JP2007153773A - Xanthone derivative, and skin care preparation and pharmaceutical composition each containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new xanthone derivative having excellent skin brightening effect and exerting excellent effects in fading and preventing pigmentation, fleckles, chloasma or the like after skin sunburn. <P>SOLUTION: The new xanthone derivative of a specific structure is provided. Skin care preparations and pharmaceutical compositions each containing the new xanthone derivative are also provided, respectively. The above xanthone derivative, which has melanogenesis-inhibitory effect and is useful as a skin brightening agent, exerts excellent skin-brightening effect through being compounded in the above preparations and compositions. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel xanthone derivative useful as a medicinal agent, and a skin external preparation and a pharmaceutical composition containing the same. More specifically, the present invention relates to a novel xanthone derivative having a melanin production inhibitory action and useful as a whitening agent having an excellent effect on skin whitening, and a skin external preparation and a pharmaceutical composition containing the same.

  Stains, freckles, and other pigmentations that occur on the skin are the result of excessive melanin pigmentation on the darkened areas of the skin. This melanin pigment is produced by melanocytes (melanocytes) existing in the vicinity of the basal layer of the epidermis and delivered to adjacent keratinocytes. The keratinocytes containing melanin are transported to the upper skin layer along with epidermal metabolism and eventually fall off the skin surface layer. Therefore, pigmentation such as spots, freckles, etc. may cause melanin production in melanocytes to increase for some reason, epidermal metabolism stagnation, or other unknown factors to locally reduce the amount of melanin in the skin. Caused by an increase.

  About the whitening agent which suppresses the production | generation of said melanin pigment, the plant-derived extract is conventionally developed variously in anticipation of the safety | security and the mildness of the irritation | stimulation to skin (for example, patent documents 1-1). 3).

  On the other hand, many whitening agents such as arbutin are found in nature as natural ingredients. For example, kojic acid is produced by bacteria such as Aspergillus and Penicillium, and arbutin is Vaccinium. It is a component such as vitis-idaea L. (bilberry), and Ellagic Acid is a component of strawberries and apples. From this, it can be said that natural active ingredient search is one effective method of whitening agent search.

  In addition, although the xanthone derivative represented by the formula (I) according to the present invention is a novel compound, various mangosteen derivatives which are naturally known xanthone derivatives are antibacterial, 5α-reductase inhibition, anti-inflammatory, antioxidant, anti-antioxidant, and the like. Actions such as cancer and antiallergy are known (see, for example, Patent Documents 4 to 6).

JP-A-8-3109939 JP-A-7-89843 Japanese Patent Laid-Open No. 9-30954 JP 2005-75791 A JP 2000-229857 A Japanese Patent Laid-Open No. 10-72357

  Thus, in the search and development of whitening agents, attempts have been made over many years to find new extracts and active ingredients that have natural whitening effects. There are few examples of research and development. A typical example is Rucinol derived from the structure of the component of Abies firma Sieb. Therefore, the present inventors have dealt with such a conventional situation, and an object thereof is to provide a new whitening agent having a novel structure by utilizing the structure of a natural product.

  This invention is made | formed in view of the said situation, The objective is to provide the novel xanthone derivative which has the outstanding whitening effect | action.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a specific derivative of mangosteen, which is a natural component, has an excellent whitening action, and have completed the present invention.

  That is, the present invention provides the following formula (I)

（Ｉ）

(I)

It is a xanthone derivative shown by. In the structure of mangosteen, the central tricyclic structure (see the above formula (I)) is called a xanthone skeleton. In the present invention, all Me in the structural formula represents a methyl group.

  Moreover, this invention is a skin external preparation containing the xanthone derivative shown by said Formula (I).

  Furthermore, this invention is a pharmaceutical composition containing the xanthone derivative shown by said Formula (I).

  The xanthone derivative represented by the above formula (I) according to the present invention has an excellent whitening action, and exhibits excellent effects for lightening and preventing pigmentation, stains, freckles, liver spots, etc. after sunburn. In addition, according to the present invention, a novel compound having excellent properties as a whitening agent can be provided. The xanthone derivative represented by the above formula (I) is blended in a skin external preparation or a pharmaceutical composition and exhibits a whitening effect.

  Hereinafter, the best mode for carrying out the present invention will be described in detail.

  The following formula (I) according to the present invention

（Ｉ）

(I)

A xanthone derivative represented by the formula (hereinafter referred to as xanthone derivative (I)) is produced by chemical conversion using α-mangosteen, β-mangosteen, γ-mangosteen or a mixture thereof (hereinafter referred to as mangosteens) as a raw material. Can do. That is, mangosteens are added in a solvent such as dimethylformamide, toluene, acetone, tetrahydrofuran, etc. in the presence of potassium carbonate or sodium hydride, and methyl iodide is added to react at ice-cooled to reflux temperature to obtain the corresponding methyl ether form. . This reaction can also be achieved using sodium hydroxide or potassium hydroxide and dimethyl sulfate, or using diazomethane. Next, the product is iced in a hydrogen atmosphere in the presence of a catalytic amount of palladium-carbon (Pd-C), a palladium-based catalyst such as palladium-black, or platinum oxide in a solvent such as methanol, ethanol, or ethyl acetate. The 2-position and 8-position (3-methyl-2-butenyl) groups are reduced and converted to the corresponding (3-methylbutyl) groups at cold to warming, preferably at room temperature. Furthermore, it can be synthesized by diimide which is an oxidation product of hydrazine. This product is reacted with a peroxide such as m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide in a solvent such as methylene chloride, chloroform, acetonitrile, etc. from ice cooling to warming, preferably at room temperature. Thus, the intended xanthone derivative (I) of the present invention can be obtained.

