Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/365—Lactones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
  • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin

Definitions

• the present invention relates to an agent for promoting proliferation and/or differentiation of preadipocytes containing a helenalin derivative.
• Adipocytes are found in the lowest layer of the skin structure, which consists of three layers: epidermis, dermis, and subcutaneous tissue, and constitute an energy storage tissue that stores fat as triglycerides.
• Adipose tissue stimulates other tissues by secreting various adipokines, such as adiponectin, which is known as a longevity hormone.
• adipose tissue also has the function of creating a beautiful appearance in women by creating plumpness and improving wrinkles through local fat accumulation.
• the problem to be solved by the present invention is to find a compound contained in arnica extract that promotes the proliferation and/or differentiation of preadipocytes, and to use this compound to increase the volume of the fat layer and create a beautiful appearance.
• Our goal is to provide cosmetics, foods, medicines, etc., and/or materials used in these products.
• the present invention has been made to solve the above problems.
• the present invention was created based on the discovery that a specific compound fractionated and purified from an arnica flower extract using column chromatography or the like promotes the proliferation and/or differentiation of preadipocytes. That is, the present invention includes the following embodiments.
• R is a hydrogen atom or an acyl group having 1 to 5 carbon atoms.
• An agent for promoting proliferation and/or differentiation of preadipocytes which contains a compound represented by the following as an active ingredient.
• the preadipocyte according to (1) wherein the compound does not contain 6-O-tigloylhelenaline or contains 6-O-tigloylhelenaline in a mass ratio equal to or less than the total amount of the active ingredients.
• a proliferation and/or differentiation promoting agent (5) An external skin preparation for promoting the proliferation and/or differentiation of preadipocytes, which contains the compound represented by the above formula (I) as an active ingredient.
• the skin external preparation according to (5) or (4) which does not contain 6-O-tigloylhelenaline or contains it at a concentration of about 1 x 10 -7 % by mass or less.
• the preadipocyte proliferation and/or differentiation promoting agent of the present invention can be used in cosmetics, foods, pharmaceuticals, etc. for promoting the proliferation and differentiation of preadipocytes, increasing the volume of the fat layer and creating a beautiful appearance, and/or We can provide materials to be mixed with these.
• FIG. 1 shows a scheme for fractionating and purifying active ingredients from arnica extract.
• FIG. 2 shows the results of a proliferation test and a differentiation test of human subcutaneous preadipocytes for each fraction obtained by extracting the arnica extract with diethyl ether and fractionating it by silica gel open column chromatography.
• FIG. 3 shows DEFr. The results of a proliferation test and a differentiation test on human subcutaneous preadipocytes for Compound 1 and Compounds 3 to 10 isolated from the 4-2 fraction using silica gel open column chromatography, preparative HPLC, etc. are shown.
• FIG. 4 shows the results of a proliferation test and a differentiation test of human subcutaneous preadipocytes using Compounds 7, 8, and 9 alone or in combination.
• FIG. 5 shows DEFr.
• FIG. 6 shows the results of human subcutaneous preadipocyte proliferation and differentiation tests for compounds 11 (Cmpd11) to 19 (Cmpd19).
• preadipocytes refer to cells derived from adipose tissue that have the ability to differentiate into adipocytes. Unlike mature adipocytes, preadipocytes do not yet contain fat within their cells and are proliferative fibroblast-like cells. Mature adipocytes refer to cells that have differentiated from these precursor adipocytes so that they can accumulate fat within the cells, and are in a state in which fat is accumulated within the cells.
• One of the causes of skin aging is the regression and reduction of subcutaneous fat due to aging and ultraviolet rays. When the volume of the subcutaneous fat layer decreases, the skin loses its firmness and the skin surface becomes uneven, leading to wrinkles and depressions.
• the "preadipocyte proliferation and/or differentiation promoting agent” refers to an agent containing active ingredients used for these purposes. It refers to compositions, etc., and is a material that can be added to cosmetics and medicines.
• This agent may be not only a liquid but also a solid, for example, and specific applications include not only a skin external preparation but also an oral composition (for example, it can be prepared as either a solid or a liquid).
• the preadipocyte proliferation and/or differentiation promoting agent of this embodiment has the following formula (I):
• R is a hydrogen atom or an acyl group having 1 to 5 carbon atoms
• the acyl group in the "acyl group having 1 to 5 carbon atoms" means a substituted carbonyl group, and is a linear, branched, cyclic, saturated, or unsaturated aliphatic hydrocarbon group, Specific examples include acetyl group, propionyl group, isopropionyl group, isobutyryl group, tigloyl group, isovaleryl group, pivaloyl group, methacryloyl group, acroyl group, crotonoyl group, and 2-methylcrotonoyl group.
