilino) vinyl] -3,4-dimethyloxazolium iodide compound (B) 2-[(N-methyl-4-ethoxycarbonylanilino) Vinyl] -3-ethyl-4-methyloxazolium iodide compound (C) 2-[(N-ethyl-4-ethoxycarbonylanilino)vinyl] -3,4-dimethyloxazolium iodide compound (D ) 2-[(N-methyl-4-butoxycarbonylanilino)vinyl] -3,4-dimethyloxazolium iodide compound (E) 2-[(N-methyl-4-ethoxycarbonylanilino)vinyl] -3,4-Dimethyloxazolium paratoluenesulfonate Compound (1) of the present invention can be synthesized by various conventionally known methods, but the following method is particularly preferred. That is, 3-alkyl-2,4-dimethyloxazolium compound () (Symbols are the same as above) and 4-alkoxycarbonyl-N-alkylaniline () (Symbols are the same as those above) are synthesized by overheating reaction with orthoformic acid ester without a solvent or in a solvent such as alcohol. The compound of the present invention () is also a 2-[N-acetylanilinovyl]-3-alkyl-4-methyloxazolium compound () (The symbol is the same as the previous one) It can also be obtained by the reaction of and (). The compound of the present invention () is also 2-[(4-alkoxycarbonylphenylamido)ethylidene]-
3-Alkyl-4-methyloxazoline () (symbols are the same as above) and alkylating agents such as alkyl halides, alkyl para-toluene sulfonates, dialkyl sulfuric acids, etc. Next, examples of the present invention will be shown. Example 1 2-[(N-methyl-4-ethoxycarbonylanilino)vinyl]-3,4-dimethyloxazolium iodide (Compound A) is described. 2-[(4-ethoxycarbonylanilino)
Vinyl] - 22.9g of 3,4-dimethyloxazolium iodide and 100ml of dimethylformamide
Add 70 ml of 5% aqueous sodium hydroxide solution to thoroughly permeate the separatory funnel, add water and suction-filter the resulting crystals to obtain 2-[(4-ethoxycarbonylphenylamide)ethylidene]-3,4. -dimethyl-4-oxazoline () is obtained. When dissolved in 10 times the amount of acetone, added 2 equivalents of iodomethyl, and heated on a hot water bath, the target substance crystallized out. After cooling, it is suction filtered and recrystallized from ethanol to obtain a pale yellow crystalline powder with a melting point of 176° and a maximum absorption of 357 mm (in methanol). Yield 74.7%. Examples 2 to 5 The compounds shown in Table 1 were obtained in the same manner as in Example 1.

[Table] Next, the effects of the compounds of the present invention on mouse skin will be described. Experimental Example 1 A shaved area with a diameter of 3 cm was made on the backs of 12 white mongrel mice weighing around 20 g, and the areas were treated with Compound A or C of the present invention.
was dissolved in distilled water and subcutaneously injected for 5 hours every day for 6 days (group 1), and a control group left for 6 days (group 2). Observation of the state of hair growth in the shaved area and histopathological examination of the skin. I went to As a result, as shown in Table 2, a marked tendency to promote hair growth was observed in the shaved areas of the first group compared to the second group, and histopathological examination also revealed that the proliferation of hair matrix cells and hair growth were significantly promoted. Ball enlargement is seen,
The hair growth promoting effect of the compound of the present invention was observed. Compound C was better than Compound A in this effect. Furthermore, no side effects such as skin irritation due to drug administration were observed.

【table】

[Table] Experimental Example 2 A group in which bergamot oil was applied to the shaved area of 18 mice in the same manner as in Experimental Example 1 every day for two weeks, and then the compound A or C of the present invention was injected subcutaneously for 5 hours every day for six days ( Macroscopic observation and histopathological examination of the skin were performed on the 3rd group) and the control group (4th group) left for 6 days. As a result, as shown in Table 3, in Group 4, the skin remained significantly flushed and no hair regrowth was observed, and histopathologically, there was strong infiltration of inflammatory cells. In the third group, there was almost no flushing and considerable hair growth was observed, the infiltration of inflammatory cells was generally mild, and the symptoms of keratosis were also mild. Furthermore, the compound of the present invention was found to have a soothing effect on experimental dermatitis, as evidenced by the active proliferation of hair matrix cells, supporting the apparent promotion of hair growth. Furthermore, in terms of the effect of the compound, A was better than C.

[Table] Next, we will discuss toxicity. Table 4 shows the results of calculating the 48-hour oral acute toxicity of the compounds shown in Table 1 to mice using the Vau der Waerder area method.

[Table] Experimental materials for acute toxicity tests of Photosensor No. 401 and its derivatives Experimental Animals AKR strain male mice, 5 weeks old, were used. The number of animals per group was 8 to 10. Experimental method Three materials were mixed with 0.5% CMC and adjusted to a predetermined concentration, and administered intraperitoneally and orally. The experiment was conducted for 3 days (intraperitoneal administration) and 7 days (oral administration) after administration, and observations of general symptoms,
Autopsy was performed on the deceased cases, and the major organs were fixed with 10% formalin and embedded in paraffin, and HE-stained tissue specimens were prepared for histopathological examination. The LD ₅₀ value was calculated by the Vau der Waerder method. Experimental results Intraperitoneal administration Clinical symptoms NK355, NK2013, NK2512 in mice
A similar course of symptoms was seen after administration for all three items. Symptoms such as decreased spontaneous movement, accelerated breathing, and piloerection were observed 30 minutes to 1 hour after administration. In the case of death, death occurred due to respiratory arrest following dyspnea and clonic convulsions. In the low-dose group, these symptoms disappeared and recovered over time. The number of deaths and time of death after administration are as shown in Table 5, and the LD ₅₀ value is NK355;
255.5±12.5mg/Kg NK2013: 26.9±1.5mg/Kg, and the compound of the present invention NK2512: 280±14mg/Kg.

