Oral compositions, skin cosmetics, and hair cosmetics

Abstract

To find compounds derived from natural products excellent in anti-metabolic syndrome action, skin-whitening action, anti-aging action, hair growth action, anti-inflammatory action or liver function-improving action, and provide: an anti-metabolic syndrome agent, a skin-whitening agent, an anti-aging agent, a hair growth agent, an anti-inflammatory agent and a liver function-improving agent that contain the compounds as active ingredients; and oral compositions, skin cosmetics and hair cosmetics comprising the compounds derived from natural products.SOLUTION: Compounds 1 to 3 represented by the general formula (I) in the figure are used.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an anti-metabolic syndrome agent, a skin whitening agent, an anti-aging agent, a hair growth agent, an anti-inflammatory agent, and an agent for improving liver function, each of which contains a compound derived from a natural product as an active ingredient.The present invention also relates to an oral composition, a skin cosmetic, and a hair cosmetic each containing the compound. [Background technology]

[0002] In recent years, lifestyle habits such as overeating and lack of exercise have led to an increase in body fat and obesity. This increase in obesity is seen not only in humans but also in pets and livestock. Obesity is a cause of metabolic syndrome, such as hyperlipidemia and arteriosclerosis, and is therefore not only a problem in terms of beauty but also a major problem in terms of health.

[0003] Here, cyclic AMP (cAMP) is known to be involved in fat decomposition in the body. cAMP activates lipase present in the body, and fat is decomposed into fatty acids and glycerol by the activated lipase. However, when cAMP phosphodiesterase is activated, the decomposition of cAMP is induced and the activation of lipase is inhibited. Therefore, it is thought that by inhibiting the activity of cAMP phosphodiesterase, the amount of cAMP in cells is increased, and fat decomposition can be promoted.

[0004] In addition, it is known that platelet aggregation, which causes inflammatory reactions, is related to the concentration of cyclic AMP (cAMP) in platelets, and when cAMP is decomposed by cAMP phosphodiesterase and the concentration of cAMP decreases, platelets become more likely to aggregate. Therefore, it is believed that platelet aggregation can be prevented by inhibiting the action of cAMP phosphodiesterase to prevent the decrease in cAMP concentration, and thus allergic diseases, inflammatory diseases, etc. can be prevented, treated, or ameliorated. As a substance having an inhibitory effect on cAMP phosphodiesterase activity, tubeimoside I (see Patent Document 1) and the like are known.

[0005] Dipeptidyl peptidase IV (hereinafter also referred to as "DPP IV") is a serine protease that recognizes the second proline or alanine from the N-terminus and has the enzymatic activity of cleaving the C-terminus side. DPP IV is expressed in epithelial and endothelial cells of tissues such as the kidney, liver, intestine, and placenta, as well as on the cell surface of T cells, and is thought to be involved in various physiological phenomena through its enzymatic activity, etc.

[0006] Substrates of DPP IV include hormones called incretins. Incretins are a general term for hormones that are secreted from the intestine by nutrient stimulation and promote insulin secretion from pancreatic β cells in a blood glucose-dependent manner, and GLP-1, GIP, etc. are known. These incretins not only promote blood glucose-dependent insulin secretion, but also have the effects of suppressing glucagon secretion from α cells, lowering blood pressure, suppressing gastric emptying, and even suppressing food intake by acting on the hypothalamus (see Non-Patent Document 1). However, since incretins are decomposed by DPP IV, it is known that, for example, the half-life of GLP-1 in the body is about 1.5 minutes. Therefore, if the enzyme activity of DPP IV can be inhibited, the half-life of incretins in the body can be extended, and it is expected that this will be useful in treating metabolic syndromes such as type 2 diabetes, obesity, hypertension, and insulin resistance through the action of the incretins described above.

[0007] DPP IV is also known to be identical to CD26, a T cell activation marker, and to use many immunoregulatory peptides as substrates and to control their activity. Therefore, it is believed that by controlling the activity of DPP IV, it is possible to control immune responses such as autoimmune diseases such as rheumatoid arthritis and transplant rejection. Furthermore, DPP IV is known to be involved in the metabolism of some neuropeptides and growth hormones; invasion, metastasis, angiogenesis, etc. in cancer; and infection of lymphocytes by HIV. Therefore, it is believed that by inhibiting the activity of DPP IV, it is possible to treat diseases such as pain, neurodegenerative diseases, and neuropsychiatric disorders (e.g., sciatica, Alzheimer's disease, depression, etc.); growth hormone deficiency and diseases for which growth hormone is used for treatment; cancer (e.g., T-cell lymphoma, acute lymphoblastic leukemia, thyroid cancer, basal cell carcinoma, breast cancer, etc.); and HIV infection (AIDS).

[0008] In the skin, melanin also plays a role in protecting the body from ultraviolet rays, but excessive production or uneven accumulation can cause skin darkening and spots. In general, melanin is thought to be formed by converting tyrosine to dopa, dopa to dopaquinone, and then through intermediates such as 5,6-dihydroxyindophenol, through the action of the enzyme tyrosinase, which is biosynthesized in pigment cells. Therefore, in order to prevent, treat, or improve skin darkening (cutaneous pigmentation), spots, freckles, etc., it is considered to be possible to inhibit the activity of tyrosinase involved in the production of melanin, or to suppress the production of melanin.

[0009] Conventionally, skin pigmentation, age spots, freckles, etc. have been prevented, treated, or improved by topical application of whitening agents containing chemically synthesized products such as hydroquinone as an active ingredient. However, chemically synthesized products such as hydroquinone may cause side effects such as skin irritation and allergies. Therefore, the development of whitening agents containing safe natural raw materials as active ingredients is desired, and examples of agents that have a tyrosinase activity inhibitory effect include Polygonum salicina extract (see Patent Document 2). Also, examples of agents that have a melanin production inhibitory effect include extracts from plants of the genus Saussurea (see Patent Document 3).

[0010] The epidermis and dermis of the skin are composed of epidermal cells, fibroblasts, and extracellular matrices such as collagen, elastin, hyaluronic acid, etc., which are present outside these cells and support the skin structure. In young skin, fibroblasts proliferate actively, and the interaction between fibroblasts, extracellular matrix components, and other skin tissues maintains homeostasis, thereby ensuring moisture retention, flexibility, elasticity, etc., and the skin is maintained in a firm, glossy, and moist state in appearance.

[0011] However, when exposed to certain external factors such as ultraviolet light, extremely dry air, and excessive skin washing, or when aging progresses, the production of collagen, elastin, and hyaluronic acid, which are the main components of the extracellular matrix, decreases and also decomposes or changes in quality. As a result, the skin's moisturizing function and elasticity decrease, and abnormal peeling of the keratin occurs, causing the skin to lose firmness and luster, and to exhibit aging symptoms such as rough skin and wrinkles. Thus, the changes associated with skin aging, such as wrinkles, dullness, changes in texture, and decreased elasticity, are related to the decrease and denaturation of matrix components such as collagen, elastin, and hyaluronic acid. Therefore, promoting the production of collagen, elastin, and hyaluronic acid is important for preventing, treating, or improving skin aging.

[0012] Among these extracellular matrix components, collagen is a fibrous protein that contributes to maintaining the structure and mechanical strength of skin tissue. It is believed that if collagen production can be promoted, it will be possible to prevent, treat, or improve skin aging symptoms such as wrinkles, sagging, coarse texture, loss of firmness, and reduced elasticity.

[0013] Collagen is also found in large amounts in bones, tendons, ligaments, corneas, blood vessels, etc., and it is known that a decrease in collagen production due to aging or the like can cause osteoporosis, etc. Furthermore, it is known that in the wound healing process, collagen production is increased and serves as a scaffold for fibroblasts, etc., thereby promoting wound healing. Therefore, promoting collagen production is important from the viewpoints of preventing or treating osteoporosis, etc., and promoting wound healing. For example, extracts from Camphor Tree (see Patent Document 4) are known to have a collagen production promoting effect.

[0014] Among the above-mentioned extracellular matrix components, elastin is a fiber that gives elasticity to skin tissue. It is believed that if the production of elastin can be promoted, wrinkles and sagging will be less likely to occur, and symptoms of skin aging such as loss of firmness and reduced elasticity can be prevented, treated, or improved. In addition, elastin is broken down by an enzyme called elastase, which is activated by exposure to ultraviolet light, accelerating the breakdown of elastin. Therefore, it is believed that inhibiting the activity of elastase will suppress the breakdown of elastin, preventing and improving symptoms of skin aging such as loss of firmness and reduced elasticity.

[0015] Furthermore, elastin is widely expressed in tissues that require elasticity in the body, such as the lungs and blood vessels, in addition to skin tissues. It is known that when normal elastin is reduced from these tissues with age, the elasticity of the lungs and blood vessels decreases, which can cause pulmonary diseases such as emphysema, hypertension, and vascular diseases such as aneurysms. It is also known that smoking and other such causes the activity of elastase in the body to increase, which may destroy the alveolar walls and lead to emphysema and other conditions. Furthermore, it is thought that the increased activity of elastase may destroy pulmonary capillaries, leading to acute respiratory distress syndrome (ARDS) such as pulmonary edema. Therefore, if the production of elastin can be promoted, the loss of elasticity in the lungs and blood vessels will be less likely to occur, and it is believed that it will be possible to prevent and treat pulmonary diseases such as emphysema, high blood pressure, vascular diseases such as aneurysms, etc. Furthermore, if the activity of elastase in the body can be inhibited, it is believed that it will be possible to prevent and treat respiratory diseases such as emphysema and pulmonary edema. For example, extracts from plants belonging to the Hippophae genus of the Elaeaceae family are known to have an elastin production promoting effect (see Patent Document 5). Also, for example, star fruit extracts are known to have an elastase activity inhibitory effect (see Patent Document 6).

[0016] On the other hand, among the above-mentioned extracellular matrix components, hyaluronic acid is a kind of mucopolysaccharide, and has a function of retaining cells by filling the gap between cells, and also has many other functions, such as retaining water in the intercellular space, imparting lubricity and flexibility to tissues, and resisting external forces such as mechanical disorders. If the production of hyaluronic acid can be promoted, it is believed that it is possible to prevent, treat, or improve skin aging symptoms such as rough skin, wrinkles, dullness, changes in texture, reduced elasticity, and reduced moisturizing function. In addition, it is believed that it is possible to prevent, treat, or improve skin aging by promoting the expression of hyaluronan synthase 3 (HAS3), which is involved in promoting the synthesis of epidermal hyaluronic acid.

[0017] Hyaluronic acid is also present in cartilage, synovial fluid, umbilical cord, vitreous body, and other connective tissues, in addition to skin tissue. Among these, hyaluronic acid contained in synovial fluid covers the surface of articular cartilage, and its lubricating function, covering and protecting cartilage, etc., contribute to the smooth operation of joints. On the other hand, it is known that the concentration of hyaluronic acid in synovial fluid is decreased in arthritis such as chronic rheumatoid arthritis. Therefore, it is considered that arthritis such as chronic rheumatoid arthritis, osteoarthritis, suppurative arthritis, gouty arthritis, traumatic arthritis, or osteoarthritis can be prevented or treated by promoting the production of hyaluronic acid. Furthermore, it is known that granulation tissue (tissue) is formed during the healing process of wounds or burns, and that hyaluronic acid increases significantly in the granulation tissue. Therefore, it is considered that the healing of wounds or burns can be promoted by promoting the production of hyaluronic acid. As a substance that has a hyaluronic acid production promoting effect, an extract from Camphor tree (see Patent Document 4 mentioned above) and the like are known. In addition, licorice leaf extract (see Patent Document 7) and the like are known to have the effect of promoting the expression of hyaluronan synthase 3 (HAS3).

[0018] On the other hand, a basement membrane exists at the boundary between the epidermis and dermis that constitute the skin. The basement membrane not only connects the epidermis and dermis, but also plays an important role in maintaining skin function (see Non-Patent Document 2). The main skeleton of the basement membrane has a mesh structure made of type IV collagen. Various glycoproteins, mainly composed of laminin-332, exist at the boundary between the basement membrane and the epidermis and connect the basement membrane and the epidermis, and this laminin-332 is produced by epidermal keratinocytes present in the epidermis. In young skin, the interaction between the epidermis and dermis is maintained at homeostasis due to the function of the basement membrane, thereby ensuring moisture retention, flexibility, elasticity, etc., and the skin is maintained in a firm, glossy, and fresh state in appearance.

[0019] However, when exposed to certain external factors such as ultraviolet light, extremely dry air, and excessive skin washing, or when aging progresses, laminin-332, the main component of the basement membrane, decomposes and changes in quality, destroying the basement membrane structure (see Non-Patent Document 3). As a result, the skin's moisturizing function and elasticity decrease, and the keratin starts to peel off abnormally, causing the skin to lose firmness and luster, and to show aging symptoms such as roughness and wrinkles. Thus, the changes associated with skin aging, i.e., wrinkles, dullness, changes in texture, and decreased elasticity, are related to the decrease in basement membrane components and structural changes in the basement membrane, and it is believed that the aging symptoms of the skin can be prevented and improved by promoting the production of laminin-332.

[0020] Laminin consists of various combinations of α, β and γ chains, and 15 types (laminin 1 to laminin 15) are currently known. Among them, laminin-332 (α3β3γ2) is present in large amounts in the basement membrane of epithelial tissues such as skin, digestive organs, kidneys and lungs. It is known that a genetic disease (lethal congenital epidermolysis bullosa, Herlitz junctional epidermolysis bullosa) caused by congenital abnormalities of the genes encoding each chain of laminin-332 shows a fatal symptom in which the epidermis peels off all over the body. It is known that laminin-332 strongly adheres cells (high cell adhesion activity) and strongly promotes cell movement (high cell movement activity) compared to other extracellular matrix molecules.

[0021] As described above, laminin-332 has high cell motility activity and is therefore known to promote cell migration in damaged skin and promote wound healing (see Patent Document 8). In other words, promoting the production of laminin-332 is important for promoting the healing of skin injuries in which the structure of the basement membrane is destroyed.

[0022] The epidermis, which functions to mitigate external stimuli and control the loss of moisture and other body components, is composed of a four-layer structure, starting from the basal layer at the bottom, followed by the spinous layer, granular layer, and stratum corneum. Most of the cells in each layer are keratinocytes differentiated from the basal layer. Keratinocytes that divide and proliferate in the basal layer differentiate as they pass through the spinous layer and granular layer to become keratinocytes, which compose the stratum corneum, which is made up of keratin protein fibers with strong cross-linking, and are eventually shed from the stratum corneum as dirt.

[0023] The stratum corneum is the outermost layer of the skin and serves as a physical barrier against external stimuli. In order to provide this barrier function, the skin repeats a cycle (keratinization) from when keratinocytes are produced in the basal layer until they become dandruff and fall off, usually in a four-week cycle, to perform the metabolism of the epidermis. However, the metabolic function of this stratum corneum also declines with age, causing skin troubles such as fine wrinkles, dullness, pigmentation, and rough skin. Therefore, it is believed that skin aging such as fine wrinkles, dullness, and pigmentation can be improved by promoting the proliferation of keratinocytes and restoring the metabolic function of the skin. Conventionally, as a substance that has an effect of promoting the proliferation of epidermal keratinocytes, such as a mother oak extract (see Patent Document 9), etc., has been known.

[0024] In addition, in order to promote cell proliferation, it is important to supply cells with the energy required for cell division. ATP is an example of an energy substance in living organisms, and it is believed that increasing the amount of ATP produced promotes energy metabolism in cells, leading to cell proliferation. However, as mentioned above, it has been reported that the amount of ATP, an energy substance, is reduced in cells with reduced function or aged cells compared to normal cells (see Patent Document 10).

[0025] Therefore, if the production of ATP in cells can be promoted, it is believed that the cells can be activated to promote cell division and restore the proliferation ability of the cells. In particular, promoting the production of ATP in skin cells is important for promoting skin turnover, restoring the metabolic function of the skin, and preventing and improving skin aging such as wrinkles, dullness, and loss of texture. Conventionally, glycogen (see Patent Document 10), extracts from natural products such as peaches (see Patent Document 11), etc. are known to have an ATP production promoting effect.

[0026] Glutathione is a tripeptide consisting of three amino acids, glutamic acid, cysteine, and glycine, and is a compound that contains the major cysteine ​​residue in cells. Intracellular glutathione functions as a radical capture, cellular function regulation by redox, xenobiotic metabolism, and SH donor for various enzymes, and is also known as an antioxidant against active oxygen. It is believed that its action is due to the cysteine ​​residue. However, it has been reported that the amount of glutathione in cells is deficient or reduced due to excessive oxidative stress, the addition of foreign substances, aging, etc., and this is thought to be one of the factors that reduces the defense ability of cells against oxidative stress and damages the components of cells, such as DNA and proteins.

[0027] Such diseases that are known to be associated with a decrease or deficiency in intracellular glutathione levels include a group of diseases caused by oxidative stress, such as the formation of age spots on the skin, as well as liver disorders (caused by excessive alcohol consumption or the ingestion of foreign substances such as heavy metals and chemicals). In other words, promoting the production of glutathione is thought to enhance the defensive ability of cells against oxidative stress, and to prevent and treat the above-mentioned group of diseases caused by a decrease or deficiency in intracellular glutathione levels. Liquiritigenin (see Patent Document 12) and the like are known to have a glutathione production promoting effect.

[0028] In addition, among the basal layer, spinous layer, granular layer, and stratum corneum that compose the epidermis, especially in the granular layer, the cell membrane thickens to form a thickened cell membrane, and the action of transglutaminase-1 causes glutamyl-lysine crosslinking between protein molecules to form strong keratin protein fibers. Furthermore, ceramide and other molecules are covalently bonded to some of these fibers, forming a hydrophobic structure, which provides the foundation for the lamellar structure of intercellular lipids and forms the basis of the keratin barrier function.

[0029] However, when the production amount of transglutaminase-1 in the epidermis decreases with age, the keratin barrier function and the skin's moisturizing function are reduced, leading to the appearance of skin aging symptoms such as rough skin and dry skin, and the development of dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.). Therefore, it is believed that skin aging symptoms and dry skin diseases can be prevented, treated, or improved by promoting the production of transglutaminase-1 in the epidermis. Extracts from Hunan Sweet Tea (see Patent Document 13) and the like are known to have the effect of promoting transglutaminase-1 expression.

[0030] Ceramide is produced from serine and palmitoyl-CoA during the keratinization process of epidermal cells by the action of enzymes including serine palmitoyltransferase (SPT), known as the rate-limiting enzyme in ceramide synthesis. Ceramide is specifically present as the main component of intercellular lipids that cover the outermost layer of the skin, and plays an important role in maintaining the skin's inherent function as a barrier membrane between the body and the outside world.

[0031] The structure of the stratum corneum can be compared to bricks and mortar, with 15 or so layers of keratinocytes held together by intercellular lipids to form a strong barrier membrane. Corneocytes retain moisture by containing natural moisturizing factors, mainly composed of amino acids, while intercellular lipids are composed mainly of about 50% ceramide, and are made up of amphipathic lipids such as cholesterol and fatty acids, and are characterized by a layered structure in which hydrophobic and hydrophilic parts are alternately repeated, known as a lamellar structure.

[0032] A decrease in the barrier function of the skin due to various internal and external factors increases the amount of transepidermal water loss, causing dryness, desquamation, itching, etc., resulting in so-called dry skin. In addition, a decrease in the barrier function of the skin increases inflammation of the skin, resulting in a vicious cycle in which the defense function against various external stimuli is reduced. Recent studies have reported that ceramide components in the keratin (so-called intercellular lipids) decrease or change in composition due to aging or in patients with atopic dermatitis, known as barrier disorders (see Non-Patent Document 4), and it has become widely known that ceramide is important for maintaining and improving the barrier function of the skin. Methods for improving the barrier function of the skin include a method of supplementing ceramide from the outside (see Non-Patent Document 5) and a method of increasing ceramide production ability inside the skin (see Non-Patent Document 6).

[0033] In skin cells, aquaporins, known as water channels, are expressed on the cell membrane and are known to play a role in taking in low molecular weight substances, including water in the intercellular space, into the cells. In humans, 13 types of aquaporins (AQP0-AQP12) are known to exist. In epidermal cells, AQP3 is mainly present, and it is thought to play a role in taking in not only water, but also low molecular weight compounds such as glycerol and urea, which are involved in the moisture retention function.

[0034] However, AQP3 decreases with age, and it has been suggested that this is one of the causes of the decline in water retention function, so it is believed that it is possible to control water retention function and barrier function caused by aging by promoting the expression of AQP3 (see Non-Patent Document 7). For example, extracts from star fruit leaves (see Patent Document 14) are known to have the effect of promoting AQP3 expression.

[0035] Filaggrin is a component of the skin and is thought to be involved in the barrier function of the skin, preventing the invasion of allergens, toxins, and infectious organisms. It is known that a decrease in function due to gene mutations of filaggrin is associated with the risk of developing atopic diseases including atopic dermatitis (eczema, skin inflammation, skin itchiness, etc.), allergies, asthma, etc., and in severe cases, it can lead to skin diseases such as ichthyosis vulgaris (see Non-Patent Document 8).

[0036] On the other hand, amino acids, which are the main components of natural moisturizing factors (NMF), are produced by decomposing filaggrin derived from keratohyalin granules in the stratum corneum. This filaggrin is expressed as profilaggrin in epidermal keratinocytes present in the granular layer just below the stratum corneum. It is then immediately phosphorylated, accumulated in keratohyalin granules, decomposed into filaggrin through dephosphorylation and hydrolysis, and transferred to the stratum corneum, where it is known to increase the aggregation efficiency of keratin filaments and participate in the internal construction of keratinocytes (see Non-Patent Document 9). In recent years, it has been known that this filaggrin is very important and essential for moisture retention in the skin, and that the synthetic ability of filaggrin decreases under conditions such as dryness, and the amount of amino acids in the stratum corneum decreases (see Non-Patent Document 10).

[0037] Therefore, it is believed that by promoting the expression of filaggrin (profilaggrin) in epidermal keratinocytes, atopic diseases including atopic dermatitis (eczema, skin inflammation, skin itchiness, etc.), allergies, asthma, etc. can be prevented, treated, or improved. In addition, it is expected that by promoting the expression of filaggrin and thereby increasing the amount of amino acids in the stratum corneum, the moisture environment of the stratum corneum can be essentially improved. As a substance having a filaggrin expression promoting effect, Gaiyo extract (see Patent Document 15) and the like are known.

[0038] Previously, it was believed that only the stratum corneum was responsible for the barrier function of the skin. However, in recent years, it has been found that the barrier function of the skin collapses when the constituent proteins of tight junctions (hereinafter sometimes referred to as "TJ") present in the granular layer of the epidermis are genetically deleted, and TJs are now believed to play an important role in the barrier function of the skin (see Non-Patent Document 11). TJs are intercellular adhesion structures that not only bring adjacent cells into close contact with each other, but also control the permeation of substances by sealing the gaps between cells. TJs are composed of cell membrane proteins such as claudins and occludin, and supporting proteins such as ZO-1 and ZO-2, and these proteins are thought to form the skeleton of the TJ strand and control the barrier function of the TJ (see Non-Patent Document 12). Here, if the expression of claudins or occludin is reduced for some reason, structural destruction of TJs occurs, and they no longer function as a barrier to permeation of substances, which is thought to be a factor in skin symptoms such as dry skin, rough skin, atopic dermatitis, and various infectious diseases.

[0039] Therefore, it is believed that by promoting the production of claudins and occludin in the epidermis and thereby promoting the formation of TJs in epidermal keratinocytes, the barrier function and moisture retention function of the skin can be enhanced, and skin conditions such as dry skin, rough skin, atopic dermatitis, and various infectious diseases can be prevented or improved. Aspalathus linearis extract (Patent Document 16) and the like are known to have the effect of promoting claudin production and occludin production.

[0040] Carbohydrates are extremely important as an energy source for humans and other living organisms. However, it is known that carbohydrates undergo glycation reactions with proteins. Glycation is a series of reactions that begin with a nonenzymatic reaction between the carbonyl group of carbohydrates and the amino group of proteins, etc., and then proceeds through Schiff bases and Amadori compounds to finally form advanced glycation end products (hereinafter sometimes referred to as "AGEs"). Glycation nonenzymatically modifies proteins with sugars, which causes denaturation of the proteins and cross-linking between proteins, resulting in reduced protein function.

[0041] Glycation not only causes direct damage by modifying and changing the structure of collagen and other proteins that constitute the extracellular matrix, but also induces cellular responses by being recognized by receptors that use glycated proteins as ligands. In particular, the impact of glycation is serious for diabetic patients who have high blood glucose levels. It is known that protein glycation is one of the causes of diabetic complications such as diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy. It is also known that glycation in the vascular wall leads to the progression of arteriosclerosis due to endothelial cell damage and accumulation of denatured proteins. Furthermore, extracellular matrix components such as collagen account for more than half of the dry weight of tissues such as bones and skin. Therefore, for example, when collagen is glycated and abnormally cross-linked, osteoporosis and osteoarthritis develop in bone and cartilage tissues, and skin loses elasticity and becomes dull due to yellowing. Furthermore, since abnormally cross-linked collagen etc. is less susceptible to degradation by collagenase etc., the expression of collagenase etc. is induced, resulting in problems such as the degradation of normal collagen as well.

[0042] Therefore, if it were possible to inhibit glycation reactions in some way, for example by inhibiting the formation of AGEs or promoting the decomposition of AGEs, it would be expected to be useful in preventing or treating the aforementioned diseases, i.e., diabetic complications, arteriosclerosis, osteoporosis, osteoarthritis, etc. Furthermore, it would be expected to be effective in preventing or improving reduced elasticity and dullness of the skin, etc. Sweet osmanthus extract (see Patent Document 17) and the like are known to have the effect of inhibiting the formation of AGEs and promoting the decomposition of AGEs.

[0043] Many steroid hormones exert their effects by binding to receptors in the molecular form secreted from the organs that produce them, but in the case of male hormones collectively known as androgens, for example, testosterone enters the cells of the target organ and is reduced to 5α-dihydrotestosterone (5α-DHT) by testosterone 5α-reductase before binding to a receptor and exerting its androgen effect.

[0044] Androgens are important hormones, but when they act excessively, they induce various undesirable symptoms, such as male pattern baldness, hirsutism, seborrhea, acne (e.g., acne), prostatic hyperplasia, prostatic tumors, and precocious puberty in boys.Therefore, in order to improve these various symptoms, a method of suppressing the action of excess androgens has been known, specifically, a method of suppressing the generation of active 5α-DHT by inhibiting the action of testosterone 5α-reductase, which reduces testosterone to active 5α-DHT.So far, as a substance that has a testosterone 5α-reductase inhibitory effect, for example, an extract from Eastern perilla (see Patent Document 18) and the like have been known.

[0045] Hair grows and falls out repeatedly according to a periodic hair cycle consisting of an anagen phase, a regressive phase, and a telogen phase. In this hair cycle, the stage in which a new hair follicle is formed from the telogen phase to the anagen phase is considered to be the most important for hair growth, and it is believed that dermal papilla cells play an important role in the proliferation and differentiation of hair follicle epithelial cells in this stage. Dermal papilla cells are cells located inside hair follicle epithelial cells, which are composed of outer root sheath cells and matrix cells near the hair root, and are located in the basement membrane-encased root part of the hair root. They act on hair follicle epithelial cells to promote their proliferation, and play an important role in the proliferation and differentiation of hair follicle epithelial cells and hair formation (see Non-Patent Document 13).

[0046] Thus, hair papilla cells play an important role in the proliferation and differentiation of hair follicle epithelial cells and hair formation, and it is believed that promoting the proliferation of hair papilla cells can prevent and improve alopecia. To date, for example, wild thyme extract (see Patent Document 19) is known to have the effect of promoting the proliferation of hair papilla cells.

[0047] There are many different causes and mechanisms of onset for inflammatory diseases, such as contact dermatitis (rash), psoriasis, pemphigus vulgaris, atopic dermatitis, and other skin inflammatory diseases accompanied by rough skin, as well as rheumatoid arthritis, osteoarthritis, asthma, etc. The causes are known to be mainly due to excessive production of nitric oxide (NO), release of histamine, enhanced activity of hyaluronidase, and production of prostaglandin E2 (PGE2).

[0048] Nitric oxide (NO) is a nitrogen oxide that is a cause of air pollution, acid rain, etc., but in recent years, it has been discovered that nitric oxide is a physiologically active substance that exhibits various functions in the body, such as endothelium-derived relaxing factor (EDRF), neurotransmitter, and a factor that damages microorganisms and tumor cells in the host defense. In the host defense, nitric oxide produced by macrophages in particular protects against bacterial and viral infections.

[0049] However, when nitric oxide is synthesized in large quantities, it is not non-toxic to the body and can cause destruction of self-tissues, leading to aggravation of inflammation and pathological conditions such as rheumatism and diabetes. It is also known that nitric oxide synthesized in large quantities can cause relaxation of vascular smooth muscle and excessive increase in permeability, resulting in a significant drop in blood pressure and causing endotoxin shock.

[0050] Therefore, in inflammatory diseases, it is important to suppress excessive production of nitric oxide. For example, Tang Dohuo, tara root bark, Japanese jiandan, psyllium sieboldii, madder root, pentaerythritol, sophora japonica, pepper (see Non-Patent Document 14), extracts from plants belonging to the genus Hydrocotyle (see Patent Document 20), malturosilarginine (see Patent Document 21), etc. are known to have the effect of suppressing the production of nitric oxide.

[0051] Histamine release is a phenomenon in which histamine in mast cells is released outside the cells, and the released histamine causes inflammatory reactions.Therefore, attempts have been made to prevent or treat allergic diseases and inflammatory diseases by using substances that inhibit or suppress histamine release.However, it is difficult to directly evaluate histamine release, and histamine release can be evaluated using the release of hexosaminidase, which has been confirmed to be released simultaneously with histamine release, as an indicator.Therefore, by suppressing the release of hexosaminidase, the release of histamine can also be suppressed at the same time, which is thought to be effective in preventing, treating, or improving inflammatory diseases, etc.

[0052] In addition, histamine mediates intercellular information transmission as a local transmitter, and is known to promote gastric acid secretion in the digestive organs, function as a neurotransmitter in the central nervous system, and contribute to maintaining a waking state. Excessive histamine release can cause ulcers due to excess gastric acid in the digestive organs, and contribute to sleep disorders in the central nervous system. As mentioned above, by inhibiting the release of hexosaminidase, the release of histamine can also be inhibited at the same time, which is believed to prevent, treat, or improve gastric ulcers, sleep disorders, and the like caused by excess gastric acid. For example, an extract from wisteria tea (see Patent Document 22) is known to have a hexosaminidase release inhibitory effect.

[0053] Hyaluronidase is a hydrolase of hyaluronic acid. Hyaluronate, which maintains affinity for body tissues, is decomposed by ultraviolet rays, oxygen, etc. in a water-containing system, and the water-retaining effect decreases with the decrease in molecular weight. Hyaluronic acid also exists as intercellular tissue in the body and is involved in vascular permeability. Furthermore, hyaluronidase exists in mast cells, but is released by degranulation caused by the activation of mast cells, and acts as an inflammatory chemical mediator. Therefore, by inhibiting the activity of hyaluronidase, it is expected to enhance moisturization and prevent and reduce inflammation. For example, extracts from Osbeckia plants (see Patent Document 23) are known to have hyaluronidase activity inhibitory effects.

[0054] Inflammation is a complex reaction that shows symptoms such as redness, edema, fever, pain, itching, and functional impairment. For example, when the skin is exposed to ultraviolet rays or comes into contact with an irritant, inflammatory cytokines are produced in the skin, causing skin inflammation. As a result, the skin tissue is damaged, and various symptoms such as rough skin, redness, edema, and pigmentation occur.

[0055] One of the inflammatory cytokines is prostaglandin E2 (PGE2). In the skin, PGE2 is produced, for example, in keratinocytes, and causes skin inflammation. It has been revealed that cyclooxygenase-2 (COX-2), an inducible cyclooxygenase, is mainly involved in the production of prostaglandins during inflammation. Therefore, it is considered that a method for treating or preventing skin inflammation is to suppress the production of PGE2 in keratinocytes or to inhibit the activity of COX-2. Pentaerythritol and the like are known as ingredients that have an inhibitory effect on PGE2 production in keratinocytes (see Patent Document 24).

[0056] The liver is an essential organ for life support, playing a central role in metabolism. Its main functions include the metabolism of sugars, proteins, lipids, and hormones, detoxification of harmful substances, bile production, and blood storage. The liver is an organ that does not show symptoms even when damaged, but if liver function is damaged by alcohol consumption, overnutrition, drug abuse, hepatitis virus, etc., fatigue, lethargy, loss of appetite, and even jaundice may appear. If liver dysfunction progresses, it may lead to lifestyle-related diseases such as hepatitis and cirrhosis, so improving liver function and protecting it from damage are extremely important for maintaining a healthy life.

[0057] Glutathione is known as a biological component that protects the liver. Glutathione is a tripeptide consisting of three amino acids, glutamic acid, cysteine, and glycine, and is a compound that has a major cysteine ​​residue inside the cell. Glutathione is mainly produced in the liver and supplied to the whole body. In addition to its role in scavenging radicals in cells, regulating cellular functions by oxidation-reduction, and acting as an SH donor for various enzymes, it is known to be involved in the detoxification mechanism in the liver and protect liver function. Hepatic glutathione is consumed in large quantities in the process of metabolizing ethanol due to drinking alcohol, or in the process of metabolizing and detoxifying drugs. A decrease in the amount of hepatic glutathione can cause liver dysfunction such as acute or chronic alcoholic hepatitis and drug-induced hepatitis, and a decrease in the amount of glutathione in the whole body can cause a variety of symptoms such as cataracts, Parkinson's disease, and the formation of age spots on the skin.

[0058] Therefore, if it is possible to promote the production of glutathione in the liver (hepatocytes), it is expected that liver function can be improved and various disorders caused by a decrease in glutathione can be prevented, treated, or improved. Liquiritin (see Patent Document 11 mentioned above) and the like are known to have the effect of promoting glutathione production in hepatocytes.

[0059] Adenosine triphosphate (ATP) is known to improve liver function. ATP is produced by the metabolism of glucose and fats and is used as an energy source. In the liver, ATP is used as an energy source for many chemical reactions that take place in the liver, such as the metabolism and detoxification of ethanol and drugs. If the amount of ATP production decreases, the efficiency of these metabolisms and detoxification processes will decrease, and the energy required for activities such as labor and exercise will be insufficient, resulting in fatigue. Therefore, if ATP production in the liver can be promoted, it is believed that it will be possible to prevent or improve various symptoms caused by ethanol intake (e.g., hangover, etc.), prevent, treat or improve liver damage caused by drugs, and promote recovery from fatigue. Extracts of long pepper (see Patent Document 25) and the like are known to have an effect of promoting ATP production in hepatocytes. [Prior art documents] [Patent documents]

[0060] [Patent Document 1] JP 2006-056855 A [Patent Document 2] JP 2004-083488 A [Patent Document 3] JP 2002-201122 A [Patent Document 4] JP 2003-146837 A [Patent Document 5] JP 2005-022993 A [Patent Document 6] JP 2003-300893 A [Patent Document 7] JP 2010-090035 A [Patent Document 8] JP 2006-063033 A [Patent Document 9] JP 2006-056854 A [Patent Document 10] JP 2003-321373 A [Patent Document 11] JP 2009-256272 A [Patent Document 12] JP 2009-269889 A [Patent Document 13] JP 2007-099698 A [Patent Document 14] JP 2009-191039 A [Patent Document 15] JP 2012-219047 A [Patent Document 16] JP 2009-256244 A [Patent Document 17] JP 2013-023487 A [Patent Document 18] JP 2010-184915 A [Patent Document 19] JP 2006-219407 A [Patent Document 20] JP 2006-28036 A [Patent Document 21] JP 2010-90076 A [Patent Document 22] JP 2003-012532 A [Patent Document 23] JP 2003-055242 A [Patent Document 24] JP 2015-214533 A [Patent Document 25] JP 2011-184381 A [Non-patent literature]

[0061] [Non-Patent Document 1] "Japanese Pharmacological Journal", 2005, Vol. 125, No. 6, p. 379-384 [Non-Patent Document 2] J. Cell Biol., 1992, Vol. 119, No. 3, p. 695-703 [Non-Patent Document 3] J. Invest. Dermatol.,1979,Vol.73,No.1,p.59-66 [Non-Patent Document 4] J. Dermatol.,1993,Vol.20,No.1,p.1-6 [Non-Patent Document 5] "Fragrance Journal", 2004, Vol. 32, No. 11, p. 23-32 [Non-Patent Document 6] Br. J. Dermatol.,2000,Vol.143,Issue 3,p.524-531 [Non-Patent Document 7] "Fragrance Journal", 2006, Vol. 34, No. 10, p. 19-23 [Non-Patent Document 8] "Nat Genet.",2006,Vol.38,No.4,p.441-446 [Non-Patent Document 9] "Fragrance Journal Special Issue", 2000, Vol. 17, p. 14-19 [Non-Patent Document 10] "Arch. Dermatol. Res.", 1996, Vol. 288, p. 442-446 [Non-Patent Document 11] J. Cell Biol.,2002,vol.156,pp.1099-1111 [Non-Patent Document 12] Journal of the Japanese Society of Cosmetic Science, 2007, vol.31, pp.296-301 [Non-Patent Document 13] Trends Genet.,1992,Vol.8,Issue 2,p.55-61 [Non-Patent Document 14] "Japanese and Chinese Medicine Journal", 1998, Vol. 15, p. 302-303 Summary of the Invention [Problem to be solved by the invention]

[0062] The present invention aims to find compounds derived from natural products that have excellent anti-metabolic syndrome, skin whitening, anti-aging, hair growth, anti-inflammatory or liver function improving effects, and to provide anti-metabolic syndrome agents, skin whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents and liver function improving agents that contain these as active ingredients. Another object of the present invention is to provide an oral composition, a skin cosmetic, and a hair cosmetic that contain a compound derived from a natural product having excellent anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improving effects and are suitable for anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improving applications. [Means for solving the problem]

[0063] In order to solve the above problems, the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent and liver function improver of the present invention are characterized in that they contain, as an active ingredient, one or more compounds selected from the group consisting of compounds 1 to 3 represented by the following general formula (I): The oral composition, skin cosmetic and hair cosmetic of the present invention are characterized by containing one or more compounds selected from the group consisting of compounds 1 to 3 represented by the following general formula (I).

[0064] [ka] Effect of the Invention

[0065] According to the present invention, by using one or more compounds selected from the group consisting of compounds 1 to 3 represented by the above general formula (I) as an active ingredient, it is possible to provide an anti-metabolic syndrome agent, a skin-whitening agent, an anti-aging agent, a hair growth agent, an anti-inflammatory agent, and an agent for improving liver function, which have excellent effects. In addition, by blending one or more compounds selected from the group consisting of compounds 1 to 3 represented by the above general formula (I), it is possible to provide an oral composition, a skin cosmetic, and a hair cosmetic that are suitable for anti-metabolic syndrome applications, skin whitening applications, anti-aging applications, hair growth applications, anti-inflammation applications, or liver function improvement applications. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0066] Hereinafter, an embodiment of the present invention will be described.

[0067] [Phenylpropionic acids] The anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent and liver function improver according to this embodiment are characterized in that they contain, as an active ingredient, one or more compounds selected from the group consisting of compounds 1 to 3 represented by the following general formula (I): In addition, the oral composition, skin cosmetic, and hair cosmetic of this embodiment are characterized by containing one or more compounds selected from the group consisting of compounds 1 to 3 represented by the following general formula (I).

[0068] [ka]

[0069] The compounds represented by the above general formula (I) are all phenylpropionic acid derivatives, with compound 1 being 3,4-dihydroxyhydrocinnamic acid, compound 2 being 3-(4-hydroxyphenyl)propionic acid, and compound 3 being 3-phenylpropionic acid. Hereinafter, in this specification, the compound represented by the above formula (I) may be referred to as "phenylpropionic acids".

[0070] The above-mentioned phenylpropionic acids can be produced, for example, by isolating and purifying from a plant extract containing phenylpropionic acids. In this case, such a plant extract containing phenylpropionic acids can be obtained by a method generally used for plant extraction. Examples of plants containing the above-mentioned phenylpropionic acids include rice, barley, wheat, soybean, red bean, corn, etc.

[0071] The phenylpropionic acids can also be produced by fermenting, for example, 3,4-dihydroxycinnamic acid, 4-hydroxycinnamic acid, or cinnamic acid (hereinafter, these three compounds may be collectively referred to as "cinnamic acids"), or a composition containing them (for example, crushed or extracted plant material, etc.) with a microorganism having a phenolic acid reductase, converting the cinnamic acids to phenylpropionic acids, and then extracting, isolating, and purifying the resulting fermented product. Examples of compositions containing cinnamic acids include crushed or extracted plants such as coffee, wheat, corn, tomato, yerba mate, mugwort, and burdock. In addition, since cinnamic acids are components of lignin in woody plants and herbaceous plants, lignin or a composition containing it may be used as a fermentation raw material. On the other hand, examples of microorganisms having phenolic acid reductase include lactic acid bacteria such as Lactobacillus plantarum, Lactobacillus fermentum, Lactobacillus gasseri, Lactobacillus johnsonii, Lactobacillus crispatus, Lactobacillus acidophilus, Lactobacillus amylovorus, Lactobacillus delbrueckii, Lactobacillus buchneri, Lactobacillus kefiranofaciens, Lactobacillus gallinarum, and Enterococcus faecalis.

[0072] The method for extracting, isolating and purifying the phenylpropionic acids from the plants or fermented products is not particularly limited and can be carried out according to a conventional method. For example, the extraction process can be carried out by drying the plants or fermented products as the extraction raw material, and then subjecting them to extraction with an extraction solvent either directly or after crushing using a crusher. Drying can be carried out in the sun or using a commonly used dryer. In addition, the raw material can be used after pretreatment such as degreasing with a nonpolar solvent such as hexane. By carrying out pretreatment such as degreasing, extraction with a polar solvent can be carried out efficiently.

[0073] As the extraction solvent, it is preferable to use a polar solvent, such as water or a hydrophilic organic solvent, which is preferably used alone or in combination of two or more at room temperature or at a temperature below the boiling point of the solvent.

[0074] Water that can be used as an extraction solvent includes pure water, tap water, well water, mineral water, hot spring water, spring water, fresh water, etc., as well as water that has been subjected to various treatments. Treatments that can be applied to water include, for example, purification, heating, sterilization, filtration, ion exchange, osmotic pressure adjustment, buffering, etc. Therefore, water that can be used as an extraction solvent in this embodiment also includes purified water, hot water, ion-exchanged water, physiological saline, phosphate buffer, phosphate buffered physiological saline, etc.

[0075] Examples of hydrophilic organic solvents that can be used as the extraction solvent include lower aliphatic alcohols having 1 to 5 carbon atoms, such as methanol, ethanol, propyl alcohol, and isopropyl alcohol; polyhydric alcohols having 2 to 5 carbon atoms, such as 1,3-butylene glycol, propylene glycol, and glycerin; and lower aliphatic ketones, such as acetone and methyl ethyl ketone.

[0076] When a mixture of two or more polar solvents is used as an extraction solvent, the mixture ratio is arbitrary and can be adjusted appropriately. For example, when a mixture of water and a hydrophilic organic solvent is used as an extraction solvent, the mixture ratio can be arbitrarily mixed and used, that is, between more than 0:100 and less than 100:0 (volume ratio, hereinafter the same), and can be adjusted appropriately. For example, when a mixture of water and a lower aliphatic alcohol is used as the extraction solvent, the mixing ratio (volume ratio) of water to lower aliphatic alcohol can be 9:1 or more, or can be 7:3 or more, or the mixing ratio of water to lower aliphatic alcohol can be 1:9 or less, or can be 2:8 or less. When a mixture of water and a polyhydric alcohol is used, the mixing ratio of water to polyhydric alcohol can be 8:2 or more, or can be 1:9 or less, and when a mixture of water and a lower aliphatic ketone is used, the mixing ratio of water to lower aliphatic ketone can be 9:1 or more, or can be 2:8 or less.

[0077] The extraction process is not particularly limited as long as the soluble components contained in the extraction raw material can be dissolved in the extraction solvent, and can be performed according to a conventional method. For example, the extraction raw material is immersed in an extraction solvent in an amount 5 to 15 times (mass ratio) of the extraction raw material, and the soluble components are extracted at room temperature or under reflux heating, and then the extraction residue is removed by filtration to obtain an extract. The solvent is distilled off from the obtained extract to obtain a paste-like concentrate, and the concentrate is further dried to obtain a dry product.

[0078] The method for isolating and purifying the above-mentioned phenylpropionic acids from the extract obtained as above, the concentrate of the extract, or the dried product of the extract is not particularly limited, and can be performed by a conventional method. For example, the extract is dissolved in a developing solvent, and subjected to column chromatography using a porous substance such as silica gel or alumina, or a porous resin such as a styrene-divinylbenzene copolymer or polymethacrylate, to recover a fraction containing phenylpropionic acids. In this case, the developing solvent may be appropriately selected depending on the stationary phase used. For example, when the extract is separated by normal phase chromatography using silica gel as the stationary phase, the developing solvent may be chloroform:methanol=95:5. Furthermore, the fraction containing phenylpropionic acids obtained by column chromatography may be purified using any organic compound purification means such as reversed phase silica gel chromatography using ODS, recrystallization, liquid-liquid countercurrent extraction, column chromatography using ion exchange resin, etc.

[0079] [Anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, liver function improver] The phenylpropionic acids obtained as described above have excellent effects in anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory and liver function improvement, so they can be used as the active ingredient of anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents and liver function improvement agents.In addition, the phenylpropionic acids can be used to manufacture anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents or liver function improvement agents. The anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, and liver function improver of the present embodiment can be used in a wide range of applications such as medicines, quasi-drugs, and cosmetics.

[0080] Here, the anti-metabolic syndrome effect of the phenylpropionic acids is preferably exerted based on the inhibitory effect on cyclic AMP (cAMP) phosphodiesterase activity and / or the inhibitory effect on dipeptidyl peptidase IV (DPP IV) activity, but is not limited to the anti-metabolic syndrome effect exerted based on the above-mentioned effects. In addition, the above-mentioned phenylpropionic acids can be used for inhibiting cAMP phosphodiesterase activity or DPP IV activity by utilizing their cAMP phosphodiesterase activity inhibitory action or DPP IV activity inhibitory action, respectively. That is, the anti-metabolic syndrome agent of the present embodiment can also be used as a cAMP phosphodiesterase activity inhibitor or DPP IV activity inhibitor containing the above-mentioned phenylpropionic acids as an active ingredient.

[0081] The whitening effect of the phenylpropionic acids is preferably exerted based on the tyrosinase activity inhibitory effect and / or the melanin production inhibitory effect, but is not limited to the whitening effect exerted based on the above effects. In addition, the phenylpropionic acids can be used for inhibiting tyrosinase activity or inhibiting melanin production by utilizing their tyrosinase activity inhibitory action or melanin production inhibitory action, respectively. That is, the skin whitening agent of the present embodiment can also be used as a tyrosinase activity inhibitor or melanin production inhibitor containing the phenylpropionic acids as an active ingredient.

[0082] The anti-aging effect of the above-mentioned phenylpropionic acids is preferably exerted based on one or more effects selected from the group consisting of type I collagen production promoting effect, elastin production promoting effect, hyaluronic acid production promoting effect, elastase activity inhibiting effect, HAS3 mRNA expression promoting effect, laminin-332 production promoting effect, epidermal keratinocyte proliferation promoting effect, ATP production promoting effect, glutathione production promoting effect, transglutaminase-1 (TGM1) mRNA expression promoting effect, serine palmitoyltransferase (SPT) mRNA expression promoting effect, aquaporin 3 (AQP3) mRNA expression promoting effect, filaggrin mRNA expression promoting effect, claudin-1 mRNA expression promoting effect, claudin-4 mRNA expression promoting effect, occludin mRNA expression promoting effect, advanced glycation end products (AGEs) formation inhibiting effect, and advanced glycation end products (AGEs) decomposition promoting effect. However, the anti-aging effect of the above-mentioned phenylpropionic acids is not limited to the anti-aging effect exerted based on the above-mentioned action. In addition, the above-mentioned phenylpropionic acids can be used for the purposes of promoting type I collagen production, promoting elastin production, promoting hyaluronic acid production, inhibiting elastase activity, promoting HAS3 mRNA expression, promoting laminin-332 production, promoting epidermal keratinocyte proliferation, promoting ATP production, promoting glutathione production, promoting TGM1 mRNA expression, promoting SPT mRNA expression, promoting AQP3 mRNA expression, promoting filaggrin mRNA expression, promoting claudin-1 mRNA expression, promoting claudin-4 mRNA expression, promoting occludin mRNA expression, inhibiting AGEs formation, or promoting AGEs decomposition, respectively. The composition can be used for promoting mRNA expression, AQP3 mRNA expression, filaggrin mRNA expression, claudin-1 mRNA expression, claudin-4 mRNA expression, occludin mRNA expression, inhibiting the formation of AGEs, or promoting the decomposition of AGEs. In other words, the anti-aging agent of this embodiment can also be used as a type I collagen production promoter, elastin production promoter, hyaluronic acid production promoter, elastase activity inhibitor, HAS3 mRNA expression promoter, laminin-332 production promoter, epidermal keratinocyte proliferation promoter, ATP production promoter, glutathione production promoter, TGM1 mRNA expression promoter, SPT mRNA expression promoter, AQP3 mRNA expression promoter, filaggrin mRNA expression promoter, claudin-1 mRNA expression promoter, claudin-4 mRNA expression promoter, occludin mRNA expression promoter, AGEs formation inhibitor, or AGEs decomposition promoter, which contains the above-mentioned phenylpropionic acids as an active ingredient.

[0083] The hair growth effect of the phenylpropionic acids is preferably exerted based on the testosterone 5α-reductase activity inhibitory effect and / or the hair papilla cell proliferation promoting effect, but is not limited to the hair growth effect exerted based on the above effects. Furthermore, the above-mentioned phenylpropionic acids can be used for inhibiting testosterone 5α-reductase activity or promoting hair papilla cell proliferation by utilizing their testosterone 5α-reductase activity inhibitory effect or hair papilla cell proliferation promoting effect, respectively. That is, the hair growth agent of the present embodiment can also be used as a testosterone 5α-reductase activity inhibitor or hair papilla cell proliferation promoting agent containing the above-mentioned phenylpropionic acids as an active ingredient.

[0084] The anti-inflammatory effect of the phenylpropionic acids is preferably exerted based on one or more actions selected from the group consisting of nitric oxide (NO) production suppression action, hyaluronidase activity inhibition action, hexosaminidase release suppression action, and prostaglandin E2 (PGE2) activity inhibition action. However, the anti-inflammatory effect of the phenylpropionic acids is not limited to the anti-inflammatory effect exerted based on the above actions. In addition, the above-mentioned phenylpropionic acids can be used for the purpose of inhibiting NO production, inhibiting hyaluronidase activity, inhibiting hexosaminidase release, or promoting PGE2 production, by utilizing their NO production inhibitory effect, hyaluronidase activity inhibitory effect, hexosaminidase release inhibitory effect, or PGE2 production promoter effect, respectively. That is, the anti-inflammatory agent of the present embodiment can also be used as an NO production inhibitor, hyaluronidase activity inhibitor, hexosaminidase release inhibitor, or PGE2 production promoter containing the above-mentioned phenylpropionic acids as an active ingredient.

[0085] The liver function improving effect of the phenylpropionic acids is preferably exerted based on the hepatocyte glutathione production promoting effect and / or the hepatocyte adenosine triphosphate (ATP) production promoting effect, but is not limited to the liver function improving effect exerted based on the above effects. In addition, the above-mentioned phenylpropionic acids can be used for promoting hepatocyte glutathione production or hepatocyte ATP production by utilizing their hepatocyte glutathione production promoting effect or hepatocyte ATP production promoting effect, respectively. That is, the liver function improver of the present embodiment can also be used as a hepatocyte glutathione production promoter or hepatocyte ATP production promoter containing the above-mentioned phenylpropionic acids as an active ingredient.

[0086] In addition, a composition containing phenylpropionic acids may be used as an active ingredient of the anti-metabolic syndrome agent, skin-whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver according to this embodiment, instead of the isolated phenylpropionic acids. Here, the "composition containing phenylpropionic acids" in this embodiment includes an extract obtained by using a plant containing the phenylpropionic acids as an extraction raw material, a fermentation product containing phenylpropionic acids, and an extract obtained by using the fermentation product as an extraction raw material. In addition, the "extract" includes an extract obtained by an extraction process, a dilution or concentration of the extract, or a dried product obtained by drying the extract.

[0087] When using a composition containing the above-mentioned phenylpropionic acids as the active ingredient of the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent or liver function improver according to this embodiment, the phenylpropionic acids in the composition are preferably 0.1% by mass or more, more preferably 5% by mass or more, and particularly preferably 50% by mass or more.By using phenylpropionic acids with a higher purity as the active ingredient, it is possible to obtain an anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent or liver function improver with a more excellent action and effect.

[0088] The anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver of the present embodiment may consist solely of the above-mentioned phenylpropionic acids or a composition containing phenylpropionic acids, or may be a formulation of phenylpropionic acids or a composition containing phenylpropionic acids.

[0089] The anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver of the present embodiment can be formulated into any dosage form such as powder, granule, tablet, liquid, etc., according to a conventional method using a pharma- ceutically acceptable carrier such as dextrin, cyclodextrin, or any other auxiliary agent. In this case, for example, excipients, binders, disintegrants, lubricants, stabilizers, flavorings, odorants, etc. can be used as auxiliary agents. The anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, and liver function improver can be used by blending with other compositions (for example, oral compositions, skin cosmetics, etc. described below), and can also be used as external liquids, patches, etc.

[0090] When the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent or liver function improver of this embodiment is formulated, the content of the phenylpropionic acids or the composition containing phenylpropionic acids is not particularly limited and can be appropriately set depending on the purpose.

[0091] In addition, the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improving agent of this embodiment can be used as an active ingredient by blending other natural extracts having anti-metabolic syndrome action, skin whitening action, anti-aging action, hair growth action, anti-inflammatory action, or liver function improving action together with the above-mentioned phenylpropionic acids or a composition containing phenylpropionic acids, as necessary.

[0092] The method of administering the anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver of this embodiment to a patient includes oral administration, transdermal administration, intraperitoneal administration, intravenous administration, subcutaneous administration, etc., and a method suitable for the prevention or treatment, etc. may be appropriately selected depending on the type of disease. The dosage of the anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver of this embodiment may be appropriately increased or decreased depending on the type and severity of the disease, individual differences between patients, administration method, administration period, etc.

[0093] The anti-metabolic syndrome agent of the present embodiment can promote fat decomposition through its anti-metabolic syndrome action, preferably through its cAMP phosphodiesterase activity inhibitory action, and as a result, can prevent and improve various lifestyle-related diseases such as obesity and associated arteriosclerosis, diabetes, and metabolic syndrome. In addition, the anti-metabolic syndrome agent of the present embodiment can prevent and treat type 2 diabetes, obesity, hypertension, insulin resistance, and the like through its anti-metabolic syndrome action, preferably through its DPP IV activity inhibitory action. However, the anti-metabolic syndrome agent of the present embodiment can be used in all applications in which it is meaningful to exert an anti-metabolic syndrome action, preferably through its cAMP phosphodiesterase activity inhibitory action or DPP IV activity inhibitory action, in addition to these applications.

[0094] For example, the anti-metabolic syndrome agent of this embodiment or the cAMP phosphodiesterase activity inhibitor described above inhibits the decomposition of cAMP and can therefore inhibit platelet aggregation, thereby making it possible to prevent, treat, or ameliorate allergic diseases, various inflammatory diseases, and the like. Furthermore, the anti-metabolic syndrome agent of this embodiment or the above-mentioned DPP IV activity inhibitor can prevent and treat autoimmune diseases such as rheumatoid arthritis and transplant rejection through its DPP IV activity inhibitory action, and can also prevent and treat diseases such as pain, neurodegenerative diseases, and neuropsychiatric disorders (e.g., sciatica, Alzheimer's disease, depression, etc.); growth hormone deficiency and diseases for which growth hormone is used in the treatment; cancer (e.g., T-cell lymphoma, acute lymphoblastic leukemia, thyroid cancer, basal cell carcinoma, breast cancer, etc.); HIV infection (AIDS), etc.

[0095] The whitening agent of the present embodiment can prevent and improve pigmentation such as skin darkening, age spots, and freckles through its whitening effect, preferably tyrosinase activity inhibitory effect and / or melanin production inhibitory effect. However, in addition to these uses, the whitening agent of the present embodiment can be used for all uses in which it is meaningful to exert a whitening effect, preferably tyrosinase activity inhibitory effect or melanin production inhibitory effect.

[0096] The anti-aging agent of the present embodiment can prevent, treat or ameliorate symptoms of skin aging such as the formation of wrinkles, reduced elasticity and reduced moisturizing function through its anti-aging effect, preferably one or more effects selected from the group consisting of type I collagen production-promoting effect, elastin production-promoting effect, hyaluronic acid production-promoting effect, elastase activity inhibitory effect, HAS3 mRNA expression-promoting effect, laminin-332 production-promoting effect, epidermal keratinocyte proliferation-promoting effect, ATP production-promoting effect, glutathione production-promoting effect, TGM1 mRNA expression-promoting effect, SPT mRNA expression-promoting effect, AQP3 mRNA expression-promoting effect, filaggrin mRNA expression-promoting effect, claudin-1 mRNA expression-promoting effect, claudin-4 mRNA expression-promoting effect, occludin mRNA expression-promoting effect, AGEs formation-inhibiting effect, and AGEs decomposition-promoting effect. However, in addition to these applications, the anti-aging agent of this embodiment can be used for all applications in which it is significant to exert an anti-aging effect, preferably an effect of promoting type I collagen production, an effect of promoting elastin production, an effect of promoting hyaluronic acid production, an effect of inhibiting elastase activity, an effect of promoting HAS3 mRNA expression, an effect of promoting laminin-332 production, an effect of promoting epidermal keratinocyte proliferation, an effect of promoting ATP production, an effect of promoting glutathione production, an effect of promoting TGM1 mRNA expression, an effect of promoting SPT mRNA expression, an effect of promoting AQP3 mRNA expression, an effect of promoting filaggrin mRNA expression, an effect of promoting claudin-1 mRNA expression, an effect of promoting claudin-4 mRNA expression, an effect of promoting occludin mRNA expression, an effect of inhibiting the formation of AGEs, or an effect of promoting the decomposition of AGEs.

[0097] For example, the anti-aging agent of this embodiment or the above-mentioned type I collagen production promoter can be used for the prevention, treatment or improvement of diseases caused by decreased collagen production such as osteoporosis, through its type I collagen production promoting action; promotion of regeneration of damaged tendons and ligaments; promotion of wound or burn healing; and the like. In addition, the anti-aging agent of this embodiment or the above-mentioned elastin production promoter or elastase activity inhibitor can be used for the prevention, treatment or improvement of lung diseases such as emphysema, hypertension, vascular diseases such as aneurysm, through its elastin production promoting action or elastase activity inhibiting action. Furthermore, the anti-aging agent of this embodiment or the above-mentioned hyaluronic acid production promoter can be used for the prevention, treatment or improvement of arthritis such as chronic rheumatoid arthritis, osteoarthritis, suppurative arthritis, gouty arthritis, traumatic arthritis, osteoarthritis, and the like; promotion of wound or burn healing; and the like, through its hyaluronic acid production promoting action.

[0098] In addition to the uses described above, the anti-aging agent of this embodiment or the laminin-332 production promoter described above can treat and improve wounds in the skin by inducing reconstruction of the basement membrane structure through its laminin-332 production promoting effect. Furthermore, the anti-aging agent of this embodiment or the laminin-332 production promoter described above can be used as an agent for preventing or treating diseases (such as epidermolysis bullosa) caused by a deficiency (deficiency) of laminin-332.

[0099] In addition to the above-mentioned uses, the anti-aging agent of this embodiment or the above-mentioned epidermal keratinocyte proliferation promoter can be used for the prevention, treatment or improvement of fine wrinkles, dullness, pigmentation, etc., by restoring skin metabolism through its epidermal keratinocyte proliferation promoting action; regenerative medicine; etc. Furthermore, the anti-aging agent of this embodiment or the above-mentioned ATP production promoter can promote turnover through its ATP production promoting action, and prevent and improve skin aging symptoms such as wrinkles, loss of texture, and loss of elasticity in the skin, and can prevent and improve symptoms such as dullness and pigmentation in the skin by restoring the metabolic function of the skin, such as the shedding of keratinocytes with abnormal accumulation of melanin from the stratum corneum. Furthermore, the anti-aging agent of this embodiment or the above-mentioned ATP production promoter or glutathione production promoter can also be used for uses based on the hepatocyte ATP production promoting action or hepatocyte glutathione production promoting action described later.

[0100] In addition to the above-mentioned uses, the anti-aging agent of this embodiment or the above-mentioned TGM1 mRNA expression promoter, SPT mRNA expression promoter, or filaggrin mRNA expression promoter can strengthen the barrier function of the skin through its TGM1 mRNA expression promoting action, SPT mRNA expression promoting action, or filaggrin mRNA expression promoting action, and can prevent, treat, or improve rough skin, dry skin, and dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.). In addition, the anti-aging agent of this embodiment or the above-mentioned filaggrin mRNA expression promoter or AQP3 mRNA expression promoter can improve moisture retention function and barrier function due to aging through its filaggrin mRNA expression promoting action or AQP3 mRNA expression promoting action.

[0101] In addition to the above-mentioned uses, the anti-aging agent of this embodiment or the above-mentioned claudin-1 mRNA expression promoter, claudin-4 mRNA expression promoter, or occludin mRNA expression promoter can promote the formation of tight junctions in epidermal keratinocytes through their claudin-1 mRNA expression promoting action, claudin-4 mRNA expression promoting action, or occludin mRNA expression promoting action, thereby enhancing the barrier function and moisture retention function of the skin, and preventing or improving skin symptoms such as dry skin, rough skin, atopic dermatitis, and various infectious diseases. In addition, the anti-aging agent of this embodiment or the above-mentioned claudin-1 mRNA expression promoter, claudin-4 mRNA expression promoter, or occludin mRNA expression promoter can improve the barrier function in the digestive tract, and prevent or improve inflammatory bowel disease, food allergies, and various infectious diseases transmitted from the digestive tract.

[0102] In addition to the uses described above, the anti-aging agent of this embodiment or the above-mentioned AGE formation inhibitor or AGE decomposition promoter can prevent or treat diabetic complications such as diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy, arteriosclerosis caused by protein glycation, osteoporosis and osteoarthritis caused by protein glycation, etc., through its AGE formation inhibitory effect or AGE decomposition promoter effect. Furthermore, the anti-aging agent of this embodiment or the above-mentioned AGE formation inhibitor can prevent or inhibit hair damage caused by protein glycation, thereby preventing or inhibiting stiffness of hair, restoring elasticity, suppleness, etc., of hair, and imparting firmness and strength to hair.

[0103] The hair growth agent of the present embodiment can prevent, treat or improve alopecia such as androgenetic alopecia, alopecia areata, trichotillomania, etc. through its hair growth action, preferably testosterone 5α-reductase activity inhibitory action and / or hair papilla cell proliferation promoting action, and is particularly suitable for preventing, treating or improving androgenetic alopecia. However, in addition to these uses, the hair growth agent of the present invention can be used for all uses where it is meaningful to exert a hair growth action, preferably testosterone 5α-reductase activity inhibitory action or hair papilla cell proliferation promoting action.

[0104] For example, the hair growth agent of this embodiment or the above-mentioned testosterone 5α-reductase activity inhibitor can, through its testosterone 5α-reductase activity inhibitory action, prevent, treat or improve diseases in which male hormones are involved, such as hirsutism, seborrhea, acne (pimples, etc.), prostatic hyperplasia, prostatic tumors, male precocious puberty, etc. Furthermore, the hair growth agent of this embodiment or the above-mentioned hair papilla cell proliferation promoter can also be used in applications in the field of regenerative medicine, such as hair regeneration using hair papilla cells, through its hair papilla cell proliferation promoting action.

[0105] The anti-inflammatory agent of the present embodiment can prevent, treat or improve various skin inflammatory diseases associated with rough skin, such as contact dermatitis (rash), psoriasis, pemphigus vulgaris, atopic dermatitis, etc., through one or more actions selected from the group consisting of its anti-inflammatory action, preferably NO production inhibitory action, hyaluronidase activity inhibitory action, hexosaminidase release inhibitory action, and PGE2 production promoting action. However, in addition to these uses, the anti-inflammatory agent of the present embodiment can be used for all uses in which it is meaningful to exert an anti-inflammatory action, preferably NO production inhibitory action, hyaluronidase activity inhibitory action, hexosaminidase release inhibitory action, or PGE2 production promoting action.

[0106] For example, the anti-inflammatory agent of this embodiment or the above-mentioned NO production inhibitor, hyaluronidase activity inhibitor, hexosaminidase release inhibitor, or PGE2 production promoter can prevent, treat, or ameliorate rheumatoid arthritis, osteoarthritis, asthma, etc. through its NO production inhibitory action, hyaluronidase activity inhibitory action, hexosaminidase release inhibitory action, or PGE2 production promoter action. In addition, the anti-inflammatory agent of this embodiment or the above-mentioned hexosaminidase release inhibitor can prevent, treat, or ameliorate gastric ulcers, sleep disorders, etc. caused by hyperacidity through its hexosaminidase release inhibitory action.

[0107] The liver function improver of this embodiment can improve liver function by its liver function improving effect, preferably by promoting glutathione production in hepatocytes and / or promoting ATP production in hepatocytes. Uses for improving liver function include: prevention, treatment, or amelioration of symptoms caused by ethanol intake (e.g., hangover, etc.); promotion of metabolism and decomposition of sugar, fat, etc.; prevention, treatment, or amelioration of fatty liver, hepatitis such as alcoholic hepatitis and drug-induced hepatitis, liver cirrhosis, etc.; etc. However, in addition to these uses, the liver function improver of this embodiment can be used for all uses in which it is meaningful to exert an effect of improving liver function, preferably an effect of promoting glutathione production or ATP production in hepatocytes.

[0108] For example, the liver function improver of this embodiment or the aforementioned hepatocyte glutathione production promoter can be used, through its hepatocyte glutathione production promoting action, for applications such as prevention, treatment, or amelioration of diseases associated with decreased in vivo glutathione concentration, such as cataracts and Parkinson's disease; prevention, treatment, or amelioration of pigmentation, such as skin darkening, age spots, and freckles; etc. Furthermore, the liver function improver of this embodiment or the aforementioned hepatocyte ATP production promoter can be used, through its hepatocyte ATP production promoting action, for applications such as recovery from fatigue and lethargy.

[0109] In addition, the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent and liver function improver of the present embodiment each have excellent anti-metabolic syndrome action, skin whitening action, anti-aging action, hair growth action, anti-inflammatory action and liver function improvement action, and therefore can be suitably used as reagents for research on the mechanisms of action of these agents.

[0110] Oral Compositions The above-mentioned phenylpropionic acids have excellent effects in anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory and liver function improvement, so they are suitable for being incorporated into oral compositions.In this case, the above-mentioned phenylpropionic acids or the composition containing phenylpropionic acids may be incorporated as is, or the anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent or liver function improvement agent prepared from phenylpropionic acids may be incorporated.

[0111] By incorporating the above-mentioned phenylpropionic acids or a composition containing phenylpropionic acids, or an anti-metabolic syndrome agent, a whitening agent, an anti-aging agent, a hair growth agent, an anti-inflammatory agent, or a liver function improving agent formulated from a composition containing phenylpropionic acids or a phenylpropionic acids, into an oral composition, it is possible to make an oral composition suitable for anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improving.Among these, anti-metabolic syndrome and liver function improving effects are preferred because they are easily exerted by being imparted to an oral composition.

[0112] Here, the oral composition refers to a composition that is unlikely to cause harm to human health and is taken orally or by administration to the digestive tract in normal social life, and is not limited to administrative classifications such as food, medicine, and quasi-drug. Therefore, the "oral composition" in this embodiment broadly includes general food, feed, health food, health functional food (specified health food, functional food, functional food and drink), quasi-drug, medicine, etc. that are taken orally. The oral composition according to this embodiment is preferably an oral composition that can display the favorable effects of the phenylpropionic acids on the oral composition or its packaging, and is particularly preferably a health functional food (specified health food, functional food, functional food), quasi-drug, or medicine.

[0113] When the above-mentioned phenylpropionic acids or a composition containing phenylpropionic acids, or an anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver formulated from phenylpropionic acids or a composition containing phenylpropionic acids, is incorporated into an oral composition, the amount of the active ingredient incorporated therein can be appropriately changed taking into consideration the purpose of use, symptoms, sex, etc., but it is preferable to adjust the daily intake of phenylpropionic acids for adults to about 1 to 1000 mg, taking into consideration the general intake of the oral composition to which it is added. When the oral composition to be added is in the form of granules, tablets, or capsules, the amount of the phenylpropionic acids or a composition containing phenylpropionic acids, or the anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver formulated from the phenylpropionic acids or a composition containing phenylpropionic acids, is usually 0.1 to 100% by mass, and preferably 5 to 100% by mass, relative to the oral composition to be added.

[0114] The oral composition of the present embodiment may be one in which the phenylpropionic acids are incorporated into any oral composition that does not interfere with their activity, or may be a nutritional supplement containing the phenylpropionic acids as a main component.

[0115] When producing the oral composition of this embodiment, any auxiliary agent can be added, for example, sugars such as dextrin, starch, etc.; proteins such as gelatin, soy protein, corn protein, etc.; amino acids such as alanine, glutamine, isoleucine, etc.; polysaccharides such as cellulose, gum arabic, etc.; fats and oils such as soybean oil, medium-chain fatty acid triglyceride, etc., to form an oral composition in any shape.

[0116] The oral compositions that can contain the above-mentioned phenylpropionic acids are not particularly limited, and specific examples thereof include beverages such as soft drinks, carbonated drinks, nutritional drinks, fruit drinks, and lactic acid drinks (including concentrated concentrates and powders for adjusting these beverages); frozen desserts such as ice cream, ice sorbet, and shaved ice; noodles such as soba, udon, harusame, gyoza wrappers, shumai wrappers, Chinese noodles, and instant noodles; sweets such as candy, chewing gum, candies, gum, chocolate, tablet sweets, snacks, biscuits, jellies, jams, creams, and baked goods; These include processed seafood and livestock foods such as maboko, ham, and sausage; dairy products such as processed milk and fermented milk; oils and fats and oil-based processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressings; seasonings such as sauces and other sauces; soups, stews, salads, side dishes, and pickles; other health and nutritional supplements in various forms; tablets, capsules, and drinks, and when the above-mentioned phenylpropionic acids are incorporated into these oral compositions, commonly used auxiliary ingredients and additives can be used in combination.

[0117] [Skin cosmetics, hair cosmetics] The above-mentioned phenylpropionic acids have excellent effects in terms of anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory and liver function improvement, and are therefore suitable for incorporation into skin or hair cosmetics. In this case, the above-mentioned phenylpropionic acids may be incorporated as they are, or anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents or liver function improvers formulated from the above-mentioned phenylpropionic acids may be incorporated.

[0118] By blending the above-mentioned phenylpropionic acids or the above-mentioned anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents, or liver function improving agents, it is possible to impart an anti-metabolic syndrome effect, whitening effect, anti-aging effect, hair growth effect, anti-inflammatory effect, or liver function improving effect to the skin cosmetic or hair cosmetic, and it is possible to provide a skin cosmetic or hair cosmetic that can be used for anti-metabolic syndrome purposes, whitening purposes, anti-aging purposes, hair growth purposes, anti-inflammatory purposes, or liver function improving purposes.

[0119] Among these, the whitening, anti-aging and anti-inflammatory effects are easily exhibited when incorporated into skin cosmetics, i.e., the skin cosmetics can be particularly suitable for whitening, anti-aging or anti-inflammatory purposes.Furthermore, the hair growth, anti-aging and anti-inflammatory effects are easily exhibited when incorporated into hair cosmetics, i.e., the hair cosmetics can be particularly suitable for hair growth, anti-aging or anti-inflammatory purposes.

[0120] The type of skin cosmetic or hair cosmetic that can contain the above-mentioned phenylpropionic acids, or the above-mentioned anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver is not particularly limited. Examples of skin cosmetic products include ointments, creams, milky lotions, skin toners, lotions, gels, beauty oils, packs, foundations, etc., and examples of hair cosmetic products include hair tonics, hair creams, hair liquids, shampoos, pomades, rinses, etc.

[0121] When the above-mentioned phenylpropionic acids, or the above-mentioned anti-metabolic syndrome agents, skin whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents, or liver function improvers are blended into skin or hair cosmetics, the blending amount can be adjusted appropriately depending on the type of skin or hair cosmetic, but a suitable blending ratio is about 0.0001 to 10 mass%, and a particularly suitable blending ratio is about 0.001 to 1 mass% calculated as a standard extract.

[0122] The skin cosmetic or hair cosmetic of this embodiment may be used in combination with a main ingredient, auxiliary agent, or other ingredient used in the manufacture of a normal skin cosmetic or hair cosmetic, such as an astringent, a germicide or antibacterial agent, a whitening agent, an ultraviolet absorber, a moisturizer, a cell activator, an anti-inflammatory or antiallergic agent, an antioxidant or active oxygen remover, oils and fats, waxes, hydrocarbons, fatty acids, alcohols, esters, surfactants, fragrances, etc., so long as the anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improving effects of the phenylpropionic acids are not hindered. By using the ingredients in combination in this way, a more general product can be obtained, and the synergistic effect with the other active ingredients used in combination may bring about an excellent effect that is greater than would normally be expected.

[0123] The skin cosmetic composition of the present embodiment has the following properties that are possessed by the above-mentioned phenylpropionic acids: whitening effect, tyrosinase activity inhibitory effect, melanin production inhibitory effect, anti-aging effect, type I collagen production promoting effect, elastin production promoting effect, hyaluronic acid production promoting effect, elastase activity inhibitory effect, HAS3 mRNA expression promoting effect, laminin-332 production promoting effect, epidermal keratinocyte proliferation promoting effect, ATP production promoting effect, glutathione production promoting effect, TGM1 mRNA expression promoting effect, SPT mRNA expression promoting effect, AQP3 mRNA expression promoting effect, filaggrin mRNA expression promoting effect, claudin-1 mRNA expression promoting effect, claudin-4 mRNA expression promoting effect, occludin Promotes mRNA expression, inhibits AGEs formation, promotes AGEs decomposition; promotes hair growth, inhibits testosterone 5α-reductase activity, promotes hair papilla cell proliferation; anti-inflammatory, inhibits NO production, inhibits hyaluronidase activity, inhibits hexosaminidase release, promotes PGE2 production; anti-metabolic syndrome, inhibits cAMP phosphodiesterase activity, DPP Through one or more actions selected from the group consisting of an IV activity inhibitory action; an action to improve liver function, an action to promote glutathione production in hepatocytes, and an action to promote ATP production in hepatocytes, it is possible to prevent, treat, or improve pigmentation such as skin darkening, age spots, and freckles; prevent, treat, or improve skin aging symptoms such as the formation of wrinkles in the skin, reduced elasticity, and reduced moisturizing function; promote the healing of wounds or burns; prevent, treat, or improve rough skin, dry skin, and other dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.); prevent, treat, or improve diseases involving male hormones such as seborrhea and acne (pimples, etc.); prevent, treat, or improve contact dermatitis (rash), psoriasis, pemphigus vulgaris, and other various skin inflammatory diseases associated with rough skin; and prevent, treat, or improve obesity and associated lifestyle-related diseases such as arteriosclerosis, diabetes, and metabolic syndrome.

[0124] In addition, the hair cosmetic composition of the present embodiment has the following properties that are possessed by the above-mentioned phenylpropionic acids: hair growth effect, testosterone 5α-reductase activity inhibitory effect, hair papilla cell proliferation promoting effect, anti-inflammatory effect, NO production inhibitory effect, hyaluronidase activity inhibitory effect, hexosaminidase release inhibitory effect, PGE2 production promoting effect, anti-aging effect, type I collagen production promoting effect, elastin production promoting effect, hyaluronic acid production promoting effect, elastase activity inhibitory effect, HAS3 mRNA expression promoting effect, laminin-332 production promoting effect, epidermal keratinocyte proliferation promoting effect, ATP production promoting effect, glutathione production promoting effect, TGM1 mRNA expression promoting effect, SPT mRNA expression promoting effect, AQP3 mRNA expression promoting effect, filaggrin mRNA expression promoting effect, claudin-1 mRNA expression promoting effect, claudin-4 mRNA expression promoting effect, occludin Through one or more actions selected from the group consisting of an action promoting mRNA expression, an action inhibiting the formation of AGEs, and an action promoting the decomposition of AGEs; an anti-metabolic syndrome action, an action inhibiting cAMP phosphodiesterase activity, and an action inhibiting DPP IV activity; a skin whitening action, an action inhibiting tyrosinase activity, and an action inhibiting melanin production; an action improving liver function, an action promoting glutathione production in hepatocytes, and an action promoting ATP production in hepatocytes, it is possible to prevent, treat, or ameliorate alopecia such as male pattern baldness, alopecia areata, and trichotillomania; prevent, treat, or ameliorate contact dermatitis (rash), psoriasis, pemphigus vulgaris, and other various inflammatory skin diseases associated with rough skin; and treat rough skin, dry skin, and the like, as well as dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.).

[0125] The anti-metabolic syndrome agents, skin whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents, liver function improving agents, oral compositions, skin cosmetics, and hair cosmetics of the present embodiment are preferably applied to humans, but can also be applied to animals other than humans (e.g., mice, rats, hamsters, dogs, cats, cows, pigs, monkeys, etc.) as long as their respective functional effects are achieved. EXAMPLES

[0126] The present invention will be specifically described below by showing test examples, but the present invention is not limited to the following examples. In these test examples, the following commercially available compounds were used as test samples.

[0127] [Table 1]

[0128] [Test Example 1] Cyclic AMP phosphodiesterase activity inhibitory effect test Compound 1 (sample 1) was tested for its inhibitory effect on cyclic AMP phosphodiesterase activity as follows.

[0129] 0.1 mL of 2.5 mg / mL bovine serum albumin solution, 0.1 mL of 0.1 mg / mL cyclic AMP phosphodiesterase solution, and 0.05 mL of test sample solution (sample 1, see Table 2 below for final concentration) were added to 0.2 mL of 50 mmol / L Tris-HCl buffer (pH 7.5) containing 5 mmol / L magnesium chloride, and the mixture was left to stand at 37°C for 5 minutes. Then, 0.05 mL of 0.5 mg / mL cyclic AMP solution was added, and the mixture was reacted at 37°C for 60 minutes. After the reaction was completed, the reaction was stopped by boiling on a boiling water bath for 3 minutes, and the mixture was centrifuged (2260×g, 10 minutes, 4°C), and the reaction substrate cyclic AMP in the supernatant was analyzed under the following high performance liquid chromatography conditions. As a control, the same operation was performed by adding only the solvent without adding the sample.

[0130] <High performance liquid chromatography conditions> Product name: Chromatocorder 12 (manufactured by SYSTEM INSTRUMENTS) Stationary phase: Wakosil C 18 -ODS 5μm (Fujifilm Wako Pure Chemical Industries, Ltd.) Column length: 250mm Mobile phase: 1mmol / L TBAP in 25mmol / L KH2PO4:CH3CN=90:10 Mobile phase flow rate: 1.0mL / min Detection: 260nm

[0131] Next, the peak area (A) of the cyclic AMP standard, the peak area (B1) of the supernatant of the reaction solution of the cyclic AMP standard and cyclic AMP phosphodiesterase without the addition of a sample, and the peak area (B2) of the supernatant of the reaction solution of the cyclic AMP standard and cyclic AMP phosphodiesterase with the addition of a test sample were determined. From the results obtained, the decomposition rate (C) of the cyclic AMP standard without the addition of a sample and the decomposition rate (D) of the cyclic AMP standard with the addition of a test sample were calculated by the following formula.

[0132] Decomposition rate of standard without sample (C,%) = (1-B1 / A) x 100 Decomposition rate of standard when test sample is added (D,%) = (1-B2 / A) x 100

[0133] Then, based on each decomposition rate (C, D) calculated by the above formula, the cyclic AMP phosphodiesterase activity inhibition rate (%) was calculated by the following formula. cAMP phosphodiesterase activity inhibition rate (%) = (1-D / C) x 100 The results are shown in Table 2.

[0134] [Table 2]

[0135] As shown in Table 2, it was confirmed that Compound 1 (Sample 1) has an excellent inhibitory effect on cyclic AMP phosphodiesterase activity.

[0136] [Test Example 2] DPP IV activity inhibitory effect test Compounds 1 to 3 (samples 1 to 3) were tested for their inhibitory effect on dipeptidyl peptidase IV (DPP IV) activity as follows.

[0137] In a 96-well plate, 25 μL of test samples (samples 1 to 3, see Table 3 below for final concentrations) prepared in 25 mM Tris-HCl buffer (pH 8.0) and 25 μL of 0.4 μg / mL DPP IV (rhCD26, manufactured by R&D Systems Co., Ltd.) solution prepared in the above buffer were mixed and pre-incubated at 37°C for 5 minutes. Then, 50 μL of 0.5 mM Gly-Pro-p-NA·Tos (manufactured by Peptide Institute Co., Ltd.) prepared in the above buffer was added and reacted at 37°C for 90 minutes. After the reaction, the absorbance at a wavelength of 415 nm was measured. From the obtained results, the DPP IV activity inhibition rate (%) was calculated using the following formula.

[0138] DPP IV activity inhibition rate (%) = {1-(CD) / (AB)} x 100 Each term in the formula represents the following: A: Absorbance at 415 nm without addition of sample and with addition of enzyme B: Absorbance at 415 nm without adding sample or enzyme C: Absorbance at 415 nm with test sample and enzyme added D: Absorbance at 415 nm with and without the addition of test sample and enzyme The results are shown in Table 3.

[0139] [Table 3]

[0140] As shown in Table 3, compound 1 (sample 1), compound 2 (sample 2), and compound 3 (sample 3) all exhibited excellent DPP IV inhibitory activity.

[0141] [Test Example 3] Tyrosinase activity inhibitory effect test Compound 3 (sample 3) was tested for its tyrosinase activity inhibitory effect as follows.

[0142] 0.2 mL of Mcllvaine buffer (pH 6.8), 0.06 mL of 0.3 mg / mL tyrosine solution, and 0.18 mL of test sample (sample 3, see Table 4 below for final concentration) dissolved in 25% DMSO solution were added to a 48-well plate, and the plate was left to stand at 37°C for 10 minutes. 0.02 mL of 1000 units / mL tyrosinase solution was added, and the plate was allowed to react for 15 minutes at 37°C. After the reaction, the absorbance at a wavelength of 475 nm was measured.

[0143] As a blank, the same procedure and absorbance measurement were performed without adding the enzyme solution. Furthermore, as a control, the same measurement was performed without adding the sample solution but with the addition of 25% DMSO solution. From the obtained measurement results, the tyrosinase activity inhibition rate (%) was calculated using the following formula.

[0144] Tyrosinase activity inhibition rate (%) = {1-(AB) / (CD)} x 100 Each term in the formula represents the following: A: Absorbance at 475 nm with test sample and enzyme added B: Absorbance at 475 nm with and without the addition of test sample and enzyme C: Absorbance at 475 nm without addition of sample and with addition of enzyme D: Absorbance at 475 nm without adding sample or enzyme The results are shown in Table 4.

[0145] [Table 4]

[0146] As shown in Table 4, compound 3 (sample 3) was found to have an excellent tyrosinase activity inhibitory effect.

[0147] [Test Example 4] Test of melanin production inhibition effect on B16 melanoma cells Compounds 1 to 3 (samples 1 to 3) were tested for their melanin production inhibitory effect on B16 melanoma cells as follows.

[0148] B16 melanoma cells were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then harvested by trypsinization. The harvested cells were 24.0 × 10 4 The cells were diluted with DMEM containing 10% FBS and 1 mmol / L theophylline to a cell density of 100 cells / mL, and then seeded at 300 μL per well on a 48-well plate and cultured for 6 hours.

[0149] After the incubation, 300 μL of the test samples (samples 1 to 3, see Table 5 below for final concentrations) dissolved in DMEM containing 10% FBS and 1 mmol / L theophylline were added to each well and incubated for 4 days. As a control, the cells were incubated in the same manner using DMEM containing 10% FBS and 1 mmol / L theophylline without adding any sample. After the incubation, the medium was removed, 200 μL of 2 mol / L NaOH solution was added, the cells were disrupted using an ultrasonic disintegrator, and the absorbance at a wavelength of 475 nm was measured. The amount of melanin was calculated from the measured absorbance value based on a calibration curve created using synthetic melanin (manufactured by SIGMA).

[0150] To measure cell viability, the cells were cultured in the same manner as above, the medium was removed, washed with 400 μL of PBS(-) buffer, and 200 μL of neutral red dissolved in 10% FBS-containing DMEM at a final concentration of 0.05 mg / mL was added to each well and cultured for 2.5 hours. After culture, the neutral red solution was removed, and 200 μL of an ethanol-acetic acid solution (ethanol:acetic acid:water = 50:1:49) was added to each well to extract the pigment. After extraction, the absorbance at a wavelength of 540 nm was measured. From the results obtained, the melanin production inhibition rate (%) corrected by the cell viability was calculated using the following formula.

[0151] Melanin production inhibition rate (%) = {1-(B / D) / (A / C)} x 100 Each term in the formula represents the following: A: Amount of melanin without sample B: Amount of melanin when test sample is added C: Absorbance at 540 nm without adding sample D: Absorbance at 540 nm when test sample is added The results are shown in Table 5.

[0152] [Table 5]

[0153] As shown in Table 5, it was recognized that Compound 1 (Sample 1), Compound 2 (Sample 2), and Compound 3 (Sample 3) all had excellent melanin production inhibitory activity.

[0154] [Test Example 5] Type I collagen production promotion test Compound 1 (sample 1) was tested for its type I collagen production promoting effect as follows.

[0155] Normal human dermal fibroblasts (NB1RGB) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 1.6 × 10 5 The cells were diluted with DMEM containing 0.25% FBS to a cell density of 100 cells / mL, and then seeded at 100 μL per well on a 96-well microplate and cultured overnight.

[0156] After the incubation, 100 μL of the test sample (sample 1, see Table 6 below for final concentration) dissolved in DMEM containing 0.25% FBS was added to each well and incubated for 3 days. As a control, incubation was performed in the same manner using DMEM containing 0.25% FBS without adding any sample. After incubation, the amount of type I collagen in the medium in each well was measured by ELISA. From the measurement results, the type I collagen production promotion rate (%) was calculated using the following formula.

[0157] Type I collagen production promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of type I collagen when test sample was added B: Amount of type I collagen without adding sample The results are shown in Table 6.

[0158] [Table 6]

[0159] As shown in Table 6, it was confirmed that Compound 1 (Sample 1) has an excellent type I collagen production promoting effect.

[0160] [Test Example 6] Elastin production promotion test Compound 2 (sample 2) and compound 3 (sample 3) were tested for their elastin production promoting effect as follows.

[0161] Normal human dermal fibroblasts (NB1RGB) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 2.2 × 10 5 After diluting with the above medium to a cell density of 100 cells / mL, the cells were seeded in a 96-well microplate at 100 μL per well and cultured overnight.

[0162] After the culture was completed, the medium was removed, and 150 μL of the test samples (samples 2 and 3, see Table 7 below for final concentrations) dissolved in DMEM containing 0.25% FBS was added to each well and cultured for 5 days. As a control, culture was performed in the same manner using DMEM containing 0.25% FBS but without the addition of any sample. After the culture was completed, the supernatant was collected, and the amount of elastin released into the culture supernatant was measured by ELISA. From the measurement results, the elastin production promotion rate (%) was calculated using the following formula.

[0163] Elastin production promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of elastin when test sample is added B: Amount of elastin without adding sample The results are shown in Table 7.

[0164] [Table 7]

[0165] As shown in Table 7, both Compound 2 (Sample 2) and Compound 3 (Sample 3) exhibited excellent elastin production promoting activity.

[0166] [Test Example 7] Elastase activity inhibitory effect test Compounds 1 to 3 (samples 1 to 3) were tested for their elastase activity inhibitory effect as follows.

[0167] In a 96-well microplate, 50 μL of test samples (samples 1 to 3, see Table 8 below for final concentrations) prepared in 0.2 mol / L Tris-HCl buffer (pH 8.0) were mixed with 50 μL of 20 μg / mL elastase type III (SIGMA-Aldrich) solution. Then, 100 μL of 0.4514 mg / mL N-succinyl-Ala-Ala-Ala-p-nitroanilide (SIGMA-Aldrich) prepared in the above buffer was added and reacted at 25°C for 15 minutes. After the reaction, the absorbance at a wavelength of 415 nm was measured. In addition, a blank test without enzyme was performed in the same manner to correct the values. From the obtained results, the elastase activity inhibition rate (%) was calculated using the following formula.

[0168] Elastase activity inhibition rate (%) = {1-(CD) / (AB)} x 100 Each term in the formula represents the following: A: Absorbance at 415 nm without addition of sample and with addition of enzyme B: Absorbance at 415 nm without adding sample or enzyme C: Absorbance at 415 nm with test sample and enzyme added D: Absorbance at 415 nm with and without the addition of test sample and enzyme The results are shown in Table 8.

[0169] [Table 8]

[0170] As shown in Table 8, compounds 1 to 3 (samples 1 to 3) were found to have excellent elastase activity inhibitory effect.

[0171] [Test Example 8] Hyaluronic acid production promotion test Compound 1 (sample 1) and compound 2 (sample 2) were tested for their hyaluronic acid production promoting effect as follows.

[0172] Normal human dermal fibroblasts (NB1RGB) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 1.6 × 10 5 The cells were diluted with DMEM containing 0.25% FBS to a cell density of 100 cells / mL, and then seeded at 100 μL per well on a 96-well plate and cultured overnight.

[0173] After the incubation, 100 μL of the test samples (samples 1 and 2, see Table 9 below for final concentrations) dissolved in 0.25% FBS-containing DMEM was added to each well and incubated for 3 days. As a control, incubation was performed in the same manner using 0.25% FBS-containing DMEM without the addition of samples. After incubation, the amount of hyaluronic acid in the medium of each well was measured by the sandwich method using hyaluronic acid binding protein (HABP). From the results obtained, the hyaluronic acid production promotion rate (%) was calculated using the following formula.

[0174] Hyaluronic acid production promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of hyaluronic acid when test sample was added B: Amount of hyaluronic acid without adding sample The results are shown in Table 9.

[0175] [Table 9]

[0176] As shown in Table 9, it was confirmed that Compound 1 (Sample 1) and Compound 2 (Sample 2) have excellent hyaluronic acid production promoting activity.

[0177] [Test Example 9] Hyaluronan synthase 3 (HAS3) mRNA expression promoting effect test Compound 1 (sample 1) was tested for its effect of promoting HAS3 mRNA expression as follows.

[0178] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0179] After 24 hours of incubation, the medium was removed and 2 mL of the test sample (sample 1, see Table 10 below for final concentration) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0180] Using this total RNA as a template, the expression levels of mRNA for HAS3 and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green(R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of HAS3 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The HAS3 mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0181] HAS3 mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 10.

[0182] [Table 10]

[0183] As shown in Table 10, compound 1 (sample 1) had an excellent effect of promoting HAS3 mRNA expression.

[0184] [Test Example 10] Laminin-332 production promotion test Compound 1 (sample 1) was tested for its laminin-332 production promoting effect as follows.

[0185] Normal human neonatal epidermal keratinocytes (NHEK) were cultured at 75 cm 2 The cells were pre-cultured in a flask using normal human epidermal keratinocyte growth medium (KGM) and harvested by trypsinization. The harvested cells were 1.0 × 10 5 The cells were diluted with KGM medium without BPE (KGM-BPE) to a cell density of 100 cells / mL, and then seeded at 500 μL per well on a 24-well plate and cultured for one day.

[0186] After incubation, the medium was removed and 500 μL of the test sample (sample 1, see Table 11 below for final concentration) dissolved in KGM-BPE was added to each well and incubated for 48 hours. As a control, incubation was performed in the same manner using KGM-BPE without the addition of sample. After incubation, 100 μL of the medium supernatant was transferred to an ELISA plate and allowed to adsorb to the plate at 37°C for 2 hours, after which the amount of adsorbed laminin-332 was measured by ELISA. From the measurement results, the laminin-332 production promotion rate (%) was calculated using the following formula.

[0187] Laminin-332 production promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of laminin-332 when test sample was added B: Amount of laminin-332 without sample The results are shown in Table 11.

[0188] [Table 11]

[0189] As shown in Table 11, it was confirmed that Compound 1 (Sample 1) had an excellent effect of promoting laminin-332 production.

[0190] [Test Example 11] Epidermal keratinocyte proliferation promotion test Compound 1 (sample 1) was tested for its epidermal keratinocyte proliferation promoting effect as follows.

[0191] Normal human neonatal epidermal keratinocytes (NHEK) were cultured in normal human epidermal keratinocyte growth medium (KGM), and the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 3.0 × 10 4After diluting with KGM to a cell density of 100 cells / mL, 100 μL was seeded per well on a collagen-coated 96-well plate and cultured overnight. After the culture was completed, 100 μL of the test sample (sample 1, see Table 12 below for final concentration) dissolved in KGM was added to each well and cultured for 3 days. As a control, KGM without sample was used and cultured in the same manner.

[0192] The epidermal keratinocyte proliferation promoting effect was measured using the MTT assay. After 3 days of culture, the medium was removed, and 100 μL of MTT dissolved in PBS(-) buffer at a final concentration of 0.4 mg / mL was added to each well. After 2 hours of culture, blue formazan produced in the cells was extracted with 100 μL of 2-propanol. After extraction, the absorbance at a wavelength of 570 nm was measured. At the same time, the absorbance at a wavelength of 650 nm was measured as turbidity, and the difference between the two was taken as the amount of blue formazan produced. From the results obtained, the epidermal keratinocyte proliferation promoting rate (%) was calculated using the following formula.

[0193] Epidermal keratinocyte proliferation promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of blue formazan produced when test sample is added B: Amount of blue formazan produced without adding sample The results are shown in Table 12.

[0194] [Table 12]

[0195] As shown in Table 12, compound 1 (sample 1) was found to have an excellent epidermal keratinocyte proliferation promoting effect.

[0196] [Test Example 12] ATP production promotion test (epidermal keratinocytes) Compound 1 (sample 1) and compound 2 (sample 2) were tested for their ATP production promoting effect as follows.

[0197] Normal human neonatal epidermal keratinocytes (NHEK) were cultured in normal human epidermal keratinocyte growth medium (KGM), and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 2.0 × 10 5 After diluting with KGM to a cell density of 100 cells / mL, 100 μL was seeded per well on a collagen-coated 96-well plate and cultured overnight. After culture was completed, the medium was removed and 100 μL of KGM containing test samples (samples 1 and 2, see Table 13 below for final concentrations) was added to each well and cultured for 2 hours. As a control, KGM without sample was used and cultured in the same manner.

[0198] The ATP production promotion effect was measured by measuring the amount of ATP in the cells using the firefly luciferase luminescence method. That is, after 2 hours of culture, 100 μL of ATP measurement reagent (manufactured by Toyo B-Net Co., Ltd., product name "Cellular ATP Measurement Reagent") was added to each well, and a chemiluminescence reaction was performed using luciferase. After the reaction, the amount of chemiluminescence proportional to the amount of ATP in the cells was measured using a chemiluminescence measurement device (manufactured by Thermo Fisher Scientific, product name: Varioskan LUX multimode microplate reader). From the obtained results, the ATP production promotion rate (%) was calculated using the following formula.

[0199] ATP production promotion rate (%)=A / B×100 Each term in the formula represents the following: A: Chemiluminescence amount when test sample is added B: Chemiluminescence amount without sample added The results are shown in Table 13.

[0200] [Table 13]

[0201] As shown in Table 13, Compound 1 (Sample 1) and Compound 2 (Sample 2) were found to have excellent ATP production promoting activity.

[0202] [Test Example 13] Glutathione production promotion test (skin fibroblasts) Compounds 1 to 3 (samples 1 to 3) were tested for their glutathione production promoting effect in skin fibroblasts as follows.

[0203] Normal human skin fibroblasts (NB1RGB) were cultured in α-modified Eagle's minimum essential medium (α-MEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 2.0 × 10 5 The cells were diluted with α-MEM containing 10% FBS to a cell density of 100 cells / mL, and then seeded at 200 μL per well on a 48-well plate and cultured for 48 hours.

[0204] After the incubation, the medium was removed, and 200 μL of the test samples (samples 1 to 3, see Table 14 below for final concentrations) dissolved in 1% FBS-containing Dulbecco's modified Eagle's medium (DMEM) was added to each well and incubated for 24 hours. As a control, incubation was performed in the same manner using DMEM containing 1% FBS without the addition of the test samples. After incubation, the medium was removed from each well, and the wells were washed with 400 μL of PBS(-) buffer, and then the cells were lysed using 150 μL of M-PER (PIERCE).

[0205] Of these, 100 μL was used to quantify total glutathione. That is, 100 μL of the dissolved cell extract, 50 μL of 0.1 mol / L phosphate buffer, 25 μL of 2 mmol / L NADPH, and 25 μL of 3.2 unit / mL glutathione reductase were added to a 96-well plate, and the plate was heated at 37°C for 10 minutes. After that, 25 μL of 10 mmol / L 5,5'-dithiobis(2-nitrobenzoic acid) was added, and the absorbance at a wavelength of 412 nm was measured for 5 minutes, and ΔOD / min was calculated. The total glutathione concentration was calculated based on a calibration curve prepared using oxidized glutathione (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). The obtained value was corrected to the amount of glutathione per total protein amount, and the glutathione production promotion rate (%) was calculated using the following formula.

[0206] Glutathione production promotion rate (%) = B / A x 100 Each term in the formula represents the following: A: Amount of glutathione per total protein without sample addition B: Amount of glutathione per total protein amount when test sample was added The results are shown in Table 14.

[0207] [Table 14]

[0208] As shown in Table 14, it was confirmed that Compound 1 (Sample 1), Compound 2 (Sample 2) and Compound 3 (Sample 3) all had excellent glutathione production promoting activity in fibroblasts.

[0209] [Test Example 14] Transglutaminase-1 (TGM1) mRNA expression promoting effect test Compounds 1 to 3 (samples 1 to 3) were tested for their TGM1 mRNA expression promoting effect as follows.

[0210] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0211] After 24 hours of incubation, the medium was removed and 2 mL of test samples (samples 1 to 3, see Table 15 below for final concentrations) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0212] Using this total RNA as a template, the expression levels of mRNA for TGM1 and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The PCR was performed by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio Inc.). The primers used had the sequences 5'-AGGTGGAGCTTAGCCCTGTG-3' and 5'-GCAAGTGAAGACTGACTCCCTCTC-3'. The expression level of TGM1 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the normalized value was calculated with the GAPDH value. The TGM1 mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0213] TGM1 mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 15.

[0214] [Table 15]

[0215] As shown in Table 15, compound 1 (sample 1), compound 2 (sample 2) and compound 3 (sample 3) all had excellent TGM1 mRNA expression promoting activity.

[0216] [Test Example 15] Serine palmitoyltransferase (SPT) mRNA expression promoting effect test Compound 1 (sample 1) was tested for its effect of promoting SPT mRNA expression as follows.

[0217] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0218] After 24 hours of incubation, the medium was removed and 2 mL of the test sample (sample 1, see Table 16 below for final concentration) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0219] Using this total RNA as a template, the mRNA expression levels of SPT and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (Takara Bio Inc.) with PrimeScript TMRT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers from Takara Bio were used. The expression level of SPT mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The SPT mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0220] SPT mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 16.

[0221] [Table 16]

[0222] As shown in Table 16, compound 1 (sample 1) had an excellent effect of promoting the expression of SPT mRNA.

[0223] [Test Example 16] Aquaporin 3 (AQP3) mRNA expression promoting effect test Compound 1 (sample 1) was tested for its AQP3 mRNA expression promoting effect as follows.

[0224] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0225] After 24 hours of incubation, the medium was removed and 2 mL of the test sample (sample 1, see Table 17 below for final concentration) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0226] Using this total RNA as a template, the expression levels of mRNA for AQP3 and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (manufactured by Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of AQP3 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The AQP3 mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0227] AQP3 mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 17.

[0228] [Table 17]

[0229] As shown in Table 17, compound 1 (sample 1) had an excellent AQP3 mRNA expression promoting effect.

[0230] [Test Example 17] Filaggrin (FLG) mRNA expression promoting effect test Compounds 1 to 3 (samples 1 to 3) were tested for their FLG mRNA expression promoting effect as follows.

[0231] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0232] After 24 hours of incubation, the medium was removed and 2 mL of test samples (samples 1 to 3, see Table 18 below for final concentrations) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0233] Using this total RNA as a template, the expression levels of FLG and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (Takara Bio) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of FLG mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The FLG mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0234] FLG mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 18.

[0235] [Table 18]

[0236] As shown in Table 18, all of Compound 1 (Sample 1), Compound 2 (Sample 2) and Compound 3 (Sample 3) had excellent FLG mRNA expression promoting activity.

[0237] [Test Example 18] Claudin-1 (CLDN1) mRNA expression promoting effect test Compound 1 (sample 1) and compound 3 (sample 3) were tested for their promoting effect on CLDN1 mRNA expression as follows.

[0238] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0239] After 24 hours of incubation, the medium was removed and 2 mL of test samples (samples 1 and 3, see Table 19 below for final concentrations) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of RNA in each sample was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0240] The total RNA was used as a template to measure the expression levels of mRNA for CLDN1 and GAPDH as an internal standard. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (manufactured by Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of CLDN1 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The CLDN1 mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0241] CLDN1 mRNA expression promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 19.

[0242] [Table 19]

[0243] As shown in Table 19, both compound 1 (sample 1) and compound 3 (sample 3) had an excellent effect of promoting the expression of CLDN1 mRNA.

[0244] [Test Example 19] Claudin-4 (CLDN4) mRNA expression promoting effect test Compound 1 (sample 1) was tested for its promoting effect on CLDN4 mRNA expression as follows.

[0245] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0246] After 24 hours of incubation, the medium was removed and 2 mL of the test sample (sample 1, see Table 20 below for final concentration) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0247] The total RNA was used as a template to measure the expression levels of mRNA for CLDN4 and GAPDH as an internal standard. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (manufactured by Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of CLDN4 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the corrected value was calculated using the GAPDH value. The CLDN4 mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0248] CLDN4 mRNA expression promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 20.

[0249] [Table 20]

[0250] As shown in Table 20, compound 1 (sample 1) had an excellent CLDN4 mRNA expression promoting effect.

[0251] [Test Example 20] Occludin (OCLN) mRNA expression promoting effect test Compound 1 (sample 1) and compound 3 (sample 3) were tested for their effect of promoting OCLN mRNA expression as follows.

[0252] Normal human neonatal epidermal keratinocytes (NHEK) were precultured in growth medium for normal human epidermal keratinocytes (KGM), and the cells were harvested by trypsinization. The harvested cells were cultured at 15 × 10 4 After diluting with KGM to a cell density of 30 × 10 cells / mL, 2 mL of the cells were seeded into a 6-well plate (30 × 10 4 The cells were cultured overnight at 37℃ with 5% CO2 (cells / well). After culture, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the above KGM without the addition of growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)) and cultured for an additional 24 hours.

[0253] After 24 hours of incubation, the medium was removed and 2 mL of test samples (samples 1 and 3, see Table 21 below for final concentrations) dissolved in KBM was added to each well and incubated for 24 hours at 37°C and 5% CO2. As a control, KBM without sample was used and incubated in the same manner. After incubation, the medium was removed and total RNA was extracted using ISOGEN II (Nippon Gene Co., Ltd.). The amount of each RNA was measured using a spectrophotometer and total RNA was adjusted to 150 ng / μL.

[0254] Using this total RNA as a template, the expression levels of mRNA for OCLN and GAPDH as an internal standard were measured. Detection was performed using a real-time PCR device Thermal Cycler Dice Real Time System III (Takara Bio Inc.) with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R)The assay was carried out by a two-step real-time RT-PCR reaction using Fast qPCR Mix (Takara Bio). Primers used were from Takara Bio. The expression level of OCLN mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the addition of the test sample, and the correction value was calculated using the GAPDH value. The OCLN mRNA expression promotion rate (%) was calculated from the obtained values ​​using the following formula.

[0255] OCLN mRNA expression promotion rate (%) = A / B × 100 Each term in the formula represents the following: A: Correction value when test sample is added B: Correction value without sample The results are shown in Table 21.

[0256] [Table 21]

[0257] As shown in Table 21, both Compound 1 (Sample 1) and Compound 3 (Sample 3) had excellent OCLN mRNA expression promoting activity.

[0258] [Test Example 21] Test for inhibitory effect on the formation of advanced glycation end products (AGEs) Compound 1 (sample 1) and compound 2 (sample 2) were tested for their inhibitory effect on the formation of AGEs as follows.

[0259] A 96-well type I collagen-coated plate (Asahi Glass Co., Ltd.) was charged with 100 μL of a mixture of 0.2M D(-)-ribose prepared in PBS(-) buffer and test samples (samples 1 and 2, see Table 22 below for final concentrations) and then allowed to stand at 37°C for 20 days to allow AGEs to form. As a negative control, PBS(-) buffer alone, and as a positive control, a 0.2M D(-)-ribose solution prepared in PBS(-) buffer were both allowed to stand in the same manner. After 20 days, the amount of AGEs was measured by ELISA using an anti-AGEs antibody (Transgenic Co., Ltd.) to evaluate the inhibitory effect on AGE formation. From the results obtained, the AGE formation inhibition rate (%) was calculated using the following formula.

[0260] AGEs formation inhibition rate (%)={(BC) / (BA)}×100 Each term in the formula represents the following: A: Absorbance at 405 nm for negative control B: Absorbance at 405 nm for positive control C: Absorbance at 405 nm when test sample is added The results are shown in Table 22.

[0261] [Table 22]

[0262] As shown in Table 22, Compound 1 (Sample 1) and Compound 2 (Sample 2) exhibited excellent AGE formation inhibitory activity.

[0263] [Test Example 22] Test for promoting the decomposition of advanced glycation end products (AGEs) Compound 1 (sample 1) was tested for its effect of promoting the decomposition of AGEs as follows.

[0264] 100 μL of 0.2MD(-)-ribose solution prepared in PBS(-) buffer was added to a 96-well I-type collagen coated plate (Asahi Glass Co., Ltd.), and the plate was left to stand at 37°C for 2 weeks to form AGEs. As a negative control, only PBS(-) buffer was added and the plate was left to stand in the same manner. After 2 weeks, 100 μL of test sample (sample 1, see Table 23 below for final concentration) prepared in PBS(-) buffer was added to each well, and the plate was left to stand for another 20 days at 37°C. As a positive control, only PBS(-) buffer was used instead of the test sample, and as a negative control, only PBS(-) buffer was used in the same manner. After 20 days, the amount of AGEs was measured by ELISA using an anti-AGEs antibody (Transgenic Co., Ltd.) to evaluate the AGEs decomposition promotion effect. From the obtained results, the AGEs decomposition promotion rate (%) was calculated using the following formula.

[0265] AGEs degradation promotion rate (%)={(BC) / (BA)}×100 Each term in the formula represents the following: A: Absorbance at 405 nm for negative control B: Absorbance at 405 nm for positive control C: Absorbance at 405 nm when test sample is added The results are shown in Table 23.

[0266] [Table 23]

[0267] As shown in Table 23, compound 1 (sample 1) exhibited an excellent effect of promoting the decomposition of AGEs.

[0268] [Test Example 23] Testosterone 5α-reductase inhibitory activity test Compounds 1 to 3 (samples 1 to 3) were tested for their testosterone 5α-reductase inhibitory activity as follows.

[0269] In a V-bottom test tube with a lid, 20 μL of a 4.2 mg / mL testosterone solution (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) prepared in propylene glycol was mixed with 825 μL of 5 mmol / L Tris-HCl (pH 7.13) buffer solution containing 1 mg / mL NADPH.

[0270] Further, 80μL of the test sample (samples 1 to 3, see Table 24 below for final concentration) solution prepared with 80% ethanol was added and mixed with 75μL of S-9 (rat liver homogenate, manufactured by Oriental Yeast Co., Ltd.), and incubated at 37℃ for 60 minutes. Then, 1mL of methylene chloride was added to stop the reaction. This was centrifuged (1600×g, 10 minutes), and the methylene chloride layer was separated. The separated methylene chloride layer was subjected to gas chromatography analysis under the following conditions to quantify the concentrations of 3α-androstanediol, 5α-dihydrotestosterone (5α-DHT), and testosterone. As a control, the same amount (80μL) of sample solvent was used instead of the test sample solution, and the same treatment was performed, followed by gas chromatography analysis.

[0271] <Gas chromatography conditions> Equipment used: Shimadzu GC-2010 (manufactured by Shimadzu Corporation) Column: DB-1701 (inner diameter: 0.53 mm, length: 30 m, film thickness: 1.0 μm) (J&W Scientific) Column temperature: 240℃ Inlet temperature: 300℃ Detector: FID Sample injection volume: 1 μL Split ratio: 1:2 Carrier gas: Nitrogen gas Carrier gas flow rate: 12mL / min

[0272] The concentrations of 3α-androstanediol, 5α-DHT and testosterone were quantified by the following method. The standard samples of 3α-androstanediol, 5α-DHT and testosterone were dissolved in ethanol, and the solution was subjected to gas chromatography analysis, and the correspondence relationship between the peak area and the concentration of the compound was previously obtained from the concentration (μg / mL) and peak area of ​​these compounds.Then, the concentration per peak area of ​​each of 3α-androstanediol, 5α-DHT and testosterone after the reaction of testosterone with S-9 was calculated based on the following formula (1) using the correspondence relationship previously obtained.

[0273] A = B × C / D (1) Each term in the formula represents the following: A: 3α-androstanediol, 5α-DHT or testosterone concentration B: Peak area of ​​3α-androstanediol, 5α-DHT or testosterone C: Concentration of standard D: Peak area of ​​standard

[0274] Using the compound concentration calculated based on formula (1), the conversion rate (the concentration ratio of 3α-androstanediol and 5α-DHT produced by reduction of testosterone by testosterone 5α-reductase to the initial concentration of testosterone) was calculated based on the following formula (2).

[0275] Conversion rate = (E + F) / (E + F + G) (2) Each term in the formula represents the following: E: 3α-androstanediol concentration (μg / mL) F: 5α-DHT concentration (μg / mL) G: Testosterone concentration (μg / mL)

[0276] Using the conversion rate calculated based on formula (2), the testosterone 5α-reductase inhibition rate (%) was calculated based on the following formula (3). Testosterone 5α-reductase inhibition rate (%) = (1-H / I) × 100 (3) Each term in the formula represents the following: H: Conversion rate when test sample is added I: Conversion rate without sample addition The results are shown in Table 24.

[0277] [Table 24]

[0278] As shown in Table 24, it was confirmed that Compound 1 (Sample 1), Compound 2 (Sample 2) and Compound 3 (Sample 3) have excellent testosterone 5α-reductase inhibitory activity.

[0279] [Test Example 24] Hair papilla cell proliferation promotion effect test Compound 1 (sample 1) was tested for its hair follicle papilla cell proliferation promoting effect as follows.

[0280] Normal human hair dermal papilla cells (HFDPC, derived from the top of a male scalp) were cultured in a dermal papilla cell growth medium (PCGM, manufactured by Toyobo Co., Ltd.) containing 1% FCS and a growth additive, and then the cells were harvested by trypsinization. The harvested cells were diluted to 1.0 × 10 in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS. 4 After dilution to a cell density of 100 cells / mL, 200 μL was seeded per well on a collagen-coated 96-well plate and cultured for 3 days.

[0281] Thereafter, the medium was removed, and 200 μL of the test sample (sample 1, see Table 25 below for final concentration) dissolved in serum-free DMEM was added to each well, followed by further culturing for 4 days. As a control, the cells were similarly cultured using serum-free DMEM without the addition of the sample. After the culture was completed, the hair papilla cell proliferation promoting effect was measured by MTT assay. That is, the medium was removed, 100 μL of 0.4 mg / mL MTT prepared in serum-free DMEM was added to each well, and the cells were further cultured for 2 hours, after which the blue formazan produced in the cells was extracted with 100 μL of 2-propanol. The absorbance of this extract was measured at 570 nm, where the absorption maximum of blue formazan is located. At the same time, the absorbance at a wavelength of 650 nm was measured as turbidity, and the difference between the two was taken as the amount of blue formazan produced. From the measurement results, the hair papilla cell proliferation promoting rate (%) was calculated based on the following formula.

[0282] Hair papilla cell proliferation promotion rate (%) = A / B x 100 Each term in the formula represents the following: A: Amount of blue formazan produced when test sample is added B: Amount of blue formazan produced without adding sample The results are shown in Table 25.

[0283] [Table 25]

[0284] As shown in Table 25, compound 1 (sample 1) was found to have an excellent hair papilla cell proliferation promoting effect.

[0285] [Test Example 25] Nitric oxide (NO) production inhibitory effect test Compound 1 (sample 1) was tested for its inhibitory effect on nitric oxide (NO) production as follows.

[0286] Mouse macrophage cells (RAW264.7) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested using a cell scraper. The harvested cells were collected at a concentration of 3.0 × 10 6The cells were diluted with 10% FBS-containing phenol red-free DMEM to a cell density of 100 cells / mL, and then seeded at 100 μL per well on a 96-well plate and cultured for 4 hours.

[0287] After the culture, the medium was removed, and 100 μL of the test sample (sample 1, see Table 26 below for final concentration) dissolved in 10% FBS-containing phenol red-free DMEM containing 0.5% DMSO was added to each well, and 100 μL of lipopolysaccharide (LPS, final concentration 1 μg / mL, E. coli 0111:B4, DIFCO) dissolved in 10% FBS-containing phenol red-free DMEM was added and cultured for 48 hours. As a control, instead of the test sample solution, 10% FBS-containing phenol red-free DMEM containing 0.5% DMSO and no sample was added was used, and LPS treatment was performed in the same manner.

[0288] The amount of nitric oxide (NO) produced is proportional to the amount of nitrite ions (NO2 - ) was used as an index. After the culture was completed, the same amount of Griess reagent (5% by mass phosphoric acid solution containing 1% by mass sulfanilamide and 0.1% by mass N-1-naphthyl ethylendiamine dihydrochloride) as the culture supernatant was added to the culture solution in each well, and the reaction was allowed to proceed at room temperature for 10 minutes. After the reaction, the absorbance at a wavelength of 540 nm was measured. The inhibition rate (%) of nitric oxide (NO) production was calculated using the following formula based on the amount of nitric oxide (NO) produced when no sample was added (control).

[0289] NO production suppression rate (%)={(BA) / B}×100 Each term in the formula represents the following: A: Amount of NO when test sample is added B: Amount of NO when test sample is added The results are shown in Table 26.

[0290] [Table 26]

[0291] As shown in Table 26, it was confirmed that compound 1 (sample 1) has an excellent inhibitory effect on nitric oxide production.

[0292] [Test Example 26] Hyaluronidase activity inhibitory effect test Compounds 1 to 3 (samples 1 to 3) were tested for their inhibitory effect on hyaluronidase activity as follows.

[0293] 0.1 mL of hyaluronidase solution (SIGMA, Type IV-S, from bovine testes, 400 NF units / mL) was added to 0.2 mL of test samples (samples 1 to 3, see Table 27 below for final concentrations) dissolved in 0.1 mol / L acetate buffer (pH 3.5), and the mixture was left to stand at 37°C for 20 minutes. Furthermore, 0.2 mL of 2.5 mmol / L calcium chloride was added as an activator, and the mixture was left to stand at 37°C for 20 minutes. 0.5 mL of 0.8 mg / mL sodium hyaluronate solution (from rooster comb) was added to the mixture, and the mixture was reacted at 37°C for 40 minutes. After that, 0.2 mL of 0.4 mol / L sodium hydroxide was added to stop the reaction, and the mixture was cooled, after which 0.2 mL of boric acid solution was added to each reaction solution, and the mixture was boiled for 3 minutes. After cooling on ice, 6 mL of p-DABA reagent was added, and the mixture was reacted at 37°C for 20 minutes. Then, the absorbance at a wavelength of 585 nm was measured.

[0294] In addition, the same procedure and absorbance measurement were performed without adding the enzyme solution as a blank. Furthermore, the same measurement was performed with distilled water added without adding the sample solution as a control. From the obtained results, the hyaluronidase activity inhibition rate (%) was calculated using the following formula. Hyaluronidase activity inhibition rate (%) = {1-(AB) / (CD)} x 100 Each term in the formula represents the following: A: Absorbance at 585 nm with test sample and enzyme added B: Absorbance at 585 nm with and without the addition of test sample and enzyme C: Absorbance at 585 nm without addition of sample and with addition of enzyme D: Absorbance at 585 nm without adding sample or enzyme The results are shown in Table 27.

[0295] [Table 27]

[0296] As shown in Table 27, it was confirmed that Compound 1 (Sample 1), Compound 2 (Sample 2) and Compound 3 (Sample 3) all have excellent hyaluronidase activity inhibitory effects.

[0297] [Test Example 27] Hexosaminidase release inhibitory effect test Compound 2 (sample 2) was tested for its inhibitory effect on hexosaminidase release as follows.

[0298] Rat basophilic leukemia cells (RBL-2H3) were cultured in 15% FBS-containing Spinner's modified Eagle's minimum essential medium (S-MEM), and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 4.0 × 10 5 The cells were diluted with S-MEM containing 15% FBS to a cell density of 0.5 cells / mL, DNP-specific IgE was added to a final concentration of 0.5 μg / mL, and the cells were seeded in a 96-well plate at 100 μL per well and cultured overnight.

[0299] After the incubation, the medium was removed and the wells were washed twice with 100 μL of Silagarian buffer. Next, 30 μL of the same buffer and 10 μL of the test sample (sample 2, see Table 28 below for final concentration) dissolved in the same buffer were added to each well and left to stand at 37°C for 10 minutes. As a control, the same procedure was performed using 40 μL of Silagarian buffer without adding any sample. Next, 10 μL of 400 ng / mL DNP-BSA solution was added and left to stand at 37°C for 15 minutes to release hexosaminidase.

[0300] The 96-well plate was then placed on ice to stop the release. 10 μL of cell supernatant from each well was transferred to a new 96-well plate, and 10 μL of 1 mmol / L p-nitrophenyl-N-acetyl-β-D-glucosaminide (p-NAG) solution was added to each well and allowed to react at 37°C for 1 hour.

[0301] After the reaction, 250 μL of 0.1 mol / L Na2CO3 / NaHCO3 was added to each well, and the absorbance at wavelengths of 415 nm and 650 nm was measured. The absorbance at 650 nm was subtracted from the absorbance at 415 nm to obtain a correction value. The hexosaminidase release inhibition rate (%) was calculated from the measurement results using the following formula.

[0302] Hexosaminidase release inhibition rate (%) = {1-(B / A)} x 100 Each term in the formula represents the following: A: Absorbance at wavelengths of 415-650 nm without adding sample B: Absorbance at wavelengths of 415-650 nm when test sample is added The results are shown in Table 28.

[0303] [Table 28]

[0304] As shown in Table 28, it was confirmed that Compound 2 (Sample 2) has an excellent hexosaminidase release inhibitory effect.

[0305] [Test Example 28] Prostaglandin E2 (PGE2) production inhibitory effect test in mouse macrophages Compound 1 (sample 1) was tested for its PGE2 production inhibitory effect as follows.

[0306] Mouse macrophage cells (RAW264.7) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested using a cell scraper. The harvested cells were collected at a concentration of 2.0 × 10 5The cells were diluted with 10% FBS-containing DMEM to a concentration of 100 cells / mL, and then seeded at 100 μL per well in a 96-well plate and cultured for 18 hours.

[0307] After the culture was completed, the medium was replaced with a 500 μmol / L aspirin-containing medium and cultured for 4 hours in order to acetylate and inactivate the already existing COX-1 and the small amount of COX-2 expressed. Thereafter, the cells were washed three times with PBS(-) buffer, and 100 μL of the test sample (sample 1, see Table 29 below for final concentration) dissolved in 10% FBS-containing DMEM containing a final concentration of 0.5% DMSO was added to each well, followed by 100 μL of lipopolysaccharide (LPS) (DIFCO, E. coli 0111; B4) dissolved in 10% FBS-containing DMEM at a final concentration of 1 μg / mL, and cultured for 16 hours. As a control, the cells were cultured in the same manner using 10% FBS-containing DMEM containing a final concentration of 0.5% DMSO without the addition of the sample. After the culture was completed, the amount of prostaglandin E2 in the culture supernatant of each well was quantified using a PGE2EIA Kit (Cayman Chemical). From the obtained results, the PGE2 production inhibition rate (%) was calculated according to the following formula.

[0308] PGE2 production suppression rate (%)={1-(AC) / (BC)}×100 Each term in the formula represents the following: A: Amount of PGE2 after addition of test sample and stimulation with LPS B: Amount of PGE2 without sample and with LPS stimulation C: Amount of PGE2 without sample addition or LPS stimulation The results are shown in Table 29.

[0309] [Table 29]

[0310] As shown in Table 29, it was confirmed that Compound 1 (Sample 1) has an excellent inhibitory effect on PGE2 production in macrophages.

[0311] [Test Example 29] Glutathione production promotion test (hepatocytes) Compounds 1 to 3 (samples 1 to 3) were tested for their glutathione production promoting effect in hepatocytes as follows.

[0312] Normal human hepatocytes were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were diluted to 10 × 10 4 The cells were diluted with 10% FBS-containing DMEM to a cell density of 100 cells / mL, and then seeded at 200 μL per well on a 48-well plate and cultured overnight.

[0313] After the incubation, the medium was removed, and 200 μL of the test samples (samples 1 to 3, see Table 30 below for final concentrations) dissolved in 1% FBS-containing DMEM was added to each well, followed by further incubation for 24 hours. As a control, incubation was performed in the same manner using 1% FBS-containing DMEM without the addition of samples. After incubation, the medium was removed from each well, and the wells were washed with 400 μL of PBS(-), and then the cells were lysed using 150 μL of M-PER (PIERCE).

[0314] Total glutathione was quantified using 100 μL of this solution. That is, 100 μL of cell extract dissolved in a 96-well plate, 50 μL of 0.1 mol / L phosphate buffer, 25 μL of 2 mmol / L NADPH, and 25 μL of 3.2 unit / mL glutathione reductase were added and heated at 37°C for 10 minutes, after which 25 μL of 10 mmol / L 5,5'-dithiobis(2-nitrobenzoic acid) was added, and the absorbance at a wavelength of 412 nm was measured for 5 minutes, and ΔOD / min was calculated. The total glutathione concentration was calculated based on a calibration curve prepared using oxidized glutathione (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.). The obtained value was corrected to the amount of glutathione per total protein amount, and the glutathione production promotion rate (%) was calculated based on the following formula.

[0315] Glutathione production promotion rate (%) = B / A x 100 Each term in the formula represents the following: A: Amount of glutathione per total protein without sample addition B: Amount of glutathione per total protein amount when test sample was added The results are shown in Table 30.

[0316] [Table 30]

[0317] As shown in Table 30, compound 1 (sample 1), compound 2 (sample 2) and compound 3 (sample 3) were all recognized to have excellent glutathione production promoting activity in hepatocytes.

[0318] [Test Example 30] Test of ATP production promotion in hepatocytes Compounds 1 to 3 (samples 1 to 3) were tested for their promoting effect on ATP production in hepatocytes as follows.

[0319] Normal human hepatocytes were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then the cells were harvested by trypsinization. The harvested cells were collected at a concentration of 2.0 × 10 5 The cells were diluted with 10% FBS-containing DMEM to a cell density of 100 cells / mL, and then seeded at 100 μL per well on a 96-well plate and cultured overnight.

[0320] After the incubation, the medium was removed, and 100 μL of the test samples (samples 1 to 3, see Table 31 below for final concentrations) dissolved in 10% FBS-containing DMEM was added to each well and incubated for 2 hours. As a control, incubation was performed in the same manner using 10% FBS-containing DMEM without the sample.

[0321] The ATP production promoting effect was evaluated by measuring the amount of ATP in the cells using the firefly luciferase luminescence method. That is, after 2 hours of culture, 100 μL of ATP measuring reagent (manufactured by Toyo B-Net Co., Ltd., product name "Cellular ATP measuring reagent") was added to each well, and a chemiluminescence reaction was performed using luciferase. After the reaction, the amount of chemiluminescence proportional to the amount of ATP in the cells was measured using a chemiluminescence measuring device (manufactured by Thermo Fisher Scientific, product name: Varioskan LUX multimode microplate reader). From the obtained results, the ATP production promotion rate (%) was calculated using the following formula.

[0322] ATP production promotion rate (%)=A / B×100 Each term in the formula represents the following: A: Chemiluminescence amount when test sample is added B: Chemiluminescence amount without sample added The results are shown in Table 31.

[0323] [Table 31]

[0324] As shown in Table 31, it was confirmed that Compound 1 (Sample 1), Compound 2 (Sample 2) and Compound 3 (Sample 3) all had excellent ATP production promoting activity in hepatocytes.

[0325] [Formulation example 1] Tablets having the following composition were prepared by a conventional method. Compound 1 5.0mg Dolomite (containing 20% ​​calcium and 10% magnesium) 83.4mg Casein phosphopeptide 16.7mg Vitamin C 33.4mg Maltitol 136.8mg Collagen 12.7mg Sucrose fatty acid ester 12.0mg

[0326] [Formulation example 2] An oral liquid preparation having the following composition was produced by a conventional method. <Composition in 1 ampoule (100 mL)> Compound 2 0.3% by mass Sorbitol 12.0% by mass Sodium benzoate 0.1% by mass Fragrance 1.0% by mass Calcium sulfate 0.5% by mass Purified water remainder (100% by mass)

[0327] [Formulation example 3] Capsules having the following composition were produced by a conventional method. No. 1 hard gelatin capsules were used. <Composition in 1 capsule (1 tablet 200 mg)> Compound 3 10.0mg Cornstarch 70.0mg Lactose 100.0mg Calcium lactate 10.0mg Hydroxypropyl cellulose (HPC-L) 10.0 mg

[0328] [Formulation example 4] According to the composition below, a milky lotion was prepared by a conventional method. Compound 1 0.01g Jojoba oil 4.00g 1,3-butylene glycol 3.00g Arbutin 3.00g Polyoxyethylene cetyl ether (20E.O.) 2.50g 2.00g olive oil Squalane 2.00g Cetanol 2.00g Glyceryl monostearate 2.00g Polyoxyethylene sorbitan oleate (20E.O.) 2.00g Methyl paraoxybenzoate 0.15g Stearyl glycyrrhetinate 0.10g Phellodendron Bark Extract 0.10g Dipotassium glycyrrhizinate 0.10g Ginkgo leaf extract 0.10g Conchiolin 0.10g Phellodendron bark extract 0.10g Chamomile extract 0.10g Fragrance 0.05g Purified water Remainder (total amount is 100g)

[0329] [Formulation example 5] A cream having the following composition was prepared by a conventional method. Compound 2 0.05g Sophora root extract 0.1g Scutellaria root extract 0.1g Liquid paraffin 5.0g White beeswax 4.0g Squalane 10.0g Cetanol 3.0g Lanolin 2.0g Stearic acid 1.0g Polyoxyethylene sorbitan oleate (20E.O.) 1.5g Glyceryl monostearate 3.0g Oil-soluble licorice extract 0.1g 1,3-butylene glycol 6.0g Methyl paraoxybenzoate 1.5g Fragrance 0.1g Purified water Remainder (total amount is 100g)

[0330] [Formulation example 6] A beauty essence having the following composition was prepared by a conventional method. Compound 3 0.01g Chamomile extract 0.1g Carrot extract 0.1g Xanthan gum 0.3g Hydroxyethylcellulose 0.1g Carboxyvinyl polymer 0.1g 1,3-butylene glycol 4.0g Dipotassium glycyrrhizinate 0.1g Glycerin 2.0g Potassium hydroxide 0.25g Fragrance 0.01g Preservative (methyl parahydroxybenzoate) 0.15g Ethanol 2.0g Purified water Remainder (total amount is 100g)

[0331] [Formulation example 7] A hair tonic having the following composition was prepared in a conventional manner. Compound 1 0.2g Compound 2 0.1g Compound 3 0.1g Tocopherol acetate (appropriate amount) Cephalatin 0.002g Isopropyl methylphenol 0.1g Sodium hyaluronate 0.15g Glycerin 15.0g Ethanol 15.0g Fragrance (appropriate amount) Chelating agent (sodium edetate) appropriate amount Preservative (hinokitiol) appropriate amount Solubilizer (polyoxyethylene cetyl ether) appropriate amount Purified water Remainder (total amount is 100g)

[0332] [Formulation example 8] A shampoo having the following composition was prepared by a conventional method. Compound 1 0.2g Compound 2 0.2g Compound 3 0.2g Marjoram extract 1.0g Plum fruit extract 0.2g Sodium coconut oil fatty acid methyl taurate 10.0g Coconut oil fatty acid amidopropyl betaine 10.0g Sodium polyoxyethylene alkyl ether sulfate 20.0g Coconut oil fatty acid diethanolamide 4.0g Propylene glycol 2.0g Fragrance (appropriate amount) Purified water Remainder (total amount is 100g)

Claims

1. A liver function improver comprising, as an active ingredient, Compound 1 and / or Compound 2 represented by the following general formula (I): 【Chemistry 1】

2. The compound 3 represented by the following general formula (I) is used as an active ingredient, An agent characterized by being used for promoting glutathione production in hepatocytes and / or promoting ATP production in hepatocytes. 【Chemistry 2】

3. An anti-inflammatory agent comprising compound 1 represented by the following general formula (I) as an active ingredient: 【Chemistry 3】

4. The compound 2 represented by the following general formula (I) is used as an active ingredient, An agent characterized by being used for inhibiting hyaluronidase activity and / or suppressing hexosaminidase release. 【Chemistry 4】

5. A hyaluronidase activity inhibitor characterized by comprising compound 3 represented by the following general formula (I) as an active ingredient. 【Chemistry 5】

6. The compound 1 represented by the following general formula (I) is used as an active ingredient, An oral composition characterized by being used for improving liver function and / or for anti-inflammatory purposes. 【Chemistry 6】

7. The compound 2 represented by the following general formula (I) is used as an active ingredient, An oral composition characterized by being used for one or more purposes selected from the group consisting of improving liver function, inhibiting hyaluronidase activity, and inhibiting hexosaminidase release. 【Chemistry 7】

8. The compound 3 represented by the following general formula (I) is used as an active ingredient, An oral composition characterized by being used for one or more purposes selected from the group consisting of promoting glutathione production in hepatocytes, promoting ATP production in hepatocytes, and inhibiting hyaluronidase activity. 【Chemistry 8】

9. An anti-inflammatory skin or hair cosmetic composition comprising, as an active ingredient, Compound 1 represented by the following general formula (I): 【Chemistry 9】

10. The compound 2 represented by the following general formula (I) is used as an active ingredient, A skin or hair cosmetic composition characterized by being used for inhibiting hyaluronidase activity and / or suppressing hexosaminidase release. 【Chemistry 10】

11. The compound 3 represented by the following general formula (I) is used as an active ingredient, A skin or hair cosmetic composition characterized by being used for inhibiting hyaluronidase activity. 【Chemistry 11】

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