  In addition, the preparation method of this invention xanthone derivative (I) is not limited to said method, It is achieved by combining a well-known reagent and reaction. In addition, mangosteens, which are raw materials used here, can be obtained by extraction and purification from the mangosteen skin of plants, or by chemical synthesis using, for example, the methods described in the following documents: it can.

  Lee, Hiok-Huang, Synthesis of the mangostins.J. Chem. Soc., Perkin 1, 1981, 3205-3213., K. Iikubo, Y. Ishikawa, N. Ando, K. Umezawa, and S. Nishiyama, The first direct synthesis of α-mangostin, a potent inhibitor of the acidic sphingomyelinase.Tetrahedron Lett., 2002, 43, 291-293.

  The xanthone derivative (I) according to the present invention has an excellent melanin production inhibitory effect. Therefore, the xanthone derivative (I) according to the present invention is useful as a whitening agent. The whitening agent is applied to various wide fields such as cosmetics including quasi-drugs, pharmaceuticals, and foods.

  Furthermore, the xanthone derivative (I) according to the present invention is blended as an active ingredient in the composition and prepared as a whitening agent (hereinafter referred to as a whitening agent (composition)) as a composition.

  In the whitening agent (composition), the xanthone derivative (I) is contained in an amount effective for exerting a whitening action, and the content thereof is 0.005 to 20% in the total amount of the whitening agent (composition). It is preferably 0% by mass. More preferably, it is 0.05-10.0 mass%.

  The whitening agent (composition) contains, in addition to the above essential components, other components usually used in cosmetics, quasi-drugs, pharmaceuticals, etc., as appropriate, as long as the effects of the present invention are not impaired. Can be manufactured. Examples of the other components (optional blending components) include oils, surfactants, powders, colorants, water, alcohols, thickeners, antioxidants, ultraviolet absorbers, and humectants. In addition, metal sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine , Hot water extract of karin fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, 3-O-ethylascorbic acid, arbutin Further, whitening agents such as kojic acid, sugars such as glucose, fructose, mannose, sucrose and trehalose, vitamin A derivatives such as retinoic acid, retinol, retinol acetic acid, retinol palmitic acid and the like can be appropriately blended.

  The administration route in the case of administering the whitening agent (composition) is not particularly limited, and can be administered by any method such as oral, parenteral and topical. The dose is not particularly limited because it is appropriately adjusted depending on the subject (mammal, particularly human), age, sex, individual differences, symptoms, etc. For example, 0.1 to 500 mg as the xanthone derivative (I) of the present invention. / Kg, preferably 0.5 to 200 mg / kg can be administered orally or parenterally once or divided into several times a day.

  The whitening agent (composition) is preferably used in the form of an external preparation for skin that is applied externally to the skin, and is applied by a method of direct application or application to the skin. For example, it is excellent when applied to the skin for the face or body. Demonstrate whitening effect.

  The dosage form of the external preparation for skin which is a suitable form of the whitening agent (composition) is not particularly limited as long as it can exhibit the effects of the present invention. For example, a solution system, a solubilization system, an emulsification system, Arbitrary dosage forms such as a powder dispersion system, a water-oil two-layer system, a water-oil-powder three-layer system, a solid, an ointment, a gel, an aerosol, and a mousse can be used.

  The skin external preparation, which is a suitable form of the whitening agent (composition), is applied, for example, in the field of cosmetics and pharmaceuticals including quasi-drugs, and examples of product forms thereof include ointments, emulsions, creams, and lotions. , Gels, packs, etc. can take any form. The topical skin preparations are quasi-drugs such as lotion, milky lotion, cream, essence (beauty serum), basic cosmetics such as lotion, makeup cosmetics such as foundation and lipstick, aromatic cosmetics, cosmetics for hair, body cosmetics, etc. It may be in the form of cosmetics including

  The xanthone derivative (I) according to the present invention can be blended in an external preparation for skin, and is particularly effective in preventing and improving pigmentation / stain / freckle / liver spots after sunburn, and is excellent in skin whitening. It is useful as a skin whitening agent for whitening having an effect.

  In the skin external preparation, the amount of the xanthone derivative (I) is preferably 0.005 to 20.0 mass%, more preferably 0.05 to 10.0 mass% in the total amount of the skin external preparation. is there. If the amount is less than 0.005% by mass, the effect referred to in the present invention is not sufficiently exhibited, and if it exceeds 20.0% by mass, it is difficult to make a preparation. Moreover, the improvement of the big effect is not seen even if 10.0 mass% or more is mix | blended.

  In addition to the xanthone derivative (I), the above-mentioned external preparation for skin includes other components usually used for external preparations such as cosmetics, quasi-drugs, and pharmaceuticals, as long as the effects of the present invention are not impaired. Whitening agents, moisturizers, antioxidants, oils, UV absorbers, surfactants, thickeners, alcohols, powder components, colorants, aqueous components, water, various skin nutrients, etc., as needed can do.

  In addition, metal sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, grabrizine , Hot water extract of karin fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, 3-O-ethylascorbic acid, arbutin Further, whitening agents such as kojic acid, sugars such as glucose, fructose, mannose, sucrose and trehalose, vitamin A derivatives such as retinoic acid, retinol, retinol acetic acid, retinol palmitic acid and the like can be appropriately blended.

  The dosage form of the external preparation for skin is not particularly limited, and is not particularly limited as long as the effect of the present invention can be exhibited. For example, a solution system, a solubilization system, an emulsification system, a powder dispersion system, water- Any dosage form such as oil two-layer system, water-oil-powder three-layer system, solid, ointment, gel, aerosol, mousse and the like can be taken.

  Further, the external preparation for skin is applied in the fields of cosmetics and pharmaceuticals including quasi-drugs, for example, and the product forms include any forms such as ointments, emulsions, creams, lotions, gels, packs, etc. Can take. The topical skin preparations are quasi-drugs such as lotion, milky lotion, cream, essence (beauty serum), basic cosmetics such as lotion, makeup cosmetics such as foundation and lipstick, aromatic cosmetics, cosmetics for hair, body cosmetics, etc. It may be in the form of cosmetics including

The xanthone derivative (I) according to the present invention can be blended in a pharmaceutical composition, and is particularly effective for prevention and improvement of pigmentation / stain / freckle / liver spots etc. after sunburn, It can be expected to have actions such as 5α-reductase inhibition, anti-inflammatory, anti-oxidation, anti-cancer, anti-allergy and the like, and is useful as a therapeutic agent and preventive agent for medical purposes.

  The administration route for administering the pharmaceutical composition is not particularly limited, and can be administered by any method such as oral, parenteral, topical and the like. The dose is not particularly limited because it is appropriately adjusted depending on the subject (mammal, particularly human), age, sex, individual differences, symptoms, etc. For example, 0.1 to 500 mg as the xanthone derivative (I) of the present invention. / Kg, preferably 0.5 to 200 mg / kg can be administered orally or parenterally once or divided into several times a day.

  There are various preparation forms of the pharmaceutical composition, and examples thereof include oral solid preparations, oral solutions, injections, and suppositories. The content of the xanthone derivative (I) in the preparation is not particularly limited, but is usually preferably 0.01 to 70% by mass, more preferably 0.1 to 50% by mass in the total amount of the pharmaceutical composition. At the time of formulation, it is produced by a conventional method using a normal formulation carrier, but if necessary, a pharmacologically acceptable additive may be added.

  That is, when preparing an oral solid preparation, an excipient, further a binder, a disintegrant, a lubricant, a coloring agent, a flavoring agent, etc. are added to the xanthone derivative (I) as necessary. To form tablets, coated tablets, granules, powders, capsules and the like.

  Examples of excipients include lactose, corn starch, sucrose, glucose, sorbit, crystalline cellulose, silicon dioxide, calcium phosphate, and glycine.Examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, methyl cellulose, gum arabic, tragacanth, Gelatin, shellac, hydroxypropyl cellulose, hydroxypropyl starch, polyvinylpyrrolidone and the like are disintegrants such as starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, sodium citrate, dextrin, Pectin, alginic acid, etc. as lubricants include, for example, magnesium stearate, sodium laurate, talc, polyethylene glycol, silica, hydrogenated vegetable oil. But what is permitted to be added to pharmaceuticals as coloring agents. Examples of the corrigent include cocoa powder, menthol, aromatic acid, peppermint oil, borneol, etc. cinnamon powder is used. Tablets, granules and the like can be appropriately coated with sugar coating, gelatin coating, etc. as necessary.

  In the case of an oral solution, the xanthone derivative (I) can be made into an aqueous suspension, elixir, syrup, etc. by adding a flavoring agent, colorant, emulsifier, precipitation inhibitor, or diluent. .

  Examples of injections (intramuscular, intraperitoneal, intraarticular, subcutaneous, intravenous injection, etc.) include sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like. Moreover, you may contain adjuvants, such as a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, and a solubilizing agent, as needed. Injectables are usually sterilized by filtration (bacteria retention filter, etc.), combination of bactericides, or gamma irradiation, or processed into solid compositions by freeze drying or other methods. Used with sterile water or sterile diluent for injection. It can also be administered parenterally as a suppository or the like.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. The blending amount is mass% unless otherwise specified.

1. Production of xanthone derivative (I) Compound 1 was obtained according to the following reaction formula.

  That is, a mixture of α-mangostin, β-mangosteen and γ-mangosteen (14 g) was dissolved in dimethylformamide (70 mL), potassium carbonate (48 g) and methyl iodide (30 mL) were added in an ice bath, and the mixture was stirred at room temperature for 3 days. Stir. A saturated aqueous ammonium chloride solution was added to the reaction solution in an ice bath, and the reaction solution was dissolved in ethyl acetate / hexane (1/1, 450 mL), washed with 50 mL each of water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. And dried. A mixture (4: 1) of Compound 1 and Compound 2 obtained by evaporating the solvent under reduced pressure was dissolved in dimethylformamide (50 mL), and sodium hydride (0.21 g) and methyl iodide (0. 70 mL) and stirred at room temperature for 24 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution in an ice bath, and the reaction solution was dissolved in ethyl acetate / hexane (1/1, 450 mL), washed with 50 mL each of water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. And dried. The crude product obtained by distilling off the solvent under reduced pressure was washed with hexane to obtain Compound 1 (7.0 g) as a colorless solid.

¹ H NMR (400MHz, CDCl ₃ )
δ 1.62 (3H, s), 1.64 (3H, s), 1.77 (3H, s), 1.82 (3H, s), 3.37 (2H, d, J = 7.3Hz), 3.77 (3H, s), 3.84 ( 3H, s), 3.88 (3H, s), 3.92 (3H, s), 4.12 (2H, d, J = 6.8Hz), 5.16 (1H, t, J = 7.3Hz), 5.30 (1H, t, J = 6.8Hz), 6.54 (1H, s), 6.68 (1H, s)

¹³ C NMR (100MHz, CDCl ₃ )
δ 17.9, 18.2, 22.4, 25.8, 25.9, 26.0, 55.8, 55.9, 60.9, 61.9, 94.2, 97.7, 110.8, 114.6, 120.4, 122.7, 123.8, 131.1, 131.3, 137.2, 143.8, 154.2, 156.9, 158.5, 162.0 , 176.1

High resolution mass spectrum: m / z 452.2148 (calcd for C ₂₇ H ₃₂ O ₆ M ⁺ , 452.2199)
IR (disk): 2929, 1649, 1596, 1454cm-1
mp 107-108 ℃

  Subsequently, the compound 3 was obtained according to the following reaction formula.

  That is, Compound 1 (7.0 g) was suspended in methanol (80 mL) and stirred at room temperature in a hydrogen atmosphere in the presence of a catalytic amount of 10% Pd—C for 10 hours. The reaction solution was filtered through Celite, and the crude product obtained by concentrating the filtrate under reduced pressure was washed with methanol to obtain Compound 3 (6.5 g, 92%) as a colorless solid.

¹ H NMR (400MHz, CDCl ₃ )
δ 0.92 (6H, d, J = 6.8Hz), 0.98 (6H, d, J = 6.8Hz), 1.35 (2H, m), 1.46 (2H, m), 1.59 (1H, m), 1.76 (1H, m), 2.62 (2H, t, J = 8.0Hz), 3.35 (2H, t, J = 7.8Hz), 3.78 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.89 ( 3H, s), 6.49 (1H, s), 6.63 (1H, s)

¹³ C NMR (100MHz, CDCl ₃ )
δ 21.1, 22.5, 22.6, 24.8, 28.4, 28.7, 39.1, 40.4, 55.7, 55.8, 61.0, 61.9, 93.9, 97.4, 110.6, 114.6, 121.7, 139.1, 143.5, 154.1, 156.1, 156.6, 158.3, 162.0, 175.9

High resolution mass spectrum: m / z 456.2491 (calcd for C ₂₇ H ₃₆ O ₆ M ⁺ , 456.2512)
IR (NaCl): 2954, 1650, 1614, 1454cm ^-1

  Subsequently, xanthone derivative (I) was obtained according to the following reaction formula.

  That is, compound 3 (0.77 g) was dissolved in methylene chloride (2 mL), stirred for 10 minutes under freezing, and then m-chloroperbenzoic acid (0.83 g) dissolved in methylene chloride (5 mL) was added dropwise. After completion of the dropwise addition, the temperature was gradually raised to room temperature and stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution in an ice bath, the reaction solution was dissolved in ethyl acetate (30 mL), washed with 5 mL each of saturated aqueous sodium bicarbonate solution, water, and saturated brine, and the organic layer was dissolved in anhydrous sodium sulfate. And dried. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (toluene: acetone 50/1), starting compound 3 (0.35 g, 46%) and a pale yellow solid xanthone derivative. (I) (93 mg, 12%) was obtained.

¹ H NMR (400MHz, CDCl ₃ )
δ 0.94 (6H, d, J = 6.4Hz), 0.96 (6H, d, J = 6.4Hz), 1.43 (4H, m), 1.62 (2H, m), 1.75 (1H, m), 2.63 (2H, t, J = 8.0Hz), 3.32 (2H, t, J = 8.0Hz), 3.79 (3H, s), 3.82 (3H, s), 3.88 (3H, s), 3.95 (3H, s), 5.65 ( 1H, br), 6.73 (1H, s)

¹³ C NMR (100MHz, CDCl ₃ )
δ 22.0, 22.5, 22.6, 25.0, 28.6, 28.8, 39.9, 40.4, 55.9, 61.1, 61.2, 62.2, 97.5, 113.3, 114.4, 125.9, 132.9, 139.4, 143.3, 143.8, 148.9, 150.6, 153.9, 157.0, 176.2

High resolution mass spectrum: m / z 472.2445 (calcd for C ₂₇ H ₃₆ O ₇ M ⁺ , 472.2461)
IR (disk): 3311, 2954, 1592, 1454cm ^-1
mp 156-157 ℃

2. Melanin production inhibitory effect test method and its results Using the xanthone derivative (I) as a test sample, the melanin production inhibitory effect and cytotoxicity were evaluated. Mouse B16 melanoma cells producing melanin were seeded in a 96-well plate at 2,000-3,500 cells / well, and the test substance was added the next day (final test substance concentration: 3 × 10 ⁻⁵ , 1 × 10 ^−4). 3 × 10 ⁻⁴ wt%). Three days after the addition of the test substance, the amount of melanin produced and the number of cells were evaluated according to the following method.

  The amount of melanin produced was determined by visually observing the blackness of the cells in each well (n = 5) under a microscope and comparing the degree of blackness according to the following criteria in comparison with the test sample-free group.

2: very black, 1: black, 0: equivalent, -1: white, -2: very white

  The number of cells was subsequently measured using the plate on which the determination of the amount of melanin production was completed. The medium was aspirated and washed twice with a buffer (phosphate buffer 100 mM, pH 6.8), and then 100 μl of a medium containing 0.001% of Hoechst 33342 as a fluorescent reagent was added and reacted at 37 ° C. After 30 minutes, fluorescence was measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm, and the cell number ratio of the sample addition group to the sample addition group was calculated using the values as relative values of the number of cells. The results are shown in Table 1.

  From Table 1, the xanthone derivative (I) showed clearly stronger activity than arbutin used as a positive control.

  Below, the formulation example of the skin external preparation which concerns on this invention of various dosage forms is demonstrated as an Example.

Example 1 Cream ingredient Compounding amount (mass%)
Stearic acid 5.0
Stearyl alcohol 4.0
Isopropyl myristate 18.0
Glycerol monostearate 3.0
Propylene glycol 10.0
Xanthone derivative (I) 0.5
Caustic potash 0.2
Sodium bisulfite 0.01
Preservative Appropriate amount of perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Propylene glycol and caustic potash were added to ion-exchanged water, dissolved, and heated to maintain at 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase was gradually added to the aqueous phase, and after the addition was completed, the temperature was maintained for a while to cause the reaction. Thereafter, the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

Example 2 Cream component Compounding amount (mass%)
Stearic acid 2.0
Stearyl alcohol 7.0
Hydrogenated Lanolin 2.0
Squalane 5.0
2-Octyldodecyl alcohol 6.0
Polyoxyethylene (25 mol) cetyl alcohol ether 3.0
Glycerin monostearate ester 2.0
Propylene glycol 5.0
Tranexamic acid 0.2
Xanthone derivative (I) 0.2
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Propylene glycol was added to ion-exchanged water and heated to maintain 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase, pre-emulsified, and uniformly emulsified with a homomixer, and then cooled to 30 ° C. while stirring well.

Example 3 Cream component amount (% by mass)
Solid paraffin 5.0
Beeswax 10.0
Vaseline 15.0
Liquid paraffin 41.0
Glycerin monostearate ester 2.0
Polyoxyethylene (20 mol) sorbitan monolaurate 2.0
Soap powder 0.1
Borax 0.2
Xanthone derivative (I) 3.0
Sodium bisulfite 0.03
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Soap powder and borax were added to ion exchange water, dissolved by heating and kept at 70 ° C. (water phase). The other ingredients were mixed, heated and melted and kept at 70 ° C. (oil phase). The reaction is gradually added while stirring the oil phase in the aqueous phase. After completion of the reaction, the mixture was uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well after emulsification.

Example 4 Latex component blending amount (% by mass)
Stearic acid 2.5
Cetyl alcohol 1.5
Vaseline 5.0
Liquid paraffin 10.0
Polyoxyethylene (10 mol) monooleate 2.0
Polyethylene glycol 1500 3.0
Triethanolamine 1.0
Carboxyvinyl polymer 0.05
(Product name: Carbopol 941, BFGoodrich Chemical company)
Xanthone derivative (I) 0.01
Sodium bisulfite 0.01
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Carboxyvinyl polymer was dissolved in a small amount of ion-exchanged water (A phase). Polyethylene glycol 1500 and triethanolamine were added to the remaining ion-exchanged water, dissolved by heating and kept at 70 ° C. (aqueous phase). The other ingredients were mixed, heated and melted and kept at 70 ° C. (oil phase). The oil phase was added to the aqueous phase for preliminary emulsification, and the A phase was added, and the mixture was uniformly emulsified with a homomixer. After emulsification, the mixture was cooled to 30 ° C. while stirring well.

Example 5 Latex component blending amount (% by mass)
Microcrystalline wax 1.0
Beeswax 2.0
Lanolin 20.0
Liquid paraffin 10.0
Squalane 5.0
Sorbitan sesquioleate ester 4.0
Polyoxyethylene (20 mol) sorbitan monooleate 1.0
Propylene glycol 7.0
Xanthone derivative (I) 0.5
Sodium bisulfite 0.01
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Propylene glycol was added to ion-exchanged water and heated to maintain 70 ° C. (aqueous phase). The other components were mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto and uniformly emulsified with a homomixer. It cooled to 30 degreeC, stirring well after emulsification.

Example 6 Jelly component amount (% by mass)
95% ethyl alcohol 10.0
Dipropylene glycol 15.0
Polyoxyethylene (50 mol) oleyl alcohol ether 2.0
Carboxyvinyl polymer 1.0
(Product name: Carbopol 940, BFGoodrich Chemical company)
Caustic soda 0.15
L-Arginine 0.1
Xanthone derivative (I) 1.0
Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05
Ethylenediaminetetraacetate, 3 sodium, 2 water 0.05
Methylparaben 0.2
Perfume Appropriate amount of ion-exchanged water

(Manufacturing method)
Carbopol 940 was uniformly dissolved in ion-exchanged water, while xanthone derivative (I) and polyoxyethylene (50 mol) oleyl alcohol ether were dissolved in 95% ethanol and added to the aqueous phase. Next, after adding other components, the mixture was neutralized and thickened with caustic soda and L-arginine.

Example 7 Essence liquid component Amount (mass%)
(Phase A)
Ethyl alcohol (95%) 10.0
Polyoxyethylene (20 mol) octyldodecanol 1.0
Pantotenyl ethyl ether 0.1
Xanthone derivative (I) 0.2
Methylparaben 0.15
(Phase B)
Potassium hydroxide 0.1
(Phase C)
Glycerin 5.0
Dipropylene glycol 10.0
Sodium bisulfite 0.03
Carboxyvinyl polymer 0.2
(Product name: Carbopol 940, BFGoodrich Chemical company)
Purified water residue

(Manufacturing method)
The A phase and the C phase were uniformly dissolved, and the A phase was added to the C phase and solubilized. Next, filling was performed after adding phase B.

Example 8 Pack component Blending amount (% by mass)
(Phase A)
Dipropylene glycol 5.0
Polyoxyethylene (60 mol) hydrogenated castor oil 5.0
(Phase B)
Xanthone derivative (I) 0.1
Olive oil 5.0
Tocopherol acetate 0.2
Ethylparaben 0.2
Fragrance 0.2
(Phase C)
Sodium bisulfite 0.03
Polyvinyl alcohol 13.0
(Saponification degree 90, polymerization degree 2,000)
Ethanol 7.0
Purified water residue

(Manufacturing method)
A phase, B phase, and C phase were uniformly dissolved, and B phase was added to A phase to solubilize. This was then added to phase C and then filled.

Example 9 Solid foundation component Blending amount (% by mass)
Talc Residual Kaolin 15.0
Sericite 10.0
Zinc flower 7.0
Titanium dioxide 3.8
Yellow iron oxide 2.9
Black iron oxide 0.2
Squalane 8.0
Isostearic acid 4.0
Monooleic acid POE sorbitan 3.0
Isocetyl octoate 2.0
Xanthone derivative (I) 1.0
Preservative Appropriate amount Fragrance Appropriate amount

(Manufacturing method)
The powder components of talc to black iron oxide are mixed thoroughly with a blender, and to this, the oily components of squalane, isostearic acid, POE sorbitan monooleate, isocetyl octoate, xanthone derivative (I), preservative, and fragrance are added and kneaded well. Thereafter, the container was filled and molded.

Example 10 Emulsification Foundation (Cream Type)
Ingredient Amount (% by mass)
(Powder part)
Titanium dioxide 10.3
Sericite 5.4
Kaolin 3.0
Yellow iron oxide 0.8
Bengala 0.3
Black iron oxide 0.2
(Oil phase)
Decamethylcyclopentasiloxane 11.5
Liquid paraffin 4.5
Polyoxyethylene-modified dimethylpolysiloxane 4.0
Xanthone derivative (I) 0.5
(Water phase)
Purified water Residual 1,3-butylene glycol 4.5 remaining
Sorbitan sesquioleate 3.0
Preservative Appropriate amount Fragrance Appropriate amount

(Manufacturing method)
After the aqueous phase was heated and stirred, the powder part sufficiently mixed and ground was added and homomixed. Furthermore, after adding the heat-mixed oil phase and carrying out the homomixer process, the fragrance | flavor was added with stirring and it cooled to room temperature.

Example 11 Sunburn prevention cosmetic ingredient Compounding amount (mass%)
Stearic acid 1.5
Cetyl alcohol 3.0
Beeswax 2.0
Polyoxyethylene (10 mol addition)
Monooleate 1.0
Glycerin monostearate ester 1.0
Dimethylpolysiloxane 10.0
Decamethylcyclopentasiloxane 20.0
2-Hydroxy-4-methoxybenzophenone 3.0
Octyl p-methoxycinnamate 2.0
Xanthone derivative (I) 1.0
Perfume Appropriate amount Caustic potash Appropriate amount of ion-exchanged water Residual

(Manufacturing method)
The oil layer components other than ion-exchanged water and alkali were dissolved by heating (up to 70 ° C.), neutralized with alkali, emulsified by adding ion-exchanged water, and then cooled while stirring well after emulsification.

Example 12 Makeup base component Formulation amount (% by mass)
A W / O emulsified makeup base was prepared with the following composition.
(A) Organically modified montmorillonite 0.5
(B) Cetyl isooctanoate 2.0
(C) Octamethylcyclotetrasiloxane 2.0
(D) Decamethylcyclopentasiloxane 5.0
(E) Dimethylpolysiloxane (6cs) 5.0
(F) Liquid paraffin 3.0
(G) Dioctadecyldimethylammonium chloride 0.2
(H) Polyoxyalkylene-modified organopolysiloxane 5.0
(I) 4-t-butyl-4′-methoxydibenzoylmethane 0.3
(J) Glyceryl mono-2-ethylhexanoyl
Diparamethoxycinnamate 1.0
(K) Fine particle titanium oxide 5.0
(L) Oleyl alcohol 0.5
(M) Stearic acid 0.5
(N) Sorbitan diisostearate 4.0
(O) Antioxidant appropriate amount (P) perfume appropriate amount (q) Talc 1.5
(R) Nylon powder 1.0
(S) Ion exchange water Residual (t) Sodium citrate 0.5
(U) 1,3-butylene glycol 5.0
(V) Xanthone derivative (I) 0.3

(Manufacturing method)
(1): (b) to (j) and (l) to (p) were dissolved by heating, and (v) was mixed and dispersed.
(2): (a) was added and dispersed and swollen in (1).
(3): (k), (q), and (r) were dispersed in (2).
(4): (t) and (u) were dissolved in (s), added to (3) and emulsified.

Example 13 Oily foundation component Amount (% by mass)
(A) Fine particle titanium oxide 10.0
(B) Mica 22.4
(C) Kaolin 10.0
(D) Nylon powder 5.0
(E) Iron oxide red 0.5
(F) Iron oxide yellow 2.0
(G) Iron oxide black 0.1
(H) Liquid paraffin Residue (i) Dimethylpolysiloxane 10.0
(J) Sorbitan sesquioleate 2.0
(K) Octyl methoxycinnamate 5.0
(L) Xanthone derivative (I) 1.5
(M) Perfume appropriate amount (n) Microcrystalline wax 6.0
(O) Carnavalou 3.0

(Manufacturing method)
(1): (a) to (g) were mixed and pulverized.
(2): (h) to (k) and (m) were dissolved by heating, and (l) was mixed and dispersed.
(3): The slurry of (2) was ground using a grinder.
(4): (n) and (o) were added to (3) and dissolved by heating, and then mixed and molded.

  Hereinafter, the formulation example of the skin external preparation manufactured by the conventional method is demonstrated as an Example.

Example 14 Cream component Compounding amount (mass%)
Liquid paraffin 3.0
Vaseline 1.0
Dimethylpolysiloxane 1.0
Stearyl alcohol 1.8
Behenyl alcohol 1.6
Glycerin 8.0
Dipropylene glycol 5.0
Hydrolyzed silk extract 0.01
Macadamia nut oil 2.0
Hardened oil 3.0
Squalane 6.0
Stearic acid 2.0
Phytosteryl hydroxystearate 0.5
Cetyl 2-ethylhexanoate 4.0
Polyoxyethylene hydrogenated castor oil 0.5
Self-emulsifying glyceryl monostearate 3.0
Potassium hydroxide 0.15
Sodium hexametaphosphate 0.05
Trimethylglycine 2.0
Xanthone derivative (I) 5.0
Tocopherol acetate 0.1
Green tea extract 0.1
Paraben appropriate amount edetate trisodium 0.05
4-t-butyl-4′-methoxydibenzoylmethane 0.05
Diparamethoxycinnamic acid mono-2-ethylhexanoate glyceryl 0.05
Colorant appropriate amount Carboxyvinyl polymer 0.05
Purified water residue

Example 15 Skin lotion component Amount (% by mass)
Ethanol 10.0
Glycerin 2.0
Dipropylene glycol 1.0
Isostearic acid 0.1
Poly (oxyethylene / oxypropylene) /
Methylpolysiloxane copolymer 1.0
Lauryldimethylaminoacetic acid betaine 0.1
Citric acid 0.02
Sodium citrate 0.08
Sodium hexametaphosphate 0.01
Hydrolyzed potato protein 0.3
Xanthone derivative (I) 0.02
ONONIS EXTRACT 0.1
Hipotaurine 0.1
Chamomile extract 0.1
Lavender oil 0.001
Phenoxyethanol Suitable amount Purified water Residual

