JP2016044171A - Novel compound and mixture composition of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition which solves various problems of a current external preparation used for improvement of skin diseases which has heretofore been regarded as a problem.SOLUTION: Provided is an external composition comprising a compound represented by the following formula. Specifically, provided is an external preparation such as a cosmetic, a medicinal drug, and a quasi drug containing a novel compound represented by the following formula and the like, which exhibits a free radical inhibitory action, an anti-wrinkle action, an anti-pimple action, a moisture-retaining action, a barrier function enhancing action, an ultraviolet-derived inflammation inhibitory action of the skin, and is stable and safe.EFFECT: The external composition has a strong whitening action, a free radical inhibitory action, an anti-wrinkle action, an anti-pimple action, a moisture-retaining action, a barrier function enhancing action, an ultraviolet-derived inflammation inhibitory action, and an anti-bedsore action, is low-irritating, has high safety, and is useful as a cosmetic, a quasi drug, a medicinal drug, a food additive, a feed additive, an animal drug, and an aquatic animal drug.SELECTED DRAWING: None

Description

The present invention relates to a compound having an acetyl ester structure of (R ⁵ —C (═O) —CH ₂ —), a production method thereof, and use thereof. By containing the compound of the present invention as an active ingredient of the present compound, stronger whitening action, free radical inhibiting action, anti-wrinkle action, anti-acne action, moisturizing action, skin and mucosal barrier function enhancing action, ultraviolet ray-derived inflammation inhibition It exerts action and anti-decubitus action. The present invention relates to a stable and highly safe composition, and can be used as a composition for external use for humans and animals including cosmetics, quasi drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs.

Vitamin C (L-ascorbic acid) is an anti-scurvy agent, suppresses the deposition of melanin, which is a cause of stains, freckles, and the like, and more recently, is said to have an anticancer effect. Vitamin E (α, β, γ, δ-tocopherol and tocotrienols and their optical isomers D and L forms) have an antioxidant action and are effective in recent years for cataracts. Has been suggested. Vitamin E itself is insoluble in water and soluble in oil, but vitamin C is water-soluble. Many types of vitamin C derivatives are known, and the following known patent documents exist (Patent Documents 1 to 5).

Japanese Patent Application No. 3-250458 Japanese Patent Application No. 3-250458 JP-A-5-39280 Japanese Patent Application No. 5-61364 Japanese Patent Application No. 6-13667

On the other hand, there are four types of αβγδ in vitamin E. Currently, α-vitamin E and its derivatives are most widely used in the dermatological field. The reason why α type is used is that many organs have a high abundance ratio of α type and high reactivity with peroxy radicals (in order of α> β ^to γ> δ) (Non-patent Document 1).
α Vitamin E is fat-soluble and works as an antioxidant in the sebum layer and cell membrane in the living body, preventing the spread of lipid peroxidation chain reaction that gives serious damage to the skin (non-patent document) ( Non-patent document 2). α-vitamin E not only suppresses oxidative damage of proteins and DNA, but also functions as an ultraviolet (UV) absorber (maximum absorption: 292 nm) (non-patent document 3), and further suppresses skin immune disorders (non-patented) Document 4) (Non-patent document 5) and the effect of inhibiting DNA damage have also been reported. (Non-patent document 6). α-Vitamin E protects against UV rays by suppressing the decrease of epidermal glutathione peroxidase and SOD caused by UV irradiation and increasing the glutathione and vitamin C levels of the skin. In addition, the skin antioxidant network is controlled to suppress UV irradiation injury (Non-patent Document 7). It has been confirmed that the content ratio of γ-type vitamin E is high in some tissues such as skin, and movement to re-evaluate the role of γ-type in living bodies has occurred (Non-patent Document 8). Regarding the composition of vitamin E in the human epidermis, it is reported that the content ratio of α vitamin E: 87%, γ-vitamin E: 9%, γ-Toe: 3%, α-Toe: 1% The role of tocotrienols (Toe) as well as the γ-type has begun to be discussed (Non-patent Document 9). αToe is known to suppress UV damage and also to inhibit lipid peroxidation of benzoyl peroxide used for acne treatment and the like (Non-patent Document 10). γ and δ vitamin E have also been reported to suppress DNA thymidine dimer formation (Non-patent Document 11). There is also a report that melanin production inhibitory action is remarkable for γβδ types other than α (Non-patent Document 12)).
Conventionally, acetic acid and nicotinic acid ester of dl-α vitamin E have been used in pharmaceuticals and cosmetics for the purpose of improving peripheral circulation disorders (Non-patent Document 13). EPC in which vitamin E and vitamin C are bound by a phosphate ester has been reported to suppress oxidative damage due to ischemia (Non-patent Document 14).

Yoshida, et al. , Chem Phys Lipids. 123 (1): 63-75.2003 Niki, Chem. Phys. Lipid. 44, 227-253, 1987). Flyer. 58 (2): 304-312,1993. Yuen, Pho Vitamin Ehem Photobiol. 65 (3): 587-92, 1997 Halliday, et al. Mutat Res. 422 (1): 139-45.1998 McVean, Carcinogenesis. 18 (8): 1617-22, 1997 Lopez-Torres, et al. , Br J Dermatol, 138 (2): 207-215, 1998. Jiang, et al. Am J Clin Nutr. 74 (6): 714-22, 2001 Fuchs, et al. , Free Radic Biol Med. 34 (3): 330-336, 2003 Weber, et al. , Free Radic Biol Med, 34 (2): 170-6.2003. McVean, Mol Carcinog. 24 (3): 169-76.1999 Kamei, et al., Inhibition of melanin synthesis of vitamins, special issue of fragrance journal, No. 18, 56-63, 2003 Fumiko Harahira, Clinical Nutrition, vol. 84, no. 1, p13, 1994 Hirose, et al. , A new radical scavenger. 68 (4): 369-73.1997.

  However, there are two serious problems with vitamin C and vitamin E derivatives described in these known documents. That is, higher fatty acid ester derivatives of vitamin C-2-phosphate such as salts of vitamin C-2-phosphate (Patent Document 6) and salts of vitamin C-2-phosphate-6-palmitate (patents) Reference 7) and vitamin C-2-tocopheryl maleate (Patent Document 8) are quickly converted non-enzymatically to vitamin C due to the weak chemical bond between vitamin C and phosphate or vitamin C and maleic acid. End up. For this reason, it decomposes | disassembles in a formulation and causes problems, such as generation | occurrence | production of coloring and a nasty smell. Although these derivatives are rapidly decomposed even by biological enzymes, there is also a problem that the conversion rate to vitamin C is too fast, so that the concentration of vitamin C in the tissue is too high and prooxidants such as vitamin C radicals are easily generated.

  On the other hand, salts of vitamin C-2-sulfuric acid, L-ascorbic acid-2-O-phosphate-α-tocopherol diester (Patent Document 9), vitamin C-2-glucoside (Patent Document 10) and higher fatty acid esters thereof In salt (patent document 11) and the like, vitamin C in which two molecules are bonded with an ester is not only difficult to be decomposed non-enzymatically due to the strong binding of these esters to vitamin C, but also in the living body. It takes a long time of 24 hours or more to be decomposed even by an enzyme. Enzyme activities such as esterase that converts to vitamins alone for water-soluble and fat-soluble vitamin derivatives, not limited to vitamin C and vitamin E derivatives, depend on the stereospecificity of the enzyme and the type of tissue or cell in which the enzyme exists. It is virtually impossible to infer the conversion rate of a derivative, including the reaction rate of the enzyme, from the molecular structure of the derivative, and it can be estimated by clinical tests, tests using actual tissues, cell tests or reaction tests using actual enzymes. It becomes clear for the first time.

Therefore, for example, even if it is administered to skin tissue, it is not converted into vitamin C in 3 to 6 hours while passing through the skin, but diffuses to other tissues in the bloodstream and increases the concentration of vitamin C in the skin tissue as the target tissue. Without sufficient effect. Once diffused, vitamin C and vitamin E are mainly metabolized in the liver, and most of them are excreted from the body and are not reused. If cultured cells are not cultured for more than 24 hours, the effect cannot be exerted. This is meaningless because the experimental conditions differ from those applied to actual skin.
As described above, the conventional derivative in which vitamin C and vitamin E are bonded has a problem that the ester bond is too strong or too weak to exert a sufficient effect in the administration tissue. In order to solve this problem, we searched for a molecule having an ester structure whose chemical bond with vitamin C is not too weak or too strong. As a result, -OC (= O)-(CH2-structure) In this structure, since the oxygen of vitamin C and the R—O—C (═O) —CH 2 — structure are bonded with an ester, the present inventors have found that this is acetylated. It was named a diester-bonded vitamin C derivative, and the hydrophobicity of the acetyl diester-bonded vitamin C derivative was increased by binding hydrocarbons such as alkyl and alcohol to the acetyl diester-bonded vitamin C derivative, and the skin We have devised to increase the permeability and cell permeability, and found that binding fat-soluble vitamin E is the best in terms of toxicity and effectiveness. This structure is because the oxygen of vitamin C and the vitamin E—O—C (═O) —CH 2 — structure are linked by two esters, so we named it an acetyl diester-linked vitamin CE derivative. It was.

Patent No. 2587761 JP-A-2005-187466 Patent 4179809 Japanese Patent Application No. 2000-580631 Patent 2832848 JP-A-11-286497

In the first place, the conventional derivatives of vitamin C and vitamin E are weakly bound as in the aforementioned ascorbyl-2-maleic acid tocopherol, and hydrocarbons are rapidly released from vitamin C so that cell permeability is sufficiently exerted. Most of the derivatives that cannot be used, and ascorbic acid-2-phosphate-6-palmitate, which exerts cytotoxicity and damages cells due to its strong surface-active action, has good skin barrier penetration However, there is a problem that the merit is not sufficiently achieved even if it has permeability and cell membrane permeability.
Conventionally, when vitamin C and vitamin E are used in combination, a synergistic effect far surpassing that of each single use has been reported, and trial manufacture of a derivative in which vitamin C and vitamin E are combined has been performed. . There is also a report that combined application of vitamin C and vitamin E shows a higher protective effect due to erythema and samban cell formation and thymidine dimer formation of DNA than single application (Non-patent Document 15). Is considered effective. Not only external use but also oral administration is effective. When vitamin C and vitamin E were orally administered at the same time for 8 days, the erythema reaction due to ultraviolet rays was slowed (Non-patent Document 16). On the other hand, when a large amount of vitamin C alone is taken, active oxygen may be generated. However, natural polyphenols are also known to suppress prooxidant conversion of vitamin C (Non-patent Document 17). It has been pointed out that the combined use of A and E with other natural antioxidants is also important in enhancing the effects of vitamins C and E. For this purpose, attempts have been made in the past to modify vitamin E, which is effective in preventing cell membrane oxidation, to vitamin C, instead of hydrocarbons modified to vitamin C derivatives. In addition, since vitamin E has a hydrocarbon chain in its molecule, it can be given an appropriate hydrophobicity when combined with vitamin C. Therefore, these derivatives improve cell membrane permeability and skin barrier permeability. It is possible.

Lin, Pinnell, et al. J Am Acad Dermatol. 48 (6): 866-874, 2003 Eberlein-Konig, J Am Acad Dermatol, 38 (1): 45-48, 1998. MARIAN, et al. , Nature 405, 903-904, 2000

However, since vitamin C is water-soluble and vitamin E is highly soluble in a varicella-like fat, it is difficult to use in combination. Vitamin E is mixed with fat to reduce viscosity and emulsify. However, both of them are strong reducing agents, so they are prone to oxidative degradation, causing browning and off-flavors, and problems with cytotoxicity and irritation caused by prooxidants. There was a problem. There is also a method of using a stabilized vitamin C derivative and a vitamin E derivative together, but the problem is that it is expensive to add two derivatives at the same time, and the side chain is modified to each derivative. In order to ensure a certain amount of vitamins, there is a problem that a large amount must be added. Due to problems such as stable pH, solubility in water and hydrophobicity of two different derivatives, There was a problem that precipitation, separation, and titer reduction were observed. Therefore, an attempt was made to combine vitamin C and vitamin E into one derivative. As derivatives obtained by binding vitamin C and vitamin E, water-soluble phosphate diester compounds of vitamin E and vitamin C are already known [Patent Document 12] [Patent Document 12]. Further, tocopherol / tocotriphenol-L-vitamin C-6-dicarboxylic acid diester has been reported as a supplement to the solubility of vitamins C and E [Patent Document 14].
Further, α-tocopheryl glyceryl vitamin C is known as a vitamin C and vitamin E derivative [Patent Document 15]. Furthermore, L-vitamin C-2-O-maleic acid-α-tocopherol diester is disclosed in [Patent Document 16].
However, as described above, water-soluble phosphate diester compounds of vitamin E and vitamin C [Patent Document 17], [Patent Document 18], and tocopherol / tocotriphenol-L-vitamin C-6-dicarboxylic acid Diester [Patent Document 19] and, as vitamin C and vitamin E derivatives, α-tocopheryl glyceryl vitamin C [Patent Document 20] has an ester bond that is too strong to be enzymatically hydrolyzed in the target tissue. Can not release vitamin C efficiently. On the other hand, L-vitamin C-2-O-maleic acid-α-tocopherol diester [Patent Document 21] is a derivative because the ester bond is too weak and it is rapidly decomposed even in water in which no enzyme is present. There was a problem that the effect of could not be fully demonstrated.

JP-B-2-44478 JP 5-23274 JP-A 62-187470 JP-A-5-331166 International publication number: WO 01/04114 JP-B-2-44478 JP 5-23274 JP-A 62-187470 JP-A-5-331166 International publication number: WO 01/04114

That is, these problems are caused by the problem of the enzymatic binding force of the ester structure of vitamin C or vitamin E derivative, and here, due to the ability of bioenzymatic degradation to phosphate esters. That is, this problem can be solved by finding an ester structure molecule that can control ideal stability and degradability for biological enzymes.
Under such circumstances, as a result of intensive studies on the vitamin C and E derivatives of the present inventors, vitamin C, which is a compound having an acetyl ester structure of —O—C (═O) —CH ₂ —. It was recognized that the derivatives or vitamin E derivatives could solve the conventional problems as described above without the ester bond being too weak or too strong. That is, when the compound containing the acetyl diester-linked vitamin CE derivative of the present invention was successfully synthesized and its effect was examined, it was found that the acetyl ester structure had an appropriate decomposition efficiency, and the present invention was completed. Furthermore, it was discovered that these compounds have excellent antioxidant, radical scavenger and anti-inflammatory effects, and ideal vitamin C and vitamin E having excellent tissue target performance and vitamin C and vitamin E activity. The inventors have found that it is an E-linked derivative and have reached the present invention.
On the other hand, when adding an amphiphilic substance such as ascorbic acid-2-phosphate tocopherol to cosmetics or the like in [Patent Document 22], the present inventor has a liquid crystal structure from the viewpoint of emulsion stability, fine particle forming ability, and dispersibility. It has been found that it is preferable to make an emulsion having Furthermore, application of the liquid crystal composition to cosmetics has been found to improve the moisture retention performance of the skin, and a plurality of patents have been filed. Further, as a method for confirming these liquid crystal structures, observation of a maltase cross image using a polarizing microscope is performed. That is, in the liquid crystal composition, a maltase cross image having a shape unique to the lamellar liquid crystal can be confirmed by observation with a polarizing microscope. In addition, the liquid crystal structure can be confirmed by a transmission electron microscope (TEM) using a resin foam-embedded ultrathin cutting method or a frozen section method. [Patent Literature 23], [Patent Literature 24], [Patent Literature 25], [Patent Literature 26], [Patent Literature 27].

Japanese Patent Application No. 2005-380887 Japanese Patent Application No. 2007-237481 Japanese Patent Application No. 2008-234293 Japanese Patent Application No. 2010-6440 Japanese Patent Application No. 2012-48952 Japanese Patent No. 4854194 The present invention provides a compound comprising a vitamin C and E derivative, that is, a vitamin CE derivative in which tocopherol and vitamin C are bonded via —O—C (═O) —CH 2 —. Furthermore, the purpose of this compound is to provide cosmetics, pharmaceuticals, feed additives, food additives, and antioxidants containing these compounds.

That is, conventional vitamin C or vitamin E derivative problems are summarized as follows.
1) When vitamin C having an ester bond that is too strong and vitamin E-linked derivative bond are too strong, it is physically stable, but it is difficult to separate into vitamin C and tocopherol in the target tissue and has vitamin C activity. There is a problem that the tocopherol activity is low. Enzymes that degrade ascorbic acid-2-glucoside are extremely few in the skin, and sulfate esters and alkyl derivatives of ascorbic acid have very low vitamin C activity because there is almost no hydrolase in the living body. .
2) Vitamin C and vitamin E conjugated derivatives with too weak ester bonds If vitamin C and vitamin E are too weak, vitamin C and vitamin E will be released quickly, so vitamin C and vitamin E will be rapidly oxidized and decomposed. There is a big problem with the stability in the formulation. Vitamin C-2-phosphate Na, vitamin C-2-phosphate Mg and vitamin C-2-phosphate-6-palmitate Na, vitamin C-2-tocopheryl maleate, which are representative of derivatives with too weak bonds An aqueous solution containing 1% or more of the above is at 40 ° C. for 2 months. It causes one or more changes over time among browning, off-flavor, separation, precipitation, and titer reduction. Furthermore, there is a problem that if the released vitamin C is temporarily released in a large amount, it easily becomes a prooxidant and exhibits toxicity. Prooxidant is a kind of reactive oxygen species and causes toxic expression such as cytotoxicity and inflammation. Therefore, there is a problem that the new derivative must realize low toxicity and high effect at the same time.
3) A vitamin C derivative having a hydrocarbon side chain such as a fatty acid having excellent cell membrane permeability has a cell membrane destructive property and high cytotoxicity due to its high surface activity. In addition, it has been reported that vitamin C derivatives of fatty acid esters cause inflammation in the skin (Non-patent Document 18), and it is necessary to employ hydrophobic side chains that do not have fatty acids that express toxicity. There are several advantages of vitamin E as a hydrophobic group that modifies vitamin C. The biggest reason is that it is effectively used as vitamin E after being released from vitamin C in vivo. Further, in the presence of vitamin C, vitamin E is recycled even if it becomes a vitamin E radical after scavenging the radical, and thus has a merit that the problem of prooxidant is less likely to occur. When the side chain of vitamin C is a fatty acid, it is difficult to be effectively used after release, but rather, it has a high risk of becoming a lipid peroxide and changing to one of the substances that damage the cell. Remain.
4) Problems in production Further, in order to synthesize a derivative in which vitamin C and vitamin E are bonded by the -O-C (= O) -CH2- structure, vitamin C is water-soluble, and vitamin E is fat. Since it is soluble, there is a problem that the derivative synthesis reaction is difficult to proceed, the yield is low, and the cost is high. Furthermore, since vitamin C and vitamin E are easily oxidized, they are decomposed during the reaction, and the yield is further reduced. Vitamin C in particular has four hydroxyl groups, making it difficult to react at a specific location, and it is extremely difficult to modify the side chain at a specific carbon position of vitamin C. In the present invention, a technology for developing a production method for selectively modifying vitamin E at specific carbon positions, particularly the strongest 2nd and 3rd positions of vitamin C reactivity, at low cost and efficiently has been demanded.
5) Problems of effects The problems 1), 2) and 3) described above can be said to be problems that greatly affect the manifestation of effects. When vitamin C and vitamin E are weakly bound, the stability in the formulation is poor, so there is a high possibility of oxidative degradation during distribution and storage of the product. I can't. In the case of strong binding, the enzymatic degradation efficiency in the living body becomes low, and even if it reaches the target tissue, it diffuses before being converted to vitamin C and vitamin E, and the concentration increases in the target tissue. I can't let you. Furthermore, when it becomes a causative substance of lipid peroxide after being released into vitamin C such as fatty acid, it is accompanied by problems such as increasing cytotoxicity and reducing the original effect. Unless the problems that lower these effects are drastically solved, derivatives of vitamin C and vitamin E that can provide high effects cannot be obtained.
Under such circumstances, the present inventors have conducted various studies, and as a result, the acetyl diester-bound vitamin CE derivative of the present invention is not too weak or too strong, and thus has high physiological activity and stability. The present invention has been completed by finding that it is excellent in safety, high in safety, and has a tissue target performance, and has solved many manufacturing problems.

The benefits of using vitamin C and vitamin E in combination are enormous, and their combined effects are widely recognized in various radical diseases such as pigmentation, UV radiation damage, and ischemic reperfusion disease. It was expected that derivatives bound with E would have a much more effective advantage than vitamin C derivatives combined with other fatty acids etc., but the problem was their moderate binding power. The present invention has succeeded in achieving a very ideal form by making the bonding force into a —O—C (═O) —CH 2 — structure, and has found a rational production method thereof. Could be solved.
Among the acetyl diester-linked vitamin C derivatives, when the hydrocarbon to be combined with vitamin C is a fatty acid instead of vitamin E, vitamin C is likely to be attacked and prooxidant is likely to be generated. It was found to increase toxicity. Alkyl groups are hardly metabolized as in vitro foreign substances because they are difficult to be converted into nutrients or beneficial substances after separation of vitamin C.
On the other hand, in the case of the acetyl diester-bonded vitamin CE derivative of the present invention, two types of antioxidants of vitamin C and vitamin E coexist after being decomposed by in vivo esterase, so that prooxidant formation is suppressed and toxicity. It was found that the effect of vitamin C can be exhibited in a low state.
Further, the binding of the acetyl diester-linked vitamin CE derivative of the present invention is stronger in the preparation than vitamin C-2-phosphate, vitamin C-2-phosphate-6-palmitate, etc. Stability has improved dramatically. Furthermore, in vivo it is estimated that vitamin C and vitamin E can be separated by in vivo acetyltransferases such as acetyltransferase, and in vivo utilization performance is surprisingly improved compared to vitamin C alkyl derivatives. did.
As for the production method, 5,6-isopropylidene vitamin C and a halogenated acetyl compound are reacted in the presence of a catalyst selected from an alkali catalyst, an acid catalyst and a phase transfer catalyst that do not produce a reaction product with the compound. It was found that 5,6-isopropylidene acetyl diester-linked vitamin CE derivative was obtained by hydrolyzing 5,6-isopropylidene-linked vitamin CE derivative of the obtained 5,6-isopropylidene acetyl diester-linked vitamin CE derivative.
Since the 5,6-isopropylidene acetyl diester-linked vitamin CE derivative of the present invention is also confirmed to have a stable antioxidant power and does not have the conventional problems that can be placed in enzymatic degradation, cosmetics, pharmaceuticals, food additives It can be used as a food or feed additive.
Further, 5,6-isopropylidene vitamin C and a halogenated acetyl compound are dissolved in one or more solvents of a highly polar solvent selected from DMSO, THF, CH ₂ Cl ₂ and DMF, and t- 5,6-isopropylidene-linked vitamin CE derivative of 5,6-isopropylidene obtained by reacting in the presence of one or more bases selected from BuOK, pyridine, KHCO3, K2CO3, Na2CO3, NaHCO3, CsCO3 It has been found that the acetyl diester-bonded vitamin CE derivative of the present invention can be obtained efficiently by hydrolyzing the above.
The pKas of the hydroxyl groups at the 2nd and 3rd positions of vitamin C are 4.2 and 11.8, respectively, and are present mainly as monoanions in vivo. The hydroxyl group at the 2-position of vitamin C is more reactive than the hydroxyl group at the 3-position, and the radical is rapidly stabilized by donating electrons or hydrogen from the hydroxyl group at the 2-position to the radical, and itself becomes the monoanion radical vitamin CH-. . The monoanion radical becomes a monoanion and dehydrovitamin C by a bimolecular disproportionation reaction.
Vitamin C in which the 2nd and 3rd positions are not protected can capture radicals at both the 2nd and 3rd positions (Non-patent Document 19). A reaction system in which the second-position vitamin C radical easily reacts with oxygen and generates superoxide is known (Non-patent Document 20). At the pH in the living body, the second-position vitamin C radical is 3 It is considered that the possibility of promoting the oxidation reaction is higher than that of the vitamin C radicals. It is estimated that vitamin C-2-Glu has a higher inhibitory effect on thymine degradation. Many vitamin C derivatives such as vitamin C phosphate (vitamin C-2-P) are protected only at the 2-position, and reducing 0- remains at the 3-position. It is thought that the effect as a scavenger can be exhibited even without conversion to. In addition, vitamin C derivatives such as vitamin C-2-phosphate compensate for the shortcomings of vitamin C, which induces an oxidation reaction by ester modification at the 2-position (it becomes a prooxidant and promotes the oxidation reaction). . In vivo, this derivative undergoes enzymatic degradation and is gradually converted to vitamin C. Since it has the ability to release vitamin C in vivo, it can avoid high concentrations during administration such as vitamin C. This is one of the great benefits. By the way, vitamin C-2-glucoside has the property of not easily undergoing enzymatic hydrolysis in human serum.

Swinnen I.D. and Goossens A. , Contact Dermatis, 64, 237-244 (2011) Farhataziz Ross A. B. , Selected Specific Rates of Reactions of Transients from Water in Aqueous Solutions. III. Hydroxyl Radical and Perhydrox Radical Radical and Their Radical Ions. NSRDS-NBS 59 Washington (1977) Antanes F.M. Salvador A. et al. , Free Radic. Biol Med. 21 (7), 917-943 (1996) Therefore, in order to obtain only the 2-position acetyl diester-bound vitamin CE derivative having good stability, a reaction system capable of efficiently producing the 2-position acetyl diester-bound vitamin CE derivative is required. Alternatively, a derivative only at the 2nd position must be efficiently selected and classified from the mixed acetyl diester-linked vitamin CE derivatives at the 2nd and 3rd positions.
In the conventional method of synthesizing vitamin CE derivatives, production was complicated and efficient because it was separated using a method such as chromatographic separation in order to obtain only the 2-position derivative from the 2-position and 3-position mixed vitamin CE derivatives. Was bad. There were also many synthetic reactions for obtaining a 2-position derivative, but all had problems with poor yields.
Therefore, as a result of many studies, the present inventors have determined that 5,6-isopropylidene vitamin C and a halogenated acetyl compound such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF) THF, CH ₂ Cl _{2 and the} like. Vitamin C in which only the 3-position carbon position of 5,6-isopropylidene vitamin C is modified with an acetyl compound in a high yield, including a production step in which it is dissolved in a highly polar solvent and reacted in the presence of KHCO3 as a base A method for producing acetyl tocopheryl diester derivatives has been found.
5,6-isopropylidenevitamin C and a halogenated acetyl compound, the compound being one or more selected from highly polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF) THF, and CH ₂ Cl ₂ Vitamin C acetyl modified with an acetyl compound in high yield only at the 2-position carbon position of 5,6-isopropylidene vitamin C, which includes a production step of dissolving in a solvent and reacting in the presence of t-BuOK as a base A process for producing tocopheryl diester derivatives has been found.
Existing therapeutic agents for radical diseases have problems in stability during formulation, and in particular, have problems in the delivery system because they react and deactivate in other organs before reaching the affected area. In addition, when the above other pharmaceutical ingredients are administered into the body, they have problems such as headache, nausea, vomiting, loss of appetite, nausea, rash, muscle spasm.