• R in the above formula (I) is a hydrogen atom or an acyl group having 1 to 4 carbon atoms.
• R is a hydrogen atom, an acetyl group, a methacryloyl group, or an isobutyryl group.
• the active ingredient of the present invention is 6-O-methacryloylhelenaline and/or 6-O-isobutyrylhelenaline.
• 6-O-methacryloylhelenaline is Compound 8 in which R represents a methacryloyl group in the compound represented by the above general formula (I).
• 6-O-isobutyrylhelenaline is a compound 9 in which R represents an isobutyryl group in the compound represented by the above general formula (I).
• the active ingredient of the present invention is helenaline or 6-O-acetylhelenaline.
• helenalin is the compound 12 in which R represents a hydrogen atom in the compound represented by the above general formula (I).
• 6-O-acetylhelenaline is Compound 13 in which R represents an acetyl group in the compound represented by the above general formula (I).
• These compounds may be extracted directly from arnica flowers, or may be synthesized by chemical modification using helenalin extracted from medicinal plants such as arnica as a parent compound.
• helenalin extracted from medicinal plants such as arnica as a parent compound.
• a method has been reported in which the hydroxyl group at the 6-position of helenalin is acetylated using acetic anhydride (Maria F. Beer et al., Molecules. 2019; 24(6): 1113, see Scheme 2). Based on these, those skilled in the art can easily synthesize Compound 8 and Compound 9 using helenalin and acid anhydride.
• arnica is a plant belonging to the Asteraceae family and the genus Arnica (scientific name: Arnica montana).
• Arnica montana a plant belonging to the Asteraceae family and the genus Arnica (scientific name: Arnica montana).
• An extract of arnica is produced, for example, by pulverizing the raw or dried material and then extracting it with a solvent. For example, 50 g of dried arnica flowers is immersed in 1 kg of 30% 1,3-butylene glycol solution and extracted in an environment of about 10° C. to about 30° C. for 5 to 10 days.
• 50 g of dried arnica flowers may be immersed in 1 kg of warm water at about 30° C. to about 50° C. for extraction for 2 to 10 hours.
• the solution obtained through this immersion is filtered using a predetermined filter material (Glass Fiber File retention time (Gf-75 manufactured by ADVANTEC), Mixed Cellulose ester (A045A047A manufactured by ADVANTEC), etc.).
• the filtered solution is left standing in an environment of about 0°C to about 10°C for 5 to 10 days.
• the solution is filtered again using a predetermined filter material and the resulting solution is used as an arnica extract.
• the active ingredient of this embodiment is extracted from an arnica extract using a solvent, and chromatography using various separation modes (ion exchange, hydrophilic adsorption, hydrophobic adsorption, size exclusion, ligand exchange, affinity, etc.). fractionation, molecular weight fractionation filtration using filter paper, membrane filters, ultrafiltration membranes, etc., pressurization or reduced pressure, heating or cooling, drying, pH adjustment, deodorization, decolorization, long-term static storage, etc. It is also possible to arbitrarily select and combine these methods. In one embodiment, it is preferable to carry out the reaction in combination with column chromatography, preparative HPLC, etc. used in the examples described later.
• the structure of the purified compound can be determined by NMR or mass spectrometry.
• the content ratio of each active ingredient in the agent of this embodiment is not particularly limited.
• the agent of the present embodiment may contain only one of 6-O-methacryloylhelenaline and 6-O-isobutyrylhelenaline, or may contain both in any ratio.
• Preferred embodiments include both 6-O-methacryloylhelenaline and 6-O-isobutyrylhelenaline, more preferably in approximately a 1:1 ratio.
• the agent of this embodiment may contain any compound in addition to these active ingredients.
• plants of the Asteraceae family, including arnica contain many types of helenalin, its derivatives, or its analogs. These are collectively called sesquiterpene lactones, which are lipophilic 15-carbon terpenoid compounds having a lactone ring.
• sesquiterpene lactones are used as herbal medicines for various symptoms. Their diversity is matched by the diversity of their biological activities, and they have been shown to exert anti-inflammatory, cytotoxic, anticancer, antibacterial, antifungal, insecticidal, and antiprotozoal effects. . Therefore, when the agent of the present embodiment contains sesquiterpene lactones as other components, it is necessary to pay attention to their various physiological activities, especially cytotoxicity.
• arnica extract contains many types of sesquiterpene lactones, but it is preferable to reduce the content ratio of highly cytotoxic components among them. Examples of highly cytotoxic helenalin derivatives include 6-O-tigloylhelenaline.
