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 agent for preventing metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, and liver function improving, 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 not only seen in humans, but also in pets and livestock. Obesity can cause metabolic syndrome, including hyperlipidemia and arteriosclerosis, and is therefore not only a problem in terms of beauty but also a major health issue.

[0003] Cyclic AMP (cAMP) is known to be involved in lipolysis in vivo. cAMP activates lipase present in the body, and the activated lipase breaks down fat into fatty acids and glycerol. However, activation of cAMP phosphodiesterase induces the breakdown of cAMP, inhibiting lipase activation. Therefore, it is thought that inhibiting the activity of cAMP phosphodiesterase increases intracellular cAMP and promotes fat breakdown.

[0004] Furthermore, platelet aggregation, which causes inflammatory reactions, is related to the concentration of cyclic AMP (cAMP) in platelets, and it is known that when cAMP is decomposed by cAMP phosphodiesterase and the cAMP concentration decreases, platelets become more prone to aggregation. Therefore, it is thought that platelet aggregation can be prevented by inhibiting the action of cAMP phosphodiesterase to prevent a decrease in cAMP concentration, thereby making it possible to prevent, treat, or ameliorate allergic diseases, inflammatory diseases, etc. Tubeimoside I (see Patent Document 1) and the like are known to have cAMP phosphodiesterase activity inhibitory effects.

[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 it at the C-terminus. DPP IV is expressed on the cell surface of epithelial and endothelial cells in tissues such as the kidney, liver, intestinal tract, and placenta, as well as 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 collective term for hormones secreted from the intestinal tract in response to nutrient stimulation and promote insulin secretion from pancreatic β cells in a blood glucose-dependent manner. Known examples include GLP-1 and GIP. These incretins not only promote blood glucose-dependent insulin secretion, but also suppress glucagon secretion from α cells, lower blood pressure, inhibit gastric emptying, and even suppress food intake by acting on the hypothalamus (see Non-Patent Document 1). However, since incretins are degraded by DPP IV, the half-life of GLP-1 in vivo is known to be approximately 1.5 minutes. Therefore, inhibiting the enzymatic activity of DPP IV can extend the half-life of incretins in vivo, which is expected to be useful in treating metabolic syndromes such as type 2 diabetes, obesity, hypertension, and insulin resistance through the aforementioned incretin action.

[0007] DPP IV is identical to CD26, a T cell activation marker, and is known to regulate the activity of many immunomodulatory peptides as substrates. Therefore, regulating DPP IV activity may be useful in controlling immune responses, such as autoimmune diseases like rheumatoid arthritis and transplant rejection. Furthermore, DPP IV is known to be involved in the metabolism of several neuropeptides and growth hormone; cancer invasion, metastasis, angiogenesis, and HIV infection of lymphocytes. Therefore, inhibiting DPP IV activity may be useful in treating pain, neurodegenerative diseases, neuropsychiatric disorders, and other neurological disorders (e.g., sciatica, Alzheimer's disease, depression, etc.); growth hormone deficiency and diseases for which growth hormone is used as a 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 age spots. Melanin is generally thought to be formed by the conversion of tyrosine to dopa, dopa to dopaquinone, and then via 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), age spots, freckles, etc., it is thought that the activity of tyrosinase, which is involved in melanin production, or the production of melanin can be inhibited.

[0009] Conventionally, the prevention, treatment, or improvement of skin pigmentation, age spots, freckles, etc. has been achieved by topically applying 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 ingredients as active ingredients is desired. Examples of whitening agents known to have tyrosinase activity inhibitory effects include, for example, Polygonum gracilis extract (see Patent Document 2). Also, examples of whitening agents known to have melanin production inhibitory effects include, for example, 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, and hyaluronic acid that are present outside these cells and support the skin structure. In young skin, fibroblast proliferation is active, and the interaction between fibroblasts, extracellular matrix components, and other skin tissues maintains homeostasis, ensuring moisture retention, flexibility, elasticity, and the like, and maintaining the skin in a firm, glossy, and moist state.

[0011] However, under the influence of certain external factors, such as ultraviolet radiation, extremely dry air, and excessive skin cleansing, or due to aging, the production of collagen, elastin, and hyaluronic acid, the major components of the extracellular matrix, decreases and undergoes degradation and alteration. As a result, the skin's moisturizing function and elasticity decline, 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, changes associated with skin aging, such as wrinkles, dullness, changes in texture, and loss of elasticity, are related to the reduction 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 promoting collagen production can prevent, treat, or improve skin aging symptoms such as wrinkles, sagging, coarse skin 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 collagen production increases during the wound healing process, and collagen serves as a scaffold for fibroblasts, etc., thereby promoting wound healing. Therefore, promoting collagen production is important from the perspectives of preventing or treating osteoporosis, etc., and promoting wound healing. For example, extracts from Camphor Tree (see Patent Document 4) are known to have the effect of promoting collagen production.

[0014] Among the extracellular matrix components, elastin is a fiber that provides elasticity to skin tissue. Promoting elastin production may reduce wrinkles and sagging, and may prevent, treat, or improve skin aging symptoms such as loss of firmness and elasticity. Furthermore, elastin is broken down by an enzyme called elastase, which is activated by ultraviolet light, accelerating the breakdown of elastin. Therefore, inhibiting the activity of elastase suppresses the breakdown of elastin, which is thought to prevent and improve skin aging symptoms such as loss of firmness and elasticity.

[0015] Furthermore, elastin is widely expressed in tissues requiring elasticity in the body, such as the lungs and blood vessels, in addition to skin tissue. Aging-related loss of normal elastin in these tissues is known to reduce the elasticity of the lungs and blood vessels, leading to pulmonary diseases such as emphysema, hypertension, and vascular diseases such as aneurysms. Smoking and other factors are known to increase elastase activity in the body, which may destroy alveolar walls and lead to emphysema and other conditions. Furthermore, increased elastase activity may destroy pulmonary capillaries, potentially leading to acute respiratory distress syndrome (ARDS), including pulmonary edema. Therefore, if we could promote the production of elastin, it would be possible to prevent a decrease in elasticity in the lungs and blood vessels, and to prevent and treat pulmonary diseases such as emphysema, as well as vascular diseases such as high blood pressure and aneurysms. Furthermore, if we could inhibit the activity of elastase in the body, it would be possible to prevent and treat respiratory diseases such as emphysema and pulmonary edema. For example, extracts from plants belonging to the genus Hippophae 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 aforementioned extracellular matrix components, hyaluronic acid is a type of mucopolysaccharide that fills the intercellular spaces to hold cells, and also has numerous other functions, such as retaining moisture in the intercellular spaces, providing lubrication and flexibility to tissues, and resisting external forces such as mechanical damage. Promoting the production of hyaluronic acid is believed to prevent, treat, or improve skin aging symptoms such as rough skin, wrinkles, dullness, changes in texture, loss of elasticity, and loss of moisturizing function. Furthermore, promoting the expression of hyaluronan synthase 3 (HAS3), which is involved in promoting the synthesis of epidermal hyaluronic acid, is believed to prevent, treat, or improve skin aging.

[0017] Hyaluronic acid is also present in connective tissues such as cartilage, synovial fluid, umbilical cord, vitreous body, and other tissues, in addition to skin tissue. Hyaluronic acid in synovial fluid coats the surface of articular cartilage, contributing to the smooth functioning of joints through its lubricating function, covering and protecting cartilage, and other functions. Meanwhile, it is known that the concentration of hyaluronic acid in synovial fluid decreases in cases of arthritis such as rheumatoid arthritis. Therefore, promoting the production of hyaluronic acid is believed to be effective in preventing or treating arthritis such as rheumatoid arthritis, osteoarthritis, septic arthritis, gouty arthritis, traumatic arthritis, and osteoarthritis. Furthermore, granulation tissue (tissue) is formed during the healing process of wounds or burns, and it is known that hyaluronic acid significantly increases in the granulation tissue. Therefore, promoting the production of hyaluronic acid is believed to promote the healing of wounds or burns. Extracts from Camphor Tree (see Patent Document 4, mentioned above) and other substances are known to have the effect of promoting hyaluronic acid production. In addition, licorice leaf extract (see Patent Document 7) and the like are known to have the effect of promoting the expression of hyaluronic acid synthase 3 (HAS3).

[0018] Meanwhile, a basement membrane exists at the boundary between the epidermis and dermis that make up 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 two, 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 through the function of the basement membrane, thereby ensuring moisture retention, flexibility, elasticity, etc., and maintaining the skin's appearance of firmness, luster, and freshness.

[0019] However, under the influence of certain external factors, such as ultraviolet radiation, extremely dry air, or excessive skin cleansing, or due to aging, laminin-332, a major component of basement membrane, decomposes and alters, destroying the basement membrane structure (see Non-Patent Document 3). As a result, the skin's moisturizing function and elasticity decline, and the keratin begins to peel abnormally, causing the skin to lose firmness and luster, leading to aging symptoms such as roughness and wrinkles. Thus, changes associated with skin aging, such as wrinkles, dullness, changes in texture, and loss of elasticity, are thought to be related to a decrease in basement membrane components and structural changes in the basement membrane. Therefore, promoting the production of laminin-332 may be able to prevent and improve skin aging symptoms.