Embodiments of the Invention

式中、Ｘはハロゲン。

（２）
下記の一般式［化４］ビタミンＣ−３−アセチルジエステルビタミンＥ、［化５］ビタミンＣ−２−アセチルジエステルビタミンＥから選択される１種叉は２種以上の混合物である１の化合物。［化４］及び［化５］においてＲ^６は、
−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３又は、−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３のいずれかである。

（３）
ハロゲノアセチルビタミンＥと５，６−イソプロピリデンビタミンＣを、ＤＭＳＯ、ＴＨＦ、ＣＨ_２Ｃｌ_２、ＤＭＦの４種の溶媒から選択される一種以上の単独叉は混合溶媒に溶解し、ｔ−ＢｕＯＫ、ピリジン、ＫＨＣＯ_３、Ｋ_２ＣＯ_３、Ｎａ_２ＣＯ_３、ＮａＨＣＯ_３、ＣｓＣＯ_３の７種の物質から選ばれる一種以上の単独叉は混合塩基の存在下で反応させた後、５，６−イソプロピリデンアセチルジエステル結合型ビタミンＣＥ誘導体の５，６−イソプロピリデンを加水分解する工程を有することを特徴とする（２）の化合物の製造方法。ここで、ＤＭＳＯはジメチルスルホキシド、ＤＭＦは、ジメチルホルムアミド、ＴＨＦはテトラヒドロフラン、ｔ−ＢｕＯＫはカリウム ターシャリーブトキシドである。
（４）
以下構造式［化６］で示されるハロゲノアセチルビタミンＥから選択される一種叉は２種以上の混合物である（１）の化合物。［化６］でＸは、ハロゲン原子を表す。
Ｒ^６は、−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３又は、−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３のいずれかである。

（５）
ビタミンＥを可溶化溶媒に溶解し、アルカリ触媒、酸触媒及び相間移動触媒から選択される一種以上の単独叉は混合触媒とハロゲン化アセチルを加えて反応させる製造工程を含む４の化合物の合成法。
（６）
下記の一般式［化７］で示される化合物から選択される１種または２種以上の混合物である５，６−イソピリデン−ビタミンＣ−３−アセチルジエステルビタミンＥである（１）の化合物。
Ｒ^６は、−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３又は、−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３のいずれかである。

（７）
５，６−イソピリデン−ビタミンＣと、ハロゲン化アセチル化合物を、前記化合物をＤＭＦの溶媒に溶解し、塩基として炭酸水素カリウムの存在下で反応させる製造工程を含む、６の５，６−イソピリデン−ビタミンＣ−３−アセチルジエステルビタミンＥの製造方法。
（８）
下記の一般式［化８］で示される化合物から選択される１種または２種以上の混合物であることを特徴とする（Ｒ^５−Ｃ（＝Ｏ）−ＣＨ_２−）構造を有するイソピリデンビタミンＣ−２−アセチルジエステルビタミンＥである１の化合物。このときＲ^６は、
−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３又は、−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３のいずれかである。

（９）
５，６−イソプロピリデンアスコルビン酸と、ハロゲノアセチルエステルビタミンＥをＤＭＳＯ、ＴＨＦ、ＣＨ_２Ｃｌ_２、ＤＭＦから選択される一種以上の単独叉は混合溶媒に溶解し、塩基としてｔ−ＢｕＯＫの存在下で反応させる製造工程を含む、８の５，６−イソピリデンビタミンＣ−２−アセチルジエステルビタミンＥの製造方法。
（１０）
（１）記載の化合物を配合したことを特徴とする外用組成物。
（１１）
（１）記載の化合物を配合したことを特徴とする経口用組成物。
（１２）
（１）記載の化合物を配合したことを特徴とするラジカル疾患治療薬。
（１３）
（１）記載の化合物を配合したことを特徴とする細胞培養組成物。
（１４）
（１）記載の化合物を配合したことを特徴とする抗ストレス用組成物。
（１５）
（１）記載の化合物を配合したことを特徴とする液晶乳化組成物。
（１６）
（１）記載の化合物から選択される一種以上の単独叉は複合化合物と以下のグループＡから選択される一種以上の単独又は混合化合物とグループＢから選択される一種以上の単独又は混合化合物と以下のグループＣから選択される一種以上の単独又は混合化合物とグループＤから選択される一種以上の単独又は混合化合物を同時に含有する液晶乳化組成物。
（界面活性剤：グループＡ）
ココイルグルタミン酸Ｎａ、ココイルグルタミン酸Ｋ、ココイルグルタミン酸Ｎａ、ココイルグルタミン酸ＴＥＡ、ココイルグルタミン酸ＴＥＡ、ラウロイルアスパラギン酸Ｎａ、ラウロイルグルタミン酸Ｎａ、ミリストイルグルタミン酸Ｎａ、パーム脂肪酸グルタミン酸Ｎａ，フォスファチジルコリン、リン脂質及びこれらの塩類
（水溶性物質：グループＢ）
グリセリン、ジグリセリン、トリグリセリン、ポリグリセリン、メチルブタンジオール、ブチレングリコール、イソプレングリコール、ポリエチレングリコール、ペンタンジオール、ヘキサンジオール、プロピレングリコール、ジプロピレングリコール、ポリプロピレングリコール、エチレングリコール、ジエチレングリコール、ネオペンチルグリコール、ポリエチレングリコール、ソルビトール、キシリトール、ピロリドンカルボンナトリウム、ヒアルロン酸、カラギーナン、アルギン酸、寒天、フコイダン、ペクチン、ローカストビーンガム、キサンタンガム、トラガントガム、グアーガム、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、アクリル酸・メタクリル酸共重合体、ポリグルタミン酸。
（脂質：グループＣ）
ミネラル油、スクワラン、スクワレン、パルミチン酸イソプロピル、ミリスチン酸イソプロピル、ミリスチン酸イソオクチル、ミリスチン酸イソトリデシル、ミリスチン酸オクタデシル、ミリスチン酸オクチルドデシル、イソステアリルコレステリルエステル、２−エチルヘキサン酸トリグリセリド、２−エチルヘキサン酸セチル、パーム油、ヒマワリ油、オリーブ油、ホホバ油、ツバキ油、流動パラフィン、グレープシード油、アボガド油、マカダミアナッツ油、アーモンド油、天然ビタミンＥ油、米胚芽油、丁字油、オレンジ油、トウヒ油、ステアリン酸及びパルミチン酸。
（抗酸化剤：グループＤ）
コウジ酸、アルブチン、アスコルビン酸リン酸エステルナトリウム、アスコルビン酸リン酸エステルマグネシウム、アスコルビン酸メチル、アスコルビン酸エチル、アスコルビン酸硫酸エステルナトリウム、アスコルビン酸グルコシド、アスコルビン酸リン酸パルミテートナトリウム、トコフェリルリン酸ナトリウム、（アスコルビル／トコフェリル）リン酸Ｋ、アスコルビルマレイン酸トコフェリル、カプリリルグリセリルアスコルベート、ヘキシルグリセリルアスコルベート、ミリスチルグリセリルアスコルベート、グリセリルアスコルベート、ビスグリセリルアスコルベート、ジグリセリルアスコルベート、イソステアリルアスコルビルリン酸ナトリウム、ステアリン酸アスコルビル、パルミチン酸アスコルビル、ジパルミチン酸アスコルビル、エラグ酸、レゾルシノール、ブチルレゾルシノール、カミツレ抽出物、ソウハクヒ抽出液、ユキノシタ抽出液、米糠抽出物、ジアセトキシ安息香酸、アセトキシヒドロキシ安息香酸、胎盤抽出物、アスタキサンチン、カロチン、酢酸レチノール、パルミチン酸レチノール、レチノイン酸、トコフェリルリン酸Ｎａ、トコフェリルアセテート，トコフェリルニコチネート、トコフェリルリノレート、トコフェロール、ジイソプロピルアミンジクロロアセテート、アミノヒドロキシ酪酸、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、没食子酸プロピル。
（１７）
ビタミンＥが、以下のビタミンＥ群から選択される１種または２種以上の混合物である１の化合物。
（ビタミンＥ群）
ＤＬ−α−トコフェロール、ＤＬ−β−トコフェロール、ＤＬ−γ−トコフェロール、ＤＬ−δ−トコフェロール、Ｄ−α−トコフェロール、Ｄ−β−トコフェロール、Ｄ−γ−トコフェロール、Ｄ−δ−トコフェロール、α−トコフェロール、β−トコフェロール、γ−トコフェロール、δ−トコフェロール、ＤＬ−α−トコトリエノール、ＤＬ−β−トコトリエノール、ＤＬ−γ−トコトリエノール、ＤＬ−δ−トコトリエノール、Ｄ−α−トコトリエノール、Ｄ−β−トコトリエノール、Ｄ−γ−トコトリエノール、Ｄ−δ−トコトリエノール、α−トコトリエノール、β−トコトリエノール、γ−トコトリエノール、δ−トコトリエノールThe present invention includes the following items.
(1)
A compound having the acetyl ester structure of (R ⁵ —O—C (═O) —CH ₂ —) or a pharmacology thereof, which is represented by the following general formula [Chemical Formula 1] or [Chemical Formula 2] Acceptable salt. In the formula, R ¹ R ² is H or R ⁵ —O—C (═O) —CH ₂ —, wherein R ⁵ is a hydrocarbon, a solvent-soluble hydrocarbon, a benzene ring, a chroman ring, benzopyran, a vitamin E and their ^{salts, (R 5 -O-C (} = O) -CH 2 -) R 5 in structure -O-C (= O) -CH 2 - bond and ^{R 5} The atoms on the side are not oxygen. However, R ¹ R ² is not H at the same time. Further, R ³ R ⁴ is H at the same time, or R ³ R ⁴ is a hydrocarbon constituting one isopyridene group at the same time. When R ⁵ is vitamin E, the carbon at the 6-position of the chroman ring of vitamin E is in contact with R ^{5 of} (R ⁵ —O—C (═O) —CH ₂ —) as shown in [Chemical Formula 3]. Combines with oxygen.
R ⁶ represents —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂₎ -CH _{3, or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C (-CH 2) it is any one of -CH _3.

In the formula, X is halogen.

(2)
One compound selected from the following general formula [Chemical Formula 4] Vitamin C-3-acetyl diester vitamin E and [Chemical Formula 5] Vitamin C-2-acetyl diester vitamin E, or one compound which is a mixture of two or more. In [Chemical Formula 4] and [Chemical Formula 5], R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

(3)
Halogenoacetyl vitamin E and 5,6-isopropylidene vitamin C are dissolved in one or more single or mixed solvents selected from four solvents of DMSO, THF, CH ₂ Cl ₂ and DMF, and t-BuOK, After reacting in the presence of one or more single or mixed bases selected from seven substances of pyridine, KHCO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , CsCO ₃ , 5,6-isopropyl The method for producing a compound according to (2), comprising a step of hydrolyzing 5,6-isopropylidene of a redeneacetyl diester-linked vitamin CE derivative. Here, DMSO is dimethyl sulfoxide, DMF is dimethylformamide, THF is tetrahydrofuran, and t-BuOK is potassium tertiary butoxide.
(4)
The compound of (1) which is one or a mixture of two or more selected from halogenoacetylvitamin E represented by the following structural formula [Chemical Formula 6]. In [Chemical Formula 6], X represents a halogen atom.
R ⁶ represents —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂₎ -CH _{3, or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C (-CH 2) it is any one of -CH _3.

(5)
A method for synthesizing four compounds comprising a production step in which vitamin E is dissolved in a solubilizing solvent and reacted by adding acetyl halide with one or more single or mixed catalysts selected from alkali catalysts, acid catalysts and phase transfer catalysts .
(6)
The compound of (1), which is 5,6-isopyridene-vitamin C-3-acetyl diester vitamin E, which is one or a mixture of two or more selected from compounds represented by the following general formula [Chemical Formula 7].
R ⁶ represents —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂₎ -CH _{3, or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C (-CH 2) it is any one of -CH _3.

(7)
5,6-isopyridene-vitamin C and a halogenated acetyl compound, which comprises a production step in which the compound is dissolved in a solvent of DMF and reacted in the presence of potassium hydrogen carbonate as a base, Method for producing vitamin C-3-acetyl diester vitamin E.
(8)
An isopyri having a (R ⁵ —C (═O) —CH ₂ —) structure, which is a mixture of one or more selected from compounds represented by the following general formula [Chemical Formula 8] 1 compound which is denvitamin C-2-acetyl diester vitamin E. At this time, R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

(9)
5,6-isopropylidene ascorbic acid and halogenoacetyl ester vitamin E are dissolved in one or more single or mixed solvents selected from DMSO, THF, CH ₂ Cl ₂ and DMF, and in the presence of t-BuOK as a base. 8. A process for producing 5,6-isopyridene vitamin C-2-acetyl diester vitamin E according to 8, which comprises a production step of reacting in step 1.
(10)
(1) A composition for external use, comprising the compound according to the description.
(11)
(1) An oral composition comprising the compound described above.
(12)
(1) A therapeutic agent for a radical disease, comprising the compound described above.
(13)
(1) A cell culture composition comprising the compound described above.
(14)
(1) An anti-stress composition comprising the compound described above.
(15)
(1) A liquid crystal emulsion composition comprising the compound described above.
(16)
(1) One or more single or mixed compounds selected from the compounds described in the following, one or more single or mixed compounds selected from the following group A, and one or more single or mixed compounds selected from group B: A liquid crystal emulsion composition containing at least one single or mixed compound selected from Group C and one or more single or mixed compounds selected from Group D at the same time.
(Surfactant: Group A)
Cocoyl glutamate Na, cocoyl glutamate K, cocoyl glutamate Na, cocoyl glutamate TEA, cocoyl glutamate TEA, lauroyl aspartate Na, lauroyl glutamate Na, myristoyl glutamate Na, palm fatty acid glutamate Na, phosphatidylcholine, phospholipids and salts thereof ( Water-soluble substances: Group B)
Glycerin, diglycerin, triglycerin, polyglycerin, methylbutanediol, butylene glycol, isoprene glycol, polyethylene glycol, pentanediol, hexanediol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, neopentyl glycol, polyethylene Glycol, sorbitol, xylitol, pyrrolidone carboxyl sodium, hyaluronic acid, carrageenan, alginic acid, agar, fucoidan, pectin, locust bean gum, xanthan gum, tragacanth gum, guar gum, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, active ingredient Le acid-methacrylic acid copolymer, polyglutamic acid.
(Lipid: Group C)
Mineral oil, squalane, squalene, isopropyl palmitate, isopropyl myristate, isooctyl myristate, isotridecyl myristate, octadecyl myristate, octyldodecyl myristate, isostearyl cholesteryl ester, 2-ethylhexanoic acid triglyceride, cetyl 2-ethylhexanoate , Palm oil, sunflower oil, olive oil, jojoba oil, camellia oil, liquid paraffin, grape seed oil, avocado oil, macadamia nut oil, almond oil, natural vitamin E oil, rice germ oil, clove oil, orange oil, spruce oil, Stearic acid and palmitic acid.
(Antioxidant: Group D)
Kojic acid, arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, ascorbyl maleate tocopheryl, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl phosphate Sodium, ascorbyl stearate, ascorbyl palmitate, aspartic dipalmitate Rubyl, ellagic acid, resorcinol, butyl resorcinol, chamomile extract, Sakuha extract, Yukinosita extract, rice bran extract, diacetoxybenzoic acid, acetoxyhydroxybenzoic acid, placenta extract, astaxanthin, carotene, retinol acetate, retinol palmitate, Retinoic acid, tocopheryl phosphate Na, tocopheryl acetate, tocopheryl nicotinate, tocopheryl linoleate, tocopherol, diisopropylamine dichloroacetate, aminohydroxybutyric acid, butylhydroxyanisole, butylhydroxytoluene, propyl gallate.
(17)
1 compound in which vitamin E is one or a mixture of two or more selected from the following vitamin E group.
(Vitamin E group)
DL-α-tocopherol, DL-β-tocopherol, DL-γ-tocopherol, DL-δ-tocopherol, D-α-tocopherol, D-β-tocopherol, D-γ-tocopherol, D-δ-tocopherol, α- Tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, DL-α-tocotrienol, DL-β-tocotrienol, DL-γ-tocotrienol, DL-δ-tocotrienol, D-α-tocotrienol, D-β-tocotrienol, D-γ-tocotrienol, D-δ-tocotrienol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol

The solvent of the solvent-soluble hydrocarbon according to the first aspect of the present invention means that when a single solvent such as methylene chloride, DMSO, THF, CH ₂ Cl ₂ , or DMF or a mixed solvent is heated to 40 ° C., DL-α-tocopherol is It is a solvent that can dissolve 1% by weight or more. Therefore, the solvent-soluble hydrocarbon of the present invention is a hydrocarbon compound that can be dissolved in this solvent at 40 ° C. by 1% by weight or more. Incidentally, vitamin E corresponds to any of hydrocarbon, solvent-soluble hydrocarbon, benzene ring, chroman ring, and benzopyran. The solvent-soluble hydrocarbon of the present invention can be used in the present invention even when it is not dissolved in the solvent at 40 ° C. at 1% by weight or more, but it is difficult to use because the reaction efficiency is lowered and the production cost is increased.
Vitamin C used in the synthesis of the present invention includes L-ascorbic acid or a salt thereof. Examples of the salt herein include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt, but other salts are pharmacologically acceptable salts. Any one may be used.
It is known that there are a plurality of types of vitamin E. Tocopherol and tocotrienol are broadly classified, but vitamin E usable in the present invention is tocopherol and tocotrienol. Either the salt or its salt may be used, and its structure is as follows. Vitamin E that can be used in the present invention includes D-type and L-type due to optical activity, and both types can be used in the present invention, and the mixed DL-type and all-rac-type can also be used. Furthermore, as shown in the following chemical formula and Table 1, vitamin E has four types of α, β, γ, and δ depending on the position of the methyl group. Tocotrienols also have the same vitamin E activity as tocopherols and can therefore be used in the present invention. The structures of tocopherol and tocotrienol that can be used in the present invention are shown below.
The salt of vitamin E that can be used for the synthesis of the compound having an acetyl diester structure of the present invention is an alkali metal salt such as sodium salt or potassium salt and an alkali metal salt such as calcium salt or magnesium salt. Any salt other than the above, such as an ammonium salt, may be used as long as it is a pharmacologically acceptable salt. Furthermore, vitamin E that can be used in the synthesis of the present invention uses both d-type (dextro-rotatory = dextrorotatory (+)) and type 1 (levo-rotatory = left-handed (−)), which have different optical rotations. it can. In addition, both D and L stereoisomers of the D / L notation named by corresponding to glyceraldehyde can be used. Furthermore, a racemic mixture (denoted as rac-) or a DL type (denoted as DL-) which is a mixture thereof can also be used as the production raw material of the present invention.

上記ビタミンＥのＲ６が
−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３であるとき、トコフェロールの構造を示す。また、Ｒ６が又は、
−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３であるとき、トコトリエノールの構造を示す。以下、同様な式でＲ６をビタミンＥを構成する炭化水素と称するが、具体的には、Ｒ^６は、
−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_２−ＣＨ_２−ＣＨ_２−ＣＨ（−ＣＨ_２）−ＣＨ_３又は、−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ２）−ＣＨ_２−ＣＨ_２−ＣＨ＝Ｃ（−ＣＨ_２）−ＣＨ_３のいずれかである。
上記トコフェロール及びトコトリエノールの構造式において、Ｒ１，Ｒ２，Ｒ３は、そのα、β、γ、δの各タイプにより次の化学構造を有する。即ち、α型：Ｒ１＝ＣＨ３、Ｒ２＝ＣＨ３、Ｒ３＝ＣＨ３。β型：Ｒ１＝ＣＨ３、Ｒ２＝Ｈ、Ｒ３＝ＣＨ３。γ型：Ｒ１＝Ｈ、Ｒ２＝ＣＨ３、Ｒ３＝ＣＨ３。δ型：Ｒ１＝Ｈ、Ｒ２＝Ｈ、Ｒ３＝ＣＨ３である。
本名発明のビタミンＣとは、Ｌ−アスコルビン酸とＤ−アスコルビン酸であるが、生物活性の問題からＬ−アスコルビン酸が望ましい。

R6 of the vitamin E is —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH ( When it is —CH ₂ ) —CH _3, it indicates the structure of tocopherol. R6 or
When _{-CH 2 -CH 2 -CH = C (} -CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C (-CH 2) a -CH _3, The structure of tocotrienol is shown. Hereinafter, referred to as hydrocarbon constituting the vitamin E and R6 in formula similar to, specifically, R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.
In the structural formulas of tocopherol and tocotrienol, R1, R2, and R3 have the following chemical structures depending on their α, β, γ, and δ types. That is, α type: R1 = CH3, R2 = CH3, R3 = CH3. β-type: R1 = CH3, R2 = H, R3 = CH3. γ-type: R1 = H, R2 = CH3, R3 = CH3. δ type: R1 = H, R2 = H, R3 = CH3.
Vitamin C of the present invention is L-ascorbic acid and D-ascorbic acid, but L-ascorbic acid is desirable from the viewpoint of biological activity.

  As vitamin E that can be used for the compound having an acetyl diester structure of the present invention, all vitamin E described above can be used. Specific examples of vitamin E that can be used in the present invention are tocopherol and tocotrienol, and all four types of αβγδ can be used for each. Namely, D-α-tocopherol, D-β-tocopherol, D-γ-tocopherol, D-δ-tocopherol, D-α-tocotrienol, D-β-tocotrienol, D-γ-tocotrienol, D-δ-tocotrienol, L-α-tocopherol, L-β-tocopherol, L-γ-tocopherol, L-δ-tocopherol, L- DL-α-tocopherol, DL-β-, which are α-tocotrienols, L-β-tocotrienols, L-γ-tocotrienols, L-δ-tocotrienols, and mixed types thereof Tocopherol, DL-γ-tocopherol, DL-δ-tocopherol, DL-α-tocotrienol, DL-β-tocotrienol, DL-γ-tocotrienol, DL-β-tocotrienol Selected from these Tanemata may be a mixture of two or more.

  Examples of the pharmacologically acceptable salt of the present invention include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and ammonium salt. Any salt other than these can be used as appropriate as long as it is a pharmacologically acceptable salt.

The compound having an acetyl diester structure of the present invention can be appropriately synthesized, for example, by the following synthesis method or according thereto.
The production method of the present invention will be described below, but the protecting group for the hydroxyl groups at the 5- and 6-positions of vitamin C is not limited to the following isopropylidene group, but may be an acyl group such as a benzylidene group. An isopropylidene group is common. These protecting groups can be easily removed by acidifying the reaction solution. For acidification, a general acidic compound such as an inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid or an organic acid such as acetic acid or citric acid can be used.

In a nitrogen atmosphere, L (+)-vitamin C is dissolved in a solvent capable of dissolving 10% or more by weight of vitamin C, such as acetone, and a halogenated acetyl compound such as acetyl chloride is added for 3 hours at room temperature. Stir. Thereafter, the solid is filtered off, and the obtained solid is washed with a solvent capable of dissolving 10% or more by weight of vitamin C, such as acetone, and then dried, and is a white solid, which is a 5,6-isopropyl compound of Formula 8 below. Reden vitamin C was obtained (where R ¹ R ² is simultaneously H).
Furthermore, it is shown in the following chemical formula 8 that R ³ R ^{4 according} to claim 1 constitutes one isopyridene group at the same time (where R ¹ R ² is not H at the same time).

５，６−イソプロピリデンビタミンＣ−３−アセチルジエステルビタミンＥをメタノ−ルなどの適当な溶媒に溶解し、塩酸などの前記記載の一般的な酸性化合物を加えて加温して反応撹拌する。その後ろ過し固体を集め、クロロホルムや酢酸エチルなどを加えて薄め、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、硫酸ナトリウムをろ過などで除去する。無水硫酸ナトリウムで乾燥しないで抽出溶媒を留去した残渣に１−プロパノ−ルまたは１−プロパノ−ルと前記のｎ−ヘキサン、シクロヘキサン、石油エ−テルなどの１種以上の有機溶媒との混液を添加し、本化合物を結晶化させてもよい。
溶媒を留去し、ろ過によって集めた固体とあわせ、得られた残留物をカラムクロマトグラフィ−などで精製しビタミンＣ−３−アセチルジエステルビタミンＥを固体として得ることができる。このときＲ^６は、ビタミンＥを構成する炭化水素である。

Under anaerobic conditions such as a nitrogen atmosphere, vitamin E is dissolved in a solvent capable of dissolving 5% or more by weight such as methylene chloride, and an alkali catalyst such as pyridine, an acid catalyst and a phase transfer catalyst, and acetyl halide such as bromoacetyl bromide are added Stir at room temperature. After completion of the reaction, chloroform and ethyl acetate are added to dilute, and the organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration and the like. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane and petroleum ether. After crystallization of this compound, the solvent is distilled off, and the resulting residue is purified by column chromatography or the like to obtain the halogenated vitamin E acetyl monoester represented by [Chem. 6] as an oily substance. it can. When acetyl halide is reacted using bromoacetyl bromide, X in [Chemical Formula 6] becomes Br (bromine).
The manufacturing method of vitamin C-3-acetyl diester vitamin E is as follows. 5,6-isopropylidene vitamin C and halogenated vitamin E acetyl monoester are converted into dimethyl sulfoxide (DMSO, dimethylsulfoxide), dimethylformamide (DMF, N, N-dimethylformamide), tetrahydrofuran (THF, tetrahydrofuran, Oxolane), CH ₂ Cl _2. Dissolve in a highly polar solvent such as ₂ , add alkali carbonate such as potassium bicarbonate, sodium carbonate or potassium carbonate, stir, add water to the reaction mixture, dilute with chloroform or ethyl acetate, and organic The layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration and the like. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane and petroleum ether. May be added to crystallize the compound. The obtained residue can be purified by column chromatography or the like to obtain 5,6-isopropylidene vitamin C-3-acetyl diester vitamin E represented by [Chemical Formula 11] as a solid. At this time, R ⁶ is a hydrocarbon constituting vitamin E.

5,6-Isopropylidene vitamin C-3-acetyl diester vitamin E is dissolved in a suitable solvent such as methanol, the above-mentioned general acidic compound such as hydrochloric acid is added, and the mixture is heated and stirred. Thereafter, the solid is collected by filtration, and diluted with chloroform or ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane and petroleum ether. May be added to crystallize the compound.
The solvent is distilled off and combined with the solid collected by filtration, and the resulting residue is purified by column chromatography or the like to obtain vitamin C-3-acetyl diester vitamin E as a solid. At this time, R ⁶ is a hydrocarbon constituting vitamin E.

５，６−イソプロピリデンビタミンＣ−２−アセチルジエステルビタミンＥをアルコ−ルなどの適当な溶媒に溶解し、ＨＣｌなどの前記記載の一般的な酸性化合物を加えて撹拌反応させる。反応混合物に水を加えクロロホルムや酢酸エチルなどを加えて薄め、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、硫酸ナトリウムをろ過などで除去する。無水硫酸ナトリウムで乾燥しないで抽出溶媒を留去した残渣に１−プロパノ−ルまたは１−プロパノ−ルと前記のｎ−ヘキサン、シクロヘキサン、石油エ−テルなどの１種以上の有機溶媒との混液を添加し、本化合物を結晶化させてもよい。乾燥剤をろ過した後に溶媒を留去し、得られた残留物をカラムクロマトグラフィ−などで精製しＬ−ビタミンＣ−２−アセチルジエステルビタミンＥを個体として得ることができる。このときＲ^６は、ビタミンＥを構成する炭化水素である。

The method for producing vitamin C-2-acetyl diester vitamin E of the present invention is as follows. One type selected from highly polar solvents such as DMSO, DMF, THF, and CH ₂ Cl ₂ with t-BuOK (potassium tert-butoxide, potassium 2-methylpropan-2-olate) in a hypoxic state Suspended in the above solvent, cooled, and the highly polar solvent in which 5,6-isopropylidene vitamin C was dissolved was added dropwise. Then, the highly polar solvent of halogenated vitamin E acetyl monoester is added and stirred. Add general acidic compound as described above such as HCl and water, dilute by adding chloroform or ethyl acetate, wash organic layer with water and saturated brine, dry over anhydrous sodium sulfate, filter sodium sulfate, etc. Remove with. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane and petroleum ether. May be added to crystallize the compound.
After filtration, the solvent is distilled off, and the obtained residue is purified by column chromatography or the like to obtain 5,6-isopropylidene vitamin C-2-acetyl diester vitamin E as an individual. At this time, R ⁶ is a hydrocarbon constituting vitamin E.

