KR20230078389A - Reelin/vegf-c production/activation promoter and skin external composition using the same - Google Patents

Abstract

(상기 화학식 1에서, 각 치환기는 명세서에 정의된 바와 같다.)An agent for promoting the production and/or activity of rilin and/or VEGF-C, including a compound represented by Formula 1 below, as an active ingredient, and an external preparation for skin containing the same are provided.
[Formula 1]

(In Formula 1, each substituent is as defined in the specification.)

Description

Production and/or activity accelerator of Rilin and/or VEGF-C and skin external preparation using the same {REELIN/VEGF-C PRODUCTION/ACTIVATION PROMOTER AND SKIN EXTERNAL COMPOSITION USING THE SAME}

The present disclosure relates to an agent for promoting the production and/or activity of Rilin and/or VEGF-C and an external skin preparation using the same.

Ederma refers to a condition in which tissue fluid is stored between tissue cells in the body, and is simply a symptom of swelling of the body. It can be caused by heart disease, kidney disease, or poor circulation in any part of the body. In the case of the legs, the blood flow to the heart is reduced because the distance from the heart is large and the influence of gravity is great, resulting in swelling. In addition, in the case of women, edema occurs during normal pregnancy or pregnancy toxemia, and edema may appear temporarily when a lot of water or salt is consumed, or when fatigue or lack of sleep occurs, but it subsides on its own. When capillary permeability increases, for example, local edema also occurs in the case of burns, trauma, local inflammation, allergic reactions, and the like. In particular, in the case of leg edema, it is easily perceived as a feeling of tight shoes because it is accompanied by edema of the feet and ankles. Systemic edema can be divided into cardiac, renal, hepatic, endocrine, and dystrophic edema, and local edema includes vascular and lymphatic occlusion and vasomotor edema. When edema occurs, the body swells, weight increases, the eyes are swollen when waking up, the rings on the fingers are tight, and the shoes seem to be small. When pressed with a finger on the tibia of the calf, pitted edema (pitting edema) may appear. It is known that edema promotes blood circulation disorders and skin aging due to local excessive moisture in the skin. Skin problems are generally known to exacerbate the condition of people with lymphedema, where there is an overload and improper functioning of the lymphatic system.

The skin is the closest contact with the external environment within the human body and is an important organ that protects the inside of the human body. Such skin is largely divided into epidermis, dermis, and hypodermis. Here, subcutaneous fat is composed of fat cells constituting adipose tissue that stores energy as fat, and plays a role in accumulating or releasing energy in vivo. In other words, subcutaneous fat is stored as neutral fat in adipocytes when the supply of energy is greater than the demand, and is decomposed into free fatty acids and glucose when energy is depleted.

Meanwhile, in modern society, the number of obese people is rapidly increasing due to a lack of exercise and a high-protein eating culture due to the improvement of living standards along with economic growth, and many diseases caused by obesity are occurring. Accordingly, in modern society, exercise therapy, diet, and drug therapy are being used to treat obesity.

However, in the case of modern people who are busy with life, it is difficult to expect appropriate effects to solve obesity and obesity-related diseases through exercise and diet, and moreover, although fat cells can be reduced in size once they are created, it is difficult to remove them naturally. It is impossible, so there is a problem that remains permanently in the human body. Accordingly, it can be said that it is appropriate to develop and use safe external skin preparations (eg, ointments, cosmetics, etc.) that can help lipolysis.

Accordingly, the present inventors have found that the compound represented by a specific formula promotes the production or activity of reelin and/or VEGF-C as an active ingredient, and further improves swelling, lymphedema, skin wrinkles and obesity. After confirming, it came to complete this invention.

One embodiment is to provide an accelerator that promotes the production or activity of Rilin and VEGF-C.

Another embodiment is to provide an external preparation for skin using the accelerator.

According to one embodiment, an agent for promoting the production and/or activity of rillin and/or VEGF-C, comprising a compound represented by Formula 1 below as an active ingredient, is provided.

