KR101252335B1 - Composition for Preventing Skin Aging - Google Patents

Abstract

The present invention relates to a composition for preventing skin aging comprising the compound of formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

(Formula 1)

Compounds of formula (1), isomers or pharmaceutically acceptable salts thereof, which are included in the composition according to the present invention, act as a neuropathic pain receptor (TRPV1) antagonist without causing skin irritation. As it exerts an inhibitory effect on matrix metalloprotease activity, it can be suitably used as an active ingredient of a composition for preventing skin aging.

Skin anti aging

Description

Composition for Preventing Skin Aging

The present invention relates to a composition for preventing skin aging.

All living things age with age, and the skin is aging as well. Efforts to delay such aging have been continuously conducted, and thus questions about the nature of aging and why aging occurs.

Aging of the skin can be classified into two types depending on the factors. One of them, extrinsic aging, is caused by accumulated external stress such as sunlight, and natural aging (intrinsic aging) causes the skin's structure and physiological function to continue to decline with age.

In particular, the ultraviolet rays of sunlight is one of the well-known causes of aging, the skin exposed to ultraviolet rays for a long time, the stratum corneum thickens and collagen and elastin, the major components of the skin, degeneration of the skin loses its elasticity and wrinkles. As such, aging of the skin involves various functional and structural changes.

In addition, looking at the structural changes of the skin according to natural aging, the thickness of the epidermis, dermis and subcutaneous tissue, which is a component of the skin becomes thin. The extracelluar matrix (ECM) component of the dermal tissue responsible for skin elasticity and tension is changed. ECM consists of two main components. One is elastic fiber, which accounts for about 2-4% of the total ECM, and the other is collagen, which accounts for about 70-80% of the total ECM. As aging progresses, the elasticity of the skin is greatly reduced due to a decrease in collagen and elastin.

Collagen and elastin are regulated by several factors. Collagen and elastin produced by the expression of matrix metallo protease, such as collagenase and elastase, are degraded, resulting in skin The collagen content in the inside is reduced. As collagen and elastin are reduced in the dermis, the skin's epidermis becomes rough and aging causes a decrease in elasticity and thus wrinkles increase. Various studies have been conducted on a method for effectively suppressing the reduction of collagen and elastin, which causes the decrease in elasticity.

The most effective solution to date is to use retinol and retinoic acid. However, in addition to the positive effect of wrinkle improvement or elasticity, retinoids have the disadvantage that irritation occurs even when only a small amount is applied to the skin. . Thus, studies for stabilizing retinoids continue to be conducted, but the situation of stimulation to the skin, that is, the safety has not yet been solved.

Therefore, an object of the present invention is to solve the technical problem that has been requested from the past. Specifically, an object according to an embodiment of the present invention is to provide a skin anti-aging composition exhibiting an excellent skin anti-aging effect without causing skin irritation.

In order to achieve this object, the present invention comprises as an active ingredient a compound of formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof.

Wherein R ₁ is hydrogen, halogen or C ₁ -C ₅ alkyl,

R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen, nitro, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl,

R _6, R ₇ , R ₈ and R ₉ are each independently hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, halo (C ₁ -C ₁₀ ) alkyl, C ₂ -C ₁₀ alkenyl , C ₂ -C ₁₀ alkynyl, carboxy, C ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkylcarbonyl, substituted or unsubstituted phenyl, or C ₁ -C ₁₀ alkylamino.

The composition according to the present invention acts as an antagonist of a neuropathic pain receptor (TRPV1) without causing skin irritation, thereby exerting an effect of inhibiting matrix metalloprotease activity. Excellent skin anti-aging effect.

The term "alkyl group" refers to a monovalent saturated aliphatic hydrocarbon group, which hydrocarbon may have a straight or branched structure.

The term "alkoxy" may be represented by the group -OR, where R is an alkyl group as previously defined.

The term “alkoxycarbonyl” means —C (═O) —O—R, wherein R is an alkyl group as previously defined.

The term "alkenyl" refers to a monovalent olefinically unsaturated hydrocarbon group, which may be straight or branched, and may have one or more double bonds.

The term "alkynyl" refers to an acetylenically unsaturated hydrocarbon group, which may be straight or branched, and may have one or more triple bonds.

The term "alkylamino" refers to the group -NHR ', wherein R' is an alkyl group as previously defined.

The term "amino" means -NH ₂ and the term "aryl" means aromatic hydrocarbons.

The term "carboxy" means -C (= 0) OH, the term "cyano" means -C≡N and the term "nitro" means -NO ₂ .

The term "halo" or "halogen" means fluoro, chloro, bromo and iodo.

The term "isomer" refers not only to optical isomers (eg, essentially pure enantiomers, essentially pure diastereomers and mixtures thereof), but also to structural isomers (ie, the angle of one or more chemical bonds). Different isomers), positional isomers (particularly tautomers) and geometric isomers.

“Essentially pure” associated with the enantiomers and stereoisomers is at least about 90%, preferably at least about 95%, more preferably at least about 97%, more preferably at least about 98%, more preferably at least about 99%, More preferably about 99.5% (w / w) or greater of the enantiomer or stereoisomer.

The term "pharmaceutically acceptable" means that when used in an amount generally applied in drug administration, the substantial toxic effect can be avoided, so that the term "pharmaceutically acceptable salt" means By salts is meant salts of the compounds according to the invention. For example, the salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid , 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3 Acid addition formed by organic acids such as phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like salt; Or (2) salts formed when the acidic protons present in the parent compound are substituted.

In one embodiment, R ₂ , R ₃ , R ₄ and R ₅ in Formula 1 are each independently hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, R _6, R ₇ , R ₈ and R ₉ are each independently hydrogen, halogen, C ₁ -C ₅ alkyl or halo (C ₁ -C ₃ ) It may be alkyl.

In one embodiment, R ₁ in Formula ₁ is hydrogen or methyl; R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, vinyl or acetylenyl ), R ₆ is hydrogen, R ₇ and R ₈ are each independently hydrogen, chloro, bromo, iodo, C ₁ -C ₄ alkyl or halo (C ₁ -C ₂ ) alkyl, R ₉ may be hydrogen.

In one embodiment, R ₁ in formula 1 is hydrogen, R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, fluoro, chloro or methyl, R ₆ is hydrogen, R ₇ and R ₈ are each independently hydrogen or C ₁ -C ₄ alkyl, and R ₉ may be hydrogen.

In one embodiment, R ₁ in formula 1 is hydrogen, R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, fluoro or methyl, R ₆ and R ₇ are hydrogen, and R ₈ is Hydrogen, isobutyl or tertiarybutyl and R ₉ may be hydrogen.

Specifically, specific examples corresponding to the compound of Formula 1 are as follows:

7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide (7-tert-Butyl-2H-chromene-3-carboxylic acid 3-fluoro-4-methanesulfonylamino -benzylamide),

7-Isopropyl-2H-chromene-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide (7-Isopropyl-2H-chromene-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide),

7-isopropyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide (7-Isopropyl-2H-chromene-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide) And

7-tert-Butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-benzylamide (7-tert-Butyl-2H-chromene-3-carboxylic acid 4-methanesulfonylamino-benzylamide) It may be abnormal.

Research on skin aging has been mainly conducted in the dermal layer, but recently, as the research on the skin nervous system and neurotransmitters has been actively conducted, the skin is connected to nerves and various neurotransmitters may affect the skin. Interesting studies include Transient receptor potential family V 1: TRPV-1.

The neuropathic sensory receptors are expressed in all nervous systems such as skin, brain, and spinal cord, for example, senses changes in heat, pH, and ions, and induces substance P, an inflammatory neurotransmitter. It is a receptor that integrates nociceptive stimuli in neurons. Typically, neuropathic sensory receptors express expression of neurotransmitters such as substance P and calcitonin gene-related peptide (CGRP) in nerve fibers by heat and pH changes caused by external stimuli. It is known to promote and cause a neurogenic inflammatory response. Such neuropathic sensory receptors are known to be expressed in neurons as well as epithelial and epidermal cells.

On the other hand, the activation of neuropathic sensory receptors has been reported to be associated with the promotion of cell proliferation, death, differentiation and the release of various cytokines (enzymes). As it has been shown to inhibit the in matrix metal proteases, there is a growing interest as a target for skin wrinkle improvement (J. Investigative Dermatology 2007; 127: 2328-2335). The matrix metalloprotease is an enzyme that promotes collagen degradation to induce the transformation of the dermal layer. If the production and degradation of collagen are not properly controlled, the skin elasticity is reduced and wrinkles are formed. It is the main cause.

In this regard, the inventors of the present application can inhibit the expression of the matrix metalloprotease by acting as an antagonist of the neuropathic pain receptor without the compound having the structure of Formula 1 irritating the skin Found out.

Accordingly, the composition comprising the compound having the structure of Formula 1 as an active ingredient, for example, the group consisting of reduced expression of collagenase, prevention of skin aging through induction of blood circulation, and prevention or improvement of wrinkle formation Can perform one or more functions selected in.

The composition for preventing skin aging according to the present invention may be, for example, a pharmaceutical composition or a cosmetic composition.

The anti-aging pharmaceutical composition may further contain pharmaceutical supplements such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances. According to various oral or parenteral dosage forms. Parenteral dosage forms may be transdermal dosage forms, for example, but not limited to, lotion, ointment, gel, cream, patch or spray formulations.

Determination of the dosage of the active ingredient is within the level of those skilled in the art, and the daily dosage of the drug depends on various factors such as less progression, onset, age, health condition, complications, etc. of the subject to be administered. Generally, the composition may be administered by dividing the composition 1 μg / kg to 200 mg / kg, preferably 50 μg / kg to 50 mg / kg once or three times a day, and the dosage may be any method. Also, the scope of the present invention is not limited.

The cosmetic composition for preventing skin aging is not particularly limited in formulation, and may be appropriately selected according to the purpose. For example, softening cream (skin lotion and milk lotion), nourishing cream, essence, nourishing cream, massage cream, pack, gel, essence, eye cream, eye essence, cleansing cream, cleansing foam, cleansing water, pack, powder, It may be prepared in any one or more formulations selected from the group consisting of body lotion, body cream, body oil and body essence, but is not limited thereto.

The content of the active ingredient is not particularly limited, but may be included in an amount of 0.01 to 20 wt% based on the total weight of the composition. When the active ingredient satisfies the content, it may exhibit excellent efficacy without side effects.

Hereinafter, the present invention will be described in more detail through experimental examples, but the following experimental examples are for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1 Preparation of 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide

1-1) Preparation of 7-tert-butyl-2H-chromen-3-carboxylic acid

To a solution of 4-tert-butylsalicylaldehyde (3.80 g, 21.3 mmol) and t-butyl acrylate (7.6 mL) in t-butanol (40 mL) was added potassium t-butoxide (730 mg), The mixture was stirred at reflux for 66 hours. The mixture was poured into water, the aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with water, 1N sodium hydroxide and brine in that order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was purified through column chromatography (hexane / ethyl acetate = 8/1) to obtain 7-tert-butyl-2H-chromen-3-carboxylic acid t-butyl ester (3.26 g, 53%). This ester (65 mg, 0.22 mmol) was dissolved in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) and hydrolyzed with 1N lithium hydroxide (2.0 mL). Acidified with 1N hydrochloric acid, then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 7-tert-butyl-2H-chromen-3-carboxylic acid (40 mg, 83%).

¹ H NMR (300 MHz, CDCl ₃ ) 7.56 (s, 1H), 7.11 (d, 1H, J = 8.1 Hz), 6.98 (m, 1H), 6.91 (s, 1H), 5.00 (s, 2H), 1.30 (s, 9 H)

1-2) Preparation of 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide

N- (4-aminomethyl-2-fluorophenyl) -methanesulfonamide, hydrochloride (100 mg, 0.35 mmol) was suspended in tetrahydrofuran and N-methylmoline (60 μL, 0.55 mmol) was added. After the mixture was stirred for 5 minutes, 7-tert-butyl-2H-chromen-3-carboxylic acid (73 mg, 0.35 mmol) and DMTMM (96.5 mg, 0.35 mmol) were added. The mixture was stirred overnight and then diluted with water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This was purified by column chromatography (from 50% to 67% of ethyl acetate in hexane) to 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide ( 120 mg, 79%).

¹ H NMR (300 MHz, CDCl ₃ ) 7.54 (t, 1H, J = 8.1 Hz), 7.13 (m, 2H), 6.99 (m, 4H), 6.51 (bs, 1H), 6.20 (bs, 1H), 5.02 (s, 2H), 4.52 (d, 2H, J = 5.7 Hz), 3.3 (s, 3H), 1.29 (s, 9H)

Example 2 Preparation of 7-isopropyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide

2-1) Preparation of 7-isopropyl-2H-chromen-3-carboxylic acid

Prepared in substantially the same manner as in Example 1-1, except using 4-isobutylsalicylaldehyde as starting material.

¹ H NMR (300 MHz, CDCl ₃ ) 7.55 (s, 1H), 7.09 (d, 1H, J = 7.8 Hz), 6.82 (d, 1H, J = 7.8 Hz), 6.75 (s, 1H), 4.99 ( s, 2H), 2.86 (m, 1H), 1.23 (d, 6H, J = 6.9 Hz)

2-2) Preparation of 7-isopropyl-2H-chromen-3-carboxylic acid 3-methyl-4-methanesulfonylamino-benzylamide

Substantially similar to Example 1-2, except using N- (4-aminomethyl-2-methylphenyl) -methanesulfonamide, hydrochloride and 7-isopropyl-2H-chromen-3-carboxylic acid as starting materials Prepared in the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) 9.01 (s, 1H), 8.72 (bs, 1H), 7.18 (m, 5H), 6.83 (d, 1H, J = 6.0 Hz), 6.73 (s, 1H ), 4.90 (s, 2H), 4.32 (d, 2H, J = 5.4 Hz), 2.95 (s, 3H), 2.82 (m, 1H), 2.29 (s, 3H), 1.16 (d, 6H, J = 6.9 Hz)

Example 3 Preparation of 7-isopropyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide

Examples 1-2 were used except that N- (4-aminomethyl-2-fluorophenyl) -methanesulfonamide, hydrochloride and 7-isopropyl-2H-chromen-3-carboxylic acid were used as starting materials. Prepared in substantially the same manner.

¹ H NMR (300 MHz, DMSO-d ₆ ) 9.54 (s, 1H), 8.78 (t, 1H, J = 5.1 Hz), 7.34 (m, 2H), 7.18 (m, 3H), 6.84 (d, 1H , J = 7.8 Hz), 6.74 (s, 1H), 4.90 (s, 2H), 4.35 (d, 2H, J = 5.7 Hz), 3.00 (s, 3H), 2.83 (m, 1H), 1.17 (d , 6H, J = 6.9 Hz)

Example 4 Preparation of 7-tert-butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-benzylamide

In substantially the same manner as in Example 1-2, except that N- (4-aminomethyl) -methanesulfonamide, hydrochloride and 7-tert-butyl-2H-chromen-3-carboxylic acid were used as starting materials. Prepared.

¹ H NMR (300 MHz, DMSO-d ₆ ) 9.66 (s, 1H), 8.72 (t, 1H, J = 5.1 Hz), 7.22 (m, 6H), 6.98 (d, 1H, J = 7.8 Hz), 6.85 (s, 1H), 4.90 (s, 2H), 4.33 (d, 2H, J = 5.1 Hz), 2.95 (s, 3H), 1.24 (s, 9H)

Test Example 1 Screening of Pain Receptor Inhibitors (Ca ²⁺  influx assay)

(1) Spinal Cord Dorsal Ganglion Isolation and Primary Culture of Neonatal Mice

Sprague Dawely within 2-3 days of age in ice for 5 minutes, followed by low temperature anesthesia, disinfection with 70% ethanol, and dissection of the dorsal root gan-glion (DRG) at the top of the spinal cord. It was collected (Wood et al., 1988, J. Neurosci. 8, pp3208-3220) in DME / F12 medium supplemented with 1.2 g / L sodium bicarbonate and 50 mg / L gentamicin. 200 U / ml collagenase, 2.5 mg / ml trypsin were treated with DRG at 37 ° C. for 30 minutes each. Wash the DRG twice with DME / F12 medium containing 10% horse serum, pass it through the heat treated Paster pipette several times, filter through a Nitex 80 membrane to obtain a single cell suspension once Further washed. After centrifugation, the cells were resuspended by adjusting the cell concentration to a certain level in the culture medium. Cell culture media included DME / F12 medium containing 10% horse serum and C6-glioma (C6-glioma-conditioned medium for 2 days on a confluent monolayer) Mix 1: 1 and add NGF (nerve growth factor) to a final concentration of 200 ng / ml. To kill divisible non-neuronal cells, the cells were grown for two days in a medium containing 100 uM of cytosine arabinoside (Ara-C) and then exchanged with a medium without Ara-C. Resuspended cells were plated to a density of 1500-2000 neuron / well on a Terasaki plate coated with poly-D-ornithine at a concentration of 10 g / ml.

(2) ⁴⁵ Ca introduction experiment

Neurons isolated from primary cultured DRG for 2 days were washed four times with H-HBSS (HEPES (10 mM pH-7.4) -buffered Ca ²⁺ , Mg ²⁺ -free HBSS) to equilibrate. The solution of each well was removed, a test solution prepared by mixing capsaicin (final concentration 0.5 M) and ⁴⁵ Ca (final concentration 10 Ci / ml) using H-HBSS as a solvent was added thereto, and left at room temperature for 10 minutes. Terrasaki plates were washed 5 times with H-HBSS and dried at room temperature. 10 Ca of 0.3% SDS (Sodium-1-sulfonatooxydodecane) was added to each well to elute ⁴⁵ Ca, and a scintillation cocktail was added to measure ⁴⁵ Ca. Inhibitory activity of the test substance to the pain sensory receptor was calculated as a percentage of the effect of the test substance to inhibit the effect of 0.5 micromolar capsaicin as the maximum response, and the results are shown in Table 1 expressed in IC ₅₀ .

[Table 1]

Referring to Table 1, it was confirmed that the compounds of Examples 1 to 4 exhibit the pain sensitizing receptor (TRPV1) antagonistic effect.

[Test Example 2] Changes of nerve pain sensory receptor (TRPV-1) in keratinocyte line HaCaT after UV irradiation

Immunized human keratinocyte cell line (Immortalized human keratinocyte cell line: HaCaT) in DMEM (Dulbecco's modified eagle medium) medium containing 10% fetal bovine serum at a concentration of 5 X 10 ⁶ and incubated at 37 ° C. Irradiation (75 mJ / cm ² ) After 4, 8, 24 and 48 hours of ultraviolet irradiation, cells were lysed to quantify proteins, and Western blots for neuropathic pain receptors (TRPV-1) were performed. 1, it can be seen from the test results that the expression of the neuropathic pain receptor (TRPV-1) was increased by the ultraviolet rays. After correcting with (actin) it was compared with the control group.

Test Example 3 Confirmation of Matrix Metalloprotease Inhibitory Effect on Keratin Cell Line HaCaT after UV Irradiation

Infinite proliferation human keratinocyte cell line was placed in Dulbecco's Modified Eagles medium (DMEM) containing 10% fetal bovine serum and cultured under 37 ° C. and 5% CO 2. The cultured cells were placed in a 6-well microtiter plate so that the number of cells per well was 2 X 10 ⁵ , and after attaching the cells, the cells were attached to DMEM medium without fetal calf serum and 70-80%. Incubate until growth. Then, the cells were irradiated with ultraviolet light at 40 mJ / cm ² using an ultraviolet irradiator. At this time, Examples 1 to 4 were treated to cells immediately after ultraviolet irradiation and incubated for 48 hours. After 48 hours of incubation, the amount of matrix metalloproteinase 1 secreted into the culture was measured using an ELISA kit, and the results are shown in Table 2. The expression level of the matrix metalloproteinase 1 was calculated by Equation 1 below. At this time, the reaction absorbance of the cultured cell culture medium of the group not treated with Example was used as a control.

[Equation 1]

Matrix metalloproteinase 1 expression level (%) = (absorbance of material treated cell group / absorbance of control group) X100

 [Table 2]

Referring to Table 2, it was confirmed that the concentration of matrix metalloprotease was decreased in a concentration-dependent manner in the group treated with Examples 1 to 4, which were TRPV-1 antagonists after UV irradiation, and the negative control capsaicin was matrix metal. It was confirmed that increased expression of proteases was observed. This suggests that the expression level of collagenase can be regulated through inhibition of TRPV-1, and it was confirmed that Examples 1 and 4 showed the same or more inhibition rate with retinoic acid as a positive control.

[Test Example 3] Evaluation of skin irritation in human testing

Healthy volunteers who have not taken nonsteroidal anti-inflammatory drugs and other steroid preparations during the month prior to testing are assessed according to the Safety Testing Guidelines of the Cosmetic Toiletry and Fragrance Association (CTFA) (1981, p3). It was. That is, the composition formulated as shown in the following Table 3 was applied twice a day (50 μl / 1.5 × 1.5 cm 2) inside the forearm of 15 subjects, and wrapped in a wrap for 3 hours to aid absorption. Put it. The test period was adjusted in consideration of the response level and skin condition of the subject, and was up to 3 weeks. The test was carried out daily before the patch and the final test was carried out up to 8 days from the patch's date. Evaluation was continued even after the end of the patch to reflect the degree of recovery of stimulation, and no score was given when erythema completely disappeared and only pigmentation remained. At each test time point, the degree of stimulation was evaluated according to the determination method of Table 4 below, and the stimulation relaxation rate was calculated by the above equation 1 from the sum and the results are shown in Table 5 below.

[Table 3]

[Table 4]

[Table 5]

Referring to Table 5, the composition according to the present invention was free of skin irritation in human skin. Therefore, it can be seen that the composition according to the present invention has less skin irritation, while maintaining an anti-aging effect such as skin wrinkle improvement compared to conventional retinol or retinoic acid.

Examples of the formulation of the composition according to the present invention will be described below, but the pharmaceutical composition and the cosmetic composition are applicable to various formulations, which are intended to explain in detail only, not intended to limit the present invention.

Formulation Example 1 Flexible Cosmetic (Skin Lotion)

According to the composition described in Table 6 below to prepare a flexible longevity in a conventional manner.

TABLE 6

Formulation Example 2 Nutritious Longevity (Milk Lotion)

Nutritional longevity was prepared in a conventional manner according to the composition shown in Table 7.

[Table 7]

[Formulation Example 3] Nourishing cream

Nutritional cream was prepared in a conventional manner according to the composition shown in Table 8.

[Table 8]

[Formulation Example 4] Massage cream

To prepare a massage cream in a conventional manner according to the composition shown in Table 9.

TABLE 9

[Formulation Example 5] Pack

To prepare a pack in a conventional manner according to the composition shown in Table 10,

[Table 10]

[Formulation Example 6] Ointment in the external preparation for skin

The ointment was prepared in a conventional manner according to the composition described in Table 11.

TABLE 11

Figure 1 is a photograph showing the results of Western blot for nerve pain sensory receptor (TRPV-1) after ultraviolet irradiation in the test example of the present invention.

Claims (10)

A cosmetic composition for preventing or improving wrinkle formation comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. (Formula 1)

Wherein R ₁ is hydrogen, halogen or C ₁ -C ₅ alkyl, R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, halogen, nitro, cyano, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl, R _6, R ₇ , R ₈ and R ₉ are each independently hydrogen, halogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, halo (C ₁ -C ₁₀ ) alkyl, C ₂ -C ₁₀ alkenyl , C ₂ -C ₁₀ alkynyl, carboxy, C ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkylcarbonyl, phenyl, or C ₁ -C ₁₀ alkylamino. The method of claim 1, In Formula 1, R ₂ , R ₃ , R _4, and R ₅ are each independently hydrogen, halogen, cyano, C ₁ -C ₅ alkyl, halo (C ₁ -C ₅ ) alkyl, C ₂ -C ₅ alkenyl Or C ₂ -C ₅ alkynyl, R _6, R ₇ , R ₈ and R ₉ are each independently hydrogen, halogen, C ₁ -C ₅ alkyl or halo (C ₁ -C ₃ ) alkyl cosmetic composition for preventing or improving wrinkle formation. The method of claim 1, R ₁ in Formula 1 is hydrogen or methyl; R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, fluoro, chloro, bromo, cyano, methyl, trifluoromethyl, vinyl or acetylenyl ), R ₆ is hydrogen, R ₇ and R ₈ are each independently hydrogen, chloro, bromo, iodo, C ₁ -C ₄ alkyl or halo (C ₁ -C ₂ ) alkyl, R ₉ is hydrogen cosmetic composition for the prevention or improvement of wrinkles generation. The method of claim 1, R ₁ in Formula 1 is hydrogen, R ₂ , R ₃ , R ₄ and R ₅ are each independently hydrogen, fluoro, chloro or methyl, R ₆ is hydrogen, R ₇ and R ₈ are each independently hydrogen or C ₁ -C ₄ alkyl, R ₉ is hydrogen cosmetic composition for the prevention or improvement of wrinkles generation. The method of claim 1, R ₁ and R ₂ in Formula 1 are hydrogen, R ₃ and R ₄ are each independently hydrogen, fluoro or methyl, R ₅ , R ₆ and R ₇ are hydrogen, R ₈ is isobutyl or tertiarybutyl, R ₉ is hydrogen cosmetic composition for the prevention or improvement of wrinkles generation. The method of claim 1, Compound of Formula 1 is 7-tert-butyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide, 7-isopropyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-3-methyl-benzylamide, 7-isopropyl-2H-chromen-3-carboxylic acid 3-fluoro-4-methanesulfonylamino-benzylamide and 7-tert-butyl-2H-chromen-3-carboxylic acid 4-methanesulfonylamino-benzylamide A cosmetic composition for preventing or improving wrinkle formation, which is at least one selected from the group consisting of: The method of claim 1, The active ingredient is a cosmetic composition for preventing or improving wrinkle generation that is an antagonist of nerve pain sensory receptor (TRPV1: Transient Receptor Potential family V 1). The method of claim 7, wherein The active ingredient is a cosmetic composition for preventing or improving wrinkle production that inhibits the expression of matrix metalloprotease. The method of claim 7, wherein The active ingredient reduces the expression of collagenase, cosmetic composition for preventing or improving the production of wrinkles. The method of claim 1, The active ingredient is a cosmetic composition for the prevention or improvement of wrinkles, which comprises 0.01 to 20% by weight based on the total weight of the composition.

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