5,6-Isopropylidene vitamin C-2-acetyl diester vitamin E is dissolved in a suitable solvent such as alcohol, and the above-mentioned general acidic compound such as HCl is added and stirred. Water is added to the reaction mixture, and the mixture is diluted with chloroform and ethyl acetate. The organic layer is washed with water and saturated brine, dried over anhydrous sodium sulfate, and sodium sulfate is removed by filtration. The residue obtained by evaporating the extraction solvent without drying over anhydrous sodium sulfate was mixed with 1-propanol or 1-propanol and one or more organic solvents such as n-hexane, cyclohexane and petroleum ether. May be added to crystallize the compound. After the desiccant is filtered, the solvent is distilled off, and the resulting residue is purified by column chromatography or the like to obtain L-vitamin C-2-acetyl diester vitamin E as an individual. At this time, R ⁶ is a hydrocarbon constituting vitamin E.

  The present compound thus obtained may be obtained as a pharmacologically acceptable salt by a known method. Conversion to a salt may be performed after isolation from the reaction solution, or may be performed without isolation from the reaction solution.

  This compound has radical scavenging action, active oxygen scavenging action, anti-inflammatory action, and anti-acne action, so it suppresses erythema, which is inflammation caused by ultraviolet rays, sun protection method by ultraviolet rays, skin and whitening (stains, freckles, etc.) Prevention of melanin pigmentation, etc.) and anti-wrinkle, and also has a collagen producing action, so as to stabilize wound healing agents and other cosmetic ingredients (antioxidation) -It can be added as appropriate to cosmetics and pharmaceuticals such as lotion agents and lotions.

  Furthermore, the following components can be simultaneously blended in the pharmaceutical, quasi-drug, cosmetic, feed additive, food additive, and antioxidant formulation containing the compound of the present invention as required. Examples of these components include nicotinic acids such as nicotinic acid, nicotinic acid amide and benzyl nicotinate, vitamins such as retinoic acid, retinoic acetate, and vitamin A oil, riboflavin, riboflavin acetate, and flavin adenine dinucleotide. Vitamin B2 such as pyridoxine hydrochloride, pyridoxine dioctanoate, etc., vitamin C such as L-vitamin C, L-vitamin C-2-sodium sulfate, L-vitamin C dipalmitate, Pantothenic acids such as calcium pantothenate, pantothenyl ethyl ether, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, vitamin Ds such as cholecalciferol, ergocalciferol, α- Tocopherol, tocopherol acetate, nicotinic acid dl-α-toco Ferritol, vitamin E such as dl-α-tocopherol succinate, and other vitamins; glycine, alanine, phenylalanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, aspartate, glutamine Amino acids such as glutamic acid, glutamate, lysine, methionine, cysteine, cystine, arginine, histidine, tryptophan, proline, hydroxyproline, N-coconut oil fatty acid-sodium L-glutamate, N-palmitoyl-L-aspartate, etc. N-acyl acidic amino acid salt, sodium lauroylmethyl-β-alanine, acyl neutral amino acid salt such as coconut oil fatty acid sarcosine triethanolamine, pyrrolidone carboxylic acid and its salt, polyoxyethylene hard Castor oil monopyroglutamic acid monoisostearic acid diester, amino acid derivatives such as coconut oil fatty acid-L-arginine ethyl ester-dl-pyrrolidone carboxylate, rice bran oil, peanut oil, balm oil, beef fat, avocado fat, jojoba fat , Lanolin, liquid paraffin, squalane, carnauba wax, isostearyl alcohol, isostearyl palmitate, glycerol tri-2-ethylhexanoate, glycerin, sorbitol, mannitol, 1,3- Polyhydric alcohols such as butylene glycol, polyhydric alcohol ethers such as polyethylene glycol, collagen, sodium hyaluronate, chondroitin sodium sulfate, sodium dextran sulfate, etc., parahydroxyanisole Such as sodium erythorbate Antioxidants, carboxyvinyl polymers, carboxymethyl cellulose, cellulose derivatives such as hydroxypropylmethyl cellulose, sodium stearyl sulfate, diethylamine cetyl sulfate, cetyltrimethylammonium saccharin, polyethylene glycol isostearate, Diglyceryl diisostearate, surfactants such as phospholipids, preservatives such as ethyl paraben, propyl paraben, butyl paraben, hinokitiol, salicylic acid derivatives, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, allantoin, zinc oxide, etc. Examples include flame retardants, other pH adjusting agents, buffers, fragrances, and coloring agents.

Furthermore, the following components can be simultaneously blended in the pharmaceutical, quasi-drug, cosmetic, feed additive, food additive, and antioxidant formulation containing the compound of the present invention as required. Sodium L-vitamin C-2-phosphate, magnesium L-vitamin C-2-phosphate, L-vitamin C-2-glucoside, sodium L-vitamin C-2-phosphate-6-palmitate, sodium L- Vitamin C-2-phosphate-6-isopalmitic acid, L-vitamin C-2,3,5,6-tetrahexyldecanoic acid, L-vitamin C-3-ethyl, vitamin C-3-glucoside, sodium tocopheryl One or more compounds selected from phosphoric acid, sodium tocopheryldimethylglycine, and tocopheryl retinoic acid can be contained at the same time.

The compounds of the present invention can be used in pharmaceuticals, quasi drugs and cosmetics effective for the following diseases. Radical disease, adult disease, cerebral infarction, myocardial infarction, cardiovascular disorder, analgesic effect, inflammation, necrosis, diabetes, pigmentation, acne, seborrhea, wrinkles, sagging, obesity, swelling, hair loss, pore enlargement, rough skin, Wounds, growth inhibition, stress.
Specific examples of the above radical diseases include skin aging, pigmentation, hemorrhoids, cancer, seborrhea, sunburn, cancer, acne, burns, sagging skin, obesity, hair loss, stress, psychosis, dementia, Parkinson Disease, HIV, cold, influenza, infection, myocardial infarction, ischemic heart disease, heart failure, angina, arrhythmia, arteriosclerosis, liver lipid metabolism disorder, hyperlipidemia, essential hypertension, hypertension, arteriosclerosis Disease, coronary atherosclerosis, thrombosis, obstructive arteriosclerosis, vascular disorder, peripheral vascular disorder, cholestasis, hypercholesterolemia, pancreatic disorder, organ failure, acute chronic hepatitis, gastric ulcer, duodenal ulcer, ulcer Ulcerative colitis, digestive organ disorder cholecystitis, diabetes, arthritis treatment, rheumatism, liver failure, liver disorder, ischemic liver disorder, liver lipid metabolism disorder, gallbladder disorder, organ transplant disorder, diabetes, poisoning, organ transplant disorder, Ischemic reperfusion injury , Is ischemic disease.
It is known from literatures cited in (Non-patent Document 21) and (Non-patent Document 22) that these radical diseases are caused by radicals or one of the causative factors thereof is an in vivo radical. That is, since the compound of the present invention is converted into vitamin C and tocopherol which can eliminate radicals in vivo, it is considered to be effective against these diseases.

“Reactive Oxygen and Pathology” edited by Inoue, Academic Publishing Center, 1992 and “Antioxidant”, Futaki et al., Academic Publishing Center, 1994 “Contemporary Medicine” vol. 25, no. 10, 1993

Specific examples of the radical disease related to the present invention include the following diseases. That is, the radical diseases that are the targets of the drug of the redox control composition of the present invention include organ failure and tissue damage at the time of organ transplantation performed for tissue replacement. That is, cells and tissues due to heart transplantation surgery such as heart, liver, kidney, pancreas, gallbladder, thymus, stomach, lung, intestine, skin, coronary artery recanalization and the like, bypass surgery, and diseases and events described below And organ damage associated with the stoppage or delay of blood flow flowing into the body, and damage to cells and tissues that occur during or after reperfusion after the stoppage of blood flow, damage to death or organ failure, etc. The present invention is effective for these diseases. In addition, the present invention relates to vascular thrombosis, anemia, ischemia, vascular sclerosis, vasoconstriction, hemorrhage (OBAYASHI, PROC. SOC. EXP. BIOL. WED., 196, 196, 164-169, 1990). Examples include, for example, damage to cells and tissues associated with physical reduction or cessation of blood flow velocity caused by the above, death, and diseases and insufficiency of organs including blood vessels. The redox control composition of the present invention includes oxygen deficiency caused by a decrease in oxygen pressure in blood vessels, and temporary deficiency of oxygen deficient tissues in cells or tissues caused by chemical substances such as agricultural chemicals and carbon monoxide poisoning. Organs including cell death, blood vessel damage, death or blood vessels found when blood flow is sent to cells or tissue under normal or close conditions by appropriate treatment or event such as blood transfusion Diseases and insufficiency, and the like are also effective. The redox control composition of the present invention is also effective for ischemic reperfusion diseases, and examples thereof include ischemic reperfusion myocardial injury (NARITA.WJ, J.LAB.CLIN.MED., 110, 153-158, 1987, Smith, LL Phil. Trans. R. Soc., 311, 647-657, 1985), ischemia-reperfusion liver injury (INOUE, M, INMUCOSAL IMMUNOLOGY, 527-530, ELSEVIER, AMSTERDAM, 1990, Nakahama, Liver, 32: 1110-1123, 1991, Takekawa, Liver, 30: 459-467, 1989, Shirasugi, Nissho Gaijin, 26: 358, 1993) Ischemia / Reperfusion Kidney Disorder , Ischemia-reperfusion pancreatic injury (ISAJI, S .: MIE MED. J., 35: 109-123 1985), ischemia-reperfusion gallbladder disorder (TAOKA, GASTROENT.JPN, 26: 633-644, 1991), ischemia-reperfusion cardiovascular disorder, ischemia-reperfusion gastrointestinal disorder (Iwai, Nisshokai, 87: 1662-1669, 1990, NAITO, Y., FREE RED. RES. COMMS, 16: 13.5, 1992), ischemia-reperfusion muscular disorder, ischemia-reperfusion vascular disorder, ischemia-reperfusion ophthalmopathy book, etc. It is also effective for ischemia-reperfusion skin disorders. The redox control composition of the present invention is also effective in the following various disorders induced by active oxygen. Specific examples thereof include Behcet's disease, radiation damage, side effects of anticancer drugs, bacterial shock, cachexia, autoimmune disease, burns, herpes virus, adult T cell leukemia, thioredoxin syndrome, traumatic shock, bacteria These include amyotrophic lateral sclerosis and asexual myocardial infarction. Furthermore, the present invention provides the human epidermal keratinization as described above for growing human epidermal keratinocytes by adding to a serum-free medium for human epidermal keratinocytes, or for treating burns, wounds or aza A composition for promoting cell proliferation and tissue formation is included.
The following inflammations are included in the radical diseases that are treated symmetrically by the pharmaceuticals of the present invention. This is because radicals such as nu-oxide anions are generated in these inflammations, and suppressing these radicals leads to suppression of inflammation.
Specific inflammatory diseases to be treated by the present invention include hemorrhoids, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, osteoarthritis, low back pain, gout attack, acute otitis media, cystitis, prostate Examples include inflammation, toothache, conjunctivitis, keratitis, iridocyclitis, pleurisy, sinusitis and the like.

This compound is suitably used as a pharmaceutical orally or parenterally. As a form of the preparation, any form such as a solid preparation such as a tablet, a granule, a powder and a capsule or a liquid preparation such as an injection and an eye drop can be prepared by a known method. For these preparations, commonly used excipients, binders, thickeners, dispersants, resorption accelerators, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilization Various additives such as an agent and a pH adjuster may be appropriately used.
The anti-inflammatory agent of the present compound may appropriately contain other anti-inflammatory agents or other kinds of medicinal components as long as the object of the present invention is not violated.

Further, for example, the treatment of burns, wounds, aza and the like of the present invention can be used as a specific purpose. Moreover, the method of administration is performed parenterally, and examples of the administration form include a cream agent, an ointment, a poultice, and a mask agent.

One specific form of the pharmaceutical, quasi-drug, cosmetic, and veterinary drug of the present invention is a tissue absorption-promoting pharmaceutical and cosmetic. These products contain a water-absorbing polymer composition in the formulation or product and contain substances that suppress moisture evaporation for a long time. Since these preparations can be kept wet with water for a long time, the main components dissolved and dispersed in water can continue to penetrate into the tissue, and the amount of drug transferred to the tissue can be greatly increased. . At this time, the permeability can be further increased by using a vice with light of a sonication, an ultrasonic device, a laser, etc., and further, an ionic substance such as a salt is dissolved in the water. By conducting electricity, the drug permeability to the tissue can be increased more effectively using a device such as iontophoresis or electroporation.

That is, the following components are simultaneously added to prescriptions of pharmaceuticals, quasi-drugs, cosmetics, feed additives, food additives, and antioxidants containing the water-absorbing polymer composition containing the compound of the present invention as necessary. Can be blended. The water-absorbing polymer used in the present invention is not particularly limited as long as it has the ability to absorb and retain moisture. As the polymer that can be used in the present invention, any of those conventionally used as a polymer composition for cosmetics and medical use can be used. For example, polyglycolic acid (PGA), polylactic acid (PLA), poly (α-hydroxy acid) polymer, poly-β-hydroxybutyric acid (PHB), poly (β-hydroxyalkanoate) polymer, poly-ε-caprolactone (PCL), poly ( ω-hydroxyalkanoate), polybutylene succinate (PBS), polyethylene succinate (PES), polyalkylene alkanoate, polyester polymer, polypropylene polymer, polyamide polymer, Polytetrafluoroethylene polymer, PGA-PLA polymer, polydioxanone polymer, chitin / chitosan polymer, ethylene Methacrylic acid copolymer ionomer, ethylene-acrylic acid copolymer ionomer, propylene-methacrylic acid copolymer ionomer, propylene-acrylic acid copolymer ionomer, butylene-acrylic acid copolymer ionomer, ethylene- Vinyl sulfonic acid copolymer ionomer, styrene-methacrylic acid copolymer ionomer, sulfonated polystyrene ionomer, fluorine ionomer, telechelic polybutadiene acrylic acid ionomer, sulfonated ethylene-propylene-diene copolymer ionomer Hydrogenated polypentamer ionomer, polypentamer ionomer, poly (vinylpyridium salt) ionomer, poly (vinyltrimethylammonium salt) ionomer, poly (vinylbenzylphosphonium salt) ionomer -, Styrene-butadiene acrylic acid copolymer ionomer, polyurethane ionomer, sulfonated styrene-2-acrylamido-2-methylpropane sulfate ionomer, acid-amine ionomer, aliphatic ionene, aromatic System ionene, polyethylene-polyamide graft copolymer (PE-PA GP), polypropylene-polyamide graft copolymer (PP-PA GP) and the like. Further, it contains at least one group selected from the group consisting of alkoxy groups, amino groups, mercapto groups, vinyl groups, epoxy groups, acetal groups, maleic acid groups, oxazoline groups, and carboxylic acid groups, And a copolymer polymer having a low viscosity of 1 or more, specifically, methyl methacrylate-butadiene-styrene resin, acrylonitrile-butadiene rubber, EVA / PVC / graft copolymer, vinyl acetate-ethylene Copolymer resin, ethylene-α-olefin copolymer, propylene-α-olefin copolymer, hydrogenated styrene-isopropylene-block copolymer, polyamino acid polymer, polysaccharide chain polymer, polynucleic acid Polymers, hydroxyapatite polymers, calcium phosphate polymers, cellulose, hydroxymethyl and hydro Poly (α-hydroxy acids) such as xylpropyl cellulose, hyaluronic acid, alginic acid, gums, aliphatic polyester water-absorbing resin, polyglycolic acid (PGA), polylactic acid (PLLA); poly-β- Poly (β-hydroxyalkanoate) such as hydroxybutyric acid (PHB); poly (ω-hydroxyalkanoate) such as poly-ε-caprolactone (PCL); polybutylene succinate (PBS), polyethylene Polyalkylene alkanoates such as succinate (PES), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polyethylene naphthalate (PEN), polyethylene terephthalate Polyester trees such as copolymers of polybutylene terephthalate, copolymers of polyethylene naphthalate, etc. Fats; nylon resins; styrene resins; and polyolefin resins such as polyethylene and polypropylene. Polyethylene includes very low density polyethylene, low density polyethylene, linear low density polyethylene, medium density polyethylene, and high density polyethylene. The inclusion of the polymer improves practical problems such as the brittleness of the water-absorbing polymer. In particular, when a polyolefin-based resin is contained, a hydrophobic effect can be obtained and the hydrolysis resistance of the water-absorbing polymer can be improved.

In the present invention, a compatibilizing agent for compatibilizing these polymers can also be contained by a conventional method. Examples thereof include ionomer resins, oxazoline-based compatibilizing agents, elastomer-based compatibilizing agents, and reactions. Examples of such compatibilizers and copolymer compatibilizers are not limited thereto. By containing the compatibilizing agent, the compatibility between the water-absorbing polymer and the other polymer is improved, and the action of the highly decomposable polymer becomes more effective.

If necessary, ions can be added to these polymer compositions.
For example, alkali metal ions such as Li +, Na +, K +, alkaline earth metal ions such as Mg2 +, Ca2 +, Sr2 +, Ba2 +, transition metal ions such as Zn2 +, Cu2 +, Mn2 +, Ni2 +, Co2 +, Co3 +, Fe3 +, Cr3 + are used. It is done. In addition, an anion such as Cl-, Br-, or I- can be added to the cation host polymer.

If necessary, a reactive compatibilizing agent can be added to the polymer composition of the present invention. Specific examples thereof include a compound having a double bond, a carboxyl group, an epoxy group, an isocyanate group (low molecular weight). Compound or polymer) that reacts with one or both of the polymers to be compatibilized in the molding process and acts as a surfactant based on the graft or block structure to function as a compatibilizer. (Reference: “Polymer Roy” Fundamentals and Applications, edited by the Society of Polymer Science, published in 1993). Examples of the reactive compatibilizing agent that can be used in the present invention include ethylene glycidyl methacrylate copolymer (E-GMA; copolymer weight composition, for example, E / GMA = 100/6 to 12), ethylene glycidyl methacrylate. -To-vinyl alcohol copolymer (E-GMA-VA; copolymer weight composition, for example, E / GMA / VA = 100/3 to 12/8 to 5), ethylene glycidyl methacrylate-methacrylate copolymer Examples thereof include polymers (E-GMA-MA; copolymer weight composition, for example, E / GMA / MA = 100/3 to 6/30). Specifically, manufactured by Sumitomo Chemical Co., Ltd., Bond First E, Bond First 2C; manufactured by Nippon Polyolefin, Lexpar RA, Lexpar ET, Lexpar RC, ethylene maleic anhydride ethyl acrylate copolymer (E -MAH-EA; manufactured by Sumitomo Chemical Co., Bondine), ethylene glycidyl methacrylate-acrylonitrile styrene (EGMA-AS; copolymer weight composition, for example, EGMA / AS = 70/30), ethylene glycidyl methacrylate-polystyrene ( EGMA-PS; copolymer weight composition, eg EGMA / PS = 70/30) ethylene glycidyl methacrylate-polymethyl methacrylate (EGMA-PMMA, eg EGMA / PMMA = 70/30), acid-modified polyethylene Wax (APEW; made by Mitsui Chemicals, high wax), OOH polyethylene graft polymer, COOH polypropylene graft polymer, isocyanate - DOO based on 5-30% by weight including polyisocyanate - DOO. Specifically, Degussa (VESTANAT T1890) is mentioned. Only one of these reactive compatibilizers may be used, or two or more thereof may be mixed and used as necessary.
In addition, since the formulation and preparation of the present invention have a porous structure in which fine holes or spaces having a diameter of 1 nm to 1 mm are present, such as a commercially available membrane filter for removing bacteria, more anti-inflammatory factors can be obtained. It is effective because it can incorporate a simple substance or a complex molecule selected from a free radical scavenging factor, a cell growth factor, an anti-infective factor, and a tissue formation inducing factor. When the present invention is a fiber, a hollow fiber structure is selected from more anti-inflammatory factors, free radical scavenging factors, cell growth factors, anti-infective factors, and tissue formation inducing factors, or a single molecule or a complex molecule thereof It is effective to be able to capture.

The following thickeners and film-forming materials can be used in combination with the compound of the present invention. For example, a cationic polymer, anionic polymer, nonionic polymer thickener may be used, such as calcium hydride, calcium sulfate, polyvinylpyrrolidone (PVP) (average molecular weight = 40,000), sodium polymer. Methacrylate, (average molecular weight = 6000), sodium polymethacrylate, CMC (carboxymethylcellulose), hydroxypropylmethylcellulose, hydroxyethylcellulose, complex hydroxypropyl, hydroxypropylcellulose , Polyacrylic acid and derivatives thereof, polyacrylamide and derivatives thereof, carrageenan, xanthan gum, guar gum, karaya gum, agar, locust bean gum, pectin, gati gum, polyethyleneimines, carrageenan, complex carrageenan There are other natural gums. Specific product names include, for example, polyvinyl alcohol film MONOSOL (Fuller Co., Ltd., St. Paul, Minnesota).

In these water-absorbing polymers, inorganic salts and organic acids can be added as stabilizers. Examples of these stabilizers are as follows. ZnO, MgO, MnO, CaO, calcium hydroxide, aluminum oxide, aluminum hydroxide, aluminum salt, zinc acetate, glucan, gelatin, quaternary ammonium salt, ethanolamines, alginic acid, cetyltrimethylammonium bromide, calcium alginate, Calcium oxide, alginic acid, alginic acid / zinc, sodium alginate, kelp extract, zinc chloride, calcium hydroxide, zinc oxide, sodium chloride, calcium chloride, ammonium calcium alginate, complex ammonium calcium alginate, and the like.
In the present invention, a crosslinking agent that changes the viscosity of these water-absorbing polymers can be added, and specific examples thereof include Kymene 5 (available from Hercules, Wilmington, Del.). is there.

The following reducing agents can be used in combination with the compound of the present invention as a quality-preserving agent. For example, sulfites such as sodium hydrogen sulfite, sodium sulfite and sodium dithionite, thiols including thiols, alcohols (eg 2-mercaptoethanol, dithiothreitol and dithioerythritol), mercapto Thiocyanate such as acetic acid, sodium thioglycolate, thiolactic acid, thioglycolamide, glycerol monothio, borohydride (eg, sodium borohydride, lithium borohydride), tertiary amine, eg, sodium thiocyanate Thiosulfates such as sodium thiosulfate, cyanides such as sodium cyanide, thiophosphates such as sodium thio, arsenous acid such as sodium arsenite, phosphines such as triphenylphosphine, phenol Thiophenol and p Nitorofenon, betaine, lithium aluminum hydride, aluminum chloride, guanidine hydrochloride, stannous chloride, hydroxylamine.

The following raw materials widely used as cosmetics and pharmaceutical raw materials can also be added to the compounds of the present invention. For example, clay materials such as bentonite clay or montmorillonite clay, fumed silica, kaolin, allantoin, aluminum hydroxide gel, calamine, cocoa butter, dimethicone, cod liver oil, glycerin, kaolin, petrolatum, lanolin, mineral oil, shark Liver oil, white petrolatum, talc, starch, zinc acetate, zinc carbonate, zinc oxide, yeast extract, aldioxa, aluminum acetate, microporous cellulose, cholecalciferol, colloidal oatmeal, cysteine hydrochloride, dexpanthanol, per-balsam oil, protein hydrolyzate, racemethionine, sodium bicarbonate, vitamin A, sucrose fatty acid ester, polyethylene glycol and its derivatives, fatty acid ester system, alkyl ethoxylate type, fatty acid ester Terethoxylate, fatty alcohols, polysiloxanes, propylene glycol and derivatives thereof, glycerin and derivatives thereof, glycerides, acetoglycerides, fatty acids including ethoxylated glycerides, triethylene glycol and derivatives thereof, spermaceti Or other waxes, fatty acids, fatty alcohol ethers, fatty acids having 12 to 28 carbon atoms such as stearic acid, propoxylated fatty alcohols, fatty acid ester polyhydroxy alcohols, lanolin and derivatives thereof, There are waxes such as cetyl alcohol, stearyl alcohol, behenyl alcohol, ethanol, carnauba, ozokerite, beeswax, candelilla, paraffin, ceresin, esparto, ouricuri, rezowax and the like.

When the water-absorbing polymer composition used in the present invention is a biodegradable polymer, it is particularly suitable when it is preferable for a living body not to remain as a foreign body because it is absorbed after wound healing.
The compound of the present invention can be used by being incorporated in a porous material. Examples of porous materials that can be used in the present invention include polyolefins containing fibrous structures, PET, cellulose, and cellulose-based fibers, as well as reticulated foams, cellulose sponges, polyurethane foams, and Foams including porous, open cell foams such as HIPS can be used.

In the present invention, the water-absorbing polymer material further includes other additives such as organic or inorganic fillers, flame retardants, anti-blocking agents, crystallization accelerators, gas adsorbents, anti-aging agents (esters, amides). Etc.), antioxidants, ozone degradation inhibitors, UV absorbers, light stabilizers, tackifiers, plasticizers (fatty acids such as stearic acid and oleic acid or their metal salts), softeners (mineral oil, wax, etc.) , Paraffins, etc.), stabilizers, lubricants, mold release agents, antistatic agents, modifiers, colorants, coupling agents, preservatives, antifungal agents and the like may be appropriately blended.

A water-absorbing polymer, a polymer other than the water-absorbing polymer, and a water-absorbing polymer material containing a compatibilizing agent are molded by conventional methods to obtain various molded articles. Further, if necessary, an additive may be added to the water-absorbing polymer material to form a coating material, a coating material, or an adhesive material.
Various molded articles from the water-absorbing polymer material can be produced by a conventional molding method. For example, extrusion molded products, injection molded products, blow molded products, sheets or films extruded from T dies, inflation films, fibers, yarns, strings, ropes, multifilaments by melt spinning, Fibrous structures such as monofilaments, flat yarns, staple fibers, spunbond nonwoven fabrics, flash spun nonwoven fabrics, and various foam molded products can be obtained.

The compounds of the present invention can be used in combination with the following vitamin derivatives. Sodium L-vitamin C-2-phosphate, magnesium L-vitamin C-2-phosphate, L-vitamin C-2-glucoside, sodium L-vitamin C-2-phosphate-6-palmitate, sodium L- Vitamin C-2-phosphate-6-isopalmitic acid, L-vitamin C-2,3,5,6-tetrahexyldecanoic acid, L-vitamin C-3-ethyl, vitamin C-3-glucoside, sodium tocopheryl Phosphoric acid, sodium tocopheryl dimethylglycine, tocopheryl retinoic acid.
In addition, in a formulation or preparation containing the compound of the present invention, components generally used in pharmaceuticals, medical materials, and cosmetics can be blended in amounts that do not impair the effects of the present invention. Examples of materials that can be added to the production of the present invention (for example, oil, higher alcohol, fatty acid, UV absorber, powder, pigment, surfactant, polyvalent alcohol / sugar, polymer, physiologically active ingredient, Solvents, antioxidants, fragrances, preservatives, etc.) are listed below, but the present invention is of course not limited to these examples. Although it does not specifically limit as a component which can be mix | blended with this invention, For example, the component as described in the following [patent document 12] is mentioned.