• the agent of the present embodiment does not contain 6-O-tigloylhelenaline or contains 6-O-tigloylhelenaline in a mass ratio equal to or less than the total amount of the active ingredients. This is because, in addition to suppressing the cytotoxic effects of other ingredients, a synergistic effect with the active ingredients of this embodiment can also be expected.
• composition of active ingredients contained in external skin preparations One use of the agent of this embodiment is as a skin external preparation.
• the content of each active ingredient in the skin external preparation is not particularly limited, as long as it can achieve the effect of promoting the proliferation and/or differentiation of preadipocytes, taking into account its dosage form and administration method. isn't it.
• the content of each active ingredient is preferably 0.1 x 10 -9 mass % or more, more preferably 0.1 x 10 -7 mass % (used as an aqueous solution), based on the total weight of the skin external preparation.
• 0.1 ng/mL) or more more preferably 0.3 ⁇ 10 ⁇ 7 % by mass or more, still more preferably 1 ⁇ 10 ⁇ 7 % by mass or more.
• the amount is preferably 1 ⁇ 10 ⁇ 2 mass % or less, more preferably 1 ⁇ 10 ⁇ 3 mass % or less, and still more preferably 1 ⁇ 10 ⁇ 4 mass % or less.
• 6-O-tigloylhelenaline compound 7
• it is preferably contained at a concentration of about 1 ⁇ 10 ⁇ 7 mass % or less, or not contained.
• the skin external preparation according to the present invention includes 1) pharmaceuticals, 2) quasi-drugs, in an appropriate form for use such as ampoules, capsules, powders, granules, liquids, gels, bubbles, emulsions, sheets, mist, and sprays.
• Topical or systemic skin preparations for example, basic cosmetics such as lotion, milky lotion, cream, ointment, lotion, oil, pack, etc., facial cleansers and skin cleansing such as bar soap, liquid soap, hand wash, etc.
• Make-up cosmetics such as cosmetics, massage agents, cleansing agents, hair removal agents, depilatory agents, shaving agents, aftershave lotions, pre-shave lotions, shaving creams, foundations, lipsticks, blushers, eye shadows, eyeliners, mascara, etc. , perfumes, nail polishes, nail enamels, nail enamel removers, poultices, plasters, tapes, sheets, patches, aerosols, etc.
• Medicinal and/or applied to the scalp and hair for example, basic cosmetics such as lotion, milky lotion, cream, ointment, lotion, oil, pack, etc., facial cleansers and skin cleansing such as bar soap, liquid soap, hand wash, etc.
• Make-up cosmetics such as cosmetics, massage agents, cleansing agents, hair removal
• Cosmetic preparations e.g. shampoos, conditioners, hair treatments, pre-hair treatments, permanent solutions, hair dyes, hair styling products, hair tonics, hair growth/nourishing products, poultices, plasters, tapes, etc.
• sheet preparations, aerosol preparations, etc. 5) bath preparations that are added to bathwater, and 6) other products such as underarm odor preventers, deodorants, antiperspirants, sanitary products, sanitary cotton, and wet tissues.
• compositions of external skin preparations can be manufactured by arbitrarily selecting and combining the ingredients and additives listed below as long as they do not impair the effects of the present invention. Although there is no particular restriction on the amount to be added, it is generally considered preferable to be about 0.0001 to 50%.
• oils and fats avocado oil, almond oil, fennel oil, perilla oil, olive oil, orange oil, orange laffa oil, sesame oil, cacao butter, chamomile oil, carrot oil, cucumber oil, beef tallow fatty acid, kukui nut oil, safflower oil , shea butter, liquid shea butter, soybean oil, camellia oil, corn oil, rapeseed oil, persic oil, castor oil, cottonseed oil, peanut oil, turtle oil, mink oil, egg yolk oil, palm oil, palm kernel oil, Japanese oak, palm oil Oil, beef tallow, lard, squalene, squalane, pristane, hydrogenated products of these fats and oils (hardened oil, etc.), etc.
• Alcohols Natural alcohols such as ethanol, isopropanol, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, cholesterol, phytosterol, phenoxyethanol, synthetic alcohols such as 2-hexyldecanol, isostearyl alcohol, 2-octyldodecanol, etc. .
• Esters Isopropyl myristate, Isopropyl palmitate, Butyl stearate, Hexyl laurate, Myristyl myristate, Oleyl oleate, Decyl oleate, Octyldodecyl myristate, Hexyldecyl dimethyloctoate, Cetyl lactate, Myristyl lactate, Diethyl phthalate, dibutyl phthalate, lanolin acetate, ethylene glycol monostearate, propylene glycol monostearate, propylene glycol dioleate, etc.
