JPS58225059A - Pantethine tetraoctanoyl ester compound and skin quality improving agent containing said pantethine tetraoctanoyl ester compound - Google Patents

Abstract

NEW MATERIAL:A pantethine tetraoctanoyl ester compound of the formula (R is 8C straight chain acyl). USE:A skin quality improving agent, capable of improving the abnormality in lipid metabolism, e.g. the skin roughness or chapped skin, etc. and effective for improving fine wrinkles, texture of the skin, tensity and chromatosis, etc., and stable to heat and light without causing changes with time, e.g. discoloration, change in smell, decomposition, inactivation, etc. even in formulating as a pharmaceutical, nor toxicity or skin disorder. PROCESS:Pantethine is reacted with octylic acid chloride in a solvent, e.g. quinoline, pyridine or dimethylformamide, in the presence of a base, e.g. triethylamine, to give the compound of the formula. In case a basic solvent, e.g. the pyridine or quinoline, is used, the reaction is carried out in the absence of the base. The amount of the octylic acid chloride to be used is 4.4-6.9 equivalents based on one equivalent pantethine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pantethine tetraoctanoyl ester compound and a skin quality improving agent containing the same.

General K. Abnormalities in the skin, especially abnormalities in the lipid glands, are thought to be caused by dysfunction in the sebaceous glands, and may appear as dry skin symptoms such as rough skin or chapped skin, or vice versa. Symptoms such as acne formation due to excessive sebum secretion are observed. Other skin abnormalities include hyperpigmentation, such as age spots, freckles, and dark skin.

Conventionally, placenta preparations and vitamins have been mainly used as substances to normalize the skin by dealing with rough skin and rough skin, but they have not been sufficiently effective in an essential sense. Other methods include the use of male hormones, but excessive use of these can alter the balance of sebum secretion and may even interfere with normal metabolism. Furthermore, the use of female hormones can be considered to treat excessive sebum shunts, but in contrast to male hormones, dryness symptoms tend to become excessively evident, so neither method is satisfactory.

Therefore, the present inventors have found that it is possible to adjust lipid metabolism in the skin according to the aspect of symptoms, and to improve changes caused by abnormalities in lipid metabolism such as rough skin, chapped skin, and excessive sebum secretion, as well as to improve pigmentation and other disorders. In order to develop a new substance that is effective for skin abnormalities, as a result of intensive research, we synthesized a new ξ-ntetine tetraoctanoyl heptester compound, and further added this as an essential compound to a skin quality improving agent. As a result, the present invention was completed.

The present invention includes a novel pantethine tetraoctanoyl ester compound and a pantethine tetraoctanoyl ester compound represented by the general formula (1) (in which R represents a straight chain acyl group having 8 carbon atoms) as essential components. The present invention relates to a skin quality improving agent characterized by the following.

The novel tl-ntetine tetraoctanoyl ester compound of the present invention is extremely stable against heat and light, and does not undergo changes over time such as discoloration, odor, or decomposition and inactivation even when made into a preparation, and can be used for various external purposes. It is extremely advantageous in that it can be easily blended into the base. Furthermore, there is no concern about toxicity or skin damage, and it can be used safely.

The method for producing the pantethine tetraoctanoyl ester compound of the present invention involves dissolving pantethine in a polar solvent such as quinoline, pyridine, dimethylformamide (DMF), dimethyl sulfoxide (DM80), or hexamethylphosphotriamide (HM9Tt). The most common method is to carry out an esterification reaction with octylic acid chloride in the presence of a base such as triethylamine (however, when using a basic solvent such as pyridine or quinoline) (acid chloride method), but other It can also be synthesized by the dicyclohexylcarbodiimide method (DCC method). When using the acid chloride method, nonantechin can be dissolved in a solvent that has a deoxidizing effect (e.g. pyridine, quinoline, etc.), or in a polar solvent containing a base such as triethylamine (
(For example, DMF% DMSO, HMPT, etc.) and reacted with octylic acid chloride to obtain the desired esterified product. As a cover for octylic acid chloride, it is preferable to use 4.4 to 6.0 equivalents per 1 equivalent of ζntetine. The reaction is initially carried out under cooling to suppress side reactions, and then the temperature is raised to room temperature to complete the reaction. Purification is carried out by conventional methods such as column chromatography. Examples of synthesis of the compounds of the present invention are shown below.