JP-A-2005-343880

  The composition for promoting cell growth and tissue formation of the present invention and the pharmaceutical and cosmetic containing the same may be in any dosage form and form as long as they are used in contact with the skin at the time of use. It is more preferable to use it in contact with the skin in the vicinity of the site where metabolism is desired. Specifically, for example, skin milk, skin cream, foundation cream, massage cream, cleansing cream, shaving cream, cleansing foam, lotion, lotion, pack Lipstick, blusher, eye shadow, nail polish, soap, body shampoo, hand soap, shampoo, rinse, hair tonic, treatment, hair cream, hair spray, hair restorer, hair nourishing agent, hair dye, hair styling , Hair removal agent, anti-dandruff agent, toothpaste, denture adhesive, gargle, permanent wave agent, curling agent, styling agent, ointment, poultice, tape bath, antiperspirant, A sunscreen agent and the like are included in a broad sense, and any type can be used as long as it can be brought into contact with the skin during use. Regardless of the gender and age of the user. Furthermore, in addition to humans, those that come into contact with animal skin are also included. Moreover, the composition for promoting cell growth and tissue formation of the present invention and the cosmetic containing the composition may be in any shape, and in addition to solid, liquid, semi-solid, gas, powder, granule, tablet shape Although many forms, such as a gel form and a foam form, are mentioned, it is not limited to this in particular. In addition, the cosmetics of this invention can use what can generally be used as cosmetics among the other components mentioned above, In addition to these, the existing cosmetic raw material can also be used further. For example, Cosmetic Material Standards Second Edition Annotation, edited by Japan Standards Association, 1984 (Pharmaceutical Daily Report), Cosmetic Raw Material Standards Ingredient Standard, Ministry of Health and Welfare Pharmaceutical Affairs Bureau Examination Division Supervision, 1993 (Pharmaceutical Daily Report), Cosmetic Raw Material Standards Ingredients Standards supplement, supervised by Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), permission standards by cosmetics type, supervision by Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), Standards for ingredients by cosmetic variety, Ministry of Health and Welfare Supervised by the Examination Division, uses all cosmetic raw materials described in 1997 (Pharmaceutical Daily), Cosmetic Raw Material Dictionary, 1991 (Nikko Chemicals) and new cosmetic functional materials 300, 2002 (CMC Publishing) be able to. The composition for promoting cell growth and tissue formation and the cosmetic of the present invention are prepared by dissolving, mixing, or dispersing the above-described components according to a conventional method according to the mode using the above-described components so as to have a predetermined content. Can be manufactured.

When the composition for promoting cell growth and tissue formation of the present invention is administered parenterally, additives such as a stabilizer, a buffer, a preservative, and an isotonic agent can be contained.
When this compound is used as an external preparation for cosmetics, quasi-drugs and pharmaceuticals, or used as an external preparation such as a pack, patch, or tape, the type of the compound, the type of cosmetic to be formulated, Although it depends on the purpose of blending, it is usually preferable to blend approximately 0.001 to 50 (w / w)%. In the case of a powder, 100 (w / w)% bulk powder can be used.
The dose of the present invention varies depending on the weight and age of the patient and the target animal, the type and state of the target disease, and the administration method. For example, in the case of an injection, the dose is about 1 mg to about 1 mg once a day. In the case of about 50 g, orally and orally administered, 60 kg body weight is preferably administered several times a day, about 1 mg to about 50 g once a day. In the case of an eye drop, it is preferable to administer an eye drop having a concentration of about 0.001 to 1 (w / v)% several times a day for a 60 kg body weight. The effective amount administered as a composition with a suitable diluent of the present invention and a pharmacologically usable carrier is 0.001 to 1 g / cm 2 skin / day, divided into once to several times a day. For at least 2 days. The masking agent is a patch for adsorbing the substance of the present invention together with water on a face or other skin with a water absorbent substance for the purpose of pigmentation, wrinkles, acne care and the like. The amount of this compound added to products as cosmetics, external preparations and oral preparations varies depending on the type of the compound, the type of product to be blended, the blending purpose, etc., but usually about 0.001 to 5 (w / W)%, preferably about 0.005 to 2 (w / w)%.

The radical disease of claim 13 of the present invention includes arrhythmia, arteriosclerosis, ischemic heart disease, heart failure, myocardial infarction, liver injury, ischemic liver injury, digestive organ failure, vascular disorder, pancreatic disorder, gallbladder disorder, organ transplant disorder These include adult diseases such as diabetes, hypertension, organ failure, and lifestyle-related diseases. Among them, diseases caused by free radicals in the living body or active oxygen are one of the basic causes or the causative factors. There are the following references as documents describing diseases in which it is pointed out that in vivo free radicals or active oxygen is one of the basic causes or causative factors. Since hydrogen peroxide is not a free radical but an active oxygen, a disease in which active oxygen is associated as a cause is also included in the radical disease of the present invention. This is because the compound of claim 1 of the present invention has an activity capable of erasing not only free radicals but also active oxygen.

Reactive oxygen and pathology, Inoue, Academic Publishing Center, 1992 Antioxidants, Futaki et al., Society Press Center, 1994, Reactive Oxygen, History of Medicine, Vol.247, No.9, November 30, 2013 Pharmacology and Treatment 42/6 June 2014 Issue, Life Sciences Publishing, Publication Date: 2014-06-20 Miracle cures to get rid of illness, MT Planning Publishing, Mitsuo Terasawa, Akifumi Aoki, Publication date: 2014-05-31 Development and Market of Antioxidant Materials, CMC Publishing, Eiji Yamashita, Hirofumi Goto, Yuji Takahashi, Jun Watanabe, Manabu Wakaki, Yuko Ishikawa (Yuko Takano), Shoichi Lee, Chrysanthemum? Yasue, Koji Ota, Kenji Fukuzawa, Koichi Aizawa, Tomoki Tachifuji, Tomoki Ikuta, Nakako Tani, Kiyoshi Fukuhara (Author), Publication Date: 2014-05-20 Kidney and dialysis, 76/4, April 2014 issue, Tokyo Medical Company, Advances in AKI medical care, Publication date: 2014-04-25 Blood Pressure 21/3 March 2014 Issue, Advanced Medicine, Anti-aging and Blood Pressure Diabetes Strategie 4/1 2014 Winter, Advanced Medical Company, Considering Diet Therapy for Diabetes Care, Publication Date: 2014-02-10 Experimental medicine separate volume direct transmission! Flow cytometry, Yodosha, Publication date: 2014-02-01 Journal of Japanese Pharmacology, 142/6, December 2013, Pharmacological Society of Japan Target validation strategy for the creation of schizophrenia treatment, published date: 2013-12-01 Turn on the longevity circuit! Anti-aging drugs that have become visible, CMC Publishing, David Stip (Author), Atsuko Teramachi (translation), Publication date: 2012-06-30

  By making the compound of the present invention into an emulsion composition having a liquid crystal structure, the stability can be further improved, the transdermal absorbability can be improved, and the moisture retention performance of the skin can be improved.

The presence of the emulsion composition having a liquid crystal structure, which is characterized by blending the compound of the present invention, can be easily confirmed by observing a maltase cross image with a polarizing microscope. In addition, the liquid crystal structure can be confirmed by a transmission electron microscope (TEM) using a resin foam-embedded ultrathin cutting method or a frozen section method.

Effect of the invention

The present invention contains physiologically active components including the compound of the present invention, and has a strong whitening effect, free radical inhibitory effect, anti-wrinkle effect, anti-acne action, moisturizing action, barrier function enhancing action, ultraviolet ray-derived inflammation It exhibits inhibitory action, anti-decubitus action, etc. and is highly safe with low irritation, useful as cosmetics, quasi drugs, feed additives, food additives, pharmaceuticals, veterinary drugs, aquatic animal drugs A composition for external use can be provided.
In a particularly preferred embodiment, it contains an ascorbic acid derivative, which is a compound of the present invention, as an active ingredient, and has a strong whitening action, free radical inhibitory action, anti-wrinkle action, anti-acne action, moisturizing action, and barrier function enhancing action. The present invention provides a composition for external use, which has a UV-derived inflammation-inhibiting action and an anti-decubitus action, is stable, has low irritation and is safe, and includes cosmetics, quasi-drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs. be able to.
The compound of the present invention has a conventional evaluation of the existing vitamins in a comprehensive evaluation that summarizes the results of titer change, tissue absorption, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation. Compared to derivatives with C and vitamin E, any of the changes in titer over time, safety, tissue absorption, enzymatic degradation and antioxidant activity of skin tissue homogenate, and skin irritation In the evaluation, it was confirmed that it had extremely excellent performance. Due to these combined actions, the present invention exhibits extremely useful effects in the industry as compared with conventional known vitamin C and vitamin E derivatives.
Further, from the results of the effect test and skin irritation test described in the examples below, it is indicated that the concentration of the compound of the present invention in the preparation is suitably in the range of 0.000001 to 0.1% by weight. The effective concentration range in the preparations of the present invention is the conventional pigmentation inhibitor kojic acid, arbutin, sodium L-ascorbate, methyl L-ascorbate, ethyl L-ascorbate, L-ascorbic acid-2-glucoside, L-ascorbic acid-2-phosphate-6-palmitate 3Na, isostearyl ascorbyl phosphate 2Na, ellagic acid, resorcinol, L-cysteine, hydroquinone, tranexamic acid has a formulation effective concentration of 0.1 to 10.0% by weight Compared to the range, it is equivalent to 100 times to 100,000 times and has a surprisingly strong effect.
Other objects, features, excellence and aspects of the present invention will be apparent to those skilled in the art from the following description. However, it is understood that the description of the present specification, including the following description and the description of specific examples and the like, show preferred embodiments of the present invention and are presented only for explanation. I want. Various changes and / or modifications (or modifications) within the spirit and scope of the present invention disclosed herein will occur to those skilled in the art based on the following description and knowledge from other parts of the present specification. Will be readily apparent. All patent documents and references cited herein are cited for illustrative purposes and are not to be construed as a part of this specification. is there.

  Next, the present invention will be described more specifically with reference to production examples, examples (formulation examples), and test examples, which are provided merely for the description of the present invention and for reference of specific embodiments thereof. It is what has been. These are for the purpose of describing specific specific embodiments of the present invention, but are not intended to limit or limit the scope of the invention disclosed in the present application. In the present invention, it should be understood that various embodiments based on the idea of the present specification are possible. All production examples, examples (formulation examples), and test examples, except those described in detail elsewhere, have been performed or can be performed using standard techniques. It is well-known and customary for traders. In the following, all parts are by weight, and all% are by weight.

As vitamin C, L-ascorbic acid (55 mmol) manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in acetone, acetyl chloride (15 mmol) was added, and the mixture was stirred for 3 hours. The solid was filtered off, and the obtained solid was washed with acetone and then dried, and this was a known compound, 5,6-isopiden vitamin C (also known as 5,6-isopidenascorbic acid) of formula 12 (44) .2 mmol) was obtained as a white solid.

MP Biomedicals D-α-tocopherol (50% by weight), MP Biomedicals D-α-tocopherol (5% by weight), Kanto Kagaku rac-β-tocopherol tocopherol (5% weight), D-γ-tocopherol (5% weight) manufactured by Kanto Chemical Co., Inc. rac-γ-tocopherol-tocopherol (5% weight) manufactured by Kanto Chemical Co., D manufactured by MP Biomedicals -Δ-tocopherol (5% by weight), D-α-tocotrienol (5% by weight) manufactured by Sigma-Aldrich, D-β-tocotrienol (5% by weight) manufactured by Sigma-Aldrich, Sigma-Aldrich D-γ-tocotrienol (5% weight), Sigma-Aldrich D-δ-tocotrienol (5% weight) , ITO Co. D-beta-tocopherol - was vitamin E oil mixture by mixing Le (5% weight).

The vitamin E mixed oil (10 mmol) prepared in the previous section was dissolved in methylene chloride, pyridine (12 mmol) and bromoacetyl bromide 4 (12 mmol) were added, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 80: 1) to obtain bromoacetylvitamin E as a kind of claim 4 of the present invention. Obtained as a colorless oil. The ¹ H NMR, ¹³ C NMR, IR, and HPLC of this compound are as follows. ¹ H NMR (400 MHz, D ₂ O): δ 4.05 (2H, s), 2.58 (2H, t, J = 6.8 Hz), 2.07 (3H, s), 2.05 (3H , S), 2.00 (3H, s), 1.81-1.71 (2H, m), 1.57-1.05 (24H, m), 0.88-0.84 (12H, m) ), ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.5, 166.6, 149.5, 147.7, 139.7, 126.6, 125.0, 123.3, 120.8, 117. 4, 110.5, 75.8, 75.1, 74.2, 66.8, 65.2, 39.3, 37.5, 37.1, 32.6, 32.5, 31.1, 27.8, 26.1, 25.2, 24.6, 24.4, 22.67, 22.58, 20.8, 20.4, 19.5, 19. , 12.8,11.8,11.5. IR (NaCl) 3301, 2929, 2872, 1774, 1702, 1453, 1381, 1338, 1250, 1181, 1151, 1071 cm ⁻¹ . HPLC: Column: SUPELCOSIL-TM ABZ + PLUS 4.6 mm i. d. × 150 mm, 5 μm (supplico), mobile phase: MeOH: H 2 O = 89: 11, flow rate: 1.0 mL / min, detection wavelength: UV 285 nm, fluorescence ex. 285 nm, em. As a standard when measured at 330 nm, injection volume: 20 μL. δ-Toc, 2. β-Toc, 3. γ-Toc, 4. When α-Toc was simultaneously quantified, bromoacetylvitamin E of the present invention was detected with an HPLC retention time of 15 min. It was confirmed by detection between γ-Toc and α-Toc without overlapping with δ-Toc, β-Toc, γ-Toc and α-Toc.

5,6-Isopiden vitamin C (0.778 g, 3.6 mmol) and bromoacetylvitamin E (2 g, 3.6 mmol) prepared in the previous section were dissolved in DMF (10 ml), and potassium bicarbonate (0.37 g , 3.7 mmol) and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 5: 1), and the 5,6-isopyridene- of the present invention [Claim 6]. Vitamin C-3-acetyl diester vitamin E (1.47 g, 2.13 mmol) was obtained as a white solid. ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.42 (1H, bs), 5.26 (2H, q, J = 16.8, 11.6), 4.69 (1H, d, J = 4) .4), 4.30 (1H, dt, J = 6.4, 2), 4.20 (1H, dd, J = 8.8, 8.4), 4.06 (1H, dd, J = 6.8, 6.4), 2.60 (2H, t, J = 6.8 Hz), 2.07 (3H, s), 2.01 (3H, s), 1.97 (3H, s) , 1.83-1.73 (2H, m), 1.59-1.02 (30H, m), 0.88-0.82 (12H, m). ¹³ C NMR (75 MHz, CDCl ₃ ): δ 169.0, 167.5, 150.4, 145.3, 138.8, 135.6, 124.5, 122.1, 120.1, 118.1, 76.1, 75.1, 73.0, 70. 66.4, 65.9, 63.1, 39.3, 38.1, 37.4, 37.2, 33.1, 31.9, 30.5, 30.2, 28.1, 24. 2, 24.0, 23.1, 21.9, 20.9, 20.4, 19.5, 19.3, 12.4, 11.9, 11.0, IR (NaCl) 3395, 2925 , 2866, 1759, 1680, 1461, 1085 cm ⁻¹ .

The 5,6-isopyridene-vitamin C-3-acetyl diester vitamin E (0.04 g, 0.058 mmol) prepared in the previous section was dissolved in methanol (5 ml), and 2N HCl (0.1 ml) was added to add 50. Stir at 0 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the vitamin C-3-acetyl diester of the present invention [Claim 2]. Vitamin E (0.022 g, 0.033 mmol) was obtained as a white solid. This compound ¹ H NMR, ¹³ C NMR, IR is as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 5.63 (1H, d, J = 16.8), 5.04 (1H, d, J = 17.2), 4.80 (1H, s), 4.13 (1H, dt, J = 5.6, 4.8), 3.87 (1H, dd, J = 7.2, 7.6), 3.75 (1H, dd, J = 1.11. 2, 12.4), 2.57 (2H, bt), 2.08 (3H, s), 2.02 (3H, s), 1.97 (3H, s), 1.82-1.72. (2H, m), 1.55-1.05 (24H, m), 0.87-0.83 (12H, m), ¹³ C NMR (75 MHz, CDCl ₃ ): δ 169.8, 167.8, 149.5, 145.5, 138.9, 135.7, 125.3, 123.2, 120.2, 117.5, 76.0, 75.0, 72.4, 69. 66.5, 66.0, 62.7, 39.2, 37.40, 37.38, 37.1, 32.5, 32.4, 30.5, 30.1, 27.7, 24. 4, 24.2, 22.6, 22.4, 20.8, 20.4, 19.4, 19.5, 12.5, 11.9, 11.5; IR (NaCl) 3380, 2925 , 2866, 1753, 1680, 1461, 1425, 1372, 1319, 1205, 1158, 1085 cm ^−1.

Under a nitrogen atmosphere, t-BuOK (0.951 g, 8.48 mmol) was suspended in DMSO / THF (3: 2) (5 ml), cooled to −10 ° C., and 5,6-isopidene vitamin C ( 0.917 g, 4.24 mmol) in DMSO / THF (3: 2) (5 ml) was added dropwise. Thereafter, a solution of bromoacetylvitamin E compound (2.57 g, 4.66 mmol) described in the previous section in DMSO / THF (3: 2) (5 ml) was added dropwise, stirred for 5 minutes, and stirred at room temperature for 8 hours. 1N HCl (4.3 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to obtain 5,6-isopyridene-vitamin C-2-acetyl of the present invention. Diester vitamin E (1.34 g, 1.96 mmol) was obtained as a colorless oil. The ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 9.49 (1H, bs), 4.83 (2H, q, J = 17.6, 11.6), 4.66 (1H, d, J = 3) .2), 4.35 (1H, dt, J = 6.8, 3.2), 4.16 (1H, dd, J = 7.2, 6.8), 4.09 (1H, dd, J = 6.4, 6.8), 2.60 (2H, t, J = 6.8 Hz), 2.10 (3H, s), 1.99 (3H, s), 1.95 (3H, s), 1.86-1.75 (4H, m), 1.57-1.05 (28H, m), 0.87-0.83 (12H, m), ¹³ C NMR (100 MHz, CDCl ₃ ) : Δ 171.8, 168.5, 160.4, 150.1, 139.4, 126.1, 124.4, 123.4, 121.3, 117.4, 110.1, 7 1, 74.3, 73.5, 68.4, 65.0, 39.0, 37.38, 37.31, 37.1, 32.2, 32.5, 30.8, 27.8 , 25.7, 25.2, 24.7, 24.3, 22.4, 22.3, 20.7, 20.2, 19.3, 19.5, 12.7, 12.0, 11 4; IR (NaCl) 2925, 2865, 1770, 1680, 1460, 1376, 1334, 1252, 1206, 1144, 1065 cm ⁻¹

The 5,6-isopyridene-vitamin C-2-acetyl diester vitamin E (0.069 g, 0.1 mmol) of the present invention prepared in the previous section is dissolved in methanol (5 ml) and THF (2 ml), and 2N HCl ( 0.16 ml) was added and the mixture was stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering off sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (methylene chloride: methanol = 10: 1) to give vitamin C-2- of the present invention [Claim 2]. Acetyl diester vitamin E (0.051 g, 0.079 mmol) was obtained as a white solid. The ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 4.92 (2H, q, J = 16.8, 15.2), 4.71 (1H, s), 4.04 (1H, bs), 4. 75 (2H, bs), 2.54 (2H, bt), 2.05 (3H, s), 1.95 (3H, s), 1.91 (3H, s), 1.72 (2H, bs) ), 1.55-1.05 (24H, m), 0.87-0.83 (12H, m), ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.5, 170.4, 161.0, 149.5, 140.0, 126.7, 125.0, 124.0, 120.7, 117.5, 76.0, 75.7, 69.5, 67.7, 63.0, 39. 9, 37.3, 37.0, 33.1, 32.4, 31.5, 28.1, 24.7, 24.4, 22.3, 22. 21.0, 20.5, 19.4, 19.9, 13.2, 12.2, 11.6; IR (NaCl) 3365, 2953, 2925, 2870, 1757, 1669, 1468, 1375, 1333 , 1202, 1155, 1113, 1071, 1046 cm ⁻¹

ChromaDex, Inc. DL-α-tocopherol produced by the company was dissolved in methylene chloride, pyridine (12 mmol) and bromoacetyl bromide 4 (12 mmol) were added, and the mixture was stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 80: 1) to give the bromoacetyl-DL-α-tocopherol of the present invention colorless. As an oil. The ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 4.07 (2H, s), 2.59 (2H, t, J = 6.8 Hz), 2.09 (3H, s), 2.04 (3H, s), 2.00 (3H, s), 1.82-1.72 (2H, m), 1.56-1.05 (24H, m), 0.88-0.83 (12H, m) , ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.4, 166.6, 149.3, 147.7, 139.6, 126.5, 125.0, 123.1, 120.7, 117.4 , 110.2, 75.9, 75.0, 74.5, 66.9, 65.2, 39.2, 37.4, 37.2, 32.6, 32.5, 31.0, 27 .8, 26.0, 25.4, 24.6, 24.4, 22.68, 22.59, 20.9, 20.5, 19.6, 1 .6,12.7,11.9,11.6; IR (NaCl) 3300,2930,2870,1775,1700,1455,1380,1340,1253,1180,1152,1070 cm -1

The compound of chemical formula 12 (0.778 g, 3.6 mmol) and the compound of chemical formula 13 (2 g, 3.6 mmol) are dissolved in DMF (10 ml), and potassium hydrogen carbonate (0.37 g, 3.7 mmol) is added to room temperature. And stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 5: 1), which is a vitamin C derivative of the present invention represented by the following chemical formula 14. 5,6-Isopyridene L-ascorbic acid-3-acetyl diester-DL-α-tocopherol (1.47 g, 2.13 mmol, 59%) was obtained as a white solid. ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 5.43 (1H, bs), 5.28 (2H, q, J = 16.8, 11.6), 4.70 (1H, d, J = 4) .4), 4.31 (1H, dt, J = 6.4, 2), 4.19 (1H, dd, J = 8.8, 8.4), 4.07 (1H, dd, J = 6.8, 6.4), 2.59 (2H, t, J = 6.8 Hz), 2.09 (3H, s), 2.02 (3H, s), 1.98 (3H, s) , 1.83-1.73 (2H, m), 1.59-1.03 (30H, m), 0.88-0.83 (12H, m), ¹³ C NMR (100 MHz, CDCl ₃ ): δ 172.3, 169.1, 160.3, 150.2, 138.8, 126.0, 124.3, 122.9, 120.8, 117.3, 110.2, 75. 73.9, 74.1, 68.3, 65.2, 39.1, 36.9, 37, 3, 37.2, 33.0, 32.1, 30.6, 27.5, 26 .1, 25.1, 24.6, 23.8, 22.3, 22.2, 20.6, 19.9, 19.2, 19.4, 13.6, 12.1, 10.9 IR (NaCl) 2931, 2866, 1765, 1654, 1454, 1368, 1337, 1251, 1202, 1150, 1061 cm ⁻¹ ;

前項で作成した化学式１４の化合物（０．０４ｇ，０．０５８ｍｍｏｌ）をメタノ−ル（５ｍｌ）に溶解し、２Ｎ ＨＣｌ（０．１ｍｌ）を加えて５０℃で２時間撹拌した。反応混合物に水を加え、酢酸エチルで抽出し、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。硫酸ナトリウムをろ過した後に溶媒を留去し、得られた残留物をカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝１：１）で精製し、以下の化学式１５で示される本発明のビタミンＣ誘導体であるＬ−アスコルビン酸−３−アセチルジエステル−ＤＬ−α−トコフェロ−ル（０．０２２ｇ，０．０３３ｍｍｏｌ）を白色個体として得た。この化合物の^１Ｈ ＮＭＲ，^１３ＣＮＭＲ，ＩＲ，元素分析値は次の通り。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）；δ ５．６３（１Ｈ，ｄ，Ｊ＝１６．８），５．０４（１Ｈ，ｄ，Ｊ＝１７．２），４．８０（１Ｈ，ｓ），４．１３（１Ｈ，ｄｔ，Ｊ＝５．６，４．８），３．８７（１Ｈ，ｄｄ，Ｊ＝７．２，７．６），３．７５（１Ｈ，ｄｄ，Ｊ＝１１．２，１２．４），２．５７（２Ｈ，ｂｔ），２．０８（３Ｈ，ｓ），２．０２（３Ｈ，ｓ），１．９７（３Ｈ，ｓ），１．８２−１．７２（２Ｈ，ｍ），１．５５−１．０５（２４Ｈ，ｍ），０．８７−０．８３（１２Ｈ，ｍ）、^１３ＣＮＭＲ（７５ＭＨｚ，ＣＤＣｌ_３）：δ １６９．８，１６７．８，１４９．５，１４５．５，１３８．９，１３５．７，１２５．３，１２３．２，１２０．２，１１７．５，７６．０，７５．０，７２．４，６９．４，６６．５，６６．０，６２．７，３９．２，３７．４０，３７．３８，３７．１，３２．５，３２．４，３０．５，３０．１，２７．７，２４．４，２４．２，２２．６，２２．４，２０．８，２０．４，１９．４，１９．５，１２．５，１１．９，１１．５；ＩＲ（ＮａＣｌ）３３８０，２９２５，２８６６，１７５３，１６８０，１４６１，１４２５，１３７２，１３１９，１２０５，１１５８，１０８５ ｃｍ^−１
元素分析値：Ｃ_３７Ｈ_５８Ｏ_９・Ｈ_２Ｏとして理論値（％）＝Ｃ，６６．８４：Ｈ，９．１０。実測値（％）＝Ｃ，６６．７６：Ｈ，９．０７。

The compound of formula 14 (0.04 g, 0.058 mmol) prepared in the previous section was dissolved in methanol (5 ml), 2N HCl (0.1 ml) was added, and the mixture was stirred at 50 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1), which is a vitamin C derivative of the present invention represented by the following chemical formula 15. L-ascorbic acid-3-acetyl diester-DL-α-tocopherol (0.022 g, 0.033 mmol) was obtained as a white solid. The ¹ H NMR, ¹³ C NMR, IR, and elemental analysis values of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 5.63 (1H, d, J = 16.8), 5.04 (1H, d, J = 17.2), 4.80 (1H, s), 4.13 (1H, dt, J = 5.6, 4.8), 3.87 (1H, dd, J = 7.2, 7.6), 3.75 (1H, dd, J = 1.11. 2, 12.4), 2.57 (2H, bt), 2.08 (3H, s), 2.02 (3H, s), 1.97 (3H, s), 1.82-1.72. (2H, m), 1.55-1.05 (24H, m), 0.87-0.83 (12H, m), ¹³ C NMR (75 MHz, CDCl ₃ ): δ 169.8, 167.8, 149.5, 145.5, 138.9, 135.7, 125.3, 123.2, 120.2, 117.5, 76.0, 75.0, 72.4, 69. 66.5, 66.0, 62.7, 39.2, 37.40, 37.38, 37.1, 32.5, 32.4, 30.5, 30.1, 27.7, 24. 4, 24.2, 22.6, 22.4, 20.8, 20.4, 19.4, 19.5, 12.5, 11.9, 11.5; IR (NaCl) 3380, 2925 , 2866, 1753, 1680, 1461, 1425, 1372, 1319, 1205, 1158, 1085 cm ^−1.
Elemental analysis value: Theoretical value (%) as C ₃₇ H ₅₈ O ₉ · H ₂ O = C, 66.84: H, 9.10. Found (%) = C, 66.76: H, 9.07.