【table】

[Table] Histopathological findings No notable changes were observed in the necropsies of the dead and surviving animals for all three items. In addition, histological searches include liver, kidney, spleen, heart,
We covered the lungs, brain, and reproductive organs. Mild renal tubular epithelial degeneration was observed in the kidneys, but no significant changes were observed in other organs. Therefore, it is a patent No. 903362 compound.
NK2013 is more toxic than Photosensor No. 401 (NK355), and the compound of the present invention, NK2512, is more toxic than Photosensor No. 401 (NK355).
Similar to No. 2, it is a highly safe compound with low toxicity. In the case of oral administration Next, the LD ₅₀ values of Photosensor No. 401 (NK355) and the compound of the present invention, NK2512, were determined by oral administration. As a result, as shown in Table 6, no deaths were observed in NK2512 even at the maximum dose (5.75 g/Kg). Based on the results of the above toxicity tests, the compound of the present invention
NK2512 is extremely safe and is excellent as a cosmetic.

[Table] As is clear from the above results, the compound of the present invention exhibited hair growth promoting effects, skin function enhancing effects, anti-inflammatory effects, etc. when administered in small amounts, and was found to have extremely low toxicity. Next, we conducted a comparative experiment on stability, which is another important factor for cosmetic formulations, between Photosensor No. 401 (NK355), which has already been incorporated into cosmetics, and NK2512, the compound of the present invention. Experimental method: Take 5mg of each of the two items and add Michaelis Buffer.
(Mixture of M/30KH ₂ PO ₄ and M/30Na ₂ HPO ₄ ) 100
ml and store at 40°C. At the time of measurement, take 2 ml of the test solution, add 80% methanol to make a total volume of 25 ml, and measure each absorption maximum wavelength (NK355; 363 nm,
Absorbance was measured using NK2512 (358 nm). The absorbance at 0 hours was set as 100%, and subsequent changes over time were investigated. Note that NK2013, a compound of patent No. 903362, was excluded from this experiment because it was highly toxic. The experimental results are shown in Figure 1. The fading of the second item follows a first-order coagulation reaction. In this experiment, we obtained results with significantly improved stability in NK2512. For cosmetics, 40℃, 90
70% stability is required. The compound of the present invention, NK2512, completely satisfies this requirement. This shows that the compound of the present invention is a suitable skin physiologically active substance for the purpose of preventing rough skin, skin fatigue, hair loss, etc., treating chilblains, alopecia, and anti-inflammation, and can be sufficiently used by incorporating it into cosmetics. shown. The amount of the compound of the present invention can vary over a wide range depending on the effect of the compound itself, the dosage form of the product, its use, etc., but it is preferably about 0.01 to 0.001% for cosmetic applications. As the base used, any conventionally known base can be advantageously used. In addition, various dosage forms such as a spray agent, coating agent, wiper, etc. are possible. Next, a formulation example of the compound of the present invention will be shown. This is merely an illustration of a preferred embodiment. Therefore, the present invention is not limited to these formulation examples. Prescription example 1 (Hair tonic) Ethanol 70.0 parts Glycerin 5.0 Salicylic acid 0.3 Catiolene activator 1.0 Menthol 1.0 Compound (A) 0.002 Purified water 22.0 Fragrance Appropriate amount Prescription example 2 (Hair cream) Liquid paraffin 50.0 parts Beeswax 1.0 Stearic acid 3.0 Solpitan sesquiolate 2.2 Sorpitan monolaurate 1.8 Compound (B) 0.002 Purified water 42.0 Fragrance Appropriate amount Preservative Appropriate amount Prescription example 3 (Lotion) (A) Lanolin 1.0 parts Propylene glycol monostearate 4.0 Cholesterin higher fatty acid ester 7.0 (B) Propylene glycol 3.0 Compound (C) 0.002 Purified water 85.0 Fragrance Appropriate amount Preservative Appropriate amount Mix (A) and (B) to make a lotion. Prescription example 4 (Cream) (A) Beeswax 2.5 parts Spell wax 3.0 Liquid paraffin 30.0 Monoglyceride 12.0 Propylparapen 0.15 (B) Glycerol 7.0 Methylparapen 0.15 Compound (D) 0.002 Purified water 44.4 Fragrance Appropriate amounts (A) and (B) are mixed together. Make a cream. Prescription example 5 (Lotion) Ethyl alcohol 10.0 parts Propylene glycol 5.0 Oleyl alcohol 0.1 Polyoxyethylene sorbitan monolaurate
1.2 Compound (E) 0.002 Purified water 83.5 Antioxidant, fragrance, preservative Appropriate amount Prescription example 6 (Ointment) Polyethylene glycol 400 40.0 parts Polyethylene glycol 4000 43.95 Compound (A) 0.1 Glycerin 10 Lecithin 2 Emulgen 106 2 Fragrance Appropriate amount

Claims (1)

[Claims] 1 General formula (1) (In the formula, R ₁ and R ₂ represent the same or different lower alkyl groups, R ₃ represents an alkyl group having 1 to 4 carbon atoms, and X represents an anion.) 2 General formula (1) (In the formula, R ₁ and R ₂ represent the same or different lower alkyl groups, R ₃ represents an alkyl group having 1 to 4 carbon atoms, and X represents an anion.) Or cosmetics containing two or more types.