Synthesis Example 1 Pantethine tetraoctanoyl ester/ζ
Ntete 755.5F (0.1 mol) in pyridine 50
Octylic acid chloride 81 was dissolved in 011It and cooled with water.
．． 3 t (0.5 mol) was gradually added dropwise. After the dropwise addition was completed, the mixture was further stirred at room temperature for 3 hours to complete the reaction. After the reaction was completed, pyridine was removed under reduced pressure, and then 1 t of ethyl acetate and 1 t of water were added to the residue for extraction. The ethyl acetate layer was taken out, and ethyl acetate was distilled off under reduced pressure to obtain a crude product.

Furthermore, the obtained crude product was purified using a silica gel column.
The reaction mixture was developed using a mixed solvent of n-hexane:ethanol=9=1 to obtain the desired tetraoctanoylpantethine.

The substance was a viscous liquid.

Yield jjk74.2t (yield 70%) Elemental analysis value CHN S Experimental value 61.16 9.41 5,16 5.99 Theoretical value 61.20 9.26 5.28 6.04 Infrared absorption (Fig. 1 Reference) 3600 sub-I
CO-Sad stretching vibration 2950~2850c
m-10-H stretching vibration 1740 cm-'
-C-0-Stretching vibration 1660 strokes 1-
C-NH-Stretching vibration 1240-1160cm'
-C-0- (knee stretching vibration NMRδ value (CDCl3
, TMS standard) 3.6 (C0NHC), 2.9
(-〇±-5-s-c blood-).

2.4 (-CH2CO-), 1.3-0.9 (-C
H2-(!H5) Next, an evaluation regarding the stability of nonξntetine tetraoctanoyl ester obtained by the present invention will be shown in comparison with vitamin C.

Test Example: Heat of ζntetine tetraoctanoyl ester 95 cetanol solution and 1 volume of vitamin C 95% ethanol,
Stability tests against light and changes over time were conducted.

The test methods were as shown in (a) to (C) below, and the sample used was a 95% ethanol solution containing 1 part each of pantethine tetraoctanoyl ester and vitamin C.

(a) Thermal stability = left at 80°C for 3 hours (b) Photostability: irradiated with sunlight for 3 days (C) Stability over time: 4
Cutanoyl ester left at 0°C for 6 months has better stability than vitamin C in all respects, and is expected to be effective as a preparation.

1st Tablet 1 TOP: Zentetin Tetraoctanoyl Ester Meal 2 Vc: Vitamin C Residual Rate: ◎: 90+ ○: 80-90+ Δ: 60-
80 x: Less than 60 x Odor: None Odor: Slightly +: Yes Next, a skin quality improving agent containing the novel pantethine tetraoctanoyl ester compound of the present invention as an essential ingredient will be described.

According to the present invention, the novel pantethine tetraoctanoyl ester is used in the form of creams, lotions, powders, ointments, etc. together with excipients, diluents, adjuvants, etc. These cosmetics and pharmaceutical preparations can be manufactured by conventional methods.

The content of pantethine tetraoctanoyl ester contained in the skin quality improving agent of the present invention is usually 0.01 to 511 L!
%, preferably 01-1% by weight. 0.01% by weight
A sufficient effect cannot be obtained with a smaller amount.

Moreover, if the amount exceeds 5 times, the effect will not be enhanced and it will be uneconomical.

Next, examples of the novel skin quality improving agent containing nonantechin tetraoctamail ester according to the present invention will be shown.

Parts in the examples below refer to weight.