[Formula 1]

In Formula 1,

R ¹ to R ⁴ are each independently a hydroxy group, a substituted or unsubstituted C1 to C20 alkoxy group, a substituted or unsubstituted C1 to C20 alkyl group, or a substituted or unsubstituted C6 to C20 aryl group,

n1 is an integer from 0 to 4;

n2 is an integer from 0 to 5;

n3 and n4 are each independently an integer of 0 to 3, provided that n3 + n4 ≠ 0.

In Formula 1, R ³ may be a hydroxyl group, n3 may be an integer of 3, and n4 may be an integer of 0.

In Formula 1, R ³ may be a hydroxyl group, R ⁴ may be a substituted or unsubstituted C1 to C20 alkoxy group, n3 may be an integer of 2, and n4 may be an integer of 1.

Formula 1 may be represented by Formula 1-1 below.

[Formula 1-1]

In Formula 1-1,

R ^a to R ^h are each independently a hydroxy group or a substituted or unsubstituted C1 to C20 alkoxy group.

In Formula 1-1, R ^a to R ^h may each independently be a hydroxyl group.

In Formula 1-1, R ^a to R ^e are each independently a hydroxy group, and R ^f to R ^h are each independently a hydroxy group or a substituted or unsubstituted C1 to C20 alkoxy group, provided that at least one of R ^f to R ^h At least one may be a substituted or unsubstituted C1 to C20 alkoxy group.

The compound represented by Formula 1 may be included in a concentration range of 1 ppm to 200 ppm based on the total amount of the production and/or activity accelerator of rillin and/or VEGF-C.

Another embodiment is characterized by comprising the compound represented by Formula 1 as an active ingredient, by promoting the production and / or activity of Rilin and / or VEGF-C, swelling, lymphedema, skin wrinkles or Provided is an external preparation for skin for improving obesity.

The skin external preparation is an agent for improving swelling, and the swelling may be due to abnormal lymphatic vessel formation, lymphatic vessel dysfunction, or both.

The external skin preparation is a lymphedema improving agent, and the lymphedema may be caused by abnormal formation of lymphatic vessels, abnormal lymphatic function, or both.

The external skin preparation is an obesity improving agent, and the obesity may be caused by abnormal lymphatic vessel formation, lymphatic vessel dysfunction, or both.

According to one embodiment, by inducing the expression of rillin and/or VEGF-C to activate the lymphatic function, a new ingredient effective for preventing or controlling swelling, lymphedema, wrinkle formation, or obesity is provided.

1 is a graph showing the cytotoxicity test results of the compound represented by Formula E-1.
Figure 2 is a graph showing the results of the cytotoxicity test of the compound represented by Formula E-2.
Figure 3 is a graph showing the results of Rilin cytokine analysis of the compound represented by Formula E-1.
Figure 4 is a graph showing the results of Rilin cytokine analysis of the compound represented by Formula E-2.
5 is a graph showing the results of VEGF-C cytokine analysis of the compound represented by Formula E-1.
6 is a graph showing the results of VEGF-C cytokine analysis of the compound represented by Formula E-2.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be embodied in many different forms and is not limited to the embodiments set forth herein.

As used herein, the term "Reelin (RELN)" refers to an extracellular matrix-related molecule.

Unless otherwise specified herein, "substituted" to "substituted" means that one or more hydrogen atoms in the functional group of the present invention is a halogen atom (F, Br, Cl or I), a hydroxyl group, a nitro group, a cyano group, an amino group ( NH ₂ , NH(R ²⁰⁰ ) or N(R ²⁰¹ )(R ²⁰² ), wherein R ²⁰⁰ , R ²⁰¹ and R ²⁰² are the same or different from each other, and are each independently a C1 to C10 alkyl group), an amidino group, A hydrazine group, a hydrazone group, a carboxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alicyclic organic group, a substituted or unsubstituted aryl group, and It means substituted with one or more substituents selected from the group consisting of substituted or unsubstituted heterocyclic groups.