• Metal soaps Aluminum stearate, magnesium stearate, zinc stearate, calcium stearate, zinc palmitate, magnesium myristate, zinc laurate, zinc undecylenate, etc.
• Gummies sugars or water-soluble polymer compounds Gum arabic, benzoin gum, gum dammar, guaiac butter, Irish moss, gum karaya, gum tragacanth, gum carob, quinseed, agar, casein, lactose, fructose, sucrose or its ester, Trehalose or its derivatives, dextrin, gelatin, pectin, starch, carrageenan, carboxymethyl chitin or chitosan, hydroxyalkyl (C2-C4) chitin or chitosan to which alkylene (C2-C4) oxide such as ethylene oxide is added, low-molecular-weight chitin or chitosan, chitosan salt, sulfated chitin or chitosan, phosphorylated chitin or chitosan, alginic acid or its salt, hyaluronic acid or its salt, chondroitin sulfate or
• Surfactant Anionic surfactant (alkyl carboxylate, alkyl sulfonate, alkyl sulfate, alkyl phosphate), cationic surfactant (alkyl amine salt, alkyl quaternary ammonium salt), amphoteric Surfactants: Carboxylic acid type amphoteric surfactants (amino type, betaine type), sulfate ester type amphoteric surfactants, sulfonic acid type amphoteric surfactants, phosphate ester type amphoteric surfactants, nonionic surfactants ( Ether type nonionic surfactants, ether ester type nonionic surfactants, ester type nonionic surfactants, block polymer type nonionic surfactants, nitrogen-containing type nonionic surfactants), other surfactants ( natural surfactants, protein hydrolyzate derivatives, polymer surfactants, surfactants containing titanium and silicon, fluorocarbon surfactants), etc.
• Vitamin A group retinol, retinal (vitamin A1), dehydroretinal (vitamin A2), carotene, lycopene (provitamin A), vitamin B group: thiamine hydrochloride, thiamine sulfate (vitamin B1), Riboflavin (vitamin B2), pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), folic acids, nicotinic acids, pantothenic acids, biotin, choline, inositols, vitamin C group: vitamin C acid or its derivatives, vitamin D group: Ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), dihydrotachysterol, vitamin E group: vitamin E or its derivatives, ubiquinones, vitamin K group: phytonadione (vitamin K1), menaquinone (vitamin K2), menadione (vitamin K3), menadio
• the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples in any way.
• the unit % of the numerical value showing the addition amount of various components means mass %.
• Example 1 Component fractionation of arnica flower hot water extract
• Dried arnica flowers were soaked in warm water at about 50°C for 5 hours.
• the solution obtained through this immersion was filtered using a predetermined filtering material (glass filter paper, Gf-75, manufactured by ADVANTEC) and a cellulose mixed ester membrane filter, A045A047A, manufactured by ADVANTEC.
• the filtered solution was concentrated using an evaporator, then turned into powder using a freeze dryer, and used as an arnica extract.
• This arnica extract was fractionated according to the fractionation scheme shown in FIG.
• Arnica flower hot water extract (211.8 g) was suspended in distilled water (500 mL) and mixed with diethyl ether (5 x 250 mL, S01), ethyl acetate (5 x 250 mL, S02), butanol (5 x 250 mL, S03). Liquid-liquid partitioning was performed using a diethyl ether fraction (DEFr. 3.9 g), an ethyl acetate fraction (EFr. 2.8 g), a butanol fraction (BFr. 10.8 g), and a water fraction (WFr. (yield not measurable) was obtained.
• DEFr. 3.9 g diethyl ether fraction
• EFr. 2.8 g an ethyl acetate fraction
• BFr. 10.8 g butanol fraction
• WFr. yield not measurable
• DEFr. 9 281.9 mg was subjected to preparative HPLC (conditions 1, S06) to obtain Compound 1 (6.4 mg, retention time 19.7 min). DEFr. which showed high activity among the sub-fractions.
• the eluate was analyzed by TLC to obtain 13 fractions (DEFr.4-2-1 to DEFr.4-2-13).
• DEFr. 4-2-6 (66.5 mg) was subjected to preparative HPLC (conditions 2, S09), compound 2 (5.1 mg, retention time 31.2 min), compound 3 (13.5 mg, retention time 31.8 min) , Compound 4 (19.3 mg, retention time 32.0 min) was obtained.
• each purified fraction used in this evaluation was prepared based on the mass recovered from the arnica flower hot water extract and in the proportions present in the original extract, as described in Tables 2 and 3. did.
• each purified fraction was dissolved in DMSO to prepare a storage solution. This was dissolved in 30% BG to a concentration of 0.75%, and then added to the cells at a 1000-fold or 3000-fold dilution.
• the parent arnica flower hot water extract powder was prepared by dissolving 50 mg in 500 ⁇ L of 30% BG, diluting it in 30% BG to 0.75%, and then adding 0.75% DMSO. It was added to the cells at a 1000-fold or 3000-fold dilution. For comparison, 30% BG with 0.75% DMSO was prepared and added to cells at a 1000-fold or 3000-fold dilution.
• Human subcutaneous preadipocytes (manufactured by Lonza, PT-5020) were grown at 1 ⁇ 10 3 cells/well in a 96-well plate using Preadipocyte Growth Medium (PT-8002, manufactured by Lonza) containing 10% FBS. The cells were spread and cultured at 37° C. for 16 hours in a 5% CO 2 incubator. Thereafter, each purified fraction was added to the above concentration and cultured at 37° C. for 72 hours in a 5% CO 2 incubator. After culturing, the number of cells in the wells was measured. As a control for this experiment, wells to which 30% 1,3-butylene glycol, an extraction solvent containing no purified fractions, had been added were set up, and the number of cells in these wells was also measured. The ratio (relative value) of the number of cells in the well to which each purified fraction was added was calculated, assuming that the number of cells in the set well was 100.
• Human subcutaneous preadipocytes (manufactured by Lonza, PT-5020) were grown at 1 ⁇ 10 4 (cells)/well in a 96-well plate using Preadipocyte Growth Medium (manufactured by Lonza, PT-8002) containing 10% FBS. and cultured for 16 hours at 37°C in a 5% CO 2 incubator. After visually confirming confluence using a microscope, a differentiation induction medium (PT-8002, manufactured by Lonza) was added at 1/2 the concentration recommended by Lonza. At that time, each purified fraction was added to the above concentration and cultured at 37° C. for 10 days in a 5% CO 2 incubator.
• Preadipocyte Growth Medium manufactured by Lonza, PT-8002
• a differentiation induction medium (PT-8002, manufactured by Lonza) was added at 1/2 the concentration recommended by Lonza. At that time, each purified fraction was added to the above concentration and cultured at 37° C. for 10 days in a 5% CO 2 incubator.
• lipid droplets were fixed using Oil Red O (154-02072, Wako Pure Chemical Industries, Ltd.) saturated with 60% isopropyl alcohol. stained. After washing the wells with purified water, the stained lipid droplets were extracted using 100% isopropyl alcohol, and the absorbance was measured at 510 nm.
• the absorbance value of the well to which 30% 1,3-butylene glycol, which is an extraction solvent, was added to the above concentration instead of each purified fraction was set as 1, and the absorbance value of the well to which arnica extract was added (relative). value) was calculated and used as the differentiation rate (relative value).
• Figure 4 shows the results of the proliferation test and differentiation test of human subcutaneous preadipocytes when Cmpd7 (containing compound 7), Cmpd8 (containing compound 8), and Cmpd9 (containing compound 9) were used alone or in combination. Shown below.
• Cmpd7+8 is a combination of Cmpd7 and Cmpd8
• Cmpd7+9 is a combination of Cmpd7 and Cmpd9
• Cmpd8+9 is a combination of Cmpd8 and Cmpd9
• Cmp7+8+9 is a combination of Cmpd7, Comp8, and Cmpd9. Addition is indicated. From the results shown in FIG.
• Example 2 Of the 13 fractions (DEFr.1 to DEFr.13) obtained by fractionating the diethyl ether soluble portion obtained in Example 1 by silica gel open column chromatography, DEFr. 3 and DEFr. Each fraction 5-8 was further purified and new compounds 12-19 were isolated. The fractionation scheme for isolating this new compound is shown in Figure 5.
• KS0019 and KS0020 described as sample names represent different arnica extract lots.
• BG/DMSO represents a group containing 30% 1,3-butylene glycol and DMSO, which is an extraction solvent that does not contain purified fractions.
• Cmpd11 to Cmpd19 contain compounds 11 to 19, respectively. The concentration of each sample was adjusted so that the concentration of the compound was the same as that in the arnica extract, and it was added to the cells at a 1000-fold dilution.
• the preadipocyte proliferation and/or differentiation promoting agent of the present invention can be used industrially as cosmetics, foods, medicines, etc., and/or materials to be mixed therein.

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