Example 1 (Skin cream) Squalane 10.0 parts Vaseline
10.0 parts Beeswax 50 parts Micro wax 90 parts spermaceti 3.0 parts Isopropyl myristate 12.0 parts Sorbitan monostearate 5.0 parts Methyl paraoxybenzoate 0.1 part @1,3
-Butanediol io, o part distilled water
32.8 parts (C) Fragrance 0.
5 parts The oily component and the aqueous component (B) are separately heated to 80° C. to dissolve them, and the two are mixed and emulsified. Next, fragrance C) is added while cooling, and the mixture is cooled to 30° C. to form the main island.

Example 2 (skin cream) (4) Setanol 6.5 parts spermaceti 3.0 parts Lanolin 2.0 parts Liquid paraffin 20.0 parts Antioxidant o, i parts Rubitan monooleate 2.0 parts Polyester Oxyethylene monooleate 6.5 parts 0) Glycerin 10.0 parts Distilled water
52.0 parts (C) Fragrance
0.4 parts (g) and (B) are separately heated to 80° C. and dissolved, both are mixed and emulsified, cooled, fragrance is added, and the product is uniformly dispersed.

Example 3 (Skin ointment) Isopropyl myristate 10.0 parts Setanol 10.0 parts Carbowax 5.0 parts (J3) Fluid Zeta Rough-in 590 parts Paraffin Wanx 5.0 parts (B) Ingredients heated and dissolved Add the mixture of component (g) to this, cool and mix to obtain a product.

Example 4 (Skin powder) (b) Tarri
95 parts zinc white 2 parts zinc stearate 2 parts - (B) Hanchitin tetraoctanoyl ester
1 part (0 fragrance
After dissolving an appropriate amount of pantethine tetraoctanoyl ester (tough) in a solvent and thoroughly mixing and dispersing it in the powder component (b), the solvent is distilled off, perfume (0) is added, and the product is obtained by drying.

Example 5 (Acne lotion) Polyoxyethylene lauryl ether 1.0 parts t-menthol 0.05 parts Propylene glycol 5.0 parts Pantethine tetraoctanoyl ester 0.5 parts
, 1 alcohol 15.0 parts Fragrance 0.5 parts Distilled water is added to the above ingredients to make a total of 1.5 parts.

The skin quality improving agent containing pantethine tetraoctanoyl ester as an active ingredient according to the present invention is far more effective than those using vitamins and hormones, which are said to be effective in improving lipid metabolism. The basic rule is that by applying it directly to the skin as an external preparation, it not only improves abnormalities in lipid metabolism such as rough skin and chapped skin (it is also effective in improving fine wrinkles, skin texture, firmness, etc.).

The effects of improving lipid metabolism and treating hyperpigmentation using the skin quality improving agent of the present invention were investigated, and compared with a commercially available vitamin E-containing cream. Examples 1 to 6 are applicable methods.
The product was applied to the affected areas of the faces of 60 women aged 28 to 45 with skin abnormalities such as rough skin, rough skin, acne, and age spots, twice a day in the morning and before going to bed for three months, and The treatment status of the affected area was observed and reported. The results are shown in Table 2. It is known that the skin quality improving agent of the present invention is significantly superior to commercially available products. The skin quality improving agent of the present invention showed excellent effects on 6 women with particularly worsening symptoms.

) The degree of improvement is self-assessed. 1: No change 2: I feel like it has improved somewhat. 3: Slightly improved 4: Clearly improved The average value is shown in the table.

Q3) Comparisons with commercially available products are made using the half-face comparison method. 3: The main rule is extremely good. 2: The main rule is slightly better. 1: Equivalent to the main rule. 7. The average value is shown. Shown inside.

Table 2

[Brief explanation of drawings]

Figure 1 shows the infrared absorption spectrum of bantetentetraoctanoyl ester prepared by the method of Synthesis Example 1. Patent applicant: POLA CHEMICAL INDUSTRIES, INC.

Claims (2)

[Claims] (1) Pantethine tetraoctanoyl ester compound represented by the general formula (1) (wherein R represents a carbon 88 linear acyl group, f.) (2) Skin quality characterized by containing a noguntechine tetraoctanoyl ester compound represented by the general formula (1) (in which R represents a straight-chain acyl group having 8 carbon atoms) as an essential component. improving agent