In this specification, unless otherwise specified, "alkyl group" means a C1 to C20 alkyl group, specifically means a C1 to C15 alkyl group, and "cycloalkyl group" means a C3 to C20 cycloalkyl group, specifically C3 to C18 cycloalkyl group, "alkoxy group" means a C1 to C20 alkoxy group, specifically means a C1 to C18 alkoxy group, "aryl group" means a C6 to C20 aryl group, and specifically means a C6 to C20 alkoxy group. Means a C18 aryl group, "alkenyl group" means a C2 to C20 alkenyl group, specifically means a C2 to C18 alkenyl group, "alkylene group" means a C1 to C20 alkylene group, specifically C1 to C18 alkylene group, and "arylene group" means a C6 to C20 arylene group, specifically a C6 to C16 arylene group.

Unless otherwise defined herein, "combination" means mixing or copolymerization. Further, "copolymerization" means block copolymerization or random copolymerization, and "copolymer" means block copolymer or random copolymer.

The skin vasculature exists within the dermis and consists of blood vessels and lymphatic vessels. In order to maintain homeostasis, the tissue fluid that has migrated outside the blood vessel must return to the vein again. The veins of the skin efficiently send blood to the central region. However, the vein itself lacks the ability to accept tissue fluid. From this, it has been understood that a tissue that accepts tissue fluid, that is, a lymphatic vessel is an essential structure even in the skin.

BACKGROUND OF THE INVENTION Lymphatic vessels play an important role in maintaining a constant state of the microenvironment around cells by collecting unwanted substances present in the skin and moisture and proteins constantly leaking from blood vessels. In addition, it has been thought to play a role in resisting infectious agents or external factors from the outside world through the transport of T lymphocytes.

As a pathological condition of lymphatic dysfunction, symptoms such as swelling and lymphedema are known. In addition, it is known that the function of the lymphatic vessels plays an important role not only in swelling, but also in photoaging (wrinkle formation) of the skin due to ultraviolet rays.

From studies so far, VEGFR-3 has been identified as a transmembrane receptor specifically present in lymphatic vessels, and VEGF-C and VEGF-D have been discovered as its ligands. VEGF-C acts on the lymphatic vessels to activate the function of the lymphatic vessels by promoting the proliferation, migration, and lumen formation of lymphatic endothelial cells. In addition, the possibility of gene therapy according to the introduction of VEGF-C is being sought for edema as a pathological condition of swelling.

In recent years, it has been known that mice with mutations that cause lymphatic dysfunction show obesity when they mature. Regarding the mechanism by which abnormalities in the formation and function of lymphatic vessels lead to obesity, knowledge that lymphatic fluid flowing through lymphatic vessels promotes the differentiation of premast cells into fat can be obtained. That is, it has been reported that lymphatic fluid leaks out of the lymphatic vessel due to dysfunction of the lymphatic vessel, which leads to differentiation of fat and, consequently, to obesity. Therefore, VEGF-C promoters are expected as therapeutic agents for preventing obesity that functionally generate new lymphatic vessels.

VEGF family genes exist from VEGF-A to VEGF-E. Among them, VEGF-B and VEGF-E have been identified as factors acting only on blood vessels. VEGF-A exists in the skin and acts on the lymphatic vessels, but it is known to be a factor that deteriorates the function of the lymphatic vessels.