[0020] Laminins consist of various combinations of α, β, and γ chains, and currently 15 types (laminin 1 to laminin 15) are known. Among these, laminin-332 (α3β3γ2) is abundantly present in the basement membranes of epithelial tissues, such as the skin, digestive tract, kidneys, and lungs. A genetic disease (lethal congenital epidermolysis bullosa, or Herlitz junctional epidermolysis bullosa) caused by congenital abnormalities in the genes encoding each of the laminin-332 chains is known to cause fatal symptoms, including complete epidermal peeling. Furthermore, laminin-332 is known to strongly adhere cells (high cell adhesion activity) and strongly promote cell motility (high cell motility activity) compared to other extracellular matrix molecules.

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

[0022] The epidermis functions to mitigate external stimuli and control the loss of body components such as water, and is composed of a four-layer structure, starting with 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 that differentiate from the basal layer. Keratinocytes that divide and proliferate in the basal layer differentiate as they pass through the spinous and granular layers to become corneocytes, which then form the stratum corneum, made up of keratin protein fibers with strong cross-links, 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. To maintain this barrier function, the skin undergoes a cycle of epidermal metabolism (keratinization), typically repeated every four weeks, from the time keratinocytes are produced in the basal layer until they become dandruff and are shed. However, the metabolic function of the stratum corneum also declines with age, resulting in skin problems such as fine wrinkles, dullness, pigmentation, and rough skin. Therefore, promoting keratinocyte proliferation and restoring the skin's metabolic function is thought to improve skin aging symptoms such as fine wrinkles, dullness, and pigmentation. Conventionally, extracts of Aster crustacea (see Patent Document 9) and the like are known to have the effect of promoting epidermal keratinocyte proliferation.

[0024] Furthermore, in order to promote cell proliferation, it is important to supply cells with the energy necessary for cell division. ATP is an example of an energy substance in living organisms, and increasing the amount of ATP produced is thought to promote intracellular energy metabolism, 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 aging cells compared to normal cells (see Patent Document 10).

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

[0026] Glutathione is a tripeptide composed of three amino acids, glutamic acid, cysteine, and glycine, and is the primary intracellular cysteine ​​residue. Intracellular glutathione functions as a radical scavenger, cellular function regulator through redox, xenobiotic metabolism, and sulfhydryl donor for various enzymes. It is also known as an antioxidant against reactive oxygen species. Its effects are thought to be derived from the cysteine ​​residue. However, excessive oxidative stress, the addition of xenobiotics, and aging have been reported to cause a deficiency or decrease in intracellular glutathione levels, which is thought to reduce the cellular defense against oxidative stress and contribute to damage to cellular components such as DNA and proteins.

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

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

[0029] However, as the amount of transglutaminase-1 produced in the epidermis decreases with age, the stratum corneum barrier function and the skin's moisturizing function decline, resulting in the onset of skin aging symptoms such as rough skin and dry skin, and dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.). Therefore, it is believed that promoting the production of transglutaminase-1 in the epidermis can prevent, treat, or improve skin aging symptoms, dry skin diseases, etc. 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 natural barrier membrane function between the body and the outside world.

[0031] The structure of the stratum corneum can be likened to bricks and mortar, with about 15 layers of keratinocytes stacked together by intercellular lipids to form a strong barrier membrane.Keratinocytes retain moisture by containing natural moisturizing factors, primarily amino acids, within the cells, while intercellular lipids are composed primarily of ceramides (about 50%), as well as amphiphilic lipids such as cholesterol and fatty acids, and are characterized by a lamellar structure, in which hydrophobic and hydrophilic regions alternate.

[0032] A decline in skin barrier function due to various internal and external factors increases transepidermal water loss, causing dryness, scaling, itching, and other symptoms, resulting in so-called dry skin. Furthermore, a decline in skin barrier function increases skin inflammation, leading to a vicious cycle in which the skin's defense function against various external stimuli is impaired. Recent studies have reported a decrease and compositional changes in keratinocyte ceramide components (so-called intercellular lipids) due to aging or in patients with atopic dermatitis, known as a barrier disorder (see Non-Patent Document 4), and it has become widely known that ceramides are important for maintaining and improving skin barrier function. Known methods for improving skin barrier function include supplementing ceramides externally (see Non-Patent Document 5) and enhancing ceramide production within 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 take up small molecules such as water from the intercellular space into the cells. Thirteen types of aquaporins (AQP0-AQP12) are known to exist in humans. Epidermal cells primarily contain AQP3, which is thought to take up not only water but also small molecules such as glycerol and urea, which are involved in moisture retention.

[0034] However, AQP3 decreases with age, and it has been suggested that this is one of the reasons for the decline in water retention function. Therefore, it is thought that promoting AQP3 expression may be able to control water retention function, barrier function, and the like due to aging (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 filaggrin function due to gene mutations or the like is associated with the risk of developing atopic diseases, including atopic dermatitis (eczema, skin inflammation, skin itching, etc.), allergies, asthma, etc., and in more severe cases, can lead to skin diseases such as ichthyosis vulgaris (see Non-Patent Document 8).

[0036] Meanwhile, amino acids, the main components of natural moisturizing factors (NMFs), are produced by the degradation of filaggrin derived from keratohyalin granules within 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, accumulates in keratohyalin granules, and is degraded to filaggrin through dephosphorylation and hydrolysis. It then migrates into the stratum corneum, where it increases the aggregation efficiency of keratin filaments and is known to be involved in the internal organization of keratinocytes (see Non-Patent Document 9). In recent years, it has been discovered that filaggrin is extremely important and essential for skin moisture retention, and that conditions such as dryness reduce the ability of filaggrin synthesis, resulting in a decrease in the amount of amino acids in the stratum corneum (see Non-Patent Document 10).

[0037] Therefore, promoting the expression of filaggrin (profilaggrin) in epidermal keratinocytes is believed to be effective in preventing, treating, or ameliorating atopic diseases, including atopic dermatitis (eczema, skin inflammation, skin itching, etc.), allergies, asthma, etc. Furthermore, promoting the expression of filaggrin, thereby increasing the amount of amino acids in the stratum corneum, is expected to essentially improve the moisture environment of the stratum corneum. Extracts of Gai Ying (Patent Document 15) and the like are known to have the effect of promoting filaggrin expression.

[0038] Previously, it was believed that the skin's barrier function was solely the responsibility of the stratum corneum. However, in recent years, it has been discovered that genetic deletion of the constituent proteins of tight junctions (TJs) in the granular layer of the epidermis disrupts the skin's barrier function, and TJs are now considered to play an important role in the skin's barrier function (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 scaffolding proteins such as ZO-1 and ZO-2. These proteins are thought to form the framework of the TJ strand and control the barrier function of the TJ (see Non-Patent Document 12). If the expression of claudins or occludin is reduced for some reason, structural destruction of TJs occurs, causing them to no longer function as a permeation barrier to substances, which is thought to contribute to skin conditions such as dry skin, rough skin, atopic dermatitis, and various infectious diseases.

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

[0040] Carbohydrates are extremely important as an energy source for humans and other living organisms. However, they are known to undergo glycation reactions with proteins. Glycation is a series of reactions that begins with a non-enzymatic reaction between the carbonyl group of a carbohydrate and an amino group in a protein, leading to the formation of Schiff bases, Amadori compounds, and finally to the formation of advanced glycation end products (hereinafter sometimes referred to as "AGEs"). Glycation non-enzymatically modifies proteins with sugars, which can cause denaturation of the protein and cross-linking between proteins, resulting in a decrease in protein function.

[0041] Glycation not only causes direct damage by modifying and structurally altering extracellular matrix proteins such as collagen, but also induces cellular responses through recognition by receptors that use glycated proteins as ligands. The impact of glycation is particularly severe for diabetic patients with high blood glucose levels. Protein glycation is known to be a contributing factor in diabetic complications such as diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy. Glycation in vascular walls is also known to contribute to the progression of arteriosclerosis through endothelial cell damage and the accumulation of denatured proteins. Furthermore, extracellular matrix components, including collagen, account for more than half of the dry weight of tissues such as bone and skin. Therefore, for example, glycation of collagen, which becomes abnormally cross-linked, can lead to osteoporosis and osteoarthritis in bone and cartilage tissues, and to a decrease in skin elasticity and dullness due to yellowing. Furthermore, abnormally cross-linked collagen and the like are less susceptible to degradation by collagenase and the like, which leads to problems such as the induction of collagenase and the like, resulting in the degradation of normal collagen as well.

[0042] Therefore, if glycation reactions could be inhibited in some way, for example, by inhibiting the formation of AGEs or promoting the degradation of AGEs, it would be expected to be useful in preventing or treating the aforementioned diseases, namely, diabetic complications, arteriosclerosis, osteoporosis, osteoarthritis, etc. Furthermore, it would also be expected to be effective in preventing or improving loss of skin elasticity, dullness, etc. Extracts of sweet osmanthus (see Patent Document 17) and the like are known to have the effect of inhibiting the formation of AGEs or promoting the degradation 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 receptors and exerting its androgen effects.