Example 16 Latex component blending amount (mass%)
Dimethylpolysiloxane 3.0
Decamethylcyclopentasiloxane 4.0
Ethanol 5.0
Glycerin 6.0
1,3-butylene glycol 5.0
Polyoxyethylene methyl glucoside 3.0
Sunflower oil 1.0
Squalane 2.0
4-methoxysalicylate potassium 1.0
Potassium hydroxide 0.1
Sodium hexametaphosphate 0.05
Hydroxypropyl-β-cyclodextrin 0.1
Dipotassium glycyrrhizinate 0.05
Loquat leaf extract 0.1
Sodium L-glutamate 0.05
Xanthone derivative (I) 0.05
Fennel extract 0.1
Hydrolyzed potato protein 0.1
Thiotaurine 0.1
Yeast extract 0.1
Lavender oil 0.1
Giant extract 0.1
Dimorpholinopyridazinone 0.1
Xanthan gum 0.1
Carboxyvinyl polymer 0.1
Acrylic acid / alkyl methacrylate copolymer
(Pemulen TR-1) 0.1
Bengala Appropriate amount Yellow iron oxide Appropriate amount Paraben Appropriate amount Purified water Residual

Example 17 Skin lotion component Amount (% by mass)
Ethyl alcohol 5.0
Glycerin 1.0
1,3-butylene glycol 5.0
Polyoxyethylene polyoxypropylene
Decyl tetradecyl ether 0.2
Sodium hexametaphosphate 0.03
Trimethylglycine 1.0
Sodium polyaspartate 0.1
Thiotaurine 0.1
Green tea extract 0.1
Western mint extract 0.1
Turmeric extract 0.1
Xanthone derivative (I) 0.01
Lysolecithin 0.01
EDTA3 sodium 0.1
Carboxyvinyl polymer 0.05
Potassium hydroxide 0.02
Phenoxyethanol Appropriate amount Purified water Residual perfume Appropriate amount

Example 18 Cream component Compounding amount (mass%)
Liquid paraffin 8.0
Vaseline 3.0
Dimethylpolysiloxane 2.0
Stearyl alcohol 3.0
Behenyl alcohol 2.0
Glycerin 5.0
Dipropylene glycol 4.0
Trehalose 1.0
Hydrolyzed potato protein 0.01
Asenya extract 0.01
Tetra-2-ethylhexanoic acid pentaerythrit 4.0
Polyisoethylene glyceryl monoisostearate 2.0
Polyoxyethylene glycerol monostearate 1.0
Lipophilic glyceryl monostearate 2.0
Citric acid 0.05
Sodium citrate 0.05
Potassium hydroxide 0.015
Xanthone derivative (I) 1.5
Oil-soluble licorice extract 0.1
Retinol 0.25
Tocopherol acetate 0.1
P-Hydroxybenzoate appropriate amount phenoxyethanol appropriate amount dibutylhydroxytoluene appropriate amount edetate trisodium 0.05
4-t-butyl-4′-methoxydibenzoylmethane 0.01
2-Ethylhexyl paramethoxycinnamate 0.1
β-carotene 0.01
Polyvinyl alcohol 0.5
Hydroxyethyl cellulose 0.5
Carboxyvinyl polymer 0.05
Purified water Residual fragrance Appropriate amount

Example 19 Cream component Blending amount (% by mass)
Decamethylcyclopentasiloxane 15.0
Trimethylsiloxysilicate 5.0
Polyoxyethylene / methylpolysiloxane copolymer 5.0
Glycerin 5.0
1,3-butylene glycol 5.0
Maltitol solution 2.0
Macadamia nut oil 2.0
Squalane 2.0
Phytosteryl hydroxystearate 0.5
Cetyl 2-ethylhexanoate 2.0
Distearyldimethylammonium chloride 0.2
Xanthone derivative (I) 0.5
Retinol acetate 0.02
Tocopherol acetate 0.05
Fish collagen 0.4
Sodium chondroitin sulfate 0.01
Sodium hyaluronate 0.1
Hydrolyzed potato protein 0.01
Edetate trisodium 0.05
Diparamethoxycinnamic acid mono-2-
Glyceryl ethylhexanoate 0.05
Aluminum magnesium silicate 0.3
Paraben Appropriate amount of purified water

Example 20 Latex component blending amount (% by mass)
Dimethylpolysiloxane 2.0
Decamethylcyclopentasiloxane 25.0
Dodecamethylcyclohexasiloxane 10.0
Polyoxyethylene / methylpolysiloxane copolymer 1.5
Trimethylsiloxysilicic acid 1.0
1,3-butylene glycol 5.0
Mangosteen extract 0.01
Squalane 0.5
Talc 5.0
Xanthone derivative (I) 0.2
Dipotassium glycyrrhizinate 0.1
Tocopherol acetate 0.1
Edetate trisodium 0.05
4-t-butyl-4′-methoxydibenzoylmethane 1.0
2-Ethylhexyl paramethoxycinnamate 5.0
Diparamethoxycinnamic acid mono-2-
Glyceryl ethylhexanoate 1.0
Silicone coated fine particle titanium oxide (40 nm) 4.0
Dimethyl distearyl ammonium hectorite 0.5
Spherical polyethylene powder 3.0
Phenoxyethanol Appropriate amount Purified water Residual perfume Appropriate amount

Claims (3)

A xanthone derivative represented by the following formula (I).

(I)   A skin external preparation containing a xanthone derivative represented by the formula (I) according to claim 1.   A pharmaceutical composition comprising a xanthone derivative represented by the formula (I) according to claim 1.