In the skin, VEGF-D has been reported to be present in a small amount in the dermis, but since VEGF-D knockout mice do not cause abnormalities in the formation and function of skin lymphatic vessels, VEGF-D is an indispensable factor for skin lymphatic vessel formation. It is thought not On the other hand, it can be seen that VEGF-C in the skin is strongly expressed in the epidermis from the increase in the number of lymphatic vessels in the dermis of mice in which VEGF-C was highly expressed in the epidermis. In addition, as a result of blocking the effect of VEGF-C in the epidermis by high expression of a neutralizing antibody of VEGF-C receptor, VEGFR-3, in the epidermis, it was confirmed that the number of lymphatic vessels in the dermis was extremely reduced (Makinen, T ., Jussila, L., Veikkola, T., Karpanen, T., Kettunen, M. I., Pulkkanen, K. J., Kauppinen, R., Jackson, D. G., Kubo, H., Nishikawa, S., Yla-Herttuala, S. & Alitalo, K. (2001) Nat Med 7, 199-205). From this, it can be seen that the function of the lymphatic vessels present in the skin dermis is controlled by VEGF-C expressed in the epidermis, and swelling (edema) occurs when VEGF-C does not function.

Furthermore, recently, various attempts have been made to control swelling or edema, improve skin aging (wrinkles), and prevent, suppress, and treat obesity by activating or strengthening lymph or lymphatic vessels in the human body. In addition to VEGF-C, enhancement can also be achieved by stimulating the production, differentiation and activity of Rilin.

Accordingly, the present inventors have undergone numerous experiments and trials and errors to find active ingredients capable of improving swelling, lymphedema, skin wrinkles, or obesity by promoting the production or activity of Rilin and/or VEGF-C in the human body. , Finally, it was confirmed that the composition containing the compound represented by Formula 1 as an active ingredient can function as a production and/or activity promoter of rillin and/or VEGF-C, and the present invention has been completed.

[Formula 1]

In Formula 1,

R ¹ to R ⁴ are each independently a hydroxy group, a substituted or unsubstituted C1 to C20 alkoxy group, a substituted or unsubstituted C1 to C20 alkyl group, or a substituted or unsubstituted C6 to C20 aryl group,

n1 is an integer from 0 to 4;

n2 is an integer from 0 to 5;

n3 and n4 are each independently an integer of 0 to 3, provided that n3 + n4 ≠ 0.

For example, in Formula 1, R ³ may be a hydroxyl group, n3 may be an integer of 3, and n4 may be an integer of 0.

For example, in Formula 1, R ³ may be a hydroxyl group, R ⁴ may be a substituted or unsubstituted C1 to C20 alkoxy group, n3 may be an integer of 2, and n4 may be an integer of 1.

For example, Chemical Formula 1 may be represented by Chemical Formula 1-1, but is not necessarily limited thereto.

[Formula 1-1]

In Formula 1-1,

R ^a to R ^h are each independently a hydroxy group or a substituted or unsubstituted C1 to C20 alkoxy group.

For example, in Chemical Formula 1-1, R ^a to R ^h may each independently be a hydroxyl group.

For example, in Formula 1-1, R ^a to R ^e are each independently a hydroxy group, and R ^f to R ^h are each independently a hydroxy group or a substituted or unsubstituted C1 to C20 alkoxy group, provided that R ^f to R ^h At least one of them may be a substituted or unsubstituted C1 to C20 alkoxy group.

For example, the compound represented by Formula 1 is 1 ppm to 200 ppm, for example, 1 ppm or more and 200 ppm or less, 190 ppm or less, 180 ppm or less, 170 ppm or less, 160 ppm or less, based on the total amount of the production and/or activity promoters of rillin and/or VEGF-C. , 150 ppm or less, 140 ppm or less, 130 ppm or less, 120 ppm or less, 110 ppm or less, 100 ppm or less, 90 ppm or less, 80 ppm or less, 70 ppm or less, 60 ppm or less, 50 ppm or less, 40 ppm or less, 30 ppm or less, 20 ppm or less, such as a concentration range of 1 ppm to 10 ppm can be included as

The production and/or activity promoter of rilin and/or VEGF-C according to one embodiment includes the compound represented by Formula 1 as an active ingredient and satisfies the concentration range to promote the formation and function of lymphatic vessels. can be very useful. Symptoms accompanying lymphatic dysfunction may include not only swelling and lymphedema, but also photoaging (wrinkle formation, etc.) of skin caused by ultraviolet rays, obesity, and the like. According to one embodiment, the production and/or activity accelerator of Rilin and/or VEGF-C according to the present invention may be effective in preventing and suppressing swelling or lymphedema, photoaging of the skin caused by ultraviolet rays, and obesity. It may also be effective in the treatment of congenital lymphedema.