[0044] Androgens are important hormones, but excessive action of androgens can induce various undesirable symptoms, such as male pattern baldness, hirsutism, seborrheic dermatitis, acne (e.g., acne), benign prostatic hyperplasia, prostatic tumors, and precocious puberty in boys. Therefore, methods for suppressing the action of excess androgens to improve these various symptoms have been known, specifically, methods for suppressing the production of active 5α-DHT by inhibiting the action of testosterone 5α-reductase, which reduces testosterone to active 5α-DHT. To date, extracts from Eastern perilla (see Patent Document 18) and the like have been known to have testosterone 5α-reductase inhibitory activity.

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

[0046] Thus, dermal 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 dermal papilla cells can prevent and improve alopecia. To date, substances known to have the effect of promoting the proliferation of dermal papilla cells include, for example, wild thyme extract (see Patent Document 19).

[0047] Inflammatory diseases, such as contact dermatitis (rash), psoriasis, pemphigus vulgaris, atopic dermatitis, and other inflammatory skin diseases accompanied by rough skin, as well as rheumatoid arthritis, osteoarthritis, and asthma, have diverse causes and onset mechanisms. Known causes include excessive production of nitric oxide (NO), histamine release, increased hyaluronidase activity, and prostaglandin E2 (PGE2) production.

[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 to be a physiologically active substance that exhibits a variety of functions in the body, such as endothelium-derived relaxing factor (EDRF), a neurotransmitter, and a factor that damages microbial and tumor cells in the host defense. In the host defense, nitric oxide, especially that produced by macrophages, 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 autologous tissues, leading to aggravated inflammation and pathological conditions such as rheumatism and diabetes. It is also known that when nitric oxide is synthesized in large quantities, it can relax vascular smooth muscle and increase excessive permeability, causing a significant drop in blood pressure and leading to endotoxin shock.

[0050] Therefore, in inflammatory diseases, it is important to suppress the excessive production of nitric oxide. For example, Tang Ding Huo, Tara Root Bark, He Zhao Dan, Psammophila Root, Zi Fang Zi, Madder Root, Ban Zhi Lian, Sophora Flower, Sichuan Pepper (see Non-Patent Document 14), extracts from plants belonging to the genus Hydrocotyle (see Patent Document 20), maltulosylarginine (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 an inflammatory reaction. Therefore, attempts have been made to prevent or treat allergic diseases and inflammatory diseases 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 inhibiting the release of hexosaminidase, histamine release can also be inhibited, which is thought to be effective in preventing, treating, or improving inflammatory diseases, etc.

[0052] Histamine also mediates intercellular communication as a local neurotransmitter, promoting gastric acid secretion in the digestive tract and functioning as a neurotransmitter in the central nervous system, contributing to maintaining a waking state. Excessive histamine release can cause ulcers due to gastric hyperacidity in the digestive tract and contributes to sleep disorders in the central nervous system. As mentioned above, inhibiting the release of hexosaminidase can also inhibit the release of histamine, which is believed to prevent, treat, or improve gastric ulcers, sleep disorders, and other conditions caused by gastric hyperacidity. For example, extracts from wisteria tea (see Patent Document 22) are known to have the effect of inhibiting hexosaminidase release.

[0053] Hyaluronidase is a hydrolase that hydrolyzes hyaluronic acid. Hyaluronate, which maintains its affinity for body tissues, is decomposed by ultraviolet light, oxygen, etc. in aqueous systems, and its moisture-retaining effect decreases as its molecular weight decreases. Hyaluronic acid also exists in the body as intercellular tissue and is involved in vascular permeability. Furthermore, hyaluronidase is present in mast cells, but is released by degranulation caused by their activation and acts as an inflammatory chemical mediator. Therefore, inhibiting hyaluronidase activity is expected to enhance moisture retention and prevent or reduce inflammation. Extracts from plants of the genus Osbeckia (see Patent Document 23), for example, are known to have hyaluronidase activity inhibitory effects.

[0054] Inflammation is a complex reaction that manifests with 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, skin tissue is damaged, resulting in various symptoms such as rough skin, redness, edema, and pigmentation.

[0055] One example of an inflammatory cytokine is prostaglandin E2 (PGE2). PGE2 is produced in the skin, for example, by keratinocytes, and is responsible for inducing skin inflammation. It has been revealed that the production of prostaglandins during inflammation is primarily mediated by cyclooxygenase-2 (COX-2), an inducible cyclooxygenase. Therefore, a possible method for treating or preventing skin inflammation is to suppress the production of PGE2 in keratinocytes or inhibit the activity of COX-2. Pentaerythritol and other compounds are known to have an inhibitory effect on PGE2 production in keratinocytes (see Patent Document 24).

[0056] The liver is an essential organ for life, 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. Although liver damage is difficult to detect, liver dysfunction caused by alcohol consumption, overnutrition, drug abuse, hepatitis viruses, etc. can lead to fatigue, lethargy, loss of appetite, and even jaundice. Progression of liver dysfunction can lead to lifestyle-related diseases such as hepatitis and cirrhosis. Therefore, improving liver function and protecting it from damage are crucial for maintaining a healthy lifestyle.

[0057] Glutathione is known to be a biological component that protects the liver. Glutathione is a tripeptide composed of three amino acids, glutamic acid, cysteine, and glycine, and is a compound containing the major intracellular cysteine ​​residue. Glutathione is primarily produced in the liver and distributed throughout the body. It plays a role in scavenging intracellular radicals, regulating cellular function through redox reactions, and acting as an SH donor for various enzymes. In particular, glutathione is known to be involved in the detoxification mechanism and protect liver function. Hepatic glutathione is consumed in large quantities during the metabolism of ethanol after drinking alcohol and the metabolism and detoxification of drugs. Decreased hepatic glutathione levels can lead to liver dysfunction, including acute and chronic alcoholic hepatitis and drug-induced hepatitis. Systemic glutathione levels can also lead to a variety of symptoms, including cataracts, Parkinson's disease, and skin pigmentation.

[0058] Therefore, if glutathione production in the liver (hepatocytes) can be promoted, 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 through the metabolism of glucose and fat and is used as an energy source. The liver uses ATP as an energy source for many chemical reactions, including the metabolism and detoxification of ethanol and drugs. A decrease in ATP production is thought to reduce the efficiency of these reactions, as well as to result in a lack of energy for activities such as labor and exercise, leading to fatigue. Therefore, if ATP production in the liver can be promoted, it is thought that it will be possible to prevent or improve various symptoms caused by ethanol intake (e.g., hangover, etc.), prevent, treat, or improve drug-induced liver damage, and promote recovery from fatigue. Extracts of long pepper (see Patent Document 25) and the like are known to have the effect of promoting ATP production in hepatocytes. [Prior art documents] [Patent documents]

[0060] [Patent Document 1] Japanese Patent Application Laid-Open No. 2006-056855 [Patent Document 2] Japanese Patent Application Laid-Open No. 2004-083488 [Patent Document 3] Japanese Patent Application Laid-Open No. 2002-201122 [Patent Document 4] Japanese Patent Application Laid-Open No. 2003-146837 [Patent Document 5] Japanese Patent Application Laid-Open No. 2005-022993 [Patent Document 6] Japanese Patent Application Laid-Open No. 2003-300893 [Patent Document 7] Japanese Patent Application Laid-Open No. 2010-090035 [Patent Document 8] Japanese Patent Application Laid-Open No. 2006-063033 [Patent Document 9] Japanese Patent Application Laid-Open No. 2006-056854 [Patent Document 10] Japanese Patent Application Laid-Open No. 2003-321373 [Patent Document 11] Japanese Patent Application Laid-Open No. 2009-256272 [Patent Document 12] Japanese Patent Application Laid-Open No. 2009-269889 [Patent Document 13] Japanese Patent Application Laid-Open No. 2007-099698 [Patent Document 14] Japanese Patent Application Laid-Open No. 2009-191039 [Patent Document 15] Japanese Patent Application Laid-Open No. 2012-219047 [Patent Document 16] Japanese Patent Application Laid-Open No. 2009-256244 [Patent Document 17] Japanese Patent Application Laid-Open No. 2013-023487 [Patent Document 18] Japanese Patent Application Laid-Open No. 2010-184915 [Patent Document 19] Japanese Patent Application Laid-Open No. 2006-219407 [Patent Document 20] Japanese Patent Application Laid-Open No. 2006-28036 [Patent Document 21] Japanese Patent Application Laid-Open No. 2010-90076 [Patent Document 22] Japanese Patent Application Laid-Open No. 2003-012532 [Patent Document 23] Japanese Patent Application Laid-Open No. 2003-055242 [Patent Document 24] Japanese Patent Application Laid-Open No. 2015-214533 [Patent Document 25] Japanese Patent Application Laid-Open No. 2011-184381 [Non-patent literature]

[0061] [Non-Patent Document 1] Japanese Journal of Pharmacology, 2005, Vol. 125, No. 6, pp. 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, pp. 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, pp. 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, pp. 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, pp. 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 effects in the areas of anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improvement, and to provide anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents, and liver function improvers that contain these as active ingredients. Another object of the present invention is to provide oral compositions, skin cosmetics, and hair cosmetics formulated with natural product-derived compounds that have excellent anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improving effects, and that 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 by containing, 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] [Effects 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. Furthermore, by incorporating 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 oral compositions, skin cosmetics, and hair cosmetics suitable for use in anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammation, or liver function improvement. DETAILED DESCRIPTION OF THE INVENTION

[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 by containing, 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): Furthermore, 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 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 phenylpropionic acids can be produced, for example, by isolating and purifying them from a plant extract containing phenylpropionic acids. In this case, the plant extract containing phenylpropionic acids can be obtained by a method commonly used for plant extraction. Examples of plants containing phenylpropionic acids include rice, barley, wheat, soybeans, adzuki beans, and corn.