Under a nitrogen atmosphere, t-BuOK (0.951 g, 8.48 mmol) was suspended in DMSO / THF (3: 2) (5 ml), cooled to −10 ° C., and 5,6, -isopyridene ascorbic acid. A solution of (0.917 g, 4.24 mmol) in DMSO / THF (3: 2) (5 ml) was added dropwise. Thereafter, a solution of bromoacetyl-DL-α-tocopherol (2.57 g, 4.66 mmol) in DMSO / THF (3: 2) (5 ml) was added dropwise, stirred for 5 minutes, and stirred at room temperature for 8 hours. 1N HCl (4.3 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1), which is a vitamin C derivative of the present invention represented by the following chemical formula 16. 5,6-Isopyridene ascorbic acid-2-acetyl diester-DL-α-tocopherol (1.34 g, 1.96 mmol) was obtained as a colorless oil. ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 9.49 (1H, bs), 4.83 (2H, q, J = 17.6, 11.6), 4.66 (1H, d, J = 3) .2), 4.35 (1H, dt, J = 6.8, 3.2), 4.16 (1H, dd, J = 7.2, 6.8), 4.09 (1H, dd, J = 6.4, 6.8), 2.60 (2H, t, J = 6.8 Hz), 2.10 (3H, s), 1.99 (3H, s), 1.95 (3H, s), 1.86-1.75 (4H, m), 1.57-1.05 (28H, m), 0.87-0.83 (12H, m), ¹³ C NMR (100 MHz, CDCl ₃ ) : Δ 171.8, 168.5, 160.4, 150.1, 139.4, 126.1, 124.4, 123.4, 121.3, 117.4, 110.1, 7 1, 74.3, 73.5, 68.4, 65.0, 39.0, 37.38, 37.31, 37.1, 32.2, 32.5, 30.8, 27.8 , 25.7, 25.2, 24.7, 24.3, 22.4, 22.3, 20.7, 20.2, 19.3, 19.5, 12.7, 12.0, 11 4; IR (NaCl) 2925, 2865, 1770, 1680, 1460, 1376, 1334, 1252, 1206, 1144, 1065 cm ⁻¹

Under a nitrogen atmosphere, t-BuOK / pyridine / KHCO ₃ / K ₂ CO ₃ / NaCO ₃ / NaHCO ₃ / CsCO ₃ (4: 1: 1: 1: 1) (0.951 g) was added to DMSO / THF / CH ₂ Cl ₂ / DMF (6: 2: 1: 1) (5 ml), cooled to −10 ° C., and 5,6-isopyrideneascorbic acid (0.917 g, 4.24 mmol) in DMSO / THF / A solution of CH ₂ Cl ₂ / DMF (6: 2: 1: 1) (5 ml) was added dropwise. Thereafter, a solution of bromoacetyl-DL-α-tocopherol (2.57 g, 4.66 mmol) in DMSO / THF / CH ₂ Cl ₂ / DMF (6: 2: 1: 1) (5 ml) was added dropwise. Stir for minutes and stir at room temperature for 8 hours. 1N HCl (4.3 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to obtain 5,6-isopyridene which is the vitamin C derivative of the present invention. Ascorbic acid-2-acetyl diester-DL-α-tocopherol (1.2 g) was obtained as a colorless oil. When ¹ H NMR, ¹³ CNMR, IR of this compound was measured, the same result as the previous item was obtained, and it was the same 5,6-isopyrideneascorbic acid-2-acetyl diester-DL-α-tocopherol as the previous item. It was confirmed.

The 5,6-isopyrideneascorbic acid-2-acetyl diester-DL-α-tocopherol (0.069 g, 0.1 mmol) prepared in the previous section was dissolved in methanol (5 ml) and THF (2 ml). 2N HCl (0.16 ml) was added and stirred at 50 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (methylene chloride: methanol = 10: 1), and the vitamin C derivative of the present invention represented by the following chemical formula 17 Ascorbic acid-2-acetyl diester-DL-α-tocopherol (0.051 g, 0.079 mmol) was obtained as a white solid. The ¹ H NMR, ¹³ C NMR, IR, and elemental analysis values of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 4.92 (2H, q, J = 16.8, 15.2), 4.71 (1H, s), 4.04 (1H, bs), 4. 75 (2H, bs), 2.54 (2H, bt), 2.05 (3H, s), 1.95 (3H, s), 1.91 (3H, s), 1.72 (2H, bs) ), 1.55-1.05 (24H, m), 0.87-0.83 (12H, m), ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.5, 170.4, 161.0, 149.5, 140.0, 126.7, 125.0, 124.0, 120.7, 117.5, 76.0, 75.7, 69.5, 67.7, 63.0, 39. 9, 37.3, 37.0, 33.1, 32.4, 31.5, 28.1, 24.7, 24.4, 22.3, 22. 21.0, 20.5, 19.4, 19.9, 13.2, 12.2, 11.6; IR (NaCl) 3365, 2953, 2925, 2870, 1757, 1669, 1468, 1375, 1333 , 1202, 1155, 1113, 1071, 1046 cm ⁻¹ . Elemental analysis value: Theoretical value (%) as C ₃₇ H ₅₈ O ₉ · H ₂ O = C, 66.84: H, 9.10. Found (%) = C, 66.80: H, 9.08.

Under nitrogen atmosphere, L-ascorbic acid (10 g, 55 mmol) manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in acetone (40 ml), acetyl chloride (1 ml, 15 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled at 0 ° C. overnight. The solid was filtered off, and the obtained solid was washed with ice-cooled acetone and dried in vacuo to obtain a compound of formula 18 (9.55 g, 44.2 mmol) as a white solid as a known substance. The ¹ H NMR (400 MHz, D ₂ O) of this compound is as follows. δ 4.79 (1H, d, J = 2 Hz), 4.46 (1 H, ddd, J = 2, 4.8, 7.2 Hz), 4.18 (1 H, dd, J = 7.2, 9) .2 Hz), 4.05 (1H, dd, J = 4.8, 9.2 Hz), 1.25 (6H, s).

窒素雰囲気化、ＭＰ Ｂｉｏｍｅｄｉｃａｌｓ社製のＤ−α−トコフェロ−ル（（４．４１ｇ，１０ｍｍｏｌ）を塩化メチレン（５０ｍｌ）に溶解し、ピリジン（０．９７ｍｌ，１２ｍｍｏｌ）とブロモアセチルブロミド４（１．０４ｍｌ，１２ｍｍｏｌ）を加えて室温で撹拌した。反応終了後、酢酸エチルを加えて薄め、有機層を水と飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させた。硫酸ナトリウムをろ過した後に溶媒を留去し、得られた残留物をカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８０：１）で精製し、以下化学式１９で示される本発明のブロモアセチルＤ−α−トコフェロ−ル（３．２３ｇ，５．８６ｍｍｏｌ，５９％）を無色の油状物として得た。この化合物の^１Ｈ ＮＭＲ、^１３ＣＮＭＲ、及びＩＲの値は以下の通り。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ ４．０７（２Ｈ，ｓ），２．５９（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ Ｈｚ），２．０９（３Ｈ，ｓ），２．０４（３Ｈ，ｓ），２．００（３Ｈ，ｓ），１．８２−１．７２（２Ｈ，ｍ），１．５６−１．０５（２４Ｈ，ｍ），０．８８−０．８３（１２Ｈ，ｍ）；^１３ＣＮＭＲ（１００ＭＨｚ，ＣＤＣｌ_３）：δ １６５．９，１４９．８，１４０．３，１２６．６，１２４．９，１２３．３，１１７．５，７５．２，３９．５，３７．５４，３７．５１，３７．４９，３７．４，３２．９，３２．８，３１．１，２８．０，２５．１，２４．９，２４．５，２２．８，２２．７，２１．１，２０．６，１９．８４，１９．７５，１２．９，１２．０，１１．９；ＩＲ（ＮａＣｌ）２９５０，２９２６，２８６６，１７５４，１４５９，１４１４，１３７６，１２６８，１２４１，１２１３，１１５７，１１０３，１０６５ ｃｍ^−１

In a nitrogen atmosphere, MP Biomedicals D-α-tocopherol ((4.41 g, 10 mmol) was dissolved in methylene chloride (50 ml), and pyridine (0.97 ml, 12 mmol) and bromoacetyl bromide 4 (1. (04 ml, 12 mmol) was added, and the mixture was stirred at room temperature After completion of the reaction, ethyl acetate was added to dilute the organic layer, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue was purified by column chromatography (hexane: ethyl acetate = 80: 1), and bromoacetyl D-α-tocopherol of the present invention represented by the following chemical formula 19 (3.23 g). , 5.86 mmol, was obtained 59%) as a colorless oil. ¹ H ^NMR, 13 ^CNMR, and IR values of this compound As the lower _{1 H NMR (400MHz, CDCl 3} ):. Δ 4.07 (2H, s), 2.59 (2H, t, J = 6.8Hz Hz), 2.09 (3H, s), 2 .04 (3H, s), 2.00 (3H, s), 1.82-1.72 (2H, m), 1.56-1.05 (24H, m), 0.88-0.83 (12H, m); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 165.9, 149.8, 140.3, 126.6, 124.9, 123.3, 117.5, 75.2, 39. 5, 37.54, 37.51, 37.49, 37.4, 32.9, 32.8, 31.1, 28.0, 25.1, 24.9, 24.5, 22.8, 22.7, 21.1, 20.6, 19.84, 19.75, 12.9, 12.0, 11.9; IR (NaCl) 2 50,2926,2866,1754,1459,1414,1376,1268,1241,1213,1157,1103,1065 cm ^-1

5,6-Isopyridene ascorbic acid (0.726 g, 3.36 mmol) and bromoacetyl D-α-tocopherol (1.56 g, 2.8 mmol) were dissolved in DMF (10 ml), and potassium bicarbonate ( 0.336 g, 3.36 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 5: 1) to give the vitamin C derivative of the present invention of formula 20 as a 5,6- Isopyridene ascorbic acid-3-acetyl diester-D-α-tocopherol (1.06 g, 1.54 mmol) was obtained as a white solid. ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 5.55 (1H, s), 5.32 (1H, d, J = 16.4 Hz), 5.28 (1H, d, J = 16.8 Hz), 4.70 (1H, d, J = 4.4 Hz), 4.31 (1H, dt, J = 4.4, 6.8 Hz), 4.19 (1H, dd, J = 6.8, 8. 8 Hz), 4.07 (1 H, dd, J = 6.4, 8.8 Hz), 2.59 (2 H, t, J = 6.8 Hz), 2.09 (3 H, s), 2.02 ( 3H, s), 1.98 (3H, s), 1.83-1.73 (2H, m), 1.57-1.01 (30H, m), 0.87-0.83 (12H, ^{m); 13 CNMR (100MHz CDCl} 3): δ 170.6,166.8,149.8,147.9,139.8,126.6,125.0,12 3,120.8,117.6,110.3,76.1,75.2,74.9,67.0,65.4,39.4,37.5,37.3,32.8 32.7, 31.1, 28.0, 26.0, 25.5, 24.8, 24.5, 22.75, 22.65, 21.0, 20.6, 19.8, 19 7, 12.9, 12.0, 11.8; IR (NaCl) 3298, 2927, 2868, 1771, 1703, 1457, 1378, 1340, 1254, 1183, 1153, 1070 cm ⁻¹

The compound of formula 20 (1.06 g, 1.54 mmol) prepared in the previous section was dissolved in methanol (15 ml), 2N HCl (2.5 ml) was added, and the mixture was stirred at 50 ° C. for 2 hours. The solid was collected by filtration using a Kiriyama funnel, the filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, combined with the solid collected by filtration, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to give the vitamin of the present invention of formula 21 C-derivative L-ascorbic acid-3-acetyl diester-D-α-tocopherol (0.83 g, 1.28 mmol) was obtained as a white solid. The ¹ H NMR, ¹³ C NMR, IR and specific rotation values and elemental analysis values of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ): δ 5.63 (1H, d, J = 16.8 Hz), 5.04 (1H, d, J = 16.8 Hz), 4.80 (1H, d, J = 2Hz) 4.14 (1H, ddd, J = 1.6, 4.8, 7.2 Hz), 3.88 (1H, dd, J = 7.2, 11.2 Hz), 3.76 (1H) , Dd, J = 4.8, 11.2 Hz), 2.58 (2H, t, J = 7.2 Hz), 2.09 (3H, s), 2.02 (3H, s), 1.98 (3H, s), 1.81-1.03 (26H, m), 0.88-0.83 (12H, m); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 170.1, 168.3, 150.0, 146.5, 139.6, 135.8, 125.5.123.6, 120.6, 117.7, 76.2, 75 3, 72.6, 69.6, 66.6, 66.1, 62.9, 39.4, 37.44, 37.41, 37.3, 32.8, 32.7, 30.9, 30.3, 28.0, 24.8, 24.4, 22.7, 22.6, 21.0, 20.5, 19.7, 19.6, 12.9, 12.0, 11. 8;
IR (NaCl) 3383, 2926, 2867, 1754, 1682, 1462, 1427, 1375, 1321, 1208, 1160, 1087 cm ⁻¹ ; [α] ^T _D (c = g / 100 ml, solvent), [α] ²⁵ _{D +79.1 (c 0.54, CHCl 3} ). Elemental analysis value: Theoretical value (%) as C ₃₇ H ₅₈ O ₉ · H ₂ O = C, 66.84: H, 9.10. Found (%) = C, 66.77: H, 9.08.

Under a nitrogen atmosphere, t-BuOK (0.617 g, 5.5 mmol) was suspended in DMSO / THF (3: 2) (10 ml), cooled to −10 ° C., and the compound of formula 18 (0.595 g, 2 .75 mmol) in DMSO / THF (3: 2) (10 ml) was added dropwise. Thereafter, a solution of the compound of Formula 19 (1.67 g, 3.03 mmol) in DMSO / THF (3: 2) (10 ml) was added dropwise, stirred for 5 minutes, and stirred overnight at room temperature. 1N HCl (2.75 ml) and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the resulting residue was purified by column chromatography (hexane: ethyl acetate = 1: 1) to obtain 5,6-isopyridene, which is the vitamin C derivative of the present invention represented by Formula 22. Ascorbic acid-2-acetyl diester-D-α-tocopherol (0.696 g, 1.01 mmol) was obtained as a yellow solid. ¹ H NMR, ¹³ C NMR and IR of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 9.57 (1H, bs), 4.88 (1H, d, J = 17.6 Hz), 4.85 (1H, d, J = 17.6 Hz), 4.66 (1H, d, J = 3.2 Hz), 4.35 (1H, dt, J = 3.2, 6.8 Hz), 4.17 (1H, dd, J = 6.8, 8. 4 Hz), 1.09 (1 H, dd, J = 6.4, 8.4 Hz), 2.60 (2 H, t, J = 6.4 Hz), 2.10 (3 H, s), 1.99 ( 3H, s), 1.95 (3H, s), 1.84-1.74 (2H, m), 1.56-1.03 (30H, m), 0.88-0.84 (12H, ^{m); 13 CNMR (100MHz,} CDCl 3): δ 172.0,168.7,160.5,150.0,139.7,126.2,124.6, 23.5, 121.6, 117.7, 110.4, 75.3, 74.7, 73.7, 68.5, 65.2, 39.4, 37.44, 37.39, 37. 3, 32.8, 32.7, 30.9, 28.0, 25.9, 25.5, 24.8, 24.4, 22.7, 22.6, 21.0, 20.6, 19.8, 19.7, 12.9, 12.1, 11.8; IR (NaCl) 2927, 2869, 1770, 1683, 1457, 1378, 1337, 1255, 1209, 1147, 1068 cm ⁻¹

The compound of Formula 22 (0.696 g, 1.01 mmol) was dissolved in methanol (15 ml), 2N HCl (1.62 ml) was added, and the mixture was stirred at 50 ° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off, and the resulting residue was purified by column chromatography (methylene chloride: methanol = 10: 1), and the vitamin C derivative L- Ascorbic acid-2-acetyl diester-D-α-tocopherol (0.43 g, 0.66 mmol) was obtained as a brown solid. The ¹ H NMR, ¹³ C NMR, IR, specific rotation value and elemental analysis value of this compound are as follows. ¹ H NMR (400 MHz, CDCl ₃ ); δ 4.94 (1H, d, J = 16.8 Hz), 4.91 (1H, d, J = 16.8 Hz), 4.76-4.73 (1H M), 3.83 (1H, dt, J = 1.2, 6.8 Hz), 3.58 (2H, d, J = 6.8 Hz), 2.52 (2H, t, J = 6. 8 Hz), 1.98 (3H, s), 1.91 (3H, s), 1.87 (3H, s), 7.13-1.68 (2H, m), 1.48-0.97. (24H, m), 0.79-0.75 (12H, m); ¹³ C NMR (100 MHz, CDCl ₃ ): δ 170.4, 170.3, 160.9, 149.7, 139.8, 126 5, 124.9, 123.2, 120.3, 117.6, 76.3, 75.2, 69.8, 67.7, 63.1, 3 4, 37.5, 37.3, 32.8, 32.7, 31.0, 28.0, 24.8, 24.5, 22.7, 22.6, 21.0, 20.5 19.8, 19.6, 12.9, 12.0, 11.8. IR (NaCl) 3361, 2951, 2926, 2868, 1758, 1681, 1461, 1377, 1337, 1204, 1152, 1110, 1074, 1045 cm ⁻¹ ; [α] ^T _D (c = g / 100 ml, solvent), [Α] ²⁵ _D +27.9 (c 0.54, CHCl ₃ ). Elemental analysis value: Theoretical value (%) as C ₃₇ H ₅₈ O ₉ · H ₂ O = C, 66.84: H, 9.10. Found (%) = C, 66.79: H, 9.09.

Hereinafter, the compounds of the present invention synthesized above are represented by abbreviations as follows. 5,6-Isopyrodene vitamin C-3-acetyl diester vitamin E: IP-AA-3-VE. Vitamin C-3-acetyl diester vitamin E: AA-3-VE. 5,6-Isopyridene vitamin C-2-acetyl diester vitamin E: IP-AA-2-VE. Vitamin C-2-acetyl diester vitamin E: AA-2-VE. 5,6-Isopyridene ascorbic acid-3-acetyl diester-DL-α-tocopherol: IP-AA-3-DL-α-Toc. L-ascorbic acid-3-acetyl diester-DL-α-tocopherol: AA-3-DL-α-Toc. 5,6-Isopyridene-ascorbic acid-2-acetyl diester-DL-α-tocopherol: IP-AA-2-DL-α-Toc. L-ascorbic acid-2-acetyl diester-DL-α-tocopherol: AA-2-DL-α-Toc. 5,6-Isopyridene-ascorbic acid-3-acetyl diester-D-α-tocopherol: IP-AA-3-D-α-Toc. L-ascorbic acid-3-acetyl diester-d-α-tocopherol: AA-3-D-α-Toc. 5,6-Isopyridene-ascorbic acid-2-acetyl diester-D-α-tocopherol: IP-AA-2-D-α-Toc. L-ascorbic acid-2-acetyl diester-D-α-tocopherol: AA-2-D-α-Toc.
Furthermore, the substance names and abbreviations of the existing vitamin C derivative groups used for the control are as follows.
Ascorbic acid-2-phosphate Na: AA-2-P
Ascorbic acid-2-glucoside: AA-2-G
Ascorbic acid-2-potassium sulfate: AA-2-S
Ascorbic acid-3-methyl: AA-3-M
Ascorbic acid-2-phosphate-6-palmitic acid Na: AA-2-P-6-Pal
Ascorbic acid-2-phosphate tocopherol K: AA-2-P-Toc
Ascorbic acid-2-maleic acid tocopherol Na: AA-2-M-Toc
The emulsion having the liquid crystal structure of the present invention (hereinafter abbreviated as “liquid crystal emulsion”) was produced by the following method.
12 g of the compounds of the present invention described in Table 1 and 20 g of glycerin are mixed well with an electric mixer, and this is designated as A. Let B be 20 g of jojoba oil previously heated to 80 ° C. and dissolved in 5 g of cholesterol. Mix well with electric mixer while adding B to A little by little. 50 g of a pale yellow pasty mixture containing 10% by weight of 12 kinds of the present compounds was obtained. This is hereinafter abbreviated as a paste for liquid crystal emulsion. 50 g of this paste for liquid crystal emulsion was mixed well with 450 g of purified water, subjected to ultrasonic treatment for 15 minutes, and then a white emulsion was obtained through an extruder having a 0.45 μm hole. When this was diluted to an appropriate concentration with purified water and observed with a polarizing microscope, a maltase cross image having a characteristic cross structure was confirmed. This confirmed that these 12 types of emulsions had a liquid crystal structure.

(Stability test)
The 12 kinds of the synthesized compounds of the present invention, the paste for liquid crystal emulsion containing 10% by weight of the 12 kinds of the compounds of the present invention prepared above, and the control as an existing ascorbic acid derivative described above 7 types of existing vitamin C derivatives used in the water and a simple substance of vitamin C and vitamin E were made from an ITO gel base (composition content: glycerin: 34.45%, carbomer: 1.13%, polyacrylic acid (Na: 0.38%, water: 63.92%, methyl paraben: 0.09%, propyl paraben: 0.03%). At this time, the liquid crystal emulsion paste was mixed at 10% by weight to obtain the liquid crystal emulsion of the present invention. When 12 types of this liquid crystal emulsion were appropriately diluted with purified water and observed with a polarizing microscope, a maltase cross image was obtained. The results of the presence or absence of a maltase cross image at the time of observation with a polarizing microscope are shown in Table 1. This confirmed that these 12 types of emulsions were emulsions having a liquid crystal structure. Each test substance thus obtained was stored at 40 ° C. for 6 months, and each titer was measured three times by high performance liquid chromatography to obtain an average value. As a result, ◎, 95% or more remained ◎, less than 95% remained 90% or more, ○, less than 90% remaining X, the following table It was shown in 1.

From the above results, 90% or more of all 12 types of the compounds of the present invention remained ◯, and all the liquid crystal emulsions containing the compounds of the present invention remained 95% or more. On the other hand, the stability of AA-2-P, AsA-2-P-6-Pal, AsA-2-M-Toc, and vitamin C and vitamin E alone was poor and was 80% or less. The AA-2-P, AsA-2-P-6-Pal, AsA-2-M-Toc and Vitamin C derivatives of the three types of controls not only have low measured values in HPLC, but also have a bad smell. The resulting solution turned brown and was not practical. Further, two types of controls, AsA-2-P-6-Pal and AsA-2-M-Toc, had a granular precipitate and were in a state that could not withstand practical use. From the judgment that the compound with poor stability of the rule was not stable and could not be put into practical use, it was decided to exclude it from the control in the following tests. In addition, what was shown by (triangle | delta) changed into light brown and the off-flavor generate | occur | produced, and these discoloration and off-flavor reduced the commercial value of cosmetics, a foodstuff, a pharmaceutical, feed, etc. In addition, those marked with X are discolored severely to brown and have a strange odor that burns sugar. These discolorations and odors can drastically reduce the value of products containing them and cannot be used. In contrast, the compounds of the present invention have high skin absorbability, and are used as compositions for external use such as cosmetics and external medicines, as therapeutic agents for radical diseases for humans and animals, and as antioxidant compositions. It increased value and proved its usefulness and effectiveness. .

(Comparison of absorbability to skin tissue)
Vitamin C derivatives of 4 types of controls except the 12 types of the synthesized compounds of the present invention and 3 types of vitamin C derivatives except the 3 types of vitamin C derivatives for which stability could not be ensured in the stability test. , And Vitamin C and Vitamin E alone were measured for percutaneous absorption into skin tissue. Twelve types of vitamin C derivatives of the present invention and four types of control vitamin C derivatives were mixed at 1% by weight with a polyacrylic acid gel base made by ITO to obtain a dispersion. These gel dispersions were applied to a human three-dimensional epidermis model having a stratum corneum and a stratum corneum, and 0.1 g per square centimeter was applied. After culturing at 37 ° C. for 3 hours, the gel dispersions were removed and 5 ml with PBS. After washing twice, the tissue of the coated part was cut out, homogenized with 10 volumes of PBS, deproteinized with 2% metaphosphoric acid, and then the amount of ascorbic acid derivative in the supernatant was measured by high performance liquid chromatography (HPLC). . In the above experiment, the stability of the vitamin C derivative AsA-2-d-α-Toc of the present invention, which had the highest stability of 99%, was defined as 100%, and the detection amounts of other derivatives were expressed in%. Table 2 below. In addition, in order to make the results easy to understand, ◯ was given to those having a transmelanin inhibition rate of 90% or more, Δ to those meeting 70-90%, and X to 70% or less.

上記の経皮吸収性の実験結果より本発明の１２種類の全ての誘導体は優れた経皮吸収性を示したが、コントロ−ルのＡｓＡ−２−Ｇ、ＡｓＡ−２−Ｓ Ｋ、ＡｓＡ−３−Ｍ、ビタミンＣ、ビタミンＥは経皮吸収性が明らかに本発明のビタミンＣ誘導体に比較し劣っていた。安定性試験の結果と経皮吸収性の２つの結果を総合すると、本発明のビタミンＣ誘導体と同等の性能を持つ既存のコントロ−ルはＡｓＡ−２−Ｐ−Ｔｏｃのみが残った。従ってこれらの△やＸで示されたコントロールの化合物は、、これらが含有された商品の価値を目覚ましく低下し使用不能にさせるものであり、これに対し本発明の化合物は、これらの皮膚吸収性が高く化粧品や外用医薬品などの外用組成物、ヒト用や動物用のラジカル疾患治療薬、抗酸化組成物のとしての商品価値を高め、その有用性及び有効性を証明するものであった。。

From the above results of percutaneous absorbability, all 12 types of derivatives of the present invention showed excellent transdermal absorbability, but the controls AsA-2-G, AsA-2-SK, AsA- 3-M, vitamin C, and vitamin E were clearly inferior in transdermal absorbability compared to the vitamin C derivative of the present invention. By combining the results of the stability test and the percutaneous absorption, only AsA-2-P-Toc remained as an existing control having the same performance as the vitamin C derivative of the present invention. Therefore, these control compounds represented by Δ and X markedly reduce the value of the products containing them and make them unusable. On the other hand, the compounds of the present invention have their skin absorbability. Therefore, it has increased the commercial value as a composition for external use such as cosmetics and external medicines, a therapeutic agent for radical diseases for humans and animals, and an antioxidant composition, and has proved its usefulness and effectiveness. .

(Inhibiting action of melanin production using pigment cells)
Of the 12 types of synthesized compounds of the present invention and 4 types of control vitamin C derivatives, 3 types of vitamin C derivatives of control which were poorly absorbed in the above-described absorption test to skin tissue. A melanin production inhibition test using B16 melanoma cells was carried out using a vitamin C derivative of one type of control excluding.
Mouse B16 mouse melanoma 4A5 cells (B164A5) were used for the inhibitory effect test on melanin production. B16 melanoma 4A5 was seeded in a 48-well microplate and cultured in DMEM medium containing 10% FBS under conditions of 37 ° C. and 5% CO 2 for 24 hours, and then an ascorbic acid derivative equivalent to 100 μmol / LM (the present invention) And a control ascorbic acid derivative) and 1 mmol / LM theophylline-added 10% FBS-containing DMEM medium (same as above), and cultured under conditions of 37 ° C. and 5% CO 2 for 72 hours. After completion of the culture, the medium was removed and replaced with purified water, and the cells were disrupted with ultrasonic waves, and then divided into two for melanin quantification and protein quantification. For melanin quantification, the cell lysate was solubilized in 1 mol / LN NaOH at 60 ° C. for 30 minutes, and the absorbance at 405 nm was measured with an absorptiometer. Protein quantification was carried out using a Pierce BCA protein assay kit at 37 ° C. for 30 minutes, and the absorbance at 570 nm was measured with a spectrophotometer (same as above). The absorbance of melanin and protein thus obtained was divided and used for calculation of the melanin production inhibition rate as the amount of melanin per unit protein. The calculation formula for determining the melanin production inhibition rate is as follows. The absorbance of the medium containing theophylline and each compound is expressed as MLs, the absorbance of the medium containing only theophylline is expressed as MLc, and the absorbance of the medium containing neither theophylline nor each compound is expressed as MLn. It is shown by the following formula.
Melanin production inhibition rate (%) = (((MLc−MLs) / (MLc−MLn)) − 1) × 100
In order to compare the melanin production inhibition rate with other control derivatives, AsA-2-d-α- was the most effective melanin production inhibition rate of 72% among the vitamin C derivatives of the present invention in this experiment. The Toc melanin inhibition rate was set to 100%, and the detected amounts of other derivatives were expressed in% and are summarized in Table 3 below. Further, in order to make the results easier to understand, ○ was given to those having a transmelanin inhibition rate of 90% or more, Δ to those that matched 70-90%, and X to 70% or less.