Photoaging of the skin refers to changes in the appearance and function of the skin that are generally identified as a result of repeated exposure to sunlight. Ultraviolet (UV) light, a component of sunlight, particularly the intermediate UV (called UVB, with a wavelength of 290-320 nm) mainly causes photoaging. The amount of UVB exposure required to cause photoaging is currently unknown. However, repeated exposure to UVB at levels that cause erythema or sunburn usually leads to photoaging. Clinically, photoaging is characterized by skin roughness, formation of wrinkles, pigmentation of stains, discoloration, formation of sagging, development of telangiectasia, development of moles, development of purpura, susceptibility to scarring, atrophy, and removal of fibrotic pigments. It can be specified as the occurrence of a region, the onset of a premalignant tumor and a malignant tumor, and the like. Photoaging usually occurs on skin habitually exposed to sunlight, such as the face, ears, head, neck and hands.

According to another embodiment, by promoting the production and / or activity of Rilin and / or VEGF-C, characterized by comprising the compound represented by Formula 1 as an active ingredient, swelling, lymphedema, skin Provided is an external skin preparation for improving wrinkles or obesity.

For example, the external skin preparation may be an agent for improving swelling, and the swelling may be due to abnormal formation of lymphatic vessels, abnormal functioning of lymphatic vessels, or both.

For example, the external skin preparation may be a lymphedema improving agent, and the lymphedema is caused by abnormal lymphatic vessel formation, lymphatic dysfunction, or both.

For example, the external skin preparation may be an anti-obesity agent, and the obesity is caused by abnormal lymphatic vessel formation, lymphatic vessel dysfunction, or both.

The dosage, application form, and dosage form of the external skin preparation according to one embodiment may be appropriately determined according to the purpose of use. For example, the compound represented by Formula 1 may be formulated as an active ingredient at a concentration of 1 ppm to 10 ppm, such as 1 ppm to 5 ppm, such as 5 ppm to 10 ppm, such as 2 ppm to 9 ppm, such as 3 ppm to 8 ppm, based on the total concentration of skin external preparations. It is not limited to this. The application form of the skin external preparation is not particularly limited, and can be applied both by inhalation and transdermally. Formulations include, for example, perfumes, shampoos/rinses, skin care, body shampoos, body rinses, body powders, fragrances, deodorants, bath agents, lotions, creams, soaps, toothpastes, cosmetics such as aerosol products, and other fragrances in general. Any form used for It can also be used for pharmaceuticals such as inhalation drugs.

In addition, in the skin external preparation, in addition to the above essential components, components commonly used in external skin preparations such as cosmetics and pharmaceuticals, such as whitening agents, moisturizers, antioxidants, oily components, ultraviolet absorbers, surfactants, thickeners, alcohols, powder components, Colorants, aqueous components, water, various skin nutrients, etc. can be appropriately blended as needed.

In addition, metal sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, and gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, glabri Dean, hot water extract of quince fruit, various herbal medicines, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, whitening agents such as vitamin C, magnesium ascorbic acid phosphate, ascorbic acid glucoside, arbutin, kojic acid, Sugars such as glucose, fructose, mannose, sucrose and trehalose, vitamins A such as retinoic acid, retinol, retinol acetate, and retinol palmitate may also be further included as appropriate.

For example, the external skin preparation may be a cosmetic composition.

In the present specification, "cosmetics" may mean any material that may have a cosmetic function as well as an additional medical function in addition to a cosmetic function.

The formulation of the cosmetic composition is not particularly limited and may be appropriately selected according to the purpose.

For example, the cosmetic composition is formulated into a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray, etc. It may be, but is not limited thereto. More specifically, cosmetic compositions such as detergent, tonic, hairdressing agent, nutrient lotion, essence, serum, treatment, conditioner, shampoo, lotion, hair conditioner or hair dye, oil-in-water (O/W) type, water-in-oil (O/ It can be formulated as a basic cosmetic such as type W). For example, the composition is skin lotion, skin toner, astringent, lotion, milk lotion, moisture lotion, nutrient lotion, massage cream, nutrient cream, moisture cream, hand cream, ointment, foundation, essence, nutrient essence, pack, soap, cleansing It may have one formulation selected from the group consisting of foam, cleansing lotion, cleansing cream, body lotion, body cleanser, lotion, ointment, gel, cream, patch, and spray. In addition, other ingredients in addition to the above essential ingredients in each formulation can be appropriately selected and formulated by those skilled in the art according to the type or purpose of use of other external agents. For example, it may further include a sunscreen, hair conditioning agent, perfume, and the like.

The cosmetic composition may contain a cosmetically acceptable medium or base. These are all formulations suitable for topical application, for example solutions, gels, solid or pasty anhydrous products, emulsions obtained by dispersing an oily phase in an aqueous phase, suspensions, microemulsions, microcapsules, microgranules or ionic forms (liposomes) and/or It may be provided in the form of a non-ionic follicular dispersant, or in the form of a cream, toner, lotion, powder, ointment, spray or conceal stick. These compositions can be prepared according to conventional methods in the art.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizing agent or emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butyl glycol oil, fatty acid esters of glycerol, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Star cellulose, aluminum metahydroxide, bentonite, agar or tracanth and the like may be used.

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as a carrier component. can

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydrocarbon, propane / May contain a propellant such as butane or dimethyl ether.

In one embodiment of the present invention, a thickening agent may be additionally contained in the cosmetic composition. The thickening agent included in the cosmetic composition of the present invention is methyl cellulose, carboxy methyl cellulose, carboxy methyl hydroxyguanine, hydroxy methyl cellulose, hydroxyethyl cellulose, carboxy vinyl polymer, polyquaternium, cetearyl alcohol, stearic acid, Carrageenan and the like may be used, preferably at least one of carboxy methyl cellulose, carboxy vinyl polymer, and polyquaternium may be used, and most preferably carboxy vinyl polymer.

In one embodiment of the present invention, the cosmetic composition may contain various appropriate bases and additives as needed, and the types and amounts of these components may be easily selected by the inventor. Acceptable additives may be included as needed, and for example, components such as preservatives, pigments, and additives common in the art may be further included.

The preservative may specifically be phenoxyethanol or 1,2-hexanediol, and the fragrance may be artificial fragrance.

And, in one embodiment of the present invention, the cosmetic composition may include a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, high-molecular peptides, high-molecular polysaccharides, sphingolipids, and seaweed extracts. Other ingredients that may be added include fats and oils, humectants, emollients, surfactants, organic and inorganic pigments, organic powders, ultraviolet absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohols, pigments, fragrances, A blood circulation accelerator, a cooling agent, an antiperspirant, purified water, etc. are mentioned.

In addition, the blending components that may be added other than these are not limited thereto, and any of the above components can be blended within a range not impairing the objects and effects of the present invention.

Furthermore, the external skin preparation according to one embodiment may be used as a pharmaceutical composition.

Advantages and features of the present invention, and methods of achieving them, will become clear with reference to the detailed descriptions of the following examples. Hereinafter, the present invention will be described in detail by examples. However, these examples are intended to specifically explain the present invention, and the scope of the present invention is not limited to these examples.

(Example)

Test Example 1: Cytotoxicity assay

Human Dermal Lymphatic Endothelial Cells (HDLEC, PromoCell, Germany) were cultured in a new 96-well dish for one day, and then the compound represented by Formula E-1 (Biogenics) and Formula E-2 The indicated compounds (Biogenics) were treated at concentrations ranging from 0 ppm (μg/ml) to 200 ppm (μg/ml), respectively. After culturing for 24 hours and 72 hours, cell viability was confirmed by measuring absorbance at 450 nm using the QuantiMax WST-8 Cell viability assay kit, and the results are shown in FIGS. 1 and 2 .

[Formula E-1]

[Formula E-2]

1 and 2, it can be confirmed that the compound represented by Formula E-1 and the compound represented by Formula E-2 are not cytotoxic within a concentration range of 200 ppm.

Test Example 2: Rilin Cytokine Analysis

Human-derived lymphocytes were cultured in a 6-well plate for 24 hours, and no treatment (N.T) was used as a reference (100%), and the compound represented by the above formula E-1 and the above formula E- After treating the compound represented by 2 at concentrations of 1ppm and 10ppm, respectively, and incubating for 48 hours, the human reelin ELISA Kit (Mybiosource, USA) was used for manual cytokine analysis to determine the production and activity of reelin. measured, and the results are shown in FIGS. 3 and 4.

From Figures 3 and 4, in the case of the compound represented by the formula E-1 and the compound represented by the formula E-2, the production and activity of rillin are more improved than those without any treatment (control group) can confirm.

Test Example 3: VEGF-C cytokine analysis

Human-derived lymphocytes were cultured in a 6-well plate for 24 hours, and no treatment (N.T) was used as reference (100%), and the compound represented by the above formula E-1 and the above formula E- After treatment with the compound represented by 2 at concentrations of 1 ppm and 10 ppm, respectively, and incubation for 48 hours, VEGF-C cytokine analysis was performed according to the manual using the VEGFC Human ELISA Kit (ThermoFisher, USA), respectively, VEGF-C The production and activity of was measured, and the results are shown in FIGS. 5 and 6.

5 and 6, in the case of the compound represented by the formula E-1 and the compound represented by the formula E-2, the production and activity of VEGF-C were higher than those without any treatment (control group). improvement can be seen.

Test Example 4: Preparation of external skin preparation

Cosmetic composition usable as an external skin preparation according to Example 1, Example 2, Comparative Example 1 (mulberry leaf root extract; SK Bioland) and Comparative Example 2 (persimmon leaf extract; BIO-FD&C) with the composition and content shown in Table 1 below was manufactured. In the case of purified water, a cosmetic composition was prepared such that the total amount was 100% by weight when the other components were mixed with the weight.

(unit: ppm) Example 1 Example 2 Comparative Example 1 Comparative Example 2 Purified water balance balance balance balance EDTA-2Na 0.05 0.05 0.05 0.05 Lauric Acid 5 5 5 5 myristic acid 7 7 7 7 palmitic acid One One One One KOH 7.9 7.9 7.9 7.9 Guar Hydroxypropyl Trimonium Chloride 0.5 0.5 0.5 0.5 Polyquaternium-7 3.0 3.0 3.0 3.0 Compound represented by Formula E-1 5.0 - - - A compound represented by the formula E-2 - 5.0 - - Mulberry Leaf Root Extract - - 5.0 - persimmon leaf extract - - - 5.0 disodium cocodiamphoacetate 1.0 1.0 1.0 1.0

Thirty women aged 50 or older with calf edema were selected, and the compositions according to Examples 1 and 2, Comparative Example 1 and Comparative Example 2 were administered to them twice a day, in the calf area of the lower extremity with swelling. After 7 days of continuous application, each person was given i) weight change (using a scale), ii) change in circumference of the calf area where edema is the most severe (using a plastic tape measure), iii) edema state (visual observation) was measured, and the results are shown in Table 2 below.

Example 1 Example 2 Comparative Example 1 Comparative Example 2 Weight (day 0) (kg) 57 58 55 61 Weight (7 days) (kg) 56 56 55 62 Calf circumference (day 0) (cm) 36 36 35 37 Calf circumference (7 days) (cm) 33 34 35 37 edema condition ease ease no change no change

From Table 2, it can be seen that when the skin external preparation according to one embodiment is prescribed, the edema state is alleviated in one week compared to the case where it is not.

Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements of those skilled in the art using the basic concept of the present invention defined in the following claims are also present. It falls within the scope of the right of invention.

Claims (11)

An agent for promoting the production and/or activity of Rilin and/or VEGF-C, comprising a compound represented by Formula 1 below as an active ingredient.
[Formula 1]

In Formula 1,
R ¹ to R ⁴ are each independently a hydroxy group, a substituted or unsubstituted C1 to C20 alkoxy group, a substituted or unsubstituted C1 to C20 alkyl group, or a substituted or unsubstituted C6 to C20 aryl group,
n1 is an integer from 0 to 4;
n2 is an integer from 0 to 5;
n3 and n4 are each independently an integer of 0 to 3, provided that n3 + n4 ≠ 0. In paragraph 1,
Wherein R ³ is a hydroxy group,
n3 is an integer of 3,
Wherein n4 is an integer of 0, the production and/or activity promoter of rilin and/or VEGF-C. In paragraph 1,
Wherein R ³ is a hydroxy group,
R ⁴ is a substituted or unsubstituted C1 to C20 alkoxy group;
n3 is an integer of 2;
Wherein n4 is an integer of 1, the production and/or activity promoter of rillin and/or VEGF-C. In paragraph 1,
Chemical Formula 1 is a promoter for the production and/or activity of rillin and/or VEGF-C represented by the following Chemical Formula 1-1:
[Formula 1-1]

In Formula 1-1,
R ^a to R ^h are each independently a hydroxy group or a substituted or unsubstituted C1 to C20 alkoxy group. In paragraph 4,
Wherein R ^a to R ^h are each independently a hydroxyl group, rillin and/or a production and/or activity accelerator of VEGF-C. In paragraph 4,
Wherein R ^a to R ^e are each independently a hydroxyl group,
Wherein R ^f to R ^h are each independently a hydroxyl group or a substituted or unsubstituted C1 to C20 alkoxy group, provided that at least one of R ^f to R ^h is a substituted or unsubstituted C1 to C20 alkoxy group, riline and/or VEGF A promoter for the production and/or activity of -C. In paragraph 1,
The compound represented by Formula 1 is included in a concentration range of 1 ppm to 200 ppm with respect to the total amount of the production and / or activity promoter of the rillin and / or VEGF-C production and / or activity promoter of rillin and / or VEGF-C. For improving swelling, lymphedema, skin wrinkles or obesity by promoting the production and/or activity of Rilin and/or VEGF-C, characterized in that it comprises the compound represented by Formula 1 as an active ingredient External skin preparations:
[Formula 1]

In Formula 1,
R ¹ to R ⁴ are each independently a hydroxy group, a substituted or unsubstituted C1 to C20 alkoxy group, a substituted or unsubstituted C1 to C20 alkyl group, or a substituted or unsubstituted C6 to C20 aryl group,
n1 is an integer from 0 to 4;
n2 is an integer from 0 to 5;
n3 and n4 are each independently an integer of 0 to 3, provided that n3 + n4 ≠ 0. In paragraph 8,
The external skin preparation is a swelling improving agent,
The topical skin preparation, wherein the swelling is due to dysplasia of lymphatic vessels, dysfunction of lymphatic vessels, or both. In paragraph 8,
The skin external agent is a lymphedema improving agent,
The external skin preparation, wherein the lymphedema is due to abnormal formation of lymphatic vessels, abnormal lymphatic function, or both. In paragraph 8,
The skin external agent is an obesity improving agent,
The topical skin preparation, wherein the obesity is caused by dysplasia of lymphatic vessels, dysfunction of lymphatic vessels, or both.

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