[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 (e.g., crushed plant material or extract, etc.) with a microorganism having phenolic acid reductase to convert the cinnamic acids to phenylpropionic acids, and then extracting, isolating, and purifying the resulting fermentation product. Examples of compositions containing cinnamic acids include crushed plant material and extracts from plants such as coffee, wheat, corn, tomato, yerba mate, mugwort, and burdock. Furthermore, since cinnamic acids are components of lignin in woody 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 conventional methods. For example, the extraction process can be carried out by drying the plants or fermented products used as the extraction raw material, and then subjecting them to extraction with an extraction solvent either directly or after pulverization using a crusher. Drying can be carried out in the sun or using a commonly used dryer. The raw material can also be used after pretreatment such as degreasing with a nonpolar solvent such as hexane. Pretreatment such as degreasing allows for efficient extraction with a polar solvent.

[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 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 undergone 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 extraction solvents 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 can be any 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 can be mixed at any ratio, i.e., 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 even 7:3 or more, or the mixing ratio of water to lower aliphatic alcohol can be 1:9 or less, or even 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 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 2:8 or less.

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

[0078] The method for isolating and purifying the phenylpropionic acids from the extract, concentrate, or dried extract obtained as described above is not particularly limited and can be carried out by conventional methods. For example, the extract may be dissolved in a developing solvent and subjected to column chromatography using a porous material such as silica gel or alumina, or a porous resin such as a styrene-divinylbenzene copolymer or polymethacrylate, to recover a fraction containing the 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 the phenylpropionic acids obtained by column chromatography may be purified using any organic compound purification means, such as reverse-phase silica gel chromatography using ODS, recrystallization, liquid-liquid countercurrent extraction, or column chromatography using an ion-exchange resin.

[0079] [Anti-metabolic syndrome agent, 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 improving effects, and can therefore 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 improving agents.Furthermore, the phenylpropionic acids can be used to produce anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents or liver function improving agents. The anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, and liver function improver of this embodiment can be used in a wide range of applications such as pharmaceuticals, quasi-drugs, and cosmetics.

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

[0081] The whitening effect of the phenylpropionic acids is preferably exerted based on their tyrosinase activity inhibitory effect and / or melanin production inhibitory effect, but is not limited to those exerted based on the above effects. Furthermore, the phenylpropionic acids can be used to inhibit tyrosinase activity or inhibit melanin production, respectively, by utilizing their tyrosinase activity inhibitory effect or melanin production inhibitory effect. 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) degradation promoting effect. However, the anti-aging effect of the phenylpropionic acids is not limited to the anti-aging effect exerted based on the above-mentioned action. Furthermore, the above-mentioned phenylpropionic acids can be used for 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 AGE formation, or promoting AGE degradation, respectively. It can be used for promoting 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 AGE formation, or promoting the degradation of AGEs. That is, 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, AGE formation inhibitor, or AGE degradation 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 to inhibit testosterone 5α-reductase activity or promote hair papilla cell proliferation, respectively, by utilizing their testosterone 5α-reductase activity inhibitory activity or hair papilla cell proliferation promoting activity. In other words, the hair growth agent of the present embodiment can also be used as a testosterone 5α-reductase activity inhibitor or a hair papilla cell proliferation promoter 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 inhibitory action, hyaluronidase activity inhibitory action, hexosaminidase release inhibitory action, and prostaglandin E2 (PGE2) activity inhibitory action, but is not limited to the anti-inflammatory action exerted based on the above actions. Furthermore, the above-mentioned phenylpropionic acids can be used for inhibiting NO production, inhibiting hyaluronidase activity, inhibiting hexosaminidase release, or promoting PGE production, taking advantage of their NO production inhibitory effect, hyaluronidase activity inhibitory effect, hexosaminidase release inhibitory effect, or PGE production promoter effect, respectively. That is, the anti-inflammatory agent of this embodiment can also be used as an NO production inhibitor, hyaluronidase activity inhibitor, hexosaminidase release inhibitor, or PGE 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 promoting effect on glutathione production and / or adenosine triphosphate (ATP) production in hepatocytes, but is not limited to the liver function improving effect exerted based on the above-mentioned effects. Furthermore, the phenylpropionic acids can be used to promote hepatocyte glutathione production or hepatocyte ATP production, respectively, by utilizing their hepatocyte glutathione production-promoting activity or hepatocyte ATP production-promoting activity. That is, the liver function improver of this embodiment can also be used as a hepatocyte glutathione production promoter or a hepatocyte ATP production promoter containing the phenylpropionic acids as an active ingredient.

[0086] In addition, a composition containing phenylpropionic acids may be used instead of the isolated 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. Here, the "composition containing phenylpropionic acids" in this embodiment includes an extract obtained using a plant containing the phenylpropionic acids as an extraction raw material, a fermented product containing phenylpropionic acids, and an extract obtained using the fermented product as an extraction raw material. Furthermore, the "extract" includes an extract obtained by extraction treatment, a diluted or concentrated solution of the extract, or a dried product obtained by drying the extract.

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

[0088] The anti-metabolic syndrome agent, skin whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver of this 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 this embodiment can be formulated into any dosage form, such as powder, granules, tablets, or liquid, using a pharmaceutically acceptable carrier such as dextrin or cyclodextrin, or any other auxiliary agent, according to a conventional method. In this case, examples of auxiliary agents that can be used include excipients, binders, disintegrants, lubricants, stabilizers, and flavorings / flavoring agents. The anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, and liver function improver can be incorporated into other compositions (e.g., oral compositions, skin cosmetics, etc., described below) and used, or can be used as external liquids, patches, etc.

[0090] When the anti-metabolic syndrome agent, 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 set appropriately depending on the purpose.

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

[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 selected appropriately depending on the type of disease. Furthermore, 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 increased or decreased appropriately 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 this embodiment can promote fat breakdown through its anti-metabolic syndrome effect, preferably its cAMP phosphodiesterase activity inhibitory effect, and as a result, can prevent and improve obesity and various lifestyle-related diseases associated therewith, such as arteriosclerosis, diabetes, and metabolic syndrome. Furthermore, the anti-metabolic syndrome agent of this embodiment can prevent and treat type 2 diabetes, obesity, hypertension, insulin resistance, and the like through its anti-metabolic syndrome effect, preferably its DPP IV activity inhibitory effect. However, in addition to these uses, the anti-metabolic syndrome agent of this embodiment can also be used for all uses in which exerting an anti-metabolic syndrome effect, preferably its cAMP phosphodiesterase activity inhibitory effect or DPP IV activity inhibitory effect, is significant.

[0094] For example, the anti-metabolic syndrome agent of this embodiment or the cAMP phosphodiesterase activity inhibitor described above inhibits the degradation 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, through its inhibitory effect on DPP IV activity, prevent and treat autoimmune diseases such as rheumatoid arthritis and transplant rejection, as well as neurological disorders 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 darkening of the skin, age spots, and freckles through its whitening effect, preferably through its tyrosinase activity inhibitory effect and / or melanin production inhibitory effect. However, in addition to these uses, the whitening agent of the present embodiment can also be used for all uses in which it is significant to exert a whitening effect, preferably through its tyrosinase activity inhibitory effect or melanin production inhibitory effect.

[0096] The anti-aging agent of this embodiment can prevent, treat, or ameliorate symptoms of skin aging such as wrinkle formation, loss of skin elasticity, and loss of 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, AGE formation-inhibiting effect, and AGE degradation-promoting effect. However, in addition to these uses, the anti-aging agent of this embodiment can also be used for all uses in which it is significant to exert an anti-aging effect, preferably an effect of promoting type I collagen production, elastin production, 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 AGE formation, or promoting AGE degradation.

[0097] For example, the anti-aging agent of this embodiment or the aforementioned type I collagen production promoter can be used, through its type I collagen production-promoting activity, to prevent, treat, or improve diseases caused by decreased collagen production, such as osteoporosis; promote the regeneration of damaged tendons and ligaments; and promote the healing of wounds or burns. Furthermore, the anti-aging agent of this embodiment or the aforementioned elastin production promoter or elastase activity inhibitor can be used, through its elastin production-promoting activity or elastase activity-inhibiting activity, to prevent, treat, or improve pulmonary diseases, such as emphysema; vascular diseases, such as hypertension and aneurysms; and the like. Furthermore, the anti-aging agent of this embodiment or the aforementioned hyaluronic acid production promoter can be used, through its hyaluronic acid production-promoting activity, to prevent, treat, or improve arthritis, such as rheumatoid arthritis, osteoarthritis, septic arthritis, gouty arthritis, traumatic arthritis, and osteoarthritis; promote the healing of wounds or burns; and the like.

[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 skin wounds by inducing the reconstruction of basement membrane structure through its laminin-332 production-promoting activity. 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 laminin-332 deficiency (deficiency).

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

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

[0101] In addition to the uses described above, the anti-aging agent of this embodiment or the aforementioned 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 effect, claudin-4 mRNA expression promoting effect, or occludin mRNA expression promoting effect, thereby enhancing the skin's barrier function and moisture retention function and preventing or ameliorating skin conditions such as dry skin, rough skin, atopic dermatitis, and various infectious diseases. Furthermore, the anti-aging agent of this embodiment or the aforementioned claudin-1 mRNA expression promoter, claudin-4 mRNA expression promoter, or occludin mRNA expression promoter can improve the barrier function in the gastrointestinal tract and prevent or ameliorate inflammatory bowel disease, food allergies, and various infectious diseases transmitted through the gastrointestinal tract.

[0102] In addition to the uses described above, the anti-aging agent of this embodiment or the aforementioned AGE formation inhibitor or AGE degradation promoter can, through its AGE formation inhibitory effect or AGE degradation promoter effect, 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. Furthermore, the anti-aging agent of this embodiment or the aforementioned AGE formation inhibitor can, through its AGE formation inhibitory effect, prevent or suppress hair damage caused by protein glycation, thereby preventing or suppressing coarse hair, restoring hair elasticity and suppleness, and imparting firmness and body to hair.

[0103] The hair growth agent of the present embodiment can prevent, treat, or improve alopecia such as androgenetic alopecia, alopecia areata, and trichotillomania through its hair growth effect, preferably testosterone 5α-reductase activity inhibitory effect and / or hair papilla cell proliferation promoting effect, 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 also be used for all uses in which it is significant to exert a hair growth effect, preferably testosterone 5α-reductase activity inhibitory effect or hair papilla cell proliferation promoting effect.

[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 effect, prevent, treat, or ameliorate diseases associated with male hormones, such as hirsutism, seborrheic dermatitis, acne (pimples, etc.), benign 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 effect.

[0105] The anti-inflammatory agent of this embodiment can prevent, treat, or improve various inflammatory skin diseases associated with rough skin, such as contact dermatitis (rash), psoriasis, pemphigus vulgaris, atopic dermatitis, and other skin conditions, through its anti-inflammatory effect, preferably one or more effects selected from the group consisting of an inhibitory effect on NO production, an inhibitory effect on hyaluronidase activity, an inhibitory effect on hexosaminidase release, and an inhibitory effect on PGE2 production. However, in addition to these uses, the anti-inflammatory agent of this embodiment can also be used for any use in which it is significant to exert an anti-inflammatory effect, preferably an inhibitory effect on NO production, an inhibitory effect on hyaluronidase activity, an inhibitory effect on hexosaminidase release, or an inhibitory effect on PGE2 production.

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

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

[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 effect, to prevent, treat, or improve diseases associated with decreased in vivo glutathione levels, such as cataracts and Parkinson's disease; prevent, treat, or improve 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 effect, to alleviate fatigue and lethargy, etc.

[0109] Furthermore, the anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, and liver function improver of the present embodiment each have excellent effects in the areas of anti-metabolic syndrome action, 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 into the mechanisms of these actions.

[0110] Oral Composition The 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 oral compositions. In this case, the phenylpropionic acids or compositions containing phenylpropionic acids may be incorporated as they are, or an anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver formulated 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, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver formulated from a composition containing phenylpropionic acids or a phenylpropionic acid, into an oral composition, an oral composition suitable for anti-metabolic syndrome, whitening, anti-aging, hair growth, anti-inflammatory, or liver function improvement can be obtained. Among these, the anti-metabolic syndrome effect and liver function improvement effect are preferred because their functional effects are easily exerted when imparted to an oral composition.

[0112] Here, oral compositions refer to compositions that are unlikely to be harmful to human health and that are taken orally or by gastrointestinal administration in normal social life, and are not limited to administrative classifications such as foods, drugs, or quasi-drugs. Therefore, the "oral composition" in this embodiment broadly includes orally taken general foods, feeds, health foods, health functional foods (foods for specified health uses, foods with nutrient claims, and foods and beverages with functional claims), quasi-drugs, drugs, and the like. 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 (foods for specified health uses, foods with functional claims, foods with nutrient claims), quasi-drugs, or drugs.

[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 changed as appropriate taking into account the purpose of use, symptoms, gender, etc., but it is preferable to adjust the daily intake of phenylpropionic acids per adult to about 1 to 1,000 mg, taking into account 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, 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, added is usually 0.1 to 100% by mass, and preferably 5 to 100% by mass, of the oral composition to be added.

[0114] The oral composition of this embodiment may be prepared by incorporating the above-mentioned phenylpropionic acids into any oral composition that does not interfere with their activity, or may be a nutritional supplement containing the above-mentioned phenylpropionic acids as a main ingredient.

[0115] When producing the oral composition of this embodiment, any auxiliary agent can be added, such as sugars such as dextrin and starch; proteins such as gelatin, soy protein and corn protein; amino acids such as alanine, glutamine and isoleucine; polysaccharides such as cellulose and gum arabic; and fats and oils such as soybean oil and medium-chain fatty acid triglycerides, 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, vermicelli, gyoza wrappers, shumai wrappers, Chinese noodles, and instant noodles; sweets such as candy, chewing gum, candy, chewing 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-processed foods such as salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream, and dressing; seasonings such as sauces and dressings; soups, stews, salads, side dishes, and pickles; and various other forms of health and nutritional supplements; tablets, capsules, and drinks.When the above-mentioned phenylpropionic acids are incorporated into these oral compositions, commonly used auxiliary ingredients and additives can also 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 cosmetics or hair cosmetics. In this case, the above-mentioned phenylpropionic acids may be incorporated as they are, or an anti-metabolic syndrome agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver 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 agent, whitening agent, anti-aging agent, hair growth agent, anti-inflammatory agent, or liver function improver, 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 a 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 likely to be 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 likely to be 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 types of skin cosmetics or hair cosmetics that can be formulated with 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 improvers are not particularly limited. Examples of skin cosmetics include ointments, creams, emulsions, skin lotions, lotions, gels, cosmetic oils, packs, and foundations. Examples of hair cosmetics include hair tonics, hair creams, hair liquids, shampoos, pomades, and rinses.

[0121] When 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 improvers are incorporated into skin cosmetics or hair cosmetics, the amount incorporated can be adjusted appropriately depending on the type of skin cosmetics or hair cosmetics, but a suitable incorporation rate is about 0.0001 to 10% by mass, and a particularly suitable incorporation rate is about 0.001 to 1% by mass calculated as a standard extract.

[0122] The skin cosmetic or hair cosmetic of this embodiment can be used in combination with main ingredients, auxiliaries, or other ingredients typically used in the manufacture of skin cosmetics or hair cosmetics, such as astringents, bactericides / antibacterial agents, whitening agents, UV absorbers, moisturizers, cell activators, anti-inflammatory / antiallergic agents, antioxidants / active oxygen scavengers, 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 impaired. Such combinations can result in more versatile products, and the synergistic effects of the other active ingredients used in combination can sometimes bring about superior effects beyond those normally expected.

[0123] The skin cosmetic of this embodiment has the following effects of 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, and occludin Promotes mRNA expression, inhibits AGE formation, promotes AGE degradation; hair growth, inhibits testosterone 5α-reductase activity, promotes hair follicle 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, the following can be achieved: prevention, treatment, or amelioration of pigmentation such as skin darkening, age spots, and freckles; prevention, treatment, or amelioration of skin aging symptoms such as wrinkle formation, loss of elasticity, and loss of moisturizing function; promotion of wound or burn healing; prevention, treatment, or amelioration of rough skin, dry skin, and dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.); prevention, treatment, or amelioration of diseases involving male hormones such as seborrhea and acne (pimples, etc.); prevention, treatment, or amelioration of contact dermatitis (rash), psoriasis, pemphigus vulgaris, and other various inflammatory skin diseases associated with rough skin; and prevention, treatment, or amelioration of obesity and associated lifestyle-related diseases such as arteriosclerosis, diabetes, and metabolic syndrome.

[0124] Furthermore, the hair cosmetic composition of the present embodiment has the following effects of the 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, and occludin mRNA expression promoting effect. Through one or more actions selected from the group consisting of: promoting mRNA expression, inhibiting AGE formation, and promoting AGE degradation; anti-metabolic syndrome action, inhibiting cAMP phosphodiesterase activity, and inhibiting DPP IV activity; whitening action, inhibiting tyrosinase activity, and inhibiting melanin production; improving liver function, promoting hepatocyte glutathione production, and promoting hepatocyte ATP production, the compound can 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 other dry skin diseases (e.g., atopic dermatitis, psoriasis, ichthyosis, etc.).

[0125] The anti-metabolic syndrome agents, whitening agents, anti-aging agents, hair growth agents, anti-inflammatory agents, liver function improvers, oral compositions, skin cosmetics, and hair cosmetics of this embodiment are suitable for use in 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 effects are achieved. [Example]

[0126] The present invention will be specifically explained 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] To 0.2 mL of 50 mmol / L Tris-HCl buffer (pH 7.5) containing 5 mmol / L magnesium chloride, 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, final concentrations see Table 2 below) were added and incubated at 37°C for 5 minutes. Then, 0.05 mL of 0.5 mg / mL cyclic AMP solution was added and incubated at 37°C for 60 minutes. After completion of the reaction, the mixture was boiled in a boiling water bath for 3 minutes, centrifuged (2260 × g, 10 minutes, 4°C), and the reaction substrate cyclic AMP in the supernatant was analyzed using the high-performance liquid chromatography conditions described below. A control was also performed using the same procedure with the solvent alone without 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: 250 mm 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 obtained results, the decomposition rates of the cyclic AMP standard without the addition of a sample (C) and with the addition of a test sample (D) were calculated using the following formula.

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

[0133] Thereafter, based on the decomposition rates (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, final concentrations see Table 3 below) prepared in 25 mM Tris-HCl buffer (pH 8.0) was mixed with 25 μL of a 0.4 μg / mL DPP IV (rhCD26, R&D Systems) solution prepared in the same buffer, and the mixture was preincubated at 37°C for 5 minutes. Then, 50 μL of 0.5 mM Gly-Pro-p-NA·Tos (Peptide Institute) prepared in the same buffer was added, and the mixture was incubated at 37°C for 90 minutes. After the reaction, the absorbance at 415 nm was measured. The DPP IV activity inhibition rate (%) was calculated from the results using the following formula:

[0138] DPP IV activity inhibition rate (%) = {1-(CD) / (AB)} × 100 The terms in the formula represent the following: A: Absorbance at 415 nm with no sample added and enzyme added B: Absorbance at 415 nm without adding sample or enzyme C: Absorbance at 415 nm after adding test sample and enzyme D: Absorbance at 415 nm with test sample and without enzyme added 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 inhibitory effect on tyrosinase activity as follows.

[0142] A 48-well plate was charged with 0.2 mL of McIlvaine buffer (pH 6.8), 0.06 mL of 0.3 mg / mL tyrosine solution, and 0.18 mL of the test sample (Sample 3, see Table 4 below for final concentration) dissolved in 25% DMSO solution, 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 was completed, the absorbance at 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 with the addition of 25% DMSO solution without adding the sample solution. From the measurement results, the tyrosinase activity inhibition rate (%) was calculated using the following formula.

[0144] Tyrosinase activity inhibition rate (%) = {1-(AB) / (CD)} x 100 The terms in the formula represent the following: A: Absorbance at 475 nm after adding test sample and enzyme B: Absorbance at 475 nm with test sample and without enzyme added C: Absorbance at 475 nm with no sample added and enzyme added 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 inhibitory effect on tyrosinase activity.

[0147] [Test Example 4] Test of melanin production inhibitory 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 collected at a concentration of 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 in a 48-well plate at 300 μL per well and cultured for 6 hours.

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

[0150] To measure cell viability, the cells were cultured as described above, then the medium was removed and washed with 400 μL of PBS(-) buffer. 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 incubation, 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 540 nm was measured. From the results obtained, the melanin production inhibition rate (%), corrected for cell viability, was calculated using the following formula:

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

[0152] [Table 5]

[0153] As shown in Table 5, Compound 1 (Sample 1), Compound 2 (Sample 2), and Compound 3 (Sample 3) were all found to have 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 in a 96-well microplate at 100 μL per well 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, cells were incubated in the same manner using DMEM containing 0.25% FBS without any sample. After incubation, the amount of type I collagen in the medium in each well was measured by ELISA. The type I collagen production promotion rate (%) was calculated from the measurement results using the following formula:

[0157] Type I collagen production promotion rate (%) = A / B x 100 The terms in the formula represent the following: A: Amount of type I collagen when test sample is 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 promoting effect test Compound 2 (sample 2) and compound 3 (sample 3) were tested for their elastin production-promoting activity as follows.

[0161] Normal human dermal fibroblasts (NB1RGB) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then harvested by trypsinization. The harvested cells were collected at a concentration of 2.2 × 10 5 After diluting the cells 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 incubation, the medium was removed, and 150 μL of test samples (samples 2 and 3, see Table 7 below for final concentrations) dissolved in 0.25% FBS-containing DMEM was added to each well and incubated for 5 days. As a control, cells were incubated in the same manner using 0.25% FBS-containing DMEM without any sample. After incubation, the supernatant was collected, and the amount of elastin released into the culture supernatant was measured by ELISA. The elastin production promotion rate (%) was calculated from the measurement results using the following formula:

[0163] Elastin production promotion rate (%) = A / B x 100 The terms in the formula represent the following: A: Amount of elastin when test sample is added B: Amount of elastin without 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 1–3, final concentrations shown in Table 8 below) prepared in 0.2 mol / L Tris-HCl buffer (pH 8.0) was mixed with 50 μL of a 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 the mixture was incubated at 25°C for 15 minutes. After the reaction, the absorbance at 415 nm was measured. A blank test without enzyme was also performed in the same manner, and correction was performed. The elastase activity inhibition rate (%) was calculated from the results using the following formula:

[0168] Elastase activity inhibition rate (%) = {1-(CD) / (AB)} x 100 The terms in the formula represent the following: A: Absorbance at 415 nm with no sample added and enzyme added B: Absorbance at 415 nm without adding sample or enzyme C: Absorbance at 415 nm after adding test sample and enzyme D: Absorbance at 415 nm with test sample and without enzyme added 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 activity.

[0171] [Test Example 8] Hyaluronic acid production promoting effect test Compound 1 (Sample 1) and Compound 2 (Sample 2) were tested for their hyaluronic acid production promoting activity 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 in a 96-well plate and cultured overnight.

[0173] After the incubation, 100 μL of 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, cells were incubated in the same manner using 0.25% FBS-containing DMEM without sample. 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 The terms in the formula represent the following: A: Amount of hyaluronic acid when test sample is 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 an excellent effect of promoting hyaluronic acid production.

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

[0178] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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.

[0180] Using this total RNA as a template, the mRNA expression levels of HAS3 and GAPDH (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 PCR. TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green(R) A two-step real-time RT-PCR reaction was performed using Fast qPCR Mix (Takara Bio). Primers from Takara Bio were used. The expression level of HAS3 mRNA was calculated based on the total RNA samples prepared from cells cultured with and without the test sample, and the normalized 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 promoting effect test Compound 1 (Sample 1) was tested for its laminin-332 production promoting activity 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 then harvested by trypsinization. The harvested cells were collected at a concentration of 1.0 × 10 5 The cells were diluted with KGM medium minus BPE (KGM-BPE) to a cell density of 100 cells / mL, and then seeded in a 24-well plate at 500 μL per well 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, KGM-BPE without sample was used for incubation in the same manner. 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. The amount of adsorbed laminin-332 was then measured by ELISA. The laminin-332 production promotion rate (%) was calculated from the measurement results using the following formula:

[0187] Laminin-332 production promotion rate (%) = A / B x 100 The terms in the formula represent the following: A: Amount of laminin-332 when test sample is added B: Amount of laminin-332 without sample addition 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 promoting activity test Compound 1 (Sample 1) was tested for its epidermal keratinocyte proliferation-promoting activity as follows.

[0191] 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 3.0 × 10 4After diluting the cells with KGM to a cell density of 100 cells / mL, 100 μL of the cells were seeded per well of 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 the sample was used and cultured in the same manner.

[0192] The epidermal keratinocyte proliferation-promoting activity 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, the blue formazan produced within 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 used to determine the amount of blue formazan produced. From the results obtained, the epidermal keratinocyte proliferation promotion rate (%) was calculated using the following formula.

[0193] Epidermal keratinocyte proliferation promotion rate (%) = A / B x 100 The terms in the formula represent 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 effect of promoting the proliferation of epidermal keratinocytes.

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

[0197] Normal human neonatal epidermal keratinocytes (NHEK) were cultured in normal human epidermal keratinocyte growth medium (KGM) and then 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 of the medium was seeded per well of a collagen-coated 96-well plate and cultured overnight. After the culture was completed, the medium was removed, and 100 μL of KGM containing the test samples (samples 1 and 2, final concentrations are shown in Table 13 below) was added to each well and cultured for 2 hours. As a control, KGM without the sample was used and cultured in the same manner.

[0198] The ATP production promotion effect was measured using the firefly luciferase luminescence method to measure the amount of ATP in the cells. After 2 hours of incubation, 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 luciferase-mediated chemiluminescence reaction was carried out. After the reaction, the amount of chemiluminescence, which was 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 results obtained, the ATP production promotion rate (%) was calculated using the following formula:

[0199] ATP production promotion rate (%)=A / B×100 The terms in the formula represent the following: A: Chemiluminescence amount when test sample is added B: Chemiluminescence amount without sample addition 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 promoting effect test (skin fibroblasts) Compounds 1 to 3 (samples 1 to 3) were tested for their glutathione production promoting activity in skin fibroblasts as follows.

[0203] Normal human dermal fibroblasts (NB1RGB) were cultured in α-modified Eagle's minimum essential medium (α-MEM) containing 10% FBS, and then 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 in a 48-well plate at 200 μL per well and cultured for 48 hours.

[0204] After incubation, the medium was removed, and 200 μL of 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, cells were incubated in the same manner using DMEM containing 1% FBS but without the test samples. After incubation, the medium was removed from each well, and the wells were washed with 400 μL of PBS(-) buffer. The cells were then lysed using 150 μL of M-PER (Pierce).

[0205] Total glutathione was quantified using 100 μL of this solution. Specifically, 100 μL of lysed 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 incubated at 37°C for 10 minutes. After incubation, 25 μL of 10 mmol / L 5,5'-dithiobis(2-nitrobenzoic acid) was added. Absorbance at 412 nm was measured for 5 minutes, and ΔOD / min was calculated. Total glutathione concentration was calculated based on a calibration curve prepared using oxidized glutathione (Fujifilm Wako Pure Chemical Industries, Ltd.). The obtained values ​​were corrected for the amount of glutathione per total protein, and the glutathione production promotion rate (%) was calculated using the following formula:

[0206] Glutathione production promotion rate (%) = B / A x 100 The terms in the formula represent the following: A: Amount of glutathione per total protein amount without sample addition B: Amount of glutathione per total protein amount in the test sample 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 an excellent glutathione production promoting effect 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 activity as follows.

[0210] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 in 5% CO2. As a control, KBM without sample was 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.

[0212] Using this total RNA as a template, the mRNA expression levels of TGM1 and GAPDH (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) Two-step real-time RT-PCR was performed using Fast qPCR Mix (Takara Bio Inc.) with primers 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 test sample, and the normalized value was calculated using 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 SPT mRNA expression promoting effect as follows.

[0217] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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.

[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 (manufactured by Takara Bio Inc.), with PrimeScript TMRT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was performed using a two-step real-time RT-PCR reaction with Fast qPCR Mix (Takara Bio). Primers were from Takara Bio. The expression level of SPT mRNA was calculated based on total RNA samples prepared from cells cultured with and without the test sample, and the normalized 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 SPT mRNA expression.

[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 pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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.

[0226] Using this total RNA as a template, the mRNA expression levels of 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) A two-step real-time RT-PCR reaction was performed using Fast qPCR Mix (Takara Bio). Primers 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 test sample, and the normalized 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition The results are shown in Table 17.

[0228] [Table 17]

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

[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 activity as follows.

[0231] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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.

[0233] Using this total RNA as a template, the mRNA 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 (manufactured by Takara Bio Inc.), with PrimeScript TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was performed using a two-step real-time RT-PCR reaction with Fast qPCR Mix (Takara Bio). Primers 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 test sample, and the normalized 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 CLDN1 mRNA expression promoting activity as follows.

[0238] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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] Using this total RNA as a template, the mRNA expression levels of CLDN1 and GAPDH (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 performed using a two-step real-time RT-PCR reaction with Fast qPCR Mix (Takara Bio). Primers were from Takara Bio. CLDN1 mRNA expression levels were calculated based on total RNA samples prepared from cells cultured with and without the test sample, and corrected 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 × 100 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 CLDN1 mRNA expression.

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

[0245] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was 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.

[0247] Using this total RNA as a template, the mRNA expression levels of CLDN4 and GAPDH (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 PCR. TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R) The assay was performed using a two-step real-time RT-PCR reaction with Fast qPCR Mix (Takara Bio). Primers from Takara Bio were used. CLDN4 mRNA expression levels were calculated based on total RNA samples prepared from cells cultured with and without the test sample, and corrected 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 × 100 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition The results are shown in Table 20.

[0249] [Table 20]

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

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

[0252] Normal human neonatal epidermal keratinocytes (NHEK) were pre-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 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°C in 5% CO2 at 1000 x 1000 cells / well. After culturing, the medium was replaced with normal human epidermal keratinocyte basal medium (KBM, the same KGM as above but without growth additives (hEGF, BPE, insulin, antibiotics, hydrocortisone)), and the cells were 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 at 37°C in 5% CO2 for 24 hours. As a control, KBM without sample was incubated in the same manner. After incubation, the medium was removed, and total RNA was extracted using ISOGEN II (Nippon Gene). The amount of RNA in each sample was measured using a spectrophotometer, and total RNA was adjusted to 150 ng / μL.

[0254] Using this total RNA as a template, the mRNA expression levels of OCLN and GAPDH (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 PCR. TM RT Master Mix (Perfect Real Time) (Takara Bio) TB Green (R)The assay was performed using a two-step real-time RT-PCR reaction with Fast qPCR Mix (Takara Bio). Primers were from Takara Bio. The expression level of OCLN mRNA was calculated based on total RNA samples prepared from cells cultured with and without the test sample, and the normalized 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 The terms in the formula represent the following: A: Correction value when test sample is added B: Corrected value without sample addition 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 activity of promoting OCLN mRNA expression.

[0258] [Test Example 21] Test for inhibitory effect on advanced glycation end products (AGEs) formation 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 loaded 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 AGE formation. PBS(-) buffer alone served as a negative control, and a 0.2M D(-)-ribose solution prepared in PBS(-) buffer served as a positive control, and both were allowed to stand in the same manner. After 20 days, the amount of AGEs was measured by ELISA using an anti-AGE antibody (Transgenic Co., Ltd.) to evaluate the inhibitory effect on AGE formation. The AGE formation inhibition rate (%) was calculated from the results using the following formula:

[0260] AGEs formation inhibition rate (%)={(BC) / (BA)}×100 The terms in the formula represent the following: A: Absorbance at 405 nm for negative control B: Absorbance at 405 nm for positive control C: Absorbance at a wavelength of 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 ability to promote the decomposition of AGEs as follows.

[0264] 100 μL of a 0.2 M D(-)-ribose solution prepared in PBS(-) buffer was added to a 96-well type I collagen-coated plate (Asahi Glass Co., Ltd.) and allowed to stand at 37°C for two weeks to allow AGE formation. A negative control plate containing only PBS(-) buffer was also allowed to stand in the same manner. After two weeks, 100 μL of a test sample (Sample 1, see Table 23 below for final concentration) prepared in PBS(-) buffer was added to each well and allowed to stand for an additional 20 days at 37°C. As a positive control, PBS(-) buffer alone was used instead of the test sample, and as a negative control, PBS(-) buffer alone was also used. After 20 days, the amount of AGEs was measured by ELISA using an anti-AGE antibody (Transgenic Co., Ltd.) to evaluate the AGE degradation promotion effect. The AGE degradation promotion rate (%) was calculated from the obtained results using the following formula:

[0265] AGEs degradation promotion rate (%)={(BC) / (BA)}×100 The terms in the formula represent the following: A: Absorbance at 405 nm for negative control B: Absorbance at 405 nm for positive control C: Absorbance at a wavelength of 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 capped V-bottom test tube, 20 μL of a 4.2 mg / mL testosterone solution (Fujifilm Wako Pure Chemical Industries, Ltd.) prepared with propylene glycol was mixed with 825 μL of 5 mmol / L Tris-HCl (pH 7.13) buffer solution containing 1 mg / mL NADPH.

[0270] Furthermore, 80 μL of test sample (Samples 1 to 3, see Table 24 below for final concentrations) solution prepared with 80% ethanol was added to 75 μL of S-9 (rat liver homogenate, Oriental Yeast Co., Ltd.), mixed, and incubated at 37°C for 60 minutes. The reaction was then stopped by adding 1 mL of methylene chloride. The mixture was centrifuged (1600 × g, 10 minutes), and the methylene chloride layer was separated and 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 volume (80 μL) of sample solvent was used instead of the test sample solution, and the mixture was subjected to gas chromatography analysis in the same manner.

[0271] <Gas chromatography conditions> Equipment used: Shimadzu GC-2010 (Shimadzu Corporation) Column: DB-1701 (inner diameter: 0.53 mm, length: 30 m, film thickness: 1.0 μm) (manufactured by 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: 12 mL / min

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

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

[0274] Using the compound concentrations calculated based on formula (1), the conversion rate (the ratio of the concentrations 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) The terms in the formula represent 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) The terms in the formula represent 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] Test of dermal papilla cell proliferation promoting activity Compound 1 (Sample 1) was tested for its effect of promoting hair papilla cell proliferation as follows.

[0280] Normal human hair dermal papilla cells (HFDPC, derived from the male scalp) were cultured in a dermal papilla cell growth medium (PCGM, manufactured by Toyobo Co., Ltd.) containing 1% FCS and growth additives, 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 of the solution was seeded per well on a collagen-coated 96-well plate and cultured for 3 days.

[0281] The medium was then 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 and cultured for an additional 4 days. As a control, serum-free DMEM without the sample was used for similar culture. After culture was completed, the dermal papilla cell proliferation-promoting activity was measured using an MTT assay. Specifically, the medium was removed, and 100 μL of 0.4 mg / mL MTT prepared in serum-free DMEM was added to each well. After further culture for 2 hours, the blue formazan produced within 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 used to determine the amount of blue formazan produced. From the measurement results, the dermal papilla cell proliferation promotion rate (%) was calculated using the following formula:

[0282] Hair papilla cell proliferation promotion rate (%) = A / B x 100 The terms in the formula represent 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 effect of promoting proliferation of dermal papilla cells.

[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 collected using a cell scraper. The collected cells were collected at a concentration of 3.0 × 10 6The cells were diluted with phenol red-free DMEM containing 10% FBS to a cell density of 100 cells / mL, and then seeded in a 96-well plate at 100 μL per well and cultured for 4 hours.

[0287] After incubation, the medium was removed, and 100 μL of the test sample (Sample 1, final concentration: see Table 26 below) dissolved in 10% FBS-containing phenol red-free DMEM containing 0.5% DMSO was added to each well. 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 the cells were incubated for 48 hours. As a control, 10% FBS-containing phenol red-free DMEM containing 0.5% DMSO was used instead of the test sample solution, and LPS treatment was performed in the same manner.

[0288] Nitric oxide (NO) production is related to nitrite ions (NO2 - ) was measured as an index. After the incubation, 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 medium 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 nitric oxide (NO) production inhibition rate (%) 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 The terms in the formula represent 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] To 0.2 mL of test samples (samples 1–3, see Table 27 below for final concentrations) dissolved in 0.1 mol / L acetate buffer (pH 3.5), 0.1 mL of hyaluronidase solution (Sigma, Type IV-S, from bovine testes, 400 NF units / mL) was added and incubated at 37°C for 20 minutes. 0.2 mL of 2.5 mmol / L calcium chloride was added as an activator, and the mixture was incubated at 37°C for 20 minutes. 0.5 mL of 0.8 mg / mL sodium hyaluronate solution (from rooster comb) was added and incubated at 37°C for 40 minutes. 0.2 mL of 0.4 mol / L sodium hydroxide was added to stop the reaction. After cooling, 0.2 mL of boric acid solution was added to each reaction solution and boiled for 3 minutes. After cooling on ice, 6 mL of p-DABA reagent was added, and the mixture was incubated at 37°C for 20 minutes. The absorbance at 585 nm was then measured.

[0294] 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 with distilled water added without adding the sample solution. From the obtained results, the hyaluronidase activity inhibition rate (%) was calculated using the following formula. Hyaluronidase activity inhibition rate (%) = {1-(AB) / (CD)} x 100 The terms in the formula represent the following: A: Absorbance at 585 nm after adding test sample and enzyme B: Absorbance at 585 nm with test sample and without enzyme added C: Absorbance at 585 nm with no sample added and enzyme added 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 had excellent inhibitory effects on hyaluronidase activity.

[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 Spinner's modified Eagle's minimum essential medium (S-MEM) containing 15% FBS, and then harvested by trypsinization. The harvested cells were collected at a concentration of 4.0 × 10 5 The cells were diluted with 15% FBS-containing S-MEM to a cell density of 0.50 cells / mL, and DNP-specific IgE was added to a final concentration of 0.5 μg / mL. 100 μL of the cells were then seeded into a 96-well plate at each well and cultured overnight.

[0299] After 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, final concentration: see Table 28 below) dissolved in the same buffer were added to each well and allowed to stand at 37°C for 10 minutes. As a control, the same procedure was performed using 40 μL of Silagarian buffer without sample. Next, 10 μL of 400 ng / mL DNP-BSA solution was added and allowed 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 the 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 incubated at 37°C for 1 hour.

[0301] After the reaction was completed, 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 The terms in the formula represent the following: A: Absorbance at wavelengths of 415-650 nm without adding sample B: Absorbance at wavelengths of 415-650 nm after adding the test sample The results are shown in Table 28.

[0303] [Table 28]

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

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

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

[0307] After incubation, the medium was replaced with 500 μmol / L aspirin-containing medium to inactivate pre-existing COX-1 and low levels of COX-2 by acetylation. The cells were then washed three times with PBS(-) buffer. 100 μL of the test sample (Sample 1, final concentration: see Table 29 below) dissolved in 10% FBS-containing DMEM containing 0.5% DMSO was added to each well. 100 μL of lipopolysaccharide (LPS) (DIFCO, E. coli 0111; B4) dissolved in 10% FBS-containing DMEM at a final concentration of 1 μg / mL was then added and incubated for 16 hours. A control was also prepared using 10% FBS-containing DMEM containing 0.5% DMSO without the sample. After incubation, the amount of prostaglandin E2 in the culture supernatant was quantified using a PGE2 EIA Kit (Cayman Chemical). From the obtained results, the PGE2 production inhibition rate (%) was calculated using the following formula.

[0308] PGE2 production suppression rate (%)={1-(AC) / (BC)}×100 The terms in the formula represent the following: A: Amount of PGE2 after addition of test sample and stimulation with LPS B: PGE2 amount after stimulation with LPS without adding sample C: PGE2 amount without sample addition and without 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 promoting effect test (hepatocytes) Compounds 1 to 3 (samples 1 to 3) were tested for their glutathione production promoting activity in hepatocytes as follows.

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

[0313] After incubation, the medium was removed, and 200 μL of 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 incubation for another 24 hours. As a control, cells were incubated in the same manner using 1% FBS-containing DMEM without sample. After incubation, the medium was removed from each well, and the wells were washed with 400 μL of PBS(-). The cells were then lysed using 150 μL of M-PER (Pierce).

[0314] Total glutathione was quantified using 100 μL of this solution. Specifically, 100 μL of 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 incubated at 37°C for 10 minutes. 25 μL of 10 mmol / L 5,5'-dithiobis(2-nitrobenzoic acid) was then added. The absorbance at 412 nm was measured for 5 minutes, and ΔOD / min was calculated. Total glutathione concentrations were calculated based on a calibration curve prepared using oxidized glutathione (Fujifilm Wako Pure Chemical Industries, Ltd.). The values ​​obtained were corrected for the amount of glutathione per total protein, and the glutathione production promotion rate (%) was calculated using the following formula:

[0315] Glutathione production promotion rate (%) = B / A x 100 The terms in the formula represent the following: A: Amount of glutathione per total protein amount without sample addition B: Amount of glutathione per total protein amount in the test sample 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 found to have excellent glutathione production promoting activity in hepatocytes.

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

[0319] Normal human hepatocytes (hepatocytes) were cultured in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS, and then 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 μL / mL, and then seeded in a 96-well plate at 100 μL per well and cultured overnight.

[0320] After incubation, the medium was removed, and 100 μL of 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, cells were incubated in the same manner using 10% FBS-containing DMEM without any sample.

[0321] The ATP production promotion effect was evaluated by measuring the amount of intracellular ATP using the firefly luciferase luminescence method. After 2 hours of incubation, 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 luciferase-mediated chemiluminescence reaction was carried out. After the reaction, the amount of chemiluminescence, which was proportional to the amount of intracellular ATP, 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:

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

[0323] [Table 31]

[0324] As shown in Table 31, Compound 1 (Sample 1), Compound 2 (Sample 2), and Compound 3 (Sample 3) were all found to have 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 (contains 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 prepared 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 prepared 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] An emulsion was prepared in a conventional manner according to the following composition. 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 Cetyl alcohol 2.00g Glyceryl monostearate 2.00g Polyoxyethylene sorbitan oleate (20E.O.) 2.00g Methyl parahydroxybenzoate 0.15g Stearyl glycyrrhetinate 0.10g Phellodendron bark extract 0.10g Dipotassium glycyrrhizinate 0.10g Ginkgo biloba extract 0.10g Conchiolin 0.10g Phellodendron bark extract 0.10g Chamomile extract 0.10g Fragrance 0.05g Purified water Rest (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 parahydroxybenzoate 1.5g Fragrance 0.1g Purified water Rest (total amount is 100g)

[0330] [Formulation example 6] A cosmetic 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 Hydroxyethyl cellulose 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 Rest (total amount is 100g)

[0331] [Formulation example 7] A hair tonic having the following composition was prepared by a conventional method. Compound 1 0.2g Compound 2 0.1g Compound 3 0.1g Tocopherol acetate (appropriate amount) Cephalatin 0.002g Isopropylmethylphenol 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 Rest (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 Rest (total amount is 100g)

Claims

1. A liver function improver characterized by comprising Compound 1 and / or Compound 2 represented by the following general formula (I) as an active ingredient: 【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 characterized by comprising Compound 1 represented by the following general formula (I) as an active ingredient: 【Transformation 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 containing compound 3 represented by the following general formula (I) as an active ingredient. 【Transformation 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. 【Transformation 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 suppressing hexosaminidase release. 【Transformation 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. 【Transformation 8】

9. An anti-inflammatory skin or hair cosmetic composition characterized by containing, 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 to inhibit hyaluronidase activity. 【Chemistry 11】

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