From the above experimental results, all the 12 derivatives of the present invention showed excellent melanin production inhibition rate, but the control AsA-3-M and AA-2-P-Toc were melanin production inhibition. The rate was clearly inferior. Since it is already well known that free vitamin C and vitamin E separated from the derivatives are present in cells, the control compound indicated by X is melanin inhibitor. The product value of oral compositions such as cosmetics and external medicines for the purpose of, and food additives and feed additives is markedly reduced and rendered unusable. It has been shown that it has a high melanin production inhibition rate, is efficiently taken up into cells and expresses vitamin C and vitamin E activity at a high rate, and is a composition for external use such as cosmetics and external medicines for the purpose of melanin inhibition, food It increased the commercial value as an additive or feed additive, and proved its usefulness and effectiveness. .
The ascorbic acid derivative of the present invention clearly exhibits superior effects as compared with the conventional control ascorbic acid derivative by the above three tests of stability test, skin tissue absorbability test and melanin production inhibition test. It was confirmed. The reason that AA-2-M has a lower melanin production inhibitory effect than the vitamin C derivative of the present invention is that the result of absorbability into the skin was Δ, which was clearly inferior to the derivative of the present invention. Has a low molecular weight of the side chain of AA-3-methyl and a low polarity, so that the amphiphilic performance is lower than that of the vitamin C derivative of the present invention and the ability to permeate the skin barrier composed of a multilayer of fat-soluble and water-soluble barrier However, it is considered that the vitamin C derivative of the present invention was higher. Furthermore, the melanin production inhibitory action of the present invention was higher than that of the existing AA-2-P-Toc derivative because the diester derivative mediated by phosphoric acid is not very stable, It has been found that the hydrolysis action by phosphatase is extremely difficult, and it was estimated that the ascorbic acid activity in the living body was lower than that of the derivative of the present invention.

(Toxicity test for melanin-producing cells)
Toxicity tests on melanin-producing cells were carried out using the 12 kinds of synthesized compounds of the present invention and a control whitening agent.
Mouse B16 mouse melanoma 4A5 cells (B164A5) were used for the toxicity test on melanin producing cells. B16 melanoma 4A5 was seeded in a 48-well microplate, cultured in DMEM medium containing 10% FBS under conditions of 37 ° C. and 5% CO 2 for 24 hours. Ascorbic acid derivative of the present invention corresponding to 1 mmol / LM And 10% FBS-containing DMEM medium (same as above) with respect to a whitening agent other than the existing vitamin C derivative to be compared and a control containing no medium components alone, and the condition is 72 ° C. under conditions of 37 ° C. and 5% CO 2. Time culture was performed.
After completion of the culture, the medium was replaced with 10% FBS-containing DMEM medium (same as above) containing 0.5 mg / mL MTT, and after culturing for 3 hours, the medium was replaced with 0.04 mol / LN HCl / IPA to lyse the cells. The cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated. The cell growth rate is expressed by the following calculation formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
Cell proliferation rate (%) = ((MTTs / MTTc) −1) × 100
In order to compare the cell growth rate with other control derivatives, in this experiment, among the vitamin C derivatives of the present invention, those having a positive cell growth rate relative to the whitening agent-free control Toxicity to cells is evaluated as negative, and those with a cell growth rate of 0 or a negative value (cells that do not grow at all, or conversely that cells are moribund and decreased) have a cytostatic effect. The cytotoxicity was evaluated as positive.

The experimental results are summarized in Table 4 below.

  From the above results, the compound of the present invention was confirmed to have high safety because it had a melanin inhibitory effect on pigment cells, but no toxicity to pigment cells such as a cell death promoting effect was observed. On the other hand, the whitening agent containing existing natural phenols has a considerable inhibitory effect on pigment cells, and apparently the safety against pigment cells is inferior to that of the compound of the present invention. Free forms of vitamin C and vitamin E converted from derivatives are known to have an effect of reducing cytotoxicity. Since these positive control compounds are highly toxic to pigment cells, the probability of developing erythema or vitiligo in the skin tissue increases, so the value of products containing them is remarkable. It is to reduce. On the other hand, the compound of the present invention is low in toxicity to pigment cells, and is shown to be efficiently taken up into cells to express vitamin C and vitamin E activity at a high rate. Increased commercial value as a composition for external use, oral composition such as food additive and feed additive, radical disease therapeutic agent for humans and animals, cell growth promoting composition, antioxidant composition And proved its effectiveness. .

(Proliferation effect on cells)
After thawing frozen normal human fibroblasts NHDF (NB), NHDF was seeded in a 96-well microplate, cultured in DMEM medium containing 10% FBS at 37 ° C. under 5% CO 2 for 2 days, After adding the compound of the present invention equivalent to 300 μmol / LM and the same amount of the control derivative and culturing for 3 days, the medium was replaced with a DMEM medium containing 10% FBS containing 0.5 mg / mL MTT (same as above). After time culture, the cells were lysed by exchanging with 0.04 mol / LN HCl / IPA. The cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated. The cell growth rate is expressed by the following calculation formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
Cell increase rate (%) = ((MTTs / MTTc) −1) × 100
As a result, the cell increase rate after 3 days with respect to the control was measured and calculated. Those reduced are shown in Table 5 with a cross. For comparison, existing derivatives and vitamin C were used as control derivatives. It was found that when the vitamin C derivative of the present invention was cultured for 3 days under conventional cell culture conditions, the number of cells increased to a minimum of 30% or more compared to the additive-free control compared to the additive-free control. . Free forms of vitamin C and vitamin E converted from derivatives are known to increase cell growth rates. Since these control compounds represented by X have extremely low cell proliferation rates, they significantly reduce the value of the products containing them, whereas the compounds of the present invention have a cell proliferation rate. It is highly incorporated into cells and has been shown to express vitamin C and vitamin E activity at a high rate, and can be used for oral use such as cosmetics and external preparations, food additives and feed additives. It increased the commercial value as a composition, a therapeutic agent for radical diseases for humans and animals, a cell growth promoting composition, and an antioxidant composition, and proved its usefulness and effectiveness. .

Similar experiments with human epidermal keratinocytes, hair matrix cells, cardiomyocytes, hepatocytes, kidney cells, lung epithelial cells, intestinal mucosal cells, glial cells, vascular endothelial cells, adipocytes, stem cells, hematopoietic stem cells, pluripotent stem cells , Basal layer stem cells, ES cells, and iPS cells were also performed, but the compounds in Table 5 of the present invention are all ◎, and the control derivatives in Table 5 of the target group are all X. there were.

From the above experimental results, the cell proliferation rate was clearly inferior in the two types of control, AsA-3-M and AA-2-P-Toc, as compared with all the 12 derivatives of the present invention. This suggests that the conversion rate to vitamin C in the cells is superior to the conventional vitamin C derivative having good stability in the present invention. While the conventional vitamin C derivative is good in stability, it is considered that the conversion rate of vitamin C in cells is poor. Free forms of vitamin C and vitamin E converted from derivatives are known to increase cell growth rates. These control compounds represented by X are extremely low in cell proliferation rate, and thus markedly reduce the value of the products containing them. In contrast, the compound of the present invention has a cell proliferation rate. It is high and is taken up efficiently into cells and has been shown to express vitamin C and vitamin E activity at a high rate. Oral compositions such as cosmetics and external medicines, food additives and feed additives Products, human and animal radical disease therapeutic agents, cell growth promoting compositions, and antioxidant compositions, increasing their commercial value and proving their usefulness and effectiveness. .

  As a result of the above four tests of stability test, skin tissue absorbability test, melanin production inhibition test, and cell growth rate acceleration test, the ascorbic acid derivative of the present invention is clearly compared with the conventional control ascorbic acid derivative. It was confirmed that an excellent effect was exhibited. The reason why the cell growth rate of AA-2-M was lower than that of the vitamin C derivative of the present invention was that the result of absorption to the skin was Δ, which was clearly inferior to the derivative of the present invention. Since the molecular weight of the -3-methyl side chain is obviously small and low in polarity, the amphiphilic performance is lower than that of the vitamin C derivative of the present invention, and the ability to permeate the skin barrier composed of a multilayer of fat-soluble and water-soluble barriers is This is probably because the vitamin C derivative was higher.

Furthermore, the derivative of the present invention has a higher cell growth rate than the existing AA-2-P-Toc derivative because the phosphate-mediated diester derivative is not very stable, It has been found that the hydrolysis action by phosphatase is extremely difficult, and it was estimated that the ascorbic acid activity in the living body was lower than that of the derivative of the present invention. Some vitamin C derivatives that are hydrolyzed enzymatically with ascorbic acid are known to have high collagen production ability in fibroblasts, which is higher than FGF (fibroblast growth factor). There are also reports. Since the compound of the present invention does not have a phosphate diester structure having high stability and low enzymatic hydrolysis action such as AA-2-P-Toc compared with the existing vitamin C derivative, AA-2- It was presumed to have higher melanin production-inhibiting ability and fibroblast proliferation action than P-Toc.
In addition, the compound of the present invention has a promoting effect on fibroblast proliferation, but no inhibitory action was observed, and thus high safety was recognized.

(Clinical trial)
In order to examine the effects of the compounds shown in Table 6 of the present invention on acne, wrinkles and pores, the present invention is only explained to those who have fully explained to the subject and obtained consent for participation in the study. Of AA-2-dl-α-TOC. In the test, a gel base material containing 0.1% of the compound of the present invention shown in Table 6 with respect to a gel base material manufactured by ITO, and a gel base material added with the same amounts of the control derivatives and vitamin C shown in Table 6 as controls. And 3 sections of placebo gel base. It applied to all the face after washing face twice a day in the morning and evening with respect to 7 subjects per 1 ward, and the test was conducted for 1 to 2 months. As an evaluation method, the acne count was performed twice at the start of the test and at the end of the test one month later by using a facial image analyzer (VISIA and Roboscan analyzer), and the percentage improvement from the experimental start was improved. The rate was compared. As a result, ((number of acne in test group / number of acne in non-added control) × 100) −100 = cell growth rate (%) was calculated and compared using the formula of cell growth rate (%).

As a result, Table 6 shows ◎ for those improved by 30% or more, ◯ for those improved by 10% or more but less than -30%, and x for those less than 10%. As a result, in the measurement of acne, the vitamin C derivative and vitamin C of the present invention were improved by 30% or more in all test items as compared to the gel base group to which the same amount of the placebo gel base group and the control derivative were added. The effect of the vitamin C derivative of the present invention could be confirmed. The same analysis was performed on the redness area, the number of porphyrin spots, the number of pores, and the number of wrinkles using a facial image analyzer (VISIA and Roboscan analyzer). Yes, all of the control derivatives in Table 6 in the target section were X. From these results, it was shown that the compound of the present invention has a high clinical effect, is efficiently taken into cells and expresses vitamin C and vitamin E activity at a high rate, and is used for external compositions such as cosmetics and external medicines, It increased the commercial value of human and animal radical disease therapeutic agents, cell growth promoting compositions and antioxidant compositions, and proved their usefulness and effectiveness. . The increase in acne, stains and wrinkles is also reported to be due to the promotion of lipid peroxidation of the epidermis, which is a category of radical disease. Since it can be suppressed by an antioxidant composition such as vitamin E, it is considered that the use of the compound of the present invention resulted in good clinical results.

(Temperature stress cell death inhibitory effect)
Frozen normal human dermal fibroblasts were thawed, cultured in a serum-free medium for human dermal fibroblasts for 3 days, and further subcultured twice. Then, after applying a high temperature stress at 45 ° C. for 3 hours before the third passage, 300 μmol / LM equivalent of the compound of the present invention and the same amount of the control derivative were added and cultured for 3 days. The medium was replaced with 10% FBS-containing DMEM medium (same as above) containing 5 mg / mL MTT, and after culturing for 3 hours, the cells were replaced with 0.04 mol / LN HCl / IPA to lyse the cells. The cell lysate was measured for absorbance at 570 nm using an absorptiometer, and the cell growth rate was calculated. The cell growth rate is expressed by the following calculation formula, where the absorbance of cells treated with the sample is MTTs, and the absorbance of cells without added sample is expressed as MTTc.
Cell increase rate (%) = ((MTTs / MTTc) −1) × 100

As a result, when the number of cells increased by 30% or more compared to the non-added control, ◎, when the increase was less than 30%, ○, when no increase was observed or when it decreased, × The results are shown in Table 7. For comparison, existing derivatives and vitamin C were used as controls. When the compound of the present invention shown in Table 7 is added at a concentration of 1 μmol / L compared to an additive-free control and cultured for 3 days, cells are cultured in an existing medium suitable for each cell. Was found to increase compared to the additive-free control. In the additive-free control, the number of cells decreased conversely due to temperature stress. Similar experiments with human epidermal keratinocytes, hair matrix cells, cardiomyocytes, hepatocytes, kidney cells, lung epithelial cells, intestinal mucosal cells, glial cells, vascular endothelial cells, adipocytes, stem cells, hematopoietic stem cells, pluripotent stem cells The basal layer stem cells, ES cells, and iPS cells were also tested. The compounds in Table 7 of the present invention were all ◎, and the control derivatives in Table 7 of the target group were all X. From these results, it was proved that the compound of the present invention was highly effective as a food additive or feed additive for anti-stress by showing that the compound of the present invention had a high effect on temperature stress. Furthermore, since vitamin C and vitamin E are already known to reduce cell temperature stress, the present results show that the compound of the present invention is efficiently incorporated into cells and vitamin C and vitamin E at a high rate. It has been shown to exhibit activity, and external compositions such as cosmetics and external medicines, oral compositions such as food additives and feed additives, therapeutic agents for radical diseases for humans and animals, cell growth promoting compositions, It increased the commercial value as an antioxidant composition and proved its usefulness and effectiveness. .

1.0 g of a trade name “Dexon” manufactured by Davis & Greck, which is a suture made of a PGA polymer, was immersed in the 1% by weight aqueous solution of the present invention shown in Table 8 and then taken out. After air drying, a suture thread as an example of the water-absorbing polymer composition used in the present invention was obtained. For comparison, a compound that did not immerse the compound of the present invention and a compound containing the same amount of existing L-ascorbic acid-2-glucoside were used for comparison.
Next, the back of a 10-week-old guinea pig was shaved, and a 2 cm long cut was made with a scalpel in a direction perpendicular to the midline of the back. Using the yarns of each of the examples and comparative examples, the wound was repaired by absorbing the water used in the present invention at five locations at regular intervals. One week after this treatment, the guinea pig was anesthetized under ether anesthesia, a 1 cm wide strip-like skin tissue was excised from the center of the incision, and the tensile strength (g / cm) of the incision using a rheometer. Was measured. Ten guinea pigs were used for each example and comparative example, and the tensile strength (g / cm) was the average of the values obtained for these guinea pigs.
As a result, ((Tensile strength of test section / Tensile strength of non-addition control) × 100) −100 = Calculated tensile strength ratio (%) increased by a calculation formula of increased tensile strength ratio (%) was compared. When the increase in tensile strength (%) is increased by 20% or more, mark ◎ if the increase is 10% or more and less than 20%, and mark X if the increase is less than 10%. Table 8 shows the results. As a comparison, a compound containing the same amount of the existing control derivative and vitamin C in Table 8 was used as a control for comparison.

From the above results, it was confirmed that the tensile strength was greatly increased in the compound of the present invention. From these results, it was considered that the compound of the present invention showed a significant increase in the tensile strength, and thus the collagen synthesis was promoted well, the cell proliferation of the tissue was promoted, and the wound healing effect was expressed. The wound healing effect by increasing the tensile strength of the tissue is recognized even when the compound of the present invention is orally administered, and can be expected to be highly effective as a food additive or a feed additive. Since it is known to enhance healing, the present results indicate that the compound of the present invention is efficiently incorporated into tissues and expresses vitamin C and vitamin E activities at a high rate. Therefore, the compound of the present invention is a composition for external use such as cosmetics and external medicines having wound healing effect by cell proliferation, oral composition such as food additives and feed additives, therapeutic agents for radical diseases for humans and animals, cells It increased the commercial value as a growth promoting composition and an antioxidant composition, and proved its usefulness and effectiveness. .

A cell growth promoting composition having a wound healing effect by cell proliferation is shown below. Hereinafter, 84 parts by weight of polybutylene succinate PBS (Bionore 1001, Showa High Polymer Co., Ltd.), polyethylene terephthalate PET (Dianite) with respect to 0.1 parts by weight of each of the compounds of the present invention shown in Table 9. 10 parts by weight of PA-500 (manufactured by Mitsubishi Rayon) and 1 part by weight of ethylene glycidyl methacrylate copolymer E-GMA (reactive compatibilizer, Bond First E, manufactured by Sumitomo Chemical Co., Ltd.) Using an extruder (manufactured by Technobel Co., Ltd., KZW15-30MG), it is melt-kneaded in an ordinary method at 240 ° C., extruded and solidified in water with a diameter of about 3 mm, and then cut into 3 mm lengths. I got a chip. The extrusion conditions at this time were as follows.

<Extrusion conditions>
Temperature setting: feed 180 ° C., kneading section 240 ° C., head 180 ° C., rotation speed: 60 rpm
Each of the obtained chips was press-molded (press molding machine: manufactured by Shindo Metal Industry Co., Ltd.) and each femoral reinforcing material as an example of the water-absorbing polymer composition used in the present invention of the present invention and A fracture repair screw was prepared.
<Press molding conditions>
After pressing at 10 MPa for 1 minute at a press temperature of 180 ° C., pressing was performed at 20 MPa for 2 minutes. Then, it cooled for 3 minutes with the cooling press.

A cell growth promoting composition having a wound healing effect by cell proliferation is shown below. 10% by weight of hydroxyapatite (HA) prepared by spray-drying to a particle size of about 50 μm in an aqueous solution containing 1% by weight of an aqueous sodium alginate solution and 1% by weight of the compound of the present invention described in Table 10 in the previous section The mixture was mixed so that a uniform slurry was obtained. This slurry was formed into a spherical shape by dropping 3 μl each into a 1% by weight calcium chloride aqueous solution. The spherical HA molded as described above was dried at 60 ° C. for 12 hours and then sintered at 1250 ° C. for 1 hour to obtain porous spherical aggregate particles having a diameter of 0.8 ± 0.2. 1 was obtained by sterilizing an aqueous solution prepared by dissolving 10% by weight of each of the aqueous emulsified dispersion preparations prepared in the above examples in ultrapure water by vacuum decompression of the porous spherical aggregate particles using a 0.2 μm membrane filter. 1 was added, and then freeze-dried to obtain porous spherical aggregate particles for bone repair, which is an example of the water-absorbing polymer composition of the present invention containing the compound of the present invention. It was.
On the other hand, by kneading with a mixture of equimolar amounts of quaternary calcium phosphate (TeCP) and dicalcium phosphate (DCP) with ultrapure water containing 10% by weight of each aqueous emulsified dispersion preparation prepared in the above Example. A self-hardening calcium phosphate cement paste for bone repair, which is an example of the water-absorbing polymer composition used in the present invention, was prepared.

Next, the self-hardening calcium phosphate cement paste mixed with the aggregate particles so as to be 80 vol% is kneaded so that bubbles are taken into the paste, and CT data of the bone defect portion is obtained. Was filled in an impression mold having a bone defect site shape made based on the above, and was allowed to stand in the atmosphere at room temperature for 24 hours to obtain a cemented body having a bone defect site shape. By the above method, a calcium phosphate porous body having a bone defect site shape, which is an example of the water-absorbent polymer composition used in the present invention, could be obtained. In this calcium phosphate porous body, macropores of about 100 μm and micropores of several microns were distributed. The macropores are connected by micropores in the adjacent aggregate particles to form a communication hole network. When tested in a guinea pig bone defect model, the bone shape restoration speed healed several times faster than the conventional product as a result of comparison with the additive-free control same material. As a result, when the bone shape repair speed was healed more than twice as fast as the additive-free control, ◎ for those where an increase of 1 or more was observed, ○ for those where the healing speed did not improve Is shown in Table 10 with ×. As a comparison, the same amount of the existing control derivative and vitamin C in Table 10 was used as a control for comparison.

以上の結果より本発明の化合物では、治癒スピードが大きく向上したことが分かる。この結果より本発明の化合物が細胞増殖による創傷治癒効果を有する細胞増殖促進組成物としての商品価値を高め、その有用性及び有効性を証明するものであった。

From the above results, it can be seen that the healing speed is greatly improved in the compound of the present invention. From this result, the compound of the present invention has increased the commercial value as a cell proliferation promoting composition having a wound healing effect by cell proliferation, and proved its usefulness and effectiveness.

Example. Vegetable oil for edible and feed addition and method for producing the same IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2-VE, IP-AA-3-dl-α of the present invention -Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2-dl-α-Toc, IP-AA-3-d-α-Toc, AA-3 0.001 kg each of 12 kinds of compounds -d-α-Toc, IP-AA-2-d-α-Toc, and AA-2-d-α-Toc was added to 10 liters of edible soybean oil. The solution was shaken and filtered. Soybean oil was bottled, sealed and stored to obtain 12 types of soybean oil. The obtained 12 kinds of soybean oil can be used as a health food for preventing adult diseases. This edible oil has a heat stress reducing action, so it is not only for humans but also useful livestock such as cattle, horses, chickens, pigs, fish, shrimp, crab, abalone, silkworm, frog, dog, cat, It could also be used to increase the production of tropical fish, guinea pigs, mice, monkeys, earthworms, beer yeasts, baker's yeast economic animals and economic microorganisms.

Example. Biscuit-type nutrition-enriched food and animal feed and production method thereof 100 kg of wheat flour, 15 kg of margarine, 4.5 kg of flavoring additive, 7.0 kg of sugar, 2.3 kg of salt, 0.58 kg of edible soda, Carbon-ammonium salt 4 kg, citric acid 0.021 kg, starch 5 kg, and IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2-VE, IP of the present invention -AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2-dl-α-Toc, IP-AA-3-d -0.01 kg each of 12 types of compounds-α-Toc, AA-3-d-α-Toc, IP-AA-2-d-α-Toc, AA-2-d-α-Toc, and mixed well did. Subsequently, this mixture was shaken and formed into a biscuit shape, and then baked in an electric oven for 5 minutes to produce 12 types of biscuit-type food for nutrition enhancement and animal feed.

Examples of cosmetic and dermatological topical compositions Examples, scalp care cosmetics 12 types of scalp care cosmetics containing the compounds of the present invention listed in Table 11 were prepared to have the following composition% weight by weight: : About 10% isopropyl palmitate, about 3% (hereinafter weight percent) concentrated phosphatide with lecithin, about 3% bentonite clay, about 2% keratin hydrolysate, about 2% silicone wax, about Emulsification of 0.5% α-tocopherol oil essence, about 0.5% fragrance and 0.1% of each of the 12 compounds of the invention listed in Table 11 and 1% surfactin Aqueous solution, about 0.5% preservative, the rest is moisture. All of the 12 types of scalp care cosmetics obtained were used for 8 adult males (the test area was subjected to topical hair removal) for one month. The hair elongation rate and the eyelash elongation rate were significantly higher than those of the additive-free preparation. Hair elongation rate (%) = ((hair length (mm) one month after the start of the test / hair length on the test start date) -1) × 100. Eyelash elongation rate (%) = ((lash length (mm) one month after the start of the test / lash length on the test start date) -1) × 100. The results are shown in Table 11, where ◎ indicates a value significantly higher than the additive-free preparation of the compound of the present invention, and X indicates no significant difference. The scalp care cosmetic containing the compound of the present invention makes the skin healthy, promotes hair growth, revives hair, and eliminates dandruff. Vitamin C and vitamin E are known to have a hair elongation effect. In addition, when the composition of the present invention was orally administered, the hair elongation was recognized in the same manner. Therefore, it was found that the composition was effective as an oral composition for hair elongation. The results show that the compound of the present invention is efficiently taken into the skin tissue from the hair epidermis and expresses vitamin C and vitamin E activity at a high rate, and is used for external compositions and foods such as cosmetics and topical medicines. Enhance the commercial value of oral compositions such as additives and feed additives, therapeutic agents for radical diseases for humans and animals, cell growth promoting compositions and antioxidant compositions, and prove their usefulness and effectiveness. It was a thing.

Example. Effect on sunburn For the treatment of skin exposed to long-term sunlight (ultraviolet radiation), 12 ointments having the following composition (% by weight) were prepared: about 2% magnesium salt of aspartic acid, about 5 % Chamomile flower extract water-alcohol solution, about 1% vitamin A, B1, D, E, C, PP, about 4% lecithin, about 1% magnesium sulfate, about 2% sodium lactate And 12% of each of the 12 compounds listed in Table 12 of the present invention, 5% glycerin, 0.5% phenoxyethanol, 1% surfactin, and the rest is moisture. All of the 12 types of whitening and UV care cosmetics obtained for 8 adult males (the test area is unified near the center of the face with no lesions) is used for the month of summer. Both of the preparations of the present invention showed significantly lower values than the additive-free preparation of the compound of the present invention. Erythema rate (%) = ((a value of the color difference meter after one month from the start of the test / a value of the color difference meter on the test start day) −1) × 100. Pigmentation rate (%) = ((L value of color difference meter on test start date / L value of color difference meter one month after start of test) -1) × 100. The results are shown in Table 12. The results of the effect of the preparation to which the compound of the present invention was added showed that the two indices simultaneously showed significantly lower values compared to the additive-free preparation of the compound of the present invention. ◎ is indicated by X when the two indices were not significantly lower at the same time. When the preparation of the present invention was applied to the face of 0.5 g twice a day, the erythema rate and pigmentation rate showed significantly low values. The results are shown in Table 12. As a result, all of the compositions of the present invention were evaluated as “◎”, and all of the comparative control derivatives were X.

ビタミンＣやビタミンＥは日焼けに対する予防、治療効果が知られている。又、日焼けにおいては多くのフリーラジカルが産生し皮膚の皮脂の酸化が亢進することが知られており、これらの酸化された皮脂は脂質酸化物なり、細胞にダメージを与える。又、本発明の組成物を経口投与したところ、同様に日焼けに対する予防、治療効果が認められたことから、日焼け用経口用組成物としても有効であることがわかった。本結果より、本発明の化合物が皮膚組織内に効率的に取り込まれて高率でビタミンＣ及びビタミンＥ活性を発現することが示され、化粧品や外用医薬品などの外用組成物、食品添加物や飼料添加物などの経口用組成物、ヒト用や動物用のラジカル疾患治療薬、細胞増殖促進組成物、抗酸化組成物としての商品価値を高め、その有用性及び有効性を証明するものであった。

Vitamin C and vitamin E are known to be effective in preventing and treating sunburn. In addition, it is known that many free radicals are produced in sunburn, and the oxidation of sebum on the skin is promoted, and these oxidized sebum becomes lipid oxides and damages cells. In addition, when the composition of the present invention was orally administered, it was found that the composition was also effective as an oral composition for tanning because it similarly showed prevention and treatment effects against sunburn. This result shows that the compound of the present invention is efficiently taken into the skin tissue and expresses vitamin C and vitamin E activity at a high rate, and is used for external compositions such as cosmetics and topical medicines, food additives, It enhances the commercial value of oral compositions such as feed additives, therapeutic agents for radical diseases for humans and animals, cell growth promoting compositions and antioxidant compositions, and proves their usefulness and effectiveness. It was.

Examples of external compositions such as cosmetics and external medicines are shown below.
Examples of water-soluble drugs and skin lotions (shown below in% weight)
6% glycerin, 1% betaine, 1,3-butylene glycol: 5%, 0.5% phenoxyethanol, IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA of the present invention -2-VE, IP-AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2-dl-α-Toc, IP -AA-3-d-α-Toc, AA-3-d-α-Toc, IP-AA-2-d-α-Toc, AA-2-d-α-Toc, each of 12 types of compounds 0.01% was added, and finally purified water was added to make 100%.

Examples of emulsions and emulsions (1) Polyoxyethylene (10E.O.) sorbitan 1.0 monostearate: 0.5, (2) Polyoxyethylene (60E.O.) sorbit 0.5 tetraoleate : 0.5, (3) Glyceryl monostearate: 1.0, (4) F3: 0.1, (5) Behenyl alcohol: 0.5, (6) Squalane: 8.0, ( 7) Carboxyvinyl polymer: 0.1, (8) Phenoxyethanol: 0.5%, and IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2 of the present invention -VE, IP-AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2-dl-α-Toc, IP-AA -3-d-α-Toc, AA-3-d-α-Toc, IP-AA-2 d-α-Toc, it was added 12 kinds of compounds each AA-2-d-α-Toc 0.01%, and 100% by the addition of finally purified water.

Examples of ointment preparations and creams and packs (1) Polyoxyethylene (10E.O.) sorbitan 1.0 monostearate: 0.5, (2) Polyoxyethylene (60E.O.) sorbit 0.5 tetraolee -To: 0.5, (3) Glyceryl monostearate: 1.0, (4) F3: 0.1, (5) Behenyl alcohol: 0.5, (6) Squalane: 8.0 , (7) Carboxyvinyl polymer: 1.0%, (8) Phenoxyethanol: 0.5%, IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA of the present invention -2-VE, IP-AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2-dl-α-Toc, IP -AA-3-d-α-Toc, AA-3-d-α-Toc, I It was added -AA-2-d-α-Toc, AA-2-d-α-Toc of 12 types of compounds, respectively 0.01%, residues, was 100% with purified water.

An example of liquid foundation.
(1) Lanolin: 7.0, (2) Liquid paraffin: 5.0, (3) Stearic acid: 2.0, (4) Cetanol: 1.0, (5) Sunflower oil * 1: 1. 0, (6) Glycerin: 5.0, (7) Triethanolamine: 1.0, (8) Carboxymethyl cellulose: 0.7, (9) Mica: 15.0, (10) Talc: 6 0.0, (11) Titanium oxide: 3.0, (12) Color pigment: 6.0, (13) F5: 0.5, (14) Tormentilla extract * 3: 0.5, (15) 1, 3-butylene glycol: 0.02, (16) phenoxyethanol: 0.5, and IP-AA-3-VE, AA-3-VE, IP-AA-2-VE, AA-2-VE of the present invention, IP-AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-T c, AA-2-dl-α-Toc, IP-AA-3-d-α-Toc, AA-3-d-α-Toc, IP-AA-2-d-α-Toc, AA-2- Each of the 12 kinds of d-α-Toc compounds was added in an amount of 0.01%, and the residue was water.

Examples of external detergents, facial cleansers, body shampoos.
(Prescription) (%)
(1) stearic acid: 10.0, (2) palmitic acid: 8.0, (3) myristic acid: 12.0, (4) lauric acid: 4.0, (5) oleyl alcohol: 1. 5, (6) Purified lanolin: 1.0, (9) Phenoxyethanol: 0.2, (10) Glycerin: 18.0, and IP-AA-3-VE, AA-3-VE, IP- of the present invention AA-2-VE, AA-2-VE, IP-AA-3-dl-α-Toc, AA-3-dl-α-Toc, IP-AA-2-dl-α-Toc, AA-2- dl-α-Toc, IP-AA-3-d-α-Toc, AA-3-d-α-Toc, IP-AA-2-d-α-Toc, AA-2-d-α-Toc Each of the 12 types of compounds was added in an amount of 0.01%, and the balance was water.

The lotion of the present invention of the above-mentioned embodiment of the present invention and the lotion of the target area obtained by removing the 12 kinds of compounds of the present invention from the lotion of the present invention were prepared, and the stability test was conducted at 40 ° C. for 6 months. went. In the evaluation of the stability test, the color change of the preparation, the occurrence of precipitation, and the generation of odor were evaluated with the following scores, and the average score was obtained and compared. The evaluation was performed by 10 men and women from 20 to 50 years old, and the average score was obtained.
(Score)
Color change: 0 point that does not change at all, 2 points that change is observed, 3 point precipitation that changes drastically: 0 point that does not occur at all, 2 points that precipitation is observed, 3 point odor that intense precipitation is observed Change: 0 point that does not change at all, 2 points that change is observed, 3 points that change is recognized as a result. As a result, in the prescription of the present invention, all changes in color, precipitation and odor are observed over time. It was 0 points, but there was no 0 points on average in the cosmetics of the control group excluding all the stabilizers, nonionic surfactants, acetyl diester-bound vitamin CE derivatives, and UV protection agents. From 2 points to 3 points, this result proved the excellent stability of the formulation of the present invention.

1 g of each of the compounds of the present invention shown in Table 13 was completely dissolved in 512 cc of physiological saline for medical use, and then filtered through a sterilization filter for producing an injection solution and a pyrogen exclusion filter. Twelve types of injection solutions corresponding to the compound load of the present invention were produced. Furthermore, 100 kinds of the 12 kinds of liquid medicines produced above were taken in units of 100 CC, and these were mixed together to produce a liquid medicine 1200CC containing 12 kinds of the compounds of the present invention. This liquid medicine can be used as an external composition for iontophoresis, electroporation and mesotherapy, a composition for treating radical diseases, a composition for promoting cell growth, and an antioxidant composition. In the case of a composition for treating radical diseases, it can also be used as an injection for humans and animals.
■

(Effect test) The test section (hereinafter referred to as test section injection solution) composed of the 12 compounds of the present invention prepared in the Examples and 0.1% of L-ascorbic acid-2-phosphate Na The control group injection solution (hereinafter referred to as the target group injection solution) prepared by the same production method was used, and the effects of the radical disease therapeutic agent of the present invention were compared and confirmed by the following experiment.

(Effectiveness test for heart disease)
The rat was thoracotomized, and the blood flow was resumed after ligation of the left anterior descending coronary artery for 15 minutes. The test group injection solution, which is the pharmaceutical composition of the present invention at 5 mg (total compound weight) / kg · body weight, was previously administered intravenously to the rat as a test group 24 hours before the coronary artery occlusion, and the control group injection solution was used as the control group. Was injected in the same manner as in the test section. Prior to the experiment, free radical radical-dependent chemiluminescence in peripheral blood after coronary artery occlusion was measured by chemiluminescence, and a significant increase in radicals was confirmed immediately after reperfusion. During the coronary occlusion, no clear arrhythmia was observed on the electrocardiogram monitor, but when the blood flow was resumed, a clear arrhythmia, an indicator of heart disease, appeared only in the control group within a few seconds. However, in the group in which the injection solution of the test group of the present invention was intravenously administered, the arrhythmia seen in the control group was clearly suppressed, and the radical disease of the present invention showed a significant decrease in free radicals compared to the target group. The effect of therapeutic drugs for heart disease has been proven.

(Effective test for liver damage)
After the rat portal vein and coronary artery were blocked for 20 minutes and blood flow was resumed for 60 minutes, the liver was perfusion-fixed with glutaraldehyde and observed with an electron microscope. In addition, radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence before the experiment, and a significant increase in radicals was confirmed immediately after resumption of blood flow. The test group injection solution of 5 mg (total compound weight) / kg / body weight of the present invention was intravenously administered to the rats 24 hours before the rat portal vein and coronary artery blockage as a test group, and the target group injection solution was similarly used as a control group. Injection was performed in the same manner as in the test section. As a result of electron microscopic observation, in the control group, the Disse space, hepatocyte spacing, and microbile ducts were prominently enlarged, and many vacuoles were observed in the cells, and the pathology was clearly observed in the liver cells. According to the electron microscopic observation of the test group to which the injection solution was administered, the tissue structure of the liver was kept normal, and the effect of the therapeutic agent for radical diseases of the present invention was proved.

(Effectiveness test for pancreatic disease)
After the blood flow was resumed for 60 minutes after the rat coronary artery was blocked for 20 minutes, a pancreatic disease model was prepared, and amylase in the blood was measured before the coronary artery was blocked and 4 hours after the blood flow was resumed. When radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence before the experiment, a significant increase in radicals was confirmed immediately after resumption of blood flow. As a test group, the test group injection solution, which is a free radical-related disease drug of the present invention of 5 mg (total compound weight) / kg · body weight of the present invention, was intravenously administered to the rat 24 hours before the rat coronary artery blockage in advance. The injection solution was injected in the same manner as in the test group. As a result of the blood amylase measurement, the blood amylase level in the control group was significantly higher than the level before blocking, and an individual having a maximum of 7000 U / dl was clearly observed. The blood amylase level in the test group administered with 1100 U / dl at the maximum was slightly higher than that in the control group, although it was slightly higher than that in the control group. The effect on the therapeutic agent for radical disease of the present invention was proved.

(Effectiveness test for kidney damage)
After the rat coronary artery was blocked for 20 minutes and the blood flow was resumed for 60 minutes, a renal disease model in which the kidney tissue was damaged was prepared, and the average urinary protein was measured before the coronary artery was blocked and for 5 days after the blood flow was resumed. When radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence before the experiment, a significant increase in radicals was confirmed immediately after resumption of blood flow. In the test group, rats were intravenously administered to the test group injection solution of 5 mg (total compound weight) / kg · body weight 24 hours before the rat coronary artery blockage, and only Ringer's solution was injected as the control group in the same manner as the test group. As a result of the measurement of the average urinary protein for 5 days after reperfusion, the urinary protein level in the control group was significantly higher than the level before blocking, and the pathological condition of renal disease was clearly observed. The urinary protein level in the test group administered with the urine was slightly higher than that in the control group compared to the normal state before blocking, but it was significantly lower than that in the control group. The effect on therapeutic drugs has been proven.

(Effectiveness test for organ failure)
Systemic ischemia was applied for 5 minutes by the rat coronary occlusion model, and blood flow was resumed. When radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence manufactured by Showa Denko before the experiment, a significant radical increase was confirmed immediately after resumption of blood flow. The test group injection solution of 5 mg (total compound weight) / kg · body weight of the present invention was intravenously administered to the rat in advance as a test group 24 hours before the rat coronary artery blockage, and only the target group injection solution as the control group was the same as the test group. Injected into. After reperfusion also free radical involvement disease agent the same amount 5 days of the present invention, were dissected after one injection and 10 days daily, heart, liver, kidney, pancreas, gallbladder necrosis exponent ^{45 Ca} autoradiography / Determined by image analyzer. As a result, in the rats of the control group, delayed cell death in which a large number of cells were necrotized in each organ after ischemia was observed, but in the mice injected with the radical disease drug of the present invention (8 per group), It was confirmed that necrosis of each cell was remarkably prevented, and the effect on the therapeutic agent for radical diseases of the present invention was proved.

(Comparison effect test for organ failure)
In the rat coronary artery occlusion model, systemic ischemia was applied for 5 minutes and blood flow was resumed. When radical-dependent chemiluminescence in peripheral blood was measured by chemical luminescence before the experiment, a significant increase in radicals was confirmed immediately after resumption of blood flow. Ringer's solution containing 5 mg (total compound weight) / kg · body weight of the test group of the present invention intravenously administered to the rat as a test group in advance 24 hours before blocking the rat coronary artery, and human Cu-Zn type SOD as a control group Was injected in the same manner as in the test section. Even after resumption of blood flow, the same amount of the pharmaceutical composition of the present invention is injected once a day for 5 days and dissected 10 days later. The cell necrosis index of the heart, liver, kidney, pancreas and gallbladder is determined by ⁴⁵ Ca autoradiography. / Determined by image analyzer. As a result, in the control rats, delayed cell death in which many cells were necrotized in each organ after ischemia was observed by ⁴⁵ Ca autoradiography / image analyzer. It was confirmed that necrosis of each cell was remarkably prevented in the mice (8 per group) injected with the injection / infusion drug, and the effect on the therapeutic agent for radical diseases of the present invention was proved.

Examples of oral compositions for animals are as follows: Corn 75% (hereinafter% is percentage by weight), soybean flour (CP45%) 20%, calcium phosphate 1.5% and appropriate amount of inorganic mixture, yeast, ascorbic acid and vitamin E The compound of the present invention was added to the composition containing the total vitamin mixture excluding the varieties so that the ratio of each of the compounds of the present invention was 100 ppm with respect to the composition, and the mixture was sufficiently stirred with a normal pelleter machine. It was molded by heating (maximum temperature 100 ° C.) and dried (maximum temperature 82 ° C.) to prepare an oral composition for stress relaxation according to the present invention. This is hereinafter referred to as test zone feed. This composition can be used for pets such as dogs and cats, ornamental fish such as tropical fish and goldfish, livestock such as pigs, cattle, horses and sheep, poultry such as chickens and quail, hamachi, thailand, pufferfish, flounder, It can be used as an oral composition typified by feed additives such as fish for aquaculture such as tuna, salmon, salmon, trout, salmon and salmon, shellfish such as shrimp and salmon, and shellfish, and feed.

(Preparation of comparative feed composition)
Separately from the above, instead of the animal stress response mitigating agent of the present invention, L-ascorbic acid-2-phosphates (Stay C manufactured by DSM Co.) marketed as a feed additive were used in the same manner as the test group feed. A feed prepared by blending and production was prepared in the same manner as in Example 2. In other words, corn 75% (hereinafter% is weight percentage), soybean flour (CP45%) 20%, calcium phosphate 1.5%, L-sodium ascorbate 0.5% and a proper amount of inorganic mixture, yeast and ascorbic acids are excluded. A vitamin mixture was added, and the well-stirred one was thermoformed with a normal pelleter machine and dried to obtain a control feed. The thermoforming and drying of the feed were carried out to improve feed efficiency, reduce germs in the feed, and reduce livestock dust, but the conditions were about 70 degrees Celsius for the maximum product temperature in the pelleter. Was carried out at 50 ° C. for 20 minutes and then left in a room temperature environment. This was used as the target ward feed.

(Effect on pigs)
The following experiments were conducted using the above test group feed, feed composition, and target group feed to confirm the effects of suppressing the rise of plasma LDH, MDH, AspAT and blood stress protein of animal stress response mitigating agents for pigs. The effect of the present invention was confirmed. Test preparation 5 of the present invention: 100 30-day-old male pigs of Landrace x Yorkshire were divided into 10 groups of 10 each (2 groups of 20 heads of equal weight were set as 1 test group). A seed test was conducted. The test group feed was given to 10 groups of 1 test group, and the control group feed was fed to the other 10 groups. These pigs were raised with the same vitamin C-free commercial feed until 23 days of age except the lactation and weaning periods.

In the test group, the test group feed was mixed with the non-added general feed once every morning so that 0.02 mmol (total) of the compound of the present invention was orally administered per kg of body weight per day. . Body weight was measured once a week to adjust the amount of feed contained. On the other hand, in the control group, the test group feed was fed and reared so that 0.02 mmol (total) of the existing L-ascorbic acid-2-phosphate was orally administered. On the test start day, as a stressor, the pigs were moved to another piggery and reorganized in order to keep their weight at the same time. This movement and reorganization work causes stress on pigs, and problems such as a decrease in weight gain have been confirmed from past cases. 60 days after the start date of the test, the animals were raised on the test group and the control group. After 61 days, blood was collected from each pig, and plasma LDH, MDH, AspAT, blood stress protein, and weight gain were as follows. Measured by the method.

(Measurement method of LDH, MDH, AspAT)
Plasma was separated from the collected blood by centrifugation at 2,000 rpm at a temperature of 4 ° C., and the resulting supernatant fraction was used as a sample for enzyme measurement. The enzyme activity was determined by spectroscopically measuring the change in absorbance of NADH at 30 ° C. at 340 nm. The total amount of the enzyme reaction solution is 3.0 ml, and the overall configuration is as follows.
(1) For LDH and MDH: 200 mM Tris buffer, 1.0 ml (final concentration, 67 mM), 5 mM NADH, 0.1 ml (0.17 mM), 30 mM KCl, 0.1 ml (1 mM), 30 mM 2-mercaptoethanol (2-ME), 0.1 ml, substrate (pyruvic acid in LDH; oxaloacetate in MDH) 0.3 ml (sufficient amount, 5-10 mM), water 1.3 ml and plasma preparation 0.1 ml are added to the whole. Set to 3.0 ml.
(2) AspAT; 200 mM Tris buffer 1.0 ml, 5 mM NADH, 0.1 ml, 30 mM KCl, 0.1 ml, 30 mM 2-ME, 0.1 ml, 20 mM α-ketoglutarate 0.3 ml, auxiliary enzyme (MDH) 0.1 ml, 50 mM aspartic acid 0.3 ml, water 0.9 ml and plasma preparation 0.1 ml are added to make a total of 3.0 ml. Here, the enzyme activity was determined at the initial rate.

その結果、本発明の試験区飼料投与の血液中のＬＤＨ、ＭＤＨ、ＡｓｐＡＴ、ストレスプトテインの平均値は、対照区のそれに比較し１１．９％以上有意に低下し、本発明の効果を確認できた。(Stress protein measurement method) The molecular weight of the stress protein in the plasma, the number of molecular species, and the abundance of each molecular species were measured by using a electrophoresis diagram obtained by protein staining of a gel subjected to SDS-PAGE. In particular, the abundance of each protein was determined by the relative ratio from the absorbance using a gel scanner. Electrophoresis was performed within a range in which SDS-PAGE electrophoresis conditions were not changed depending on the type of plasma preparation from various animals, and they were compared with each other. The average values of the LDH, MDH, AapAT, stress protein, and body weight increase rates in blood and the values of the respective target sections corresponding thereto were determined, and the ratios to the target sections of the present invention were determined by the following formulas, and the effects were compared.

As a result, the average values of LDH, MDH, AspAT, and stress-ptothein in the blood of the test group administered with the feed of the present invention were significantly lower than those of the control group by 11.9%, confirming the effect of the present invention. did it.

(Weight gain ratio)
In both the control group and the test group, the body weight at the start of the test was measured, and the weight gain ratio obtained by comparing the values obtained by the following formula as the weight gain value after 60 days from the start of the test = ( Body weight—weight at the start of the test in the subject group) / (weight at the end of the test in the test group—weight at the start of the test in the test group) × 100
As a result, the body weight increase ratio of the test group feed administration of the present invention was significantly increased by 6.1% or more, and the feed efficiency was improved as compared to the animals of the target group feed administration.

(Effects on cattle)
In order to confirm the effect of the present invention on cattle, the following experiment was conducted to confirm the effect. A total of 50 Holstein 53-day-old bulls were used, 25 (test group feed) and 25 (target group feed). This cow used the cow raised with the same commercially available feed without vitamin Cs until 53 days old except a milking period and a weaning period.
Tested on a feed of 30% bran (below percentage by weight), 20% barley flour, 44% rice sugar, 5% soybean meal, 0.5% sodium chloride and a suitable amount of inorganic mixture, and a comprehensive vitamin mixture excluding ascorbic acids 1% by weight of the ward feed was added to the above feed, and the well-stirred one was heat-molded with an ordinary pelleter machine and dried to obtain the stress-relieving feed composition of the present invention. Separately from this, instead of the oral composition for stress in the test group, the target group feed was prepared by the same manufacturing method and composition as described above.
In the test section, the test group and the control group of cattle were transported over 500 km by truck at the start of the test, and then each feed was freely fed for 60 days. Breeding in this feeding state for 60 days, blood was collected from each cow 61 days later, and plasma LDH, MDH, AspAT, blood stress protein, and weight gain were measured in the same manner as in the above Examples. . For the measurement results, an average value was obtained for each group, and the ratio with the control group was calculated according to the same calculation formula as described above. As a result, the average values of LDH, MDH, AspAT, and stress-ptothein in the blood in the group administered with the oral composition of the present invention were significantly decreased by 12.3% or more compared to that in the control group, and the anti-stress effect was exhibited. It could be confirmed. There was also an improvement in weight gain.

(Effective test for dogs)
A pure beagle dog with an average weight of 8.7 kg, 6 females and 6 males, a total of 12 females, divided into 2 groups of 3 males and 3 females for the test group and the control group (3 males and 3 females). In the test group, the test group feed was fed with a stress relief feed composition in which 1% by weight was added to general beagle dog feed and was fed freely. In the control group, the control group feed was added 1% by weight to a general beagle dog feed and was freely fed. The test was carried out for 30 days in an open barn installed outdoors in the hot summer season. Blood was collected from each of the beagle dogs after 30 days in this breeding state, and after 31 days, plasma LDH, MDH, AspAT, blood stress protein, and weight gain were measured in the same manner as described above. For the measurement results, an average value was obtained for each group, and the ratio with the control group was calculated according to the same calculation formula as described above. As a result, the average values of LDH, MDH, AspAT, and stress protein in the blood of the oral composition group of the present invention were 9.8 compared with those of the control group, despite being bred under high temperature stress in summer. % Significantly decreased, confirming the effect of the oral composition of the present invention. In addition, weight gain was significantly improved by 5.9% or more.

(Effect on aquatic animals)
60% fish meal, 10% squid meal, 12.5% gluten, 1.5% cod liver oil, 0.1% beta carotene, 1% sodium dihydrogen phosphate, 1.5% sodium hydrogen phosphate, and vitamin C were excluded Vitamin premix 1.4%, ethoxyquin 0.02%, 1% weight of the above test group feed and corn gluten added to the residue to make 100%, and after mixing this raw material with a mixer, pellet mill , Rainbow trout, salmon, salmon, salmon, salmon, salmon, hamachi, puffer fish, flounder, tuna, horse mackerel, and prawns for aquatic animals were prepared.
The prescription for the control group was produced by the same production method after adding 1% by weight of the target group feed with the same composition. These feeds are administered to farmed rainbow trout, salmon, salmon, salmon, salmon, salmon, hamachi, puffer fish, flounder, tuna and horse mackerel, and a feeding test is conducted for 100 days. A solid was randomly extracted and the survival rate of each aquatic animal was measured to examine its effectiveness against aquatic animals. As a result, the survival rate of the test group was significantly increased by 7.8% or more compared to the survival rate of the target group, and the effect of the oral composition of the present invention on aquatic animals was confirmed.

表１５記載の１２種類の本発明の化合物をそれぞれ０．１ｇと以下記載の界面活性剤グループの界面活性剤をそれぞれ０．１ｇ混合し、さらにココイルグルタミン酸Ｎａを添加して全量で５ｇとして電動ミキサーで３分間良く混合し、これに水溶性物質グループの水溶性物質をそれぞれ０．１ｇ混合し、更にグリセリンを添加して全体を２０ｇとし電動ミキサーで３分間良く混合しこれを混合物Ｂとする。
以下の脂質グループの脂質をそれぞれ０．１ｇとり８０℃に加熱してコレステロール５ｇを混合溶解させこれにホホバオイルを添加して全量で２０ｇの脂質混合物とする。混合物Ｂに対してこの脂質混合物を少量づつ添加し、その都度電動ミキサーでそれぞれ３分間混合する。この操作を何回も繰り返し合計混合時間が１０分以上になるようにする。このようにして、界面活性剤グループと水溶性物質グループと脂質グループと抗酸化剤グループを添加した液晶乳化物用ペーストＢを得た。
表１５記載の１２種類の本発明の化合物をそれぞれ０．１ｇと以下記載の界面活性剤グループの界面活性剤をそれぞれ０．１ｇ混合し、さらにココイルグルタミン酸Ｎａを添加して全量で５ｇの界面活性剤混合物を得た。別に水溶性物質グループの水溶性物質をそれぞれ０．１ｇ混合し、更にグリセリンを添加して全体を１５ｇとしこれを水溶性物質混合物とした。別に、以下の脂質グループの脂質をそれぞれ０．１ｇとり８０℃に加熱してコレステロール５ｇを混合溶解させこれにホホバオイルを添加して全量で２０ｇの脂質混合物とした。上記で作成した、界面活性剤混合物５ｇと水溶性混合物１５ｇと脂質混合物２０ｇを一度に電動ミキサーに投入し３分間混合し比較対象の非液晶乳化物用ペーストＢ’を得た。
（界面活性剤グループ）
ココイルグルタミン酸Ｎａ、ココイルグルタミン酸Ｋ、ココイルグルタミン酸Ｎａ、ココイルグルタミン酸ＴＥＡ、ココイルグルタミン酸ＴＥＡ、ラウロイルアスパラギン酸Ｎａ、ラウロイルグルタミン酸Ｎａ、ミリストイルグルタミン酸Ｎａ、パーム脂肪酸グルタミン酸Ｎａ，フォスファチジルコリン、リン脂質及びこれらの塩類
（水溶性物質グループ）
グリセリン、ジグリセリン、トリグリセリン、ポリグリセリン、メチルブタンジオール、ブチレングリコール、イソプレングリコール、ポリエチレングリコール、ペンタンジオール、ヘキサンジオール、プロピレングリコール、ジプロピレングリコール、ポリプロピレングリコール、エチレングリコール、ジエチレングリコール、ネオペンチルグリコール、ポリエチレングリコール、ソルビトール、キシリトール、ピロリドンカルボンナトリウム、ヒアルロン酸、カラギーナン、アルギン酸、寒天、フコイダン、ペクチン、ローカストビーンガム、キサンタンガム、トラガントガム、グアーガム、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、アクリル酸・メタクリル酸共重合体、ポリグルタミン酸。
（脂質グループ）
ミネラル油、スクワラン、スクワレン、パルミチン酸イソプロピル、ミリスチン酸イソプロピル、ミリスチン酸イソオクチル、ミリスチン酸イソトリデシル、ミリスチン酸オクタデシル、ミリスチン酸オクチルドデシル、イソステアリルコレステリルエステル、２−エチルヘキサン酸トリグリセリド、２−エチルヘキサン酸セチル、パーム油、ヒマワリ油、オリーブ油、ホホバ油、ツバキ油、流動パラフィン、グレープシード油、アボガド油、マカダミアナッツ油、アーモンド油、天然ビタミンＥ油、米胚芽油、丁字油、オレンジ油、トウヒ油、ステアリン酸及びパルミチン酸。
（抗酸化剤グループ）
コウジ酸、アルブチン、アスコルビン酸リン酸エステルナトリウム、アスコルビン酸リン酸エステルマグネシウム、アスコルビン酸メチル、アスコルビン酸エチル、アスコルビン酸硫酸エステルナトリウム、アスコルビン酸グルコシド、アスコルビン酸リン酸パルミテートナトリウム、トコフェリルリン酸ナトリウム、（アスコルビル／トコフェリル）リン酸Ｋ、アスコルビルマレイン酸トコフェリル、カプリリルグリセリルアスコルベート、ヘキシルグリセリルアスコルベート、ミリスチルグリセリルアスコルベート、グリセリルアスコルベート、ビスグリセリルアスコルベート、ジグリセリルアスコルベート、イソステアリルアスコルビルリン酸ナトリウム、ステアリン酸アスコルビル、パルミチン酸アスコルビル、ジパルミチン酸アスコルビル、エラグ酸、レゾルシノール、ブチルレゾルシノール、カミツレ抽出物、ソウハクヒ抽出液、ユキノシタ抽出液、米糠抽出物、ジアセトキシ安息香酸、アセトキシヒドロキシ安息香酸、胎盤抽出物、アスタキサンチン、カロチン、酢酸レチノール、パルミチン酸レチノール、レチノイン酸、トコフェリルリン酸Ｎａ、トコフェリルアセテート，トコフェリルニコチネート、トコフェリルリノレート、トコフェロール、ジイソプロピルアミンジクロロアセテート、アミノヒドロキシ酪酸、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、没食子酸プロピル。[Liquid crystal emulsion composition]
0.4 g and 15.2 g of glycerin are added to each of the twelve kinds of compounds of the present invention described in Table 14 and mixed well with an electric mixer to obtain a mixture A. Cholesterol (5 g) is dissolved in jojoba oil (15 g) heated to 80 ° C. in advance, and a small amount of mixture A is added thereto. This operation is repeated several times so that the total mixing time is 10 minutes or more. Thus, a light brown pasty mixture A containing 12 kinds of the present compounds was obtained.
As a comparison object, 15 g of jojoba oil and 5 g of cholesterol were dissolved at 80 ° C., and 12 kinds of the compounds of the present invention shown in Table 14 were added at a time to 0.4 g and 15.2 g of glycerin at a time. Mix for only 3 minutes. When mixing for only 3 minutes, the paste for liquid crystallizing cannot be made due to insufficient mixing. This is hereinafter abbreviated as non-liquid crystal emulsion paste A ′ containing 12 kinds of compounds of the present invention.

Electric mixer which mixes 0.1g of 12 types of compounds of this invention of Table 15, and 0.1g of surfactant of the surfactant group of the following description, respectively, and also adds sodium cocoyl glutamate to make 5g in total quantity 3 minutes, and 0.1 g of each water-soluble substance of the water-soluble substance group is added to this, and glycerin is further added to make 20 g as a whole.
0.1 g of each lipid of the following lipid group is taken and heated to 80 ° C., 5 g of cholesterol is mixed and dissolved, and jojoba oil is added thereto to make a total of 20 g of lipid mixture. This lipid mixture is added to the mixture B little by little, and is mixed for 3 minutes each time with an electric mixer. This operation is repeated many times so that the total mixing time is 10 minutes or more. In this way, a paste B for liquid crystal emulsion to which a surfactant group, a water-soluble substance group, a lipid group, and an antioxidant group were added was obtained.
0.1 g of each of the 12 kinds of compounds of the present invention described in Table 15 and 0.1 g of the surfactants of the surfactant group described below were mixed, and Na cocoyl glutamate was added to give a total surface activity of 5 g. An agent mixture was obtained. Separately, 0.1 g of each water-soluble substance in the water-soluble substance group was mixed, and further glycerin was added to make 15 g as a whole, and this was made into a water-soluble substance mixture. Separately, 0.1 g of each lipid of the following lipid group was taken and heated to 80 ° C. to mix and dissolve 5 g of cholesterol, and jojoba oil was added thereto to make a total mixture of 20 g of lipid. 5 g of the surfactant mixture, 15 g of the water-soluble mixture and 20 g of the lipid mixture prepared above were put into an electric mixer at a time and mixed for 3 minutes to obtain a paste B ′ for non-liquid crystal emulsion for comparison.
(Surfactant group)
Cocoyl glutamate Na, cocoyl glutamate K, cocoyl glutamate Na, cocoyl glutamate TEA, cocoyl glutamate TEA, lauroyl aspartate Na, lauroyl glutamate Na, myristoyl glutamate Na, palm fatty acid glutamate Na, phosphatidylcholine, phospholipids and salts thereof ( Water-soluble substance group)
Glycerin, diglycerin, triglycerin, polyglycerin, methylbutanediol, butylene glycol, isoprene glycol, polyethylene glycol, pentanediol, hexanediol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, neopentyl glycol, polyethylene Glycol, sorbitol, xylitol, pyrrolidone carboxyl sodium, hyaluronic acid, carrageenan, alginic acid, agar, fucoidan, pectin, locust bean gum, xanthan gum, tragacanth gum, guar gum, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, active ingredient Le acid-methacrylic acid copolymer, polyglutamic acid.
(Lipid group)
Mineral oil, squalane, squalene, isopropyl palmitate, isopropyl myristate, isooctyl myristate, isotridecyl myristate, octadecyl myristate, octyldodecyl myristate, isostearyl cholesteryl ester, 2-ethylhexanoic acid triglyceride, cetyl 2-ethylhexanoate , Palm oil, sunflower oil, olive oil, jojoba oil, camellia oil, liquid paraffin, grape seed oil, avocado oil, macadamia nut oil, almond oil, natural vitamin E oil, rice germ oil, clove oil, orange oil, spruce oil, Stearic acid and palmitic acid.
(Antioxidant group)
Kojic acid, arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, ascorbyl maleate tocopheryl, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl phosphate Sodium, ascorbyl stearate, ascorbyl palmitate, aspartic dipalmitate Rubyl, ellagic acid, resorcinol, butyl resorcinol, chamomile extract, Sakuha extract, Yukinosita extract, rice bran extract, diacetoxybenzoic acid, acetoxyhydroxybenzoic acid, placenta extract, astaxanthin, carotene, retinol acetate, retinol palmitate, Retinoic acid, tocopheryl phosphate Na, tocopheryl acetate, tocopheryl nicotinate, tocopheryl linoleate, tocopherol, diisopropylamine dichloroacetate, aminohydroxybutyric acid, butylhydroxyanisole, butylhydroxytoluene, propyl gallate.

(Preparation of liquid crystal emulsion and stability test)
Electric hand so that bubbles are not formed to 100 g by adding purified water to pastes A and B for liquid crystal emulsion of the present invention prepared above and pastes A ′ and B ′ for non-liquid crystal emulsion for comparison, respectively. Agitated with a mixer for 10 minutes to completely disperse, treated with a microfluidizer, sterilized with a filter, and prepared with the liquid crystal emulsion compositions A and B of the present invention having an average particle diameter of 500 nm and a comparison target Liquid crystal emulsions A ′ and B ′ were obtained.
When these emulsions were observed with a polarizing microscope, the liquid crystal emulsion compositions A and B of the present invention obtained a maltase cross image peculiar to the liquid crystal structure, and this emulsion composition had a multilayer capsule structure (vesicle structure). It was confirmed to be a liquid crystal emulsion. On the other hand, no maltase cross image was observed in the non-liquid crystal emulsions A ′ and B ′.
When these emulsified compositions were stored at 40 ° C. for 1 month, the non-liquid crystal emulsion B ′ turned yellow and gave off a strange odor, and the non-liquid crystal emulsions A ′ and B ′ had 2 severely. Separated into layers, the commercial value was lost. No problem was observed in the liquid crystal emulsion composition of the present invention, and it was confirmed that the stability of the liquid crystal emulsion compositions A and B of the present invention was much better than that of the non-liquid crystal emulsion.

上記表１５の１２種類の本発明の化合物をそれぞれ２ｇ（合計２４ｇ）と以下の界面活性剤グループの界面活性剤をそれぞれ０．１ｇを電動ミキサーで良く混合し、これを▲１▼とする。脂質グループをそれぞれ０．１ｇとり８０℃に加熱して混合溶解させ，最後にホホバオイルを加えて合計２８ｇとしこれを▲２▼とする。
▲１▼に▲２▼を約５ｇづつ添加しながら電動ミキサーで１０分間良く混合する。この操作を繰り返し▲１▼と▲２▼を全て混合しする。これを７種類の既存誘導体配合の液晶乳化物用ペーストＤと略す。
（界面活性剤：グループＡ）
ココイルグルタミン酸Ｎａ、ココイルグルタミン酸Ｋ、ココイルグルタミン酸Ｎａ、ココイルグルタミン酸ＴＥＡ、ココイルグルタミン酸ＴＥＡ、ラウロイルアスパラギン酸Ｎａ、ラウロイルグルタミン酸Ｎａ、ミリストイルグルタミン酸Ｎａ、パーム脂肪酸グルタミン酸Ｎａ，フォスファチジルコリン、リン脂質及びこれらの塩類
（水溶性物質：グループＢ）
グリセリン、ジグリセリン、トリグリセリン、ポリグリセリン、メチルブタンジオール、ブチレングリコール、イソプレングリコール、ポリエチレングリコール、ペンタンジオール、ヘキサンジオール、プロピレングリコール、ジプロピレングリコール、ポリプロピレングリコール、エチレングリコール、ジエチレングリコール、ネオペンチルグリコール、ポリエチレングリコール、ソルビトール、キシリトール、ピロリドンカルボンナトリウム、ヒアルロン酸、カラギーナン、アルギン酸、寒天、フコイダン、ペクチン、ローカストビーンガム、キサンタンガム、トラガントガム、グアーガム、カルボキシメチルセルロース、ヒドロキシエチルセルロース、ポリビニルアルコール、ポリビニルピロリドン、カルボキシビニルポリマー、アクリル酸・メタクリル酸共重合体、ポリグルタミン酸。
（脂質：グループＣ）
ミネラル油、スクワラン、スクワレン、パルミチン酸イソプロピル、ミリスチン酸イソプロピル、ミリスチン酸イソオクチル、ミリスチン酸イソトリデシル、ミリスチン酸オクタデシル、ミリスチン酸オクチルドデシル、イソステアリルコレステリルエステル、２−エチルヘキサン酸トリグリセリド、２−エチルヘキサン酸セチル、パーム油、ヒマワリ油、オリーブ油、ホホバ油、ツバキ油、流動パラフィン、グレープシード油、アボガド油、マカダミアナッツ油、アーモンド油、天然ビタミンＥ油、米胚芽油、丁字油、オレンジ油、トウヒ油、ステアリン酸及びパルミチン酸。
（抗酸化剤：グループＤ）
コウジ酸、アルブチン、アスコルビン酸リン酸エステルナトリウム、アスコルビン酸リン酸エステルマグネシウム、アスコルビン酸メチル、アスコルビン酸エチル、アスコルビン酸硫酸エステルナトリウム、アスコルビン酸グルコシド、アスコルビン酸リン酸パルミテートナトリウム、トコフェリルリン酸ナトリウム、（アスコルビル／トコフェリル）リン酸Ｋ、アスコルビルマレイン酸トコフェリル、カプリリルグリセリルアスコルベート、ヘキシルグリセリルアスコルベート、ミリスチルグリセリルアスコルベート、グリセリルアスコルベート、ビスグリセリルアスコルベート、ジグリセリルアスコルベート、イソステアリルアスコルビルリン酸ナトリウム、ステアリン酸アスコルビル、パルミチン酸アスコルビル、ジパルミチン酸アスコルビル、エラグ酸、レゾルシノール、ブチルレゾルシノール、カミツレ抽出物、ソウハクヒ抽出液、ユキノシタ抽出液、米糠抽出物、ジアセトキシ安息香酸、アセトキシヒドロキシ安息香酸、胎盤抽出物、アスタキサンチン、カロチン、酢酸レチノール、パルミチン酸レチノール、レチノイン酸、トコフェリルリン酸Ｎａ、トコフェリルアセテート，トコフェリルニコチネート、トコフェリルリノレート、トコフェロール、ジイソプロピルアミンジクロロアセテート、アミノヒドロキシ酪酸、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、没食子酸プロピル。[Liquid crystal emulsion composition]
The compound 5g of this invention of Table 15 and 20g of glycerol are mixed well with an electric mixer, and let this be A. Let B be 20 g of jojoba oil previously heated to 80 ° C. and dissolved in 5 g of cholesterol. While adding about 5 g of B to A, mix well with an electric mixer for 10 minutes. Repeat this operation several times to mix all of A and B. In this manner, 50 g of a pale yellow paste-like mixture containing 10% by weight of 12 kinds of the present compounds was obtained. This is hereinafter abbreviated as 12 types of paste C for liquid crystal emulsion of the present invention.
As a comparison object, 12 kinds of compounds of the present invention shown in Table 15 5 g and glycerin 20 g are mixed well with an electric mixer, and this is designated as A. Let B be 20 g of jojoba oil previously heated to 80 ° C. and dissolved in 5 g of cholesterol. Mix A and B all at once and mix well with an electric mixer for 10 minutes. The liquid crystal structure cannot be prepared unless it is gradually added and mixed as in the preparation of the paste for liquid crystal emulsion of the present invention. This is hereinafter abbreviated as non-liquid crystal emulsion paste C ′ containing 12 kinds of compounds of the present invention.

2 g of each of the 12 kinds of compounds of the present invention shown in Table 15 (24 g in total) and 0.1 g of the surfactants of the following surfactant groups are mixed well with an electric mixer, and this is defined as (1). Take 0.1 g of each lipid group and heat to 80 ° C. to mix and dissolve, and finally add jojoba oil to make a total of 28 g, which is designated as (2).
While adding about 5 g of (2) to (1), mix well with an electric mixer for 10 minutes. This operation is repeated and all of (1) and (2) are mixed. This is abbreviated as paste D for liquid crystal emulsion containing 7 types of existing derivatives.
(Surfactant: Group A)
Cocoyl glutamate Na, cocoyl glutamate K, cocoyl glutamate Na, cocoyl glutamate TEA, cocoyl glutamate TEA, lauroyl aspartate Na, lauroyl glutamate Na, myristoyl glutamate Na, palm fatty acid glutamate Na, phosphatidylcholine, phospholipids and salts thereof ( Water-soluble substances: Group B)
Glycerin, diglycerin, triglycerin, polyglycerin, methylbutanediol, butylene glycol, isoprene glycol, polyethylene glycol, pentanediol, hexanediol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, neopentyl glycol, polyethylene Glycol, sorbitol, xylitol, pyrrolidone carboxyl sodium, hyaluronic acid, carrageenan, alginic acid, agar, fucoidan, pectin, locust bean gum, xanthan gum, tragacanth gum, guar gum, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, active ingredient Le acid-methacrylic acid copolymer, polyglutamic acid.
(Lipid: Group C)
Mineral oil, squalane, squalene, isopropyl palmitate, isopropyl myristate, isooctyl myristate, isotridecyl myristate, octadecyl myristate, octyldodecyl myristate, isostearyl cholesteryl ester, 2-ethylhexanoic acid triglyceride, cetyl 2-ethylhexanoate , Palm oil, sunflower oil, olive oil, jojoba oil, camellia oil, liquid paraffin, grape seed oil, avocado oil, macadamia nut oil, almond oil, natural vitamin E oil, rice germ oil, clove oil, orange oil, spruce oil, Stearic acid and palmitic acid.
(Antioxidant: Group D)
Kojic acid, arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, ascorbyl maleate tocopheryl, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl phosphate Sodium, ascorbyl stearate, ascorbyl palmitate, aspartic dipalmitate Rubyl, ellagic acid, resorcinol, butyl resorcinol, chamomile extract, Sakuha extract, Yukinosita extract, rice bran extract, diacetoxybenzoic acid, acetoxyhydroxybenzoic acid, placenta extract, astaxanthin, carotene, retinol acetate, retinol palmitate, Retinoic acid, tocopheryl phosphate Na, tocopheryl acetate, tocopheryl nicotinate, tocopheryl linoleate, tocopherol, diisopropylamine dichloroacetate, aminohydroxybutyric acid, butylhydroxyanisole, butylhydroxytoluene, propyl gallate.

Take 0.1g of each surfactant group substance and knead well for 10 minutes with an electric hand mixer. Take 0.1g each of water soluble substance group and water soluble antioxidant group, and finally add glycerin. Make a glycerin emulsifier mixture to 20 g. Mix 0.1g each of lipid group and fat-soluble antioxidant group substance, and finally add jojoba oil to make 20g mixed oil, and add 5g to this glycerin emulsifier mixture made earlier. Then, it was kneaded well with an electric hand mixer for 5 minutes to form a paste. This mixed oil addition operation and mixing operation were repeated until 50 g of a pasty mixture was finally obtained. This pasty mixture is referred to as an existing emulsifier oil paste E.
12 types of paste C for liquid crystal emulsions of the present invention, non-liquid crystal emulsion paste C 'containing 12 types of compounds of the present invention, and 7 types of existing derivative blends D and 12 types of paste C for liquid crystal emulsion of the present invention, the same amount of the existing emulsifier oil paste E is added to double the amount, and mixed well with an electric mixer for 20 minutes. A paste F for liquid crystal emulsion was obtained.

Purified water is added to each of 43 types of pastes of C, C ′, D, and F to make 100 g, and the mixture is stirred for 10 minutes with an electric hand mixer so that bubbles do not form. I got a thing. This emulsified composition was subjected to a microfluidizer treatment to obtain an emulsified composition having an average particle diameter of 500 nm. Further, it was sterilized with a membrane filter having a 45 μm hole and sealed in a sterile vial. When this emulsion composition was observed with a polarizing microscope, a maltase cross image peculiar to the liquid crystal structure was obtained, and it was confirmed that this emulsion composition had a multilayer capsule structure.
When these 43 types of emulsified compositions were stored at 40 ° C. for 1 month, L-ascorbyl 2-phosphate-6-palmitate 3Na, (ascorbyl / tocopheryl) phosphate K, 6-ascorbyl stearate The emulsion composition containing 5 kinds of ascorbyl 6-palmitate and ascorbyl 2,6-dipalmitate turned yellow, gave off an odor, and was less than 90% in the titer investigation by HPLC, so it can be used for the next test. There wasn't. In addition, the emulsion preparation prepared with the paste for non-liquid crystal emulsion containing 12 kinds of the compounds of the present invention did not show a decrease in titer by HPLC, but it was severely separated into two layers and lost commercial value. It was.
The results are shown in Table 16 below. As for the test result, X was marked in the case where a maltase cross image peculiar to the liquid crystal structure was observed when observed with a polarizing microscope, and in the case where o was not recognized. In the results of odor, X was marked for those where odor was greatly recognized, and ◯ was marked otherwise. In the results of separation, X was marked for those in which emulsification separation was clearly observed, and ○ was marked otherwise. In the results of the force value test by HPLC, those that remained 90% or more were marked with ◯, and otherwise X. As a comprehensive evaluation of the liquid crystal emulsion stability test, ◯ is marked for all ◯, and X is marked otherwise.

In order to examine the effects of accumulating and moisturizing the compounds shown in Table 17 of the present invention, after fully explaining to adult male subjects suffering from acne and obtaining consent from participation in the study freely, A clinical trial was conducted on emulsions that had been stored at 40 ° C. for 1 month and all had good stability.
After washing the subject once a day in the morning and evening, 5 cc of the emulsion shown in Table 17 below, which was prepared in the previous section, was added to a non-woven fabric mask sheet made of ITO and applied to the entire face and left for 15 minutes. This was done for five days from Monday to Friday, and not on Saturday and Sunday, but for 28 days. As an evaluation method, the number of acne was measured twice at the start of the test and 29 days after the test using a facial image analyzer (VISIA and Roboscan analyzer). The effect of moisturizing the face was measured using a skin moisture measuring device. Was measured. Comparison was made with respect to the improvement rate regarding how many percent each was improved from the time of the experimental start. Acne results were calculated by comparing (acne number at the start of experiment / number of acne at the end of experiment) × 100) −100 = acne rate (%). The result of skin moisture measurement is ((skin moisture at the end of the experiment / skin moisture at the start of the experiment) × 100) −100 = accumulation rate (%) calculated by the formula of skin moisture increase rate (%). Compared. The number of subjects in one test area was 8. As a result, an average value was obtained for each test section, and when the acne improvement rate and the water increase rate were significantly improved by 10% or more respectively, the result was evaluated as “good”, and otherwise X was recorded. The results are shown in Table 17.

この結果、既存の誘導体を添加した液晶乳化物に比較して、本発明の液晶乳化物は、臨床試験において全て良好な結果となった。

As a result, the liquid crystal emulsions of the present invention were all good in clinical trials as compared with liquid crystal emulsions added with existing derivatives.

Furthermore, the stability over time of the liquid crystal emulsion of the present invention and the liquid crystal emulsion of the present invention blended with an existing emulsifier was tested under more severe conditions. That is, each emulsion was stored at 40 ° C. for 10 months, and in the result of the force value test by HPLC, ◯ was marked for those remaining 90% or more, and X was marked otherwise. The results are shown in Table 18.

上記の結果より、既存乳化物を添加した本発明の液晶乳化物は、添加しなかったものに比較し非常に高い安定性を示した。

From the above results, the liquid crystal emulsion of the present invention to which the existing emulsion was added showed very high stability as compared with the case of not adding it.

A strong whitening action, a free radical inhibiting action, an anti-wrinkle action, an anti-acne action, a moisturizing action, characterized by containing a compound having a structure of (R ⁵ —C (═O) —CH ₂ —) as an active ingredient, A composition for external use that has a barrier function enhancing action, an ultraviolet ray-derived inflammation suppressing action, an anti-decubitus action, a low irritation and high safety, and includes cosmetics, quasi-drugs, pharmaceuticals, veterinary drugs, and aquatic animal drugs. provide. It will be apparent that the invention may be practiced otherwise than as particularly described in the foregoing description and examples. Many modifications and variations of the present invention are possible in light of the above teachings, and thus are within the scope of the claims appended hereto.

Claims (17)

A compound having the acetyl diester structure represented by the following general formula [Chemical Formula 1] or [Chemical Formula 2] (R ⁵ —O—C (═O) —CH ₂ —) or its pharmacology Acceptable salt. In the formula, R ¹ R ² is H or R ⁵ —O—C (═O) —CH ₂ —, where R ⁵ is a hydrocarbon, a solvent-soluble hydrocarbon, a benzene ring, a chroman ring, benzopyran, a vitamin E and their ^{salts, (R 5 -O-C (} = O) -CH 2 -) R 5 in structure -O-C (= O) -CH 2 - bond and ^{R 5} The atoms on the side are not oxygen. However, R ¹ R ² is not H at the same time. Further, R ³ R ⁴ is H at the same time, or R ³ R ⁴ is a hydrocarbon constituting one isopyridene group at the same time. In addition, when R ⁵ is vitamin E, the carbon at the 6-position of the chroman ring of vitamin E is oxygen which contacts R ^{5 of} [Chemical Formula 3] (R ⁵ —O—C (═O) —CH ₂ —). Join.
At this time, R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

In the formula, X is halogen.

The following general formula [Chemical Formula 4] Vitamin C-3-acetyl diester vitamin E, [Chemical Formula 5] Vitamin C-2-acetyl diester vitamin E, or one or a mixture of two or more thereof. Compound. In [Chemical Formula 4] and [Chemical Formula 5], R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

Halogenoacetyl vitamin E and 5,6-isopropylidene vitamin C are dissolved in one or more single or mixed solvents selected from four solvents of DMSO, THF, CH ₂ Cl ₂ and DMF, and t-BuOK, After reacting in the presence of one or more single or mixed bases selected from seven substances of pyridine, KHCO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , CsCO ₃ , 5,6-isopropyl 3. The method for producing a compound according to claim 2, further comprising a step of hydrolyzing 5,6-isopropylidene of the redeneacetyl diester-linked vitamin CE derivative. The compound according to claim 1, which is one or a mixture of two or more selected from halogenoacetylvitamin E represented by the following structural formula [Chemical Formula 6]. In [Chemical Formula 6], X represents a halogen atom.
At this time, R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

The compound of claim 4 comprising a production step in which vitamin E is dissolved in a solubilizing solvent and reacted by adding acetyl halide with one or more single or mixed catalysts selected from alkali catalysts, acid catalysts and phase transfer catalysts. Synthesis method. The compound according to claim 1, which is 5,6-isopyridene-vitamin C-3-acetyl diester vitamin E, which is one or a mixture of two or more selected from compounds represented by the following general formula [Chemical Formula 7].
R ⁶ represents —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂ ) —CH ₂ —CH ₂ —CH ₂ —CH (—CH ₂₎ -CH _{3, or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C (-CH 2) it is any one of -CH _3.

The process according to claim 6, wherein the process comprises the step of dissolving 5,6-isopyridene-vitamin C and a halogenated acetyl compound by dissolving the compound in a DMF solvent and in the presence of potassium bicarbonate as a base. A method for producing isopyridene-vitamin C-3-acetyl diester vitamin E. A compound having a (R ⁵ —C (═O) —CH ₂ —) structure, which is one or a mixture of two or more selected from compounds represented by the following general formula [Chemical Formula 8] The compound of claim 1 which is 6-isopyridene vitamin C-2-acetyl diester vitamin E.
At this time, R ⁶ is
_{-CH 2 -CH 2 -CH 2 -CH (} -CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH 2 -CH 2 -CH 2 -CH (-CH 2) -CH _{3 or, -CH 2 -CH 2 -CH = C} (-CH2) -CH 2 -CH 2 -CH = C (-CH2) -CH 2 -CH 2 -CH = C of _(-CH 2) -CH ₃ Either.

5,6-isopropylidene ascorbic acid and halogenoacetyl ester vitamin E are dissolved in one or more single or mixed solvents selected from DMSO, THF, CH ₂ Cl ₂ and DMF, and in the presence of t-BuOK as a base. A process for producing 5,6-isopyridene vitamin C-2-acetyl diester vitamin E according to claim 8, which comprises a production step in which the reaction is carried out. An external composition comprising the compound according to claim 1. An oral composition comprising the compound according to claim 1. A therapeutic agent for radical diseases, comprising the compound according to claim 1. A cell culture composition comprising the compound according to claim 1. An antistress composition comprising the compound according to claim 1. A liquid crystal emulsion composition comprising the compound according to claim 1. One or more single or mixed compounds selected from the compounds according to claim 1, one or more single or mixed compounds selected from the following group A, and one or more single or mixed compounds selected from group B: A liquid crystal emulsion composition containing at least one single or mixed compound selected from Group C and one or more single or mixed compounds selected from Group D at the same time.
(Surfactant: Group A)
Cocoyl glutamate Na, cocoyl glutamate K, cocoyl glutamate Na, cocoyl glutamate TEA, cocoyl glutamate TEA, lauroyl aspartate Na, lauroyl glutamate Na, myristoyl glutamate Na, palm fatty acid glutamate Na, phosphatidylcholine, phospholipids and salts thereof ( Water-soluble substances: Group B)
Glycerin, diglycerin, triglycerin, polyglycerin, methylbutanediol, butylene glycol, isoprene glycol, polyethylene glycol, pentanediol, hexanediol, propylene glycol, dipropylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, neopentyl glycol, polyethylene Glycol, sorbitol, xylitol, pyrrolidone carboxyl sodium, hyaluronic acid, carrageenan, alginic acid, agar, fucoidan, pectin, locust bean gum, xanthan gum, tragacanth gum, guar gum, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, active ingredient Le acid-methacrylic acid copolymer, polyglutamic acid.
(Lipid: Group C)
Mineral oil, squalane, squalene, isopropyl palmitate, isopropyl myristate, isooctyl myristate, isotridecyl myristate, octadecyl myristate, octyldodecyl myristate, isostearyl cholesteryl ester, 2-ethylhexanoic acid triglyceride, cetyl 2-ethylhexanoate , Palm oil, sunflower oil, olive oil, jojoba oil, camellia oil, liquid paraffin, grape seed oil, avocado oil, macadamia nut oil, almond oil, natural vitamin E oil, rice germ oil, clove oil, orange oil, spruce oil, Stearic acid and palmitic acid.
(Antioxidant: Group D)
Kojic acid, arbutin, sodium ascorbate phosphate, magnesium ascorbate phosphate, methyl ascorbate, ethyl ascorbate, sodium ascorbate sulfate, glucoside ascorbate, sodium palmitate ascorbate phosphate, sodium tocopheryl phosphate , (Ascorbyl / tocopheryl) phosphate K, ascorbyl maleate tocopheryl, caprylyl glyceryl ascorbate, hexyl glyceryl ascorbate, myristyl glyceryl ascorbate, glyceryl ascorbate, bisglyceryl ascorbate, diglyceryl ascorbate, isostearyl ascorbyl phosphate Sodium, ascorbyl stearate, ascorbyl palmitate, aspartic dipalmitate Rubyl, ellagic acid, resorcinol, butyl resorcinol, chamomile extract, Sakuha extract, Yukinoshita extract, rice bran extract, diacetoxybenzoic acid, acetoxyhydroxybenzoic acid, placenta extract, astaxanthin, carotene, retinol acetate, retinol palmitate, Retinoic acid, tocopheryl phosphate Na, tocopheryl acetate, tocopheryl nicotinate, tocopheryl linoleate, tocopherol, diisopropylamine dichloroacetate, aminohydroxybutyric acid, butylhydroxyanisole, butylhydroxytoluene, gallium butypropyl. The compound of claim 1, wherein the vitamin E is one or a mixture of two or more selected from the following vitamin E group.
(Vitamin E group)
DL-α-tocopherol, DL-β-tocopherol, DL-γ-tocopherol, DL-δ-tocopherol, D-α-tocopherol, D-β-tocopherol, D-γ-tocopherol, D-δ-tocopherol, α- Tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, DL-α-tocotrienol, DL-β-tocotrienol, DL-γ-tocotrienol, DL-δ-tocotrienol, D-α-tocotrienol, D-β-tocotrienol, D-γ-tocotrienol, D-δ-